Hypertension

High blood pressure induced by vitamin D deficiency is associated with renal overexpression and hyperphosphorylation of Na+-K+-2Cl- cotransporter type 2 Objectives: Clinical and epidemiological studies have suggested a correlation between vitamin D deficiency (VDD) and high blood pressure (BP). This study aimed to test the hypothesis that high BP induced by VDD is associated with altered expression and covalent modification of apical sodium transporters along the nephron. The contributions of the intrarenal renin–angiotensin system (RAS) and oxidative stress were also investigated. Methods: Male Wistar rats were fed a vitamin D-free (n = 26) or standard diet (n = 25) for 30 days. BP was recorded using noninvasive and invasive procedures. The expression levels of total and phosphorylated apical sodium transporters in rat renal cortex and medulla were evaluated by immunoblotting. Intrarenal RAS components were assessed by immunoblotting and ELISA. Renal oxidative stress was analyzed by measuring the concentrations of thiobarbituric acid reactive substances and reduced glutathione. Results: Higher BP levels in VDD rats than controls were accompanied by overexpression and hyperphosphorylation of renal cortical and medullary Na+-K+-2Cl- cotransporter type 2, enhanced levels of phosphorylated Na+/H+ exchanger type 3, and reduced expression levels of total and phosphorylated Na+/Cl- cotransporter. Changes in intrarenal RAS induced by VDD vs. controls included the marked elevation of medullary renin expression, higher expression of cortical angiotensinogen, higher urinary angiotensinogen excretion, and higher cortical and medullary angiotensin II content. VDD rats displayed higher thiobarbituric acid reactive substances/glutathione ratios in the renal cortex and medulla than controls. Conclusion: These results suggest that the molecular mechanisms underlying the effects of VDD on BP may include the upregulation of Na+-K+-2Cl- cotransporter type 2 and activation of intrarenal RAS and oxidative stress. Correspondence to Adriana C.C. Girardi, Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, Avenida Dr Enéas de Carvalho Aguiar, 44, 10° andar, Bloco II, 05403-900 São Paulo, SP, Brazil. Tel: +55 11 2661 5929; fax: +55 11 2661 5022; e-mail: adriana.girardi@incor.usp.br Received 2 April, 2020 Revised 27 October, 2020 Accepted 15 November, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Validity of five formulas in estimating 24-h urinary sodium via spot urine sampling in hypertensive patients living in Northeast China Objective: The objective was to evaluate the accuracy of five formulas -- the Kawasaki, Tanaka, INTERSALT, Mage, and Uechi methods -- using spot urinary sampling for 24-h urinary sodium (UNa) prediction in hypertensive patients living in northeast China. Methods: There were 1154 hypertensive patients enrolled from multiple centers. Five different formulas were used to predict 24-h UNa excretion via spot morning urinary samples. Actual UNa excretion was measured from 24-h urine samples. The estimated value was compared with the actual value by examining biases, the intraclass correlation coefficients (ICC), and Bland–Altman plots. Results: The average excretion of sodium was 2.97 ± 1.26 g/day. The formula-produced mean biases for actual UNa were 0.31 g/day for INTERSALT, 0.80 g/day for Mage, 0.88 g/day for Tanaka, 1.14 g/day for Uechi, and 1.95 g/day for Kawasaki. The ICC was 0.511 for Kawasaki, 0.499 for INTERSALT, 0.468 for Tanaka, 0.402 for Mage, and 0.378 for Uechi. The least mean bias in the lower and moderate salt intake subgroups was 1.22 and 0.07 g/day, respectively, which was calculated using the Mage and INTERSALT methods. The least mean bias in the higher salt intake subgroup was 0.10 g/day for the Uechi method. The INTERSALT method was more efficiency at the individual level, with 17.4% of participants having relative differences within 10%, and 22.3% participants having absolute differences within 393 mg. Conclusion: The INTERSALT method may exhibit a good performance in estimating 24-h urinary sodium level for the hypertensive population living in northeast China. Correspondence to Wei Song, Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, China. Tel: +86 18098875773; e-mail: songwei8124@163.com Received 1 September, 2020 Revised 10 November, 2020 Accepted 1 December, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Incremental value of carotid elasticity modulus using shear wave elastography for identifying coronary artery disease in patients without carotid plaque Background: Shear wave elastography (SWE) directly quantifies the local arterial wall stiffness by calculating the elastic modulus. However, whether carotid wall elastic modulus can predict obstructive coronary artery disease (CAD) is not well known. We aimed to investigate the value of carotid wall elastic modulus measured using SWE in identifying obstructive CAD. Materials and methods: We prospectively enrolled 61 patients without carotid plaque referred for clinically indicated coronary angiography. Twenty-seven (44.3%) patients were diagnosed with obstructive CAD (≥50% coronary stenosis). The elastic modulus of common carotid artery was quantified using SWE. Ankle--brachial index (ABI) and echocardiographic global cardiac calcium score (GCCS) were measured. Results: Patients with obstructive CAD had significantly higher elastic modulus than those without obstructive CAD. The maximum elastic modulus (EMmax) was independently associated with obstructive CAD after adjusting for the Framingham risk score, ABI, and GCCS. EMmax had the highest area under the curve (AUC) to identify obstructive CAD (AUC 0.70; P = 0.003). In the nested models, the model based on the Framingham risk score and ABI (χ2 = 3.74) improved by adding GCCS (χ2 = 9.95) and further improved by adding EMmax (χ2 = 15.86). Adding EMmax to the combined ABI and GCCS model increased integrated discrimination index from 0.10 to 0.19. Conclusion: Carotid wall elastic modulus measured using SWE is a useful predictor of obstructive CAD in patients without carotid plaque. We demonstrated the incremental and independent value of carotid wall elastic modulus in identifying obstructive CAD compared with clinical risk factors and other imaging predictors, including ABI and GCCS. Video abstract: Please see the video, in Supplemental Digital Content 1, http://links.lww.com/HJH/B551 for more insights from the authors. Correspondence to Chunyan Ma, First Hospital of China Medical University, No. 155 Nanjingbei Street, Shenyang, Liaoning 110001, China. Tel/fax: +86 24 83282114; e-mail: cmu1h_mcy@126.com Received 20 August, 2020 Revised 14 November, 2020 Accepted 6 December, 2020 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.jhypertension.com). This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Targeting persistent normal left ventricular geometry in the general population: a 25-year follow-up study Aim: Findings regarding the extent of persistence over time of normal left ventricular (LV) geometry, a reference healthy echocardiographic phenotype, in the community are scanty. We sought to assess this issue in members of the general population enrolled in the Pressioni Arteriose Monitorate e Loro Associazioni study. Methods: The study included 433 participants who attended the second and third survey of the Pressioni Arteriose Monitorate e Loro Associazioni study performed after 10 and 25 years from the initial evaluation. Data collection included medical history, anthropometric parameters, office, home, ambulatory blood pressure, routine blood examinations and echocardiography. Results: During 25-year follow-up 167 participants showed persistently normal LV mass (LVM) and LV geometry pattern, whereas 266 participants exhibited LV hypertrophy or LV concentric remodelling at any point during study. Compared with participants developing, maintaining or regressing from LV hypertrophy and LV concentric remodelling those with a persistently normal LVM index and geometry were younger (−8 years) and more frequently female (63 vs. 45%), exhibited baseline (and follow-up) lower office and out-of-office blood pressure, BMI, serum creatinine, fasting blood glucose total serum cholesterol and rate of antihypertensive treatment. In multivariate regression analysis age [odds ratio (OR): 0.93, confidence interval (CI): 0.91–0.96, P < 0.0001] BMI (OR: 0.90, CI: 0.83–0.97, P = 0.008), office SBP (OR: 0.97, CI: 0.95–0.99, P = 0.005) and fasting blood glucose (OR: 0.96, CI: 0.93–0.99, P = 0.007) were independently associated with persistent normal LVM index and geometry. Conclusion: The current long-term longitudinal study suggests that persistence of normal LV geometry is associated with normal/optimal SBP, BMI and blood glucose. Thus, a closer control of these risk factors in midlife may increase the likelihood of maintaining normal ventricular geometry and, in turn, reduce the burden of subclinical cardiac organ damage and related complications in advanced age. Correspondence to Cesare Cuspidi, Clinical Research Unit, Istituto Auxologico Italiano, Viale della Resistenza 23, 20036 Meda, Italy. Tel: +39 0362 772433; fax: +39 0362 772416; e-mail: cesare.cuspidi@unimib.it Received 26 September, 2020 Revised 3 November, 2020 Accepted 15 November, 2020 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.jhypertension.com). Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Neck-to-height ratio and arterial stiffness in Chinese adults: cross-sectional associations in a community-based cohort Objectives: The aim of this study was to investigate the association between neck-to-height ratio (NHR) and arterial stiffness in adults from a community-based Chinese cohort in a cross-sectional study. Methods: We conducted cross-sectional analysis using data from the Kailuan study, a population-based cohort research. Altogether, 18 972 individuals were included in the analysis. Brachial ankle pulse wave velocity (baPWV), anthropometric indexes and cardiovascular risk factors were recorded. Data were analyzed by multiple lineal regression model. Results: NHR was positively associated with baPWV after adjusted for age, sex, blood pressure, heart rate, BMI, waist–hip ratio, current smoking, fasting blood glucose, serum cholesterol, uric acid, high-sensitivity C reactive protein and creatinine clearance (β = 5.76, P < 0.001), while the association of neck circumference and baPWV was NS after adjusting the variables mentioned above. In subgroups analysis, the association between NHR and baPWV did not reach statistical significance in female, while in males, the association was significant. Interaction effects were observed among BMI stratifications and the individuals with metabolic syndrome and history of cardiovascular events (P for intereaction = 0.002, 0.038 and 0.003, respectively). Conclusion: The current study demonstrated for the first time that NHR was positively associated with baPWV in community-based population, NHR might be a promising independent predictor for cardiovascular disease. Correspondence to Jun Tao, Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China. E-mail: taojungz123@163.com Received 4 August, 2020 Revised 27 October, 2020 Accepted 22 November, 2020 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.jhypertension.com). This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Association between arterial stiffness and the clustering of metabolic syndrome risk factors: a systematic review and meta-analysis Objectives: Metabolic syndrome (MetS) is a cluster of different cardiometabolic risk factors (CMRFs), and its different combinations with other CMRFs, such as arterial stiffness have been hypothesized to explain, at least partially, increased risk of cardiovascular disease. Thus, in this systematic review and meta-analysis, we aimed to synthesize the evidence regarding the association between the clustering of MetS-related CMRFs and arterial stiffness measured using pulse wave velocity (PWV). Methods: Original studies analysing the association between arterial stiffness, measured using PWV, and MetS were systematically searched. Pooled effect size estimates and their respective 95% confidence intervals (CI) were calculated using the DerSimonian and Laird method for two separate analyses: the diagnosis of MetS and PWV values and the number of CMRFs and PWV values. Results: Moderate effect size estimates were observed between MetS and PWV (0.68, 95% CI: 0.54–0.82) with a slightly higher effect size for the low-risk compared with the high-risk population group (0.75, 95% CI: 0.58–0.92; and 0.51, 95% CI: 0.32–0.82, respectively). A trend between the number of MetS-related CMRFs and PWV was found with the pooled effect size nearly doubling as the number of MetS-related CMRFs increased, 0.11 (95% CI: 0.04–0.17) for one MetS-related CMRF, 0.26 (95% CI: 0.13–0.4) for two, and 0.4 (95% CI: 0.2–0.6) for three or more. Conclusion: These results demonstrated a clinically relevant association between MetS and PWV and an increasing trend in PWV values, such as a MetS-related CMRF increase. Although these results should be considered cautiously because of the considerable heterogeneity, our findings reinforce the rationale of MetS as an aggregation of risk factors with common causes, which could provide additional useful information to guide clinical management. Correspondence to Iván Cavero-Redondo, PhD, Universidad de Castilla-La Mancha, Edificio Melchor Cano, Centro de Estudios Socio-Sanitarios, Santa Teresa Jornet s/n, 16071 Cuenca, Spain. E-mail: Ivan.Cavero@uclm.es Received 8 September, 2020 Revised 31 October, 2020 Accepted 22 November, 2020 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.jhypertension.com). Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Effect of frequency and pattern of night shift on hypertension risk in female nurses: a cross-sectional study Objectives: Understanding the effect of night shift on hypertension risk in nurses is important to improve the health of nurses and ensure patient safety. This study aimed to evaluate the effect of the frequency and pattern of night shift on hypertension risk and the interaction of them in female nurses. Methods: This cross-sectional study constituted 84 697 female nurses in 13 cities in China. The main contents of the survey included SBP, DBP, the frequency and pattern of night shift, and some other factors that might be associated with hypertension. Logistic regression analyses were used to calculate ORs and 95% CIs to estimate the effect of the frequency and pattern of night shift on hypertension risk and the interaction of them in relation to hypertension risk. Results: Having more than 5 to 10 or more than 10 night shifts per month were significantly more likely to be hypertensive (OR 1.19, 95% CI 1.10–1.28; OR 1.32, 95% CI 1.13–1.54), whereas having less than or equal to 5 night shifts per month was not (OR 1.05, 95% CI 0.95–1.16). The patterns of night shift were all associated with a higher probability of hypertension and participants engaging in rapidly rotating night shift had a lower OR (1.14) than those having slowly rotating night shift (1.23) and permanent night shift (1.46). No significant interaction was observed between the frequency and the pattern of night shift (Pinteraction = 0.281). Conclusion: The frequency and pattern of night shift were associated with hypertension risk in female nurses and no significant interaction was observed between them. Correspondence to Wei Cui, Department of Cardiology, The Second Hospital of Hebei Medical University, No. 215, Heping West Road, Shijiazhuang city, Hebei Province, China. E-mail: cuiwei21c@163.com Received 25 February, 2020 Revised 15 November, 2020 Accepted 22 November, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Hemodynamic profiles in treatment-naive arterial hypertension and their clinical implication for treatment choice: an exploratory post hoc analysis Objective: Noninvasive thoracic bioimpedance by the HOTMAN System estimates hemodynamic modulators and expresses them as hemodynamic profiles. Aims of this analysis were to describe hemodynamic profiles among treatment-naive hypertensive patients compared with normotensive controls and to investigate whether a hemodynamic-guided choice of therapy improves blood pressure (BP) control within 4 weeks. Method: This exploratory post hoc analysis used data of a randomized parallel-group trial including 80 outpatients with newly diagnosed arterial hypertension (AHT), randomized to four antihypertensive first-line monotherapies, and 20 age-matched and sex-matched normotensive controls. Hemodynamic profiles were measured at baseline and after four weeks of treatment. On the basis of the hemodynamic profiles, the most appropriate pharmacological treatment was determined retrospectively and patients were categorised to have received concordant (ConTG) or discordant treatment (DisTG). Results: In the hypertensive group, hypervolemia with vasoconstriction was the predominant hemodynamic profile in 48% of patients and hypervolemia without vasoconstriction in 45%, compared with 15 and 50%, respectively, in the control group. After 4 weeks of treatment, the mean (±SD) 24-h BP was 129.9 (±11.0)/81.5 (±8.0) mmHg in the DisTG vs. 133.9 (±12.3)/84.0 (±9.1) mmHg in the ConTG (P = 0.158/0.222). The mean 24-h BP reductions were −9.7 (±10.1)/−5.0 (±6.2) mmHg in the DisTG and −12.4 (±14.8)/−6.9(±6.9) mmHg in the ConTG (P = 0.353/0.223). After 4 weeks of treatment, the BP control rate was 53.7% (43/80) among all, 55.7% (29/52) in the DisTG and 48% (12/25) in the ConTG (P = 0.628). Conclusion: Our findings do not support the hypothesis that personalized treatment initiation based on hemodynamic profiles improves BP control in newly diagnosed hypertensive outpatients. Correspondence to Thilo Burkard, Medical Outpatient and Hypertension Clinic, ESH Hypertension Centre of Excellence, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland. E-mail: thilo.burkard@usb.ch Received 6 October, 2020 Revised 29 November, 2020 Accepted 29 November, 2020 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.jhypertension.com). This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

The adrenal medulla in cardiovascular medicine: an untold story Unlike noradrenaline, the sympathetic neurotransmitter which overflows to the circulation, adrenaline (ADR) is a secreted hormone, with a low plasma concentration, and plasma concentration for biological action a log order lower than that of noradrenaline. The venous drainage of the left adrenal medulla into the left renal vein does expose this vein to uniquely high plasma ADR concentrations and possible risk of thrombosis at high rates of ADR secretion. There is typically a different timeframe for adrenal medullary and sympathetic nervous system responses: ADR release is short term in contrast with sympathetic activation persisting for years in heart failure and hypertension. The historic view of Walter Cannon, subject to recent review, that the sympathoadrenal system is a unified biological system, was deconstructed further with demonstration of frequent mismatching of adrenal medullary and sympathetic nervous responses. Under gravity stimulation with standing, there is prompt sympathetic activation without ADR release. In many diseases, notably obesity, hypertension, heart failure and depressive illness, an activated sympathetic nervous system and silent adrenal medulla coexist. The therapeutic corollary of this is that ADR blockade is much less commonly needed clinically than pharmacological antagonism of the sympathetic nervous system. Correspondence to Murray D. Esler, Baker Heart and Diabetes Institute, PO Box 6492, Melbourne 3004, VIC, Australia. Tel: +61 409 178 058; fax: +61 3 8532 1100; e-mail: murray.esler@baker.edu.au Received 19 October, 2020 Revised 15 November, 2020 Accepted 16 November, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Uterine fibroids increase the risk of hypertensive disorders of pregnancy: a prospective cohort study Objective: It is unclear whether uterine fibroids are associated with the occurrence of hypertensive disorders of pregnancy (HDP). Thus, this study aimed to evaluate the association between uterine fibroids and HDP in a prospective cohort. Methods: Overall, 2404 pregnant women who received antenatal care were enrolled in a prospective cohort in China between 2014 and 2016; 2277 women met the inclusion criteria of this study. The clinical characteristics of participants were assessed via questionnaires and physical examinations at baseline (before the 20th week of gestation), 21st–27th, 28th–34th, and 35th–39th gestational weeks. Ultrasound examination was performed before the 20th week of pregnancy to determine the presence of uterine fibroids. Linear mixed-effect and Cox proportional hazard regression models were used to analyze the association of uterine fibroids with blood pressure and HDP. Results: Of 2277 pregnant women, 242 (10.6%) had uterine fibroids, and 45 (2.0%) subsequently developed HDP. The incidence of HDP in women with and without uterine fibroids was 5% (n = 12) and 1.6% (n = 33), respectively. The longitudinal SBPs and DBPs were significantly higher in women with uterine fibroids than in those without. The multivariable Cox model showed that the presence of uterine fibroids was associated with increased HDP risk (adjusted hazard radio: 2.95, 95% confidence interval: 1.35–6.44). Conclusion: Uterine fibroids in early pregnancy were associated with an increased HDP risk. Blood pressure of women with uterine fibroids should be closely monitored, and HDP preventive measures are crucial. Correspondence to Xuerui Tan, The First Affiliated Hospital of Shantou University Medical College, 57 Changping Road, Shantou, Guangdong 515041, China. Tel: +86 754 88611690; fax: +86 754 88259850; e-mail: doctortxr@126.com. Received 26 July, 2020 Revised 8 October, 2020 Accepted 2 November, 2020 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.jhypertension.com). This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

Telephone consultation 11855 int 1193,

Maxillofacial Surgery

Organizing craniofacial surgery teams Arun K Singh National Journal of Maxillofacial Surgery 2020 11(2):157-158

Oral mucositis Vibha Singh, Akhilesh Kumar Singh National Journal of Maxillofacial Surgery 2020 11(2):159-168 Oral mucositis is one of the most common complications of cancer therapy. It is a nonhematologic complication of cytotoxic chemotherapy and radiotherapy and reduces the quality of life. It is estimated that 40% the cases on standard chemotherapy may develop oral mucositis. Patients receiving radiation, especially in the cases of head and neck cancer, have 30%–60% chances of developing mucositis. Chemotherapy and radiotherapy interfere with the normal turnover of epithelial cells, leading to mucosal injuries. These injuries can also occur due to indirect invasion of Gram negative bacteria and fungi as most of the chemo-therapeutic agents will cause neutropenia and will give a favorable environment for the development of mucositis. The patient-related factors are also responsible for developing mucositis in chemo-induced and radiation-induced mucositis. Poor oral hygiene may also be responsible for bacterial super infection followed by chemotherapy. Mucositis is of two kinds: direct and indirect mucositis. Direct mucositis - The epithelial cells of the oral mucosa undergo rapid turnover in usually 7–14 days due to which these cells are more susceptible to the effect of the cytotoxic therapy which results in oral mucositis. Indirect mucositis – it can develop due to the infection caused by Gram-negative bacteria and fungal infection. There will be a greater risk for oral infection due to neutropenia. The onset of mucositis secondary to mylo-suppression varies depending upon the timing of the neutrophil count associated with chemotherapy agents but they typically develop around 10–21 days after chemotherapy administration.

Evaluating the role of local host factors in the candidal colonization of oral cavity: A review update Imran Khan, Tanveer Ahmad, Nikhat Manzoor, Moshahid Alam Rizvi, Uqba Raza, Shubhangi Premchandani National Journal of Maxillofacial Surgery 2020 11(2):169-175 Human oral cavity is home to a number of organisms, Candida albicans being one of them. This review article aims at understanding the correlation between the oral candidal colonization and the local host factors that may influence it with special emphasis on congenital craniofacial anomalies such as cleft lip and palate (CLP). Various scientific databases were searched online and relevant articles were selected based on the inclusion criteria. A comparative study was done to understand the interdependence of various factors (including CLP) and oral candidal colonization. The results revealed a strong association of certain local host factors which may influence the oral colonization of Candida species. Factors such as mucosal barrier, salivary constituents and quantity of saliva, congenital deformities like CLP, oral prostheses such as dentures/palatal obturators and fixed orthodontic appliances (FOAs) were identified. All these factors may directly affect the growth of Candida in the oral cavity. Although numerous studies have pointed a positive correlation between Oral Candidal colonization and local host factors such as oral prostheses, FOA, and oral mucosal barrier only one study has been done, in the Indian subcontinent with respect to the correlation of candidal colonization and CLP. After the evaluation of all the factors mentioned in various case studies, it can be concluded that the presence of local host factors such as orofacial clefts, dental prostheses, FOA, xerostomia, and atrophy of the oral mucous membrane lead to significant increase in candidal colonization, but since very few studies in regard to CLP have been done worldwide and in India, in particular, further studies are warranted.

Evaluation of osseintegration between traditional and modified hydrophilic titanium dental implants – Systematic analysis Geeta Arya, Varun Kumar National Journal of Maxillofacial Surgery 2020 11(2):176-181 The aim of the study was to conduct a systematic review to access the osseointegration between traditional and modified Hydrophilic Titanium Dental Implants for period of 10 years. PUBMed articles were searched from last ten years up to 15/12/2019 from which 24 studies included in this review. This systematic review compiles the data about osseintegration in hydrophilic titanium implants in human trials. It sheds light on the mechanism of integration of hydrophilic surfaces and numeric data to support the purpose of the review.

Does diagnostic accuracy of surgeon's perception outweigh frozen section analysis in determining intraoperative clear mucosal surgical margins in oral squamous cell carcinoma patients? Chetan Gupta, Nitin Bhola, Anendd Jadhav, Apoorva Mishra, Pawan Hingnikar, Chinmay Ghavat National Journal of Maxillofacial Surgery 2020 11(2):182-185 Introduction: The lucrativeness of the frozen section for intraoperative margin assessment in head and neck squamous cell carcinoma is debatable till date. The purpose of this study was to evaluate whether surgeon's perception by gross examination (GE) of margin is an alternative to frozen section. Aim: The aim was to compare the diagnostic accuracy (DA) of surgeon's perception of tumor-free mucosal and soft-tissue surgical margins intraoperatively assessed by GE and frozen section analysis (FSA). Methodology: A prospective, observational study was conducted on 59 histologically proven cases of oral squamous cell carcinoma. Two hundred and thirty-six mucosal margins were assessed by an experienced surgeon (ES) and thereafter subjected subsequently to FSA. These results were compared with the gold standard histopathology (HPE). The sensitivity (SS), specificity (SP), positive predictor value (PPV), negative predictor value (NPV), and DA of surgeon's perception by GE were calculated and subsequently compared with FSA and HPE using descriptive and inferential statistics. Results: The SS, SP, PPV, NPV, and DA of ES by GE were 80%, 99.12%, 80%, 99.12%, and 98.30%, respectively when compared to HPE, and the SS of 90%, SP of 98.32%, PPV, NPV, and DA were 69.23%, 99.57%, and 97.98%, respectively when compared with HPE. The results of the surgeon's perception by GE were comparable to the results of FSA. Conclusion: The study concludes that surgeon's perception by GE is upfront reliable alternative intraoperative method to FSA in places where FS is not available.

Rhinoplasty in secondary nasal deformities: Subjective and objective outcome evaluation Chandmani Tigga, Majumdar Swapan Kumar, Burman Subhasish, Mishra Siddartha, Hussain Mohsina National Journal of Maxillofacial Surgery 2020 11(2):186-192 Introduction: Secondary nasal deformities are associated with trauma and secondary cleft nose (after primary cleft nose surgery). Nasal deformities affect esthetic, function, and psychological status of the patient. The goal of the secondary rhinoplasty is to correct both form and function, so that this positively impacts on their facial appearance. Aims: The study aimed to evaluate the patient satisfaction (subjective outcome) by rhinoplasty outcome evaluation questionnaire (ROEQ) preoperatively and postoperatively and esthetic outcome (objective outcome) by surgical team in patients with secondary nasal deformities. Materials and Methods: Secondary rhinoplasty was done in 13 patients of traumatic and unilateral secondary cleft nose through the external approach. Objective outcome was assessed by surgical team with clinical measurement, radiograph (lateral cephalometric), and photographic documentation pre- and postoperatively. Clinical measurements include nasolabial and nasofrontal angle. The patients completed the ROEQ for the subjective outcome evaluation. Results: There was significant improvement of subjective outcome (83.30%) based on the ROEQ and objective outcome based on the clinical measurement. Conclusion: Our study suggests that secondary rhinoplasty in trauma and cleft patients leads to both subjective and objective improvement of the facial appearance.

Management of macrocystic lymphatic malformation at uncommon site with aqueous bleomycin sclerotherapy Ankur Bhatnagar, Vijai Datta Upadhyaya, Rajnikant Yadav, Basant Kumar National Journal of Maxillofacial Surgery 2020 11(2):193-198 Introduction: Lymphangioma are rare vascular malformation that results from maldevelopment of primitive lymphatic sacs. They are most frequently found in the neck and axilla, while intra-abdominal and mediastinal lymphangiomas are uncommon. Atypical site of cystic hygroma in pediatric age group are usually difficult to diagnose clinically but can be diagnosed easily by ultrasound. The aim of the study was to evaluate the result of the intralesional bleomycin for macrocystic lymphatic malformation (LM) presenting at atypical site Material and Method: All patients of LM of other than head& neck, axilla and abdomen presenting in pediatric age group were included in the study. Mainstay of diagnosis was ultrasound and was supplemented by CT scan wherever required. All patients were managed with intralesional bleomycin (ILB) and surgical excision was done only if primary therapy failed. Result: Total 15 cases of LM presenting at atypical sites were included in the study. Series include two case of cystic hygroma of breast, 4 cases of cystic hygroma of anterior chest wall, two case of substernal LM, three cases of LM of parotid gland, one case of inguinal region cystic hygroma and 4 cases involving submandicular area. Complete resolution was observed in 13 out of 15 cases, and two cases had less than 50% reduction in size and were managed with surgical excision after second session of ILB. Conclusion: Aqueous Intralesional bleomycin is a cost effective alternative to surgery even at rare sites of LM which provide better aesthetic outcome, and avoids complication associated with surgery.

Comparative evaluation of crestal bone level in patients having low level of Vitamin D treated with dental implant with or without Vitamin D3 supplements Pooja Garg, Pankaj Ghalaut, Kiran Dahiya, Reena Ravi, Anshu Sharma, Poonam Wakure National Journal of Maxillofacial Surgery 2020 11(2):199-206 Introduction: Vitamin D has been shown to play a vital role in bone mineral homeostasis by stimulating the intestinal absorption of calcium and phosphate. The critical role of Vitamin D in bone metabolism triggered the need to evaluate the effect of Vitamin D deficiency and hence replacement of the same on osseointegration of dental implants. This prospective study evaluated the crestal bone level in patients having low level of Vitamin D treated with dental implant with or without Vitamin D3 supplements. Materials and Methods: A prospective clinical study was conducted on 32 patients based on the inclusion and exclusion criteria. Patients were divided into two groups on the basis of Vitamin D level < 30 ng/ml (Group I: patients receiving Vitamin D3 supplements, i.e., cholecalciferol 1 g sachet 60,000 IU/month) or <30 ng/ml (Group II: not receiving Vitamin D3 supplements). The crestal bone level measurements were made with the help of Digimizer Image Analysis, MedCalc software. Results: All implants showed clinically acceptable crestal bone level at interval of 1 week (baseline), 3 months, and 6 months. There was a statistically nonsignificant difference seen for the values between the groups (P > 0.05) for all other values at various time intervals. However, there was a statistically significant/highly significant difference seen for the values between the groups (P < 0.01, 0.05) for 3 months distal with higher values for Group I as compared to Group II. Conclusion: From the study, it can be concluded that cholecalciferol has systemic effects on accelerating bone formation around titanium implant.

Evaluation of polycaprolactone scaffold for guided bone regeneration in maxillary and mandibular defects: A clinical study Charudatta Naik, N Srinath, Mahesh Kumar Ranganath, DN Umashankar, Himani Gupta National Journal of Maxillofacial Surgery 2020 11(2):207-212 Objective: This study was carried out to assess bone regeneration following the use of polycaprolactone (PCL) scaffold in maxillary and mandibular osseous defects. Materials and Methods: This prospective study included ten patients with maxillary or mandibular osseous defects present due to enucleation of periapical cysts or alveolar clefts requiring bone grafting and for lateral ridge augmentation that were treated with PCL scaffold. The patients were assessed clinically for pain, swelling, infection, and graft exposure at 1 week, 3rd, and 5th month postoperatively and were also evaluated radiographically for bone fill using intraoral periapical and/or panoramic radiographs at 4th, 6th, and 9th month postoperatively. Results: PCL scaffold was used in a total of six alveolar clefts and three cases of periapical cysts and one case of lateral ridge augmentation. Nine out of ten cases demonstrated wound dehiscence and scaffold exposure in the oral cavity. Radiographically, on comparison to the control regions, all these nine cases failed to demonstrate appreciable bone density gain. Only one case of radicular cyst in the mandible was recorded to have satisfactory healing. Conclusion: Although PCL scaffold has the potential for bone regeneration in osseous defects, the scaffold exhibited marked tendency for dehiscence in intraoral defects that significantly affected bone healing. A long-term study designed with a larger sample size and categorization of the defects is required to assess its efficacy in varied defects. Moreover, comparative evaluation of PCL and autogenous or alloplastic bone grafting material could provide assenting results.

Graftless crestal hydraulic sinus lift with simultaneous implant insertion Varsha Sunil Manekar National Journal of Maxillofacial Surgery 2020 11(2):213-218 Background: The posterior maxilla is always a challenge for dental implant restoration. The presence of maxillary sinus and reduced subantral bone height are the limitations for implant insertion. The need of the hour is to make the surgical procedures simple, minimally invasive, andpredictable. Can we perform the sinus lift and simultaneous implant insertion by minimally invasive,simple, cost-effective, and less time-consuming technique? With this in consideration, the author carriedout this study for graftless crestal hydraulic sinus lift (CHSL) and simultaneous implant insertion in partially edentulous posterior maxilla for 26 implants. The aim is to evaluate the clinical and radiological success of graftless CHSL with simultaneous implant insertion. Material and Method: The sample size was 17 patients and 26 implants were inserted. The clinical as well as radiological follow-up was done for 1 year. The outcome variables were the gain in bone height and implant survival. Result: Mean Bone height Gain is 5.6 mm; Mean torque used 32 nm, Mean age of the patient was 53 years. The literature shows a success of graftless lateral and osteotome-mediated sinus lift. The concept is the blood filling the gap around the implant in tented sinus lining can eventually result in the ossification to form bone. Until now, no study has demonstrated the bone formation in the peri-implant area of CHSL with simultaneous implant insertion. CHSL, a minimally invasive sinus lift surgery is very encouraging, easy to master, and predictive. The simultaneous implant insertion acts to retain the elevated sinus lining by tenting. It also reduces treatment time. After a sinus lifting procedure, the compartment around the implants under the sinus mucosal lining in the sinus floor is filled with a blood clot from surrounding bleeding. Blood clot can be considered autologous osteogenic graft material, to which osteoprogenitors can migrate, differentiate, and regenerate bone. Conclusion: The graftless CHSL is predictable and safe for the sinus lift. The gain of up to 5–6 mm of subantral bone is possible.

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

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Dermatologica

C-reactive protein to albumin ratio: Is a new parameter for the disease severity in patients with psoriasis vulgaris? Funda Kemeriz, Burcu Tuğrul, Sibel Çiğdem Tuncer Dermatologica Sinica 2020 38(4):199-204 Background: C-reactive protein to albumin ratio (CAR) is an inflammatory marker that is considered to have prognostic value in many inflammatory diseases. Objectives: In this study, we aimed to investigate whether there is a correlation between CAR value and disease severity in patients with psoriasis. Methods: The study included 70 plaque-type psoriasis patients and 67 healthy controls. CAR value was calculated after C-reactive protein (CRP) and albumin analysis was performed, Psoriasis Area and Severity Index (PASI) scores were documented. CAR value was compared with PASI scores in patient group. White blood cell count, neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, erythrocyte sedimentation rate (ESR), and mean platelet volume and CAR values were compared among these groups. We investigated the most significant parameter for disease severity. In addition, to detect relationship between CAR, disease duration and patients' age and healthy controls, correlation analysis was performed. Results: The median CAR value was found statistically significant higher in the patient group than in the control group (P < 0.001). A significant difference of median CRP, albumin, CAR (all P values are <0.001) and ESR (P = 0.024) were found among the three groups which were arranged according to the severity of the disease. Among these parameters, CAR was found as the most associated parameter with the severity of psoriasis using receiving operator characteristic analysis. Conclusion: CAR value could be a useful parameter for evaluating disease severity, management of disease activity, and follow-up strategies.

Dermoscopic manifestations of nail diseases Sushmita Pradhan, Xin Ran, Siliang Xue, Yuping Ran Dermatologica Sinica 2020 38(4):205-216 Nail dermoscopy in recent years has become an auxiliary noninvasive tool for the diagnosis of nail diseases. It detects the differentiating characteristics of the nail units and assesses in the management of nail diseases. Dermoscopy may not be a diagnostic tool for all nail diseases; however, it is very useful for early observation with high magnification. This article discusses the important and common dermoscopic manifestations of nail disease cases in the daily practice. Currently, the indications of dermoscopy include viral, bacterial, fungal, inflammatory, pigmented, traumatic nail diseases, nail tumors, and connective tissue disease.

Clinical manifestations and neurofibromatosis type 1 gene mutations of 25 patients with neurofibromatosis type 1 from 10 Chinese pedigrees Hui Chen, Xuefei Lin, Shi Lian, Wei Zhu Dermatologica Sinica 2020 38(4):217-220 This study enrolled 25 patients with neurofibromatosis type 1 (NF1) from 10 Chinese pedigrees. Sanger sequencing analysis and multiplex ligation-dependent probe amplification analysis were used to detect mutations and large fragment losses of the NF1 gene. This study identified 10 NF1 mutations, which comprised six novel and four recurrent mutations. Majority of the mutations can lead to termination codon production, which results in the synthesis of the truncated gene product neurofibromin.

Disseminated superficial porokeratosis and disseminated superficial actinic porokeratosis: A case series of 39 patients Yu-Tung Hsueh, Tzu-Chien Hsu, Chao-Kai Hsu, Julia Yu-Yun Lee, Chao-Chun Yang Dermatologica Sinica 2020 38(4):221-224 Porokeratosis is characterized by keratotic papules or plaques with a ridge-like border. Both disseminated superficial porokeratosis (DSP) and disseminated superficial actinic porokeratosis (DSAP) manifest as numerous, small, round maculopapules with thin thread-like elevated border but differ in their distribution of lesions and the association with sunlight exposure. To analyze and compare the clinical features of DSP and DSAP, we conducted this hospital-based retrospective study. A total of 39 patients were recruited, including 19 DSP patients and 20 DSAP patients. The median age of diagnosis of DSP and DSAP patients was 63 years and 59 years, respectively. A male predominance was noted in DSP, while a female predominance was noted in DSAP. Itchiness was the most common symptom in both subtypes. Commonly used treatments included corticosteroids and retinoids, both topical and oral. Among the treatments, oral retinoid, diclofenac gel, and cryotherapy showed higher rates of improvement, but none of them yielded complete remission of the skin lesions. In conclusion, DSP and DSAP showed differences in the gender predilection, and both DSP and DSAP had prolonged clinical course and generally refractory to topical or systemic treatments.

A rare case of tumid lupus erythematosus with unilateral linear distribution in a young child Gwang Hoon Kim, Jong Heon Jeong, Jong Soo Hong, Seung Ho Lee, Ai-Young Lee Dermatologica Sinica 2020 38(4):225-227 Tumid lupus erythematosus (TLE) as a rare variant of cutaneous lupus erythematosus (CLE) is characterized by edematous, urticarial-like annular papules and plaques. TLE has similar histopathologic findings to CLE such as periadnexal lymphocytic infiltration and interstitial mucin deposition. Although TLE develops on sun-exposed areas at any age, it is rarely distributed along the Blaschko lines and develops in infancy and childhood. Unlike CLE, skin lesion of TLE heals without leaving scarring or dyspigmentation. Here, we report a rare case of unilateral linear TLE in a 4-year-old girl, which was improved by intralesional corticosteroid injection and oral antimalarial drug with leaving postinflammatory hyperpigmentation.

Vohwinkel syndrome associated with a p.Gly59Arg missense mutation in GJB2 Paul-Chen Hsieh, Chen-Chi Wu, Ni-Chung Lee, Jung-Hsien Hsieh, Yi-Hua Liao Dermatologica Sinica 2020 38(4):228-231 Vohwinkel syndrome is a rare autosomal dominant disease caused by GJB2 mutations. Patients present with sensorineural deafness, pseudoainhum, stellate keratosis on knuckles, and diffuse honeycombed palmoplantar keratoderma. We present a case of a Taiwanese patient with characteristics of Vohwinkel syndrome. A heterozygous missense mutation c.175G > C (p.Gly59Arg) was identified in the GJB2 gene, encoding the gap junction protein connexin 26. Pathogenic GJB2 mutations have been implicated in a spectrum of diseases from nonsyndromic hearing loss to syndromic hearing loss with palmoplantar keratoderma. This report expands the phenotypic spectrum of the p.Gly59Arg mutation to include Vohwinkel syndrome.

Terra firma-forme dermatosis involving the genitalia: Three pediatric case reports Hsiao-Yu Li, Hsiu-Chin Chen, Yu-Hung Wu Dermatologica Sinica 2020 38(4):232-235 Terra firma-forme dermatosis is a rare acquired keratinization disorder. Patients present with dirt-like brownish plaques on the neck, trunk, and limbs. It is often confused with dermatitis neglecta, confluent and reticulated papillomatosis, and acanthosis nigricans. Reportedly, it affects children, but genital involvement is rare. We describe three cases of uncircumcised boys with genital involvement, two of which had extragenital involvement. They all had good hygiene. Two underwent skin biopsy, and pathological examination showed papillomatosis and alternating keratinization in the stratum corneum. The disease can be diagnosed clinically by wiping off the lesions with 70% isopropyl alcohol pads, instead of water or soap.

Stevens–Johnson syndrome and toxic epidermal necrolysis related to immune checkpoint inhibitors: Two cases and literature review Ting-Jung Hsu, Kwei-Lan Liu Dermatologica Sinica 2020 38(4):236-239 Immune checkpoint inhibitor-related Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) were rarely reported. We summarized the courses and the characteristics of two cases. The first case was a 74-year-old woman receiving pembrolizumab for Stage 2 urothelial cell carcinoma of the bladder. SJS developed 27 days after the first dose of pembrolizumab. The other case was a 67-year-old woman receiving atezolizumab for Stage 4 renal urothelial cell carcinoma. TEN developed after the eighth cycle of atezolizumab. Both patients were treated with low-dose corticosteroid and supportive management. Their wounds healed without dermatologic sequelae.

Cutaneous cryptococcoma in association with CD4 lymphocytopenia: A patient with multiple sclerosis treated with fingolimod Tzu-Kun Lo, Julia Yu-Yun Lee Dermatologica Sinica 2020 38(4):240-241

Cutaneous clear cell sarcoma mimicking xanthogranuloma: A diagnostic pitfall Chung-Hao Hsu, Chi-Shun Yang, Chung-Yang Yen Dermatologica Sinica 2020 38(4):242-243

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

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Pain

The Prevalence and Potential Role of Pain Beliefs When Managing Later-Life Pain Objectives: In this study of 154 community-dwelling older adults with chronic non-cancer pain, we sought to assess participants' beliefs about pain as well as pain management treatments and determined the influence of those beliefs on participants' willingness to undertake three physician-recommended pain treatments, i.e., a pharmacologic, physical, and psychological therapy. Methods: A 16-item questionnaire was employed to ascertain participants' pain beliefs, divided into four subscales representing (1) negative beliefs about pharmacological treatments, (2) positive beliefs about physical treatment approaches, e.g., exercise; (3) positive beliefs about psychological treatments, and (4) fatalistic beliefs about pain. Participants were asked to rate their willingness to undertake a pharmacologic, physical, or psychological therapy if their physician recommended that they do so. Agreement with each belief was measured, and we examined willingness to undertake each treatment as a function of pain belief subscale scores after controlling for relevant covariates. Results: Positive beliefs about physical treatments (e.g., benefits of exercise) were the most strongly endorsed items on the pain beliefs questionnaire. All three treatment-focused pain beliefs subscales were significantly associated with willingness to undertake that form of treatment (e.g., negative beliefs about pain medication use were associated with decreased willingness to take pain medication). Fatalistic attitudes were significantly associated with a decreased willingness to undertake physical treatments. Discussion: These results support the notion that patients' beliefs about pain and pain treatments can have important effects on treatment engagement and, if assessed, can help guide clinical management of chronic pain in older adults. There are no conflicts of interest. Reprints: M. Carrington Reid, MD, PhD, Division of Geriatrics & Palliative Medicine, Weill Cornell Medical Center, New York, NY 10065, USA (e-mail: mcr2004@med.cornell.edu). Received June 22, 2020 Received in revised form November 22, 2020 Accepted November 25, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Brief Psychological Interventions for Reducing Prescription Opioid Use, Related Harm and Pain Intensity in Patients with Chronic Pain: A Systematic Review and Assessment of Patient Interest Objectives: Brief psychological interventions (BPIs) have demonstrated effectiveness in reducing substance use and related harm. No systematic review has examined their potential to reduce or prevent prescription opioid use or related harm, and/or pain intensity in opioid-using patients with chronic non-cancer pain (CNCP). Recognizing the importance of patient preferences in evidence-based practice, we also sought to assess patient interest in BPIs. Methods: A systematic review of studies published between 1980-2020 was conducted using five databases. Eligible treatment studies included patients ≥18 years old, with CNCP, and who were using prescription opioids. An adjunctive study independent of our review was also undertaken in 188 prescription opioid-using patients (77% female; Mage=49▒y) diagnosed with CNCP. Patients completed pain-related questionnaires online and indicated if they would consider BPI treatment options. Results: The review identified six studies. Given the heterogeneity across studies, a meta-analysis was not conducted. A narrative review found all of the six studies demonstrated some evidence for BPI effectiveness for reducing opioid use or related harms; these were assessed as having mostly low methodological quality. Mixed support for the effect on pain intensity was found in one study. Despite the inconclusive findings and heterogenous studies identified in the review, 92% of patients in our survey reported interest in receiving a BPI. Discussion: In combination, these findings highlight the inconsistency between patient demand and the availability of evidence for BPIs targeting opioid use, related harm and/or pain intensity. Future work should examine the effectiveness of BPIs in higher quality studies. Submission category: Review. Funding sources: No funding sources were provided. Significance: Our findings highlight the inconsistency between patient demand and the availability of evidence for brief psychological interventions (BPIs) in reducing prescription opioid use and related harm, and pain intensity. Based on the success of BPIs in reducing substance-related harm and patient preferences identified in this study, more higher quality research is needed to determine whether BPIs should be a treatment option for improving outcomes for opioid-using patients with chronic non-cancer pain. PROSPERO Pre-registration number: CRD42020149423. Author contributions: RE, JC, MS, and JL were involved in the conceptualization and design of the study. RE, JL, and SSR were involved in the design and execution of the searches with guidance from a librarian. RE and SSR conducted the screening and quality review of studies. All members of the research team were involved in the final selection of included studies. All authors discussed the results and were involved in interpretation. RE drafted the manuscript, and all authors provided critical revisions. All authors approved the final manuscript for submission. Conflict of interest: The authors have no conflicts of interest to declare. Reprints: Rachel Elphinston, PhD, Recover Injury Research Centre, Level 7, 288 Herston Road, Herston, Brisbane, Queensland, Australia 4006 (e-mail: rachelel@uq.edu.au). Received June 17, 2020 Received in revised form November 23, 2020 Accepted November 29, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Pre- versus Postoperative Scalp Block Combined with Incision Line Infiltration for Pain Control after Supratentorial Craniotomy Objective: Postoperative pain after craniotomy is a significant clinical problem which is sometimes underestimated, although moderate or severe pain in early postoperative period complicates up to 60% of cases. The purpose of this prospective randomized multicenter trial is to determine the optimal timing for selective scalp block in patients undergoing general anesthesia for supratentorial craniotomy. Methods: After ethics committee approval and informed consent, 56 adult patients were enrolled, and randomly assigned to receive a selective scalp block combined with incision line infiltration preoperatively or postoperatively. Results: Postoperative pain at 24 hours after the procedure was recorded in all 56 enrolled patients. In patients assigned to receive a scalp block preoperatively, median VAS score at 24 hours after surgery was 0 (0-2), and in patients assigned to receive a scalp block postoperatively it was 0 (0-3) (P>0,05). There was no difference in severity of pain at 24, 12, 6, and 2 hours after surgery between the two study groups, but the amount of fentanyl administered intraoperatively was lower in patients assigned to the preoperative scalp block group (1.6±0.7▒mkg/kg/h vs. 2.4±0.7▒mkg/kg/h (P=0.01)). Discussion: This study confirms and extends available clinical evidence on the safety and efficacy of selective scalp blocks for the prevention of postoperative pain. Recorded data suggest that there is no difference in terms of occurrence and severity of postoperative pain regardless of whether the scalp block is performed preoperatively (after general anesthesia induction) or postoperatively (before extubation). Patients assigned to receive a scalp block combined with incision line infiltration preoperatively needed less intraoperative opioids than those assigned to postoperative scalp block. Financial Disclosures: None Conflicts of interest: None Reprints: Alexander Kulikov, MD, PhD, 125047, 4th Tverskaya-Yamskaya St., 16, Department of Anesthesiology, Burdenko National Medical Research Center of Neurosurgery, Moscow, Russia (e-mail: akulikov@nsi.ru). Received April 25, 2019 Received in revised form August 28, 2020 Accepted November 6, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Video-based Pain Education in Schools: A Study with Adolescents Objective: School-based educational programs have shown positive changes in health-related behaviors among adolescents. The aim of this study was to analyze the changes in pain-related knowledge among adolescents and in the use of positive responses to their peers' pain behaviors after watching a brief educational video. Methods: One hundred and thirty-five adolescents (mean age=13.27; SD=1.17) participated and provided demographic and pain-related information. They also responded to a pain-related knowledge questionnaire before (T1), after (T2) and one month after (T3) watching a brief pain educational video, and to a modified version of the Inventory of Parent/Caregiver Responses to the Children's Pain Experience at T1 and at T3. Results: There was a significant increase in pain knowledge for all participants between T1 and T2 (η2p=0.73) and between T1 and T3 (η2p=0.62). An increase in responses considered to be positive to peers' pain behaviors (i.e., the promotion of well-behaviors and coping responses) one month after watching the educational video was also found. Interestingly, these results were not associated with the chronic pain status of the participant. Discussion: The findings showed that a brief and inexpensive educational video-based intervention in schools helps to increase pain-related knowledge and change responses to students with chronic pain. This has the potential to prevent chronic pain and related disability among students, and decrease bullying-like behaviors towards students with chronic pain. Conflict of interests: The authors declare no conflicts of interest in relation to this study. Reprints: Jordi Miró, PhD, Departament de Psicologia; Universitat Rovira i Virgili; Carretera de Valls, s/n; 43007 Tarragona; Spain (e-mail: jordi.miro@urv.cat). Received July 17, 2020 Received in revised form November 9, 2020 Accepted November 11, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Patients with High Chronic Postoperative Knee Pain 5 years after Total Knee Replacement Demonstrate Low-grad Inflammation, Impairment of Function and High Levels of Pain Catastrophizing Objectives: Total knee replacement (TKR) normally provides improvements of physical function and reduces pain. However, approximately 20% of the patients report chronic postoperative knee pain. The aims of the present study were to assess the pain, physical function, and physiological characteristics 5 years after TKR surgery. Methods: Eighty patients were recruited 5 years after TKR and divided into two groups based on their average 24-hour knee pain intensity assessed on a visual analog scale (VAS 0-10) ("High Pain Group": VAS≥3; "Low Pain Group": VAS<3). The patients completed the painDETECT (PD-Q), Oxford Knee Score (OKS), Pain Catastrophizing Scale (PCS), and Forgotten Joint Score (FJS-12). Furthermore, the patients underwent a clinical examination of the knees and high sensitivity serum C-reactive protein (hs-CRP) was measured as an inflammatory marker. Results: 53% of the patients in the High Pain Group was not satisfied with the outcome, while only 11% of the patients in the Low Pain Group was not satisfied, and the pain intensities in the two groups were 5.1 (4.6-5-6) and 1.1 (0.6-1.5), (P<0.001), respectively. Furthermore, the High Pain Group demonstrates worse scores in: FJS-12 (P=0.001), OKS function (P<0.001), OKS pain (P<0.001), and PCS (P<0.001). The High Pain Group demonstrated increased level of hs-CRP (4.3▒mg/L (3.2-5.5) vs. 1.7▒mg/L (1.2-2.2), P<0.001), and decreased range of motion in the knee (110-degrees ROM vs. 119-degrees ROM, P=0.013). Discussion: Patients with high chronic postoperative knee pain 5 years after TKR demonstrate decreased physical function, higher levels of catastrophizing thoughts, and increased levels of inflammation. Original paper for: Clinical Journal of Pain Article Type: Original Research Conflicts of Interest and Source of Funding: The authors declare no conflict of interest. Reprints: Peter Skrejborg, MSc, PhD-fellow, SMI, Department of Health Science and Technology, School of Medicine, Aalborg University, Fredrik Bajers Vej 7 D3, DK-9220 Aalborg, Denmark (e-mail: peter@skrejborg.dk). Received May 18, 2020 Received in revised form November 19, 2020 Accepted November 23, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Physical Activity as a Predictor of Chronic Pain Following Pediatric Spinal Surgery Objectives: (1) Characterize objective physical activity patterns via actigraphy over 4 months post-spinal fusion surgery, and (2) examine associations between activity patterns at 2-weeks and chronic post-surgical pain (CPSP) status at 4-months. Methods: Data from 109 youth (10-18▒y) who underwent spinal fusion surgery at a children's hospital in the northwestern United States were analyzed. Youth completed questionnaires and actigraphic assessment of physical activity pre-surgery, and 2-weeks and 4-months post-surgery. Results: 18% of youth developed CPSP at 4-months. Pre-surgery physical activity was similar for youth with and without CPSP. At 2-weeks post-surgery, daily activity levels were lower for youth who developed CPSP as compared to those who did not, including lower mean activity (168 vs. 212 counts/minute, P=0.01), fewer activity bouts (n=1.7 vs. 2.6, P=0.02), and shorter bout duration (27 vs. 40▒min, P=0.02). Differences in activity were maintained at 4-months such that youth with CPSP had lower mean activity (284 vs. 334 counts/min, P=0.03), as well as greater proportion time spent sedentary and lower proportion time in light activity than youth without CPSP. In adjusted models examining 2-week actigraphy as a predictor of 4-month pain status, mean activity (OR=0.99, P=0.04) and number of activity bouts (OR=0.79, P=0.02) were associated with subsequent CPSP status. Discussion: Lower activity engagement during the initial weeks following spinal fusion surgery was associated with development of CPSP, suggesting early physical activity limitations as a risk factor for CPSP in youth. Understanding recovery patterns is critical for identifying those at risk for chronic pain and implementing early interventions. https://www.seattlechildrens.org/rabbitts-lab/ Funding Source: This research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, at the National Institutes of Health under Grant No. K23HD078239 (P.I.: J.A. Rabbitts). Abbreviations: CPSP, chronic postsurgical pain; MVPA, Moderate to vigorous activity; NRS, Numeric Rating Scale; REDCap, Research Electronic Data Capture System. Conflict of Interest: The authors have no conflicts of interest to disclose. Reprints: Jennifer A. Rabbitts, MB, ChB, Seattle Children's Hospital, 4800 Sand Point Way NE MB.11.500.3, Seattle WA 98105 (e-mail: jennifer.rabbitts@seattlechildrens.org). Received April 9, 2020 Received in revised form October 9, 2020 Accepted November 11, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

The Impact of Parental Pain- and Non-pain-attending Responses upon Child Pain Behavior in the Context of Cancer-related Painful Procedures: The Moderating Role of Parental Self-oriented Distress Objectives: Literature has demonstrated inconsistent findings regarding the impact of parental responses upon child pain-related outcomes. Yet, research into factors that may underlie inconsistent findings regarding the variable impact of parental responses is lacking. The current study investigated the moderating role of parental distress in understanding the impact of parental pain-attending (e.g., reassuring the child) and non-pain-attending (e.g., distracting the child with humor) responses upon child pain behavior (e.g., crying). Methods: Children (≤18▒y) suffering from leukemia, undergoing a lumbar puncture (LP) and/or bone marrow aspiration (BMA) procedure, and one of their parents, were recruited from the Pediatric Ghent University Hospital. Parent-child interactions were videotaped after the procedure allowing coding of parental responses and child pain behavior. Parents self-reported on experienced personal distress. Results: Participants consisted of 42 children (24 boys, 18 girls) with leukemia and one of their parents. Children were 0.6-15 (7.08±4.39) years old. Findings indicated a positive association between parental pain-attending and child pain behavior, but only when parents reported high levels of distress (β=0.56, P=0.001). No association was observed for parents reporting low levels of distress (β=-0.09, ns). Parental non-pain-attending responses contributed to lower child pain behavior (β=-0.24, P=0.045), independently from parental distress (β=-0.07, ns). Discussion: The current findings point to the moderating role of parental distress in understanding the impact of parental responses upon child pain behavior and highlight the importance of interventions targeting parental emotion regulation to promote more optimal child pain outcomes. Disclosures: Grant support for Emma Rheel was provided by a Chair funded by the Berekuyl Academy / European College for Decongestive Lymphatic Therapy, the Netherlands and awarded to the Vrije Universiteit Brussel, Belgium. Kelly Ickmans is a postdoctoral research fellow, partly funded by the Research Foundation – Flanders (FWO). Line Caes was funded by the Research Foundation – Flanders (FWO). None of these sponsors played a role in the (1) study design, (2) collection, analysis and interpretation of data, (3) writing of the report, (4) decision to submit the paper for publication. The authors report no conflicts of interest. Reprints: Emma Rheel, MSc, Address of correspondence and reprints requests to Emma Rheel, Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium (e-mail: emma.rheel@vub.be). Received June 5, 2020 Received in revised form November 4, 2020 Accepted November 11, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

What Mediates Treatment Effects in a Pre-surgery Physiotherapy Treatment in Surgical Candidates with Degenerative Lumbar Spine Disorders? A Mediation and Conditional Process Analysis of the PREPARE Randomized Controlled Trial Objectives: Treatment guidelines recommend targeting both physical and psychological factors in interventions for degenerative lumbar spine disorders. Studying treatment mechanisms gives information on key factors explaining outcome improvement which can refine treatments for future research. This study explores treatment mediators in a physiotherapy treatment on disability, pain intensity and health related quality of life (HRQoL) in surgical candidates with degenerative lumbar spine disorders compared to waiting-list controls. An additional aim was to evaluate patients´ expectation as a moderator of treatment outcome. Methods: Data collected from 197 patients in a single blinded randomized controlled trial comparing 9 weeks of multifaceted physiotherapy to waiting-list were used in this conditional process analysis. Analysis was carried out on group differences for change in Oswestry Disability Index (ODI), Pain Visual Analog Scale (VAS) back pain, EuroQol-5D (EQ-5D) and EQ-VAS. The putative moderation role of expectations and mediation role of change in physical variables and psychosocial variables were tested. Results: Change in self-efficacy mediated improvement in all outcomes. Improvement in ODI was also mediated by change in depression, VAS was mediated by change in fear avoidance beliefs and EQ-VAS was mediated by change in activity level and fear avoidance beliefs. Improvements were moderated by patients´ treatment expectations. Discussion: Self-efficacy, fear avoidance beliefs, physical activity level and patients´ treatment expectations were found to be important factors explaining treatment effects. Self-efficacy was the consistent mediator for effects of the pre-surgical physiotherapy on disability, back pain intensity and HRQoL. Sources of grant support: Research Council in Southeast Sweden (grant number: FORSS*660371), the Swedish Research Council (grant number:2017*01444) and Region Östergötland (LIO-921021). Approved by the Regional Ethics Committee in Linköping (dnr 2012/167-31). Trial registration: NCT02454400. Trail registration date: August 31st, 2015, retrospectively registered. The authors declare no conflict of interest. Reprints: Maria Fors, RPT, MSc, Linkopings universitet Medicinska Fakulteten Linköping, SWEDEN (e-mail: maria.fors@liu.se). Received March 31, 2020 Received in revised form October 28, 2020 Accepted November 3, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Deep Cervical Plexus Block for Neck and Shoulder Pain Due to Myofascial Pain: A Randomized Clinical Trial Objectives: Myofascial pain is one of the most common causes of regional pain yet with no definitive treatment modality. This randomized clinical trial was conducted to assess the efficacy of deep cervical plexus block versus placebo injection (sham block) for the treatment of myofascial neck and shoulder pain in terms of analgesic consumption and pain during a follow up period of two weeks after performing the block. Methods: Patients were randomly divided into two groups. Group I (Block) received deep cervical plexus block and group II (Placebo) received normal saline. A total of 66 patients were included in the study, 34 patients in the block group and 32 patients in the placebo group. Results: Two weeks after the intervention, average pain duration was significantly lower in the block group (1.38±1.39 vs. 5.25±1.72) for the block and placebo groups respectively (P-value<0.0001). Pain intensity was significantly less in the block group such that 2.9% of patients in the block group had severe pain compared to 53.1% of patients in the placebo group (P-value<0.0001). Two weeks after receiving the block, the mean opioid consumption calculated as tramadol equivalent was 21.1±44.2▒mg compared to 166.1±118.8▒mg for the block and placebo groups respectively. Multivariate analysis revealed that patients with a longer history of pain had a higher pain score after two weeks. The possibility of recovery is affected by pain duration since patients with chronic history of pain were least affected by the block. Discussion: This technique could be an alternative to pharmacological and non-pharmacological treatments for myofascial pain. Disclosures: Funding: none Conflict of interest: none declared Reprints: Zoher Naja, MD, PhD, Anesthesia and Pain Management Department - Makassed General Hospital, P.O. Box: 11-6301 Riad EI-Solh 11072210, Beirut – Lebanon (e-mail: zouhnaja@yahoo.com). Received September 18, 2019 Received in revised form November 10, 2020 Accepted November 17, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

The Effect of Perioperative Lidocaine Infusion on Postoperative Pain and Postsurgical Recovery Parameters in Gynecological Cancer Surgery Objectives: The primary objective of this prospective non-blinded randomized study was to investigate the effect of perioperative systemic lidocaine infusion on pain control after major gynecologic oncology surgery. Patient-reported outcomes, postoperative recovery parameters, and complications were secondary endpoints of the study. Methods: Seventy-five patients with ASA I-III was divided into three groups based on perioperative analgesia methods: The opioid group: patient-controlled analgesia (PCA) with morphine, The lidocaine group: perioperative intravenous lidocaine infusion, plus PCA with morphine, and the epidural group: PCA with bupivacaine. The Visual Analog Scale (VAS) was recorded postoperatively. In addition, nausea-vomiting, time to first oral intake, time to first ambulation, time to first flatus, and length of hospital stay were recorded. Results: VAS scores (rest) at 24 hours at rest and VAS scores (cough) at 12 and 24 hours were significantly lower in the epidural group than in the opioid group (P<0.05). VAS scores were found to be similar between the lidocaine and epidural group. The nausea-vomiting incidence was lower in the lidocaine group than in the opioid group(P<0.05). Compared to the other two groups, first flatus time was shorter in the lidocaine group (P<0.05). Discussion: Perioperative lidocaine infusion is effective as epidural analgesia, which is often advocated as the gold-standard analgesic technique for abdominal surgery and is superior to the others in terms of time to first flatus, and the incidence of nausea-vomiting. Conflicts of Interest: The authors declare that they have no conflicts of interest. Reprints: Menşure Kaya, MD, Associate Professor, Department of Anesthesiology and Reanimation, University of Health Sciences Dr. AY Oncology Training and Research Hospital, Demetevler 13. Cad. 06180, Ankara, Turkey (e-mail: mensurekaya@yahoo.com). Received April 3, 2020 Received in revised form October 28, 2020 Accepted November 3, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Critical Care Medicine

Changes in the Plethysmographic Perfusion Index During an End-Expiratory Occlusion Detect a Positive Passive Leg Raising Test Objectives: The end-expiratory occlusion test for assessing preload responsiveness consists in interrupting mechanical ventilation for 15 seconds at end-expiration and measuring the cardiac index changes. The perfusion index is the ratio between the pulsatile and the nonpulsatile portions of the plethysmography signal and is, in part, determined by stroke volume. We tested whether the end-expiratory occlusion-induced changes in perfusion index could detect a positive passive leg raising test, suggesting preload responsiveness. Design: Observational study. Setting: Medical ICU. Patients: Thirty-one ventilated patients without atrial fibrillation. Interventions: We measured perfusion index (Radical-7 device; Masimo Corp., Irvine, CA) and cardiac index (PiCCO2; Pulsion Medical Systems, Feldkirchen, Germany) before and during a passive leg raising test and a 15-second end-expiratory occlusion. Measurements and Main Results: In 19 patients with a positive passive leg raising test (increase in cardiac index ≥ 10%), compared to the baseline value and expressed as a relative change, passive leg raising increased cardiac index and perfusion index by 17% ± 7% and 49% ± 23%, respectively, In these patients, end-expiratory occlusion increased cardiac index and perfusion index by 6% ± 2% and 11% ± 8%, respectively. In the 12 patients with a negative passive leg raising test, perfusion index did not significantly change during passive leg raising and end-expiratory occlusion. Relative changes in perfusion index and cardiac index observed during all interventions were significantly correlated (r = 0.83). An end-expiratory occlusion-induced relative increase in perfusion index greater than or equal to 2.5% ([perfusion index during end-expiratory occlusion–perfusion index at baseline]/perfusion index at baseline × 100) detected a positive passive leg raising test with an area under the receiver operating characteristic curve of 0.95 ± 0.03. This threshold is larger than the least significant change observed for perfusion index (1.62% ± 0.80%). Conclusions: Perfusion index could be used as a reliable surrogate of cardiac index for performing the end-expiratory occlusion test. Confirming previous results, the relative changes in perfusion index also reliably detected a positive passive leg raising test. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). Dr. Beurton collected the data, performed data analysis, drafted the article, and approved its final version. Dr. Teboul conceived the study, participated in analyzing the data and to writing the article, and approved its final version. Drs. Gavelli and De Vita contributed to data recording and approved the final version of the article. Dr. Monnet conceived the study, supervised data analysis, drafted the article, and approved its final version. All authors read and approved the final article. Dr. Teboul received funding from Getinge/Pulsion. Dr. Monnet received funding from Pulsion Medical Systems, and he received support for article research from Assistance publique-Hôpitaux de Paris. Drs. Teboul and Monnet are members of the Medical Advisory Board of Pulsion Medical Systems and have given lectures for Masimo Corp. The remaining authors have disclosed that they do not have any potential conflicts of interest. Information and consent obtained for each patient. Name of the ethics committee that approved the study and the committee's reference number: Comité pour la Protection des Personnes, Ile-de-France VII. Trial registration ID RCB: 2016-A00959-42. Registered June 27, 2016. The patients were included prospectively. Information and consent obtained for each patient. For information regarding this article, E-mail: alexandra.beurton@aphp.fr Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

CNS Complications in Adult Patients Treated With Extracorporeal Membrane Oxygenation Objectives: To describe the incidence and outcomes of radiologically confirmed acute CNS complications in extracorporeal membrane oxygenation patients at an Australian extracorporeal membrane oxygenation referral center and identify associated patient characteristics. Design: Retrospective cohort study. Setting: Single-center tertiary institution. Patients: Four-hundred twelve consecutive adult patients supported with extracorporeal membrane oxygenation from 2009 to 2017. Results: Fifty-five patients (13.3%) had a CNS complication confirmed by CT or MRI, including ischemic stroke (7.0%), intracerebral hemorrhage (3.4%), hypoxic ischemic encephalopathy (3.6%), and spinal cord injury (1.2%). CNS complication rates in the venoarterial, venovenous, and veno-pulmonary artery extracorporeal membrane oxygenation subgroups were 18.0%, 4.6%, and 13.6%, respectively. Neurologic complications were independently associated with the use of venoarterial extracorporeal membrane oxygenation (p = 0.002) and renal replacement therapy (p = 0.04). Sixty-five percent of patients with a neurologic complication died during their hospital admission compared with 32% of patients without this complication (p < 0.001). Venoarterial extracorporeal membrane oxygenation, renal replacement therapy, and days of extracorporeal membrane oxygenation support were also associated with hospital mortality and remained so after adjustment in a multivariable regression model (p = 0.01, p < 0.001, and p = 0.003, respectively). Conclusions: CNS complications appear to occur more frequently in patients requiring circulatory as opposed to respiratory support on extracorporeal membrane oxygenation and are independently associated with mortality. It remains unclear if these complications are causative of a poor outcome or a marker of severity of the underlying condition. Further research is required to better elucidate modifiable or preventable aspects through better patient selection and change in ongoing care. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). Dr. Kerr disclosed work for hire. The remaining authors have disclosed that they do not have any potential conflicts of interest. This work was performed at Department of Intensive Care Medicine, St Vincent's Hospital, Darlinghurst, NSW, Australia. For information regarding this article, E-mail: Hergen.Buscher@svha.org.au Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Mortality of Older Patients Admitted to an ICU: A Systematic Review Objectives: To conduct a systematic review of mortality and factors independently associated with mortality in older patients admitted to ICU. Data Sources: MEDLINE via PubMed, EMBASE, the Cochrane Library, and references of included studies. Study Selection: Two reviewers independently selected studies conducted after 2000 evaluating mortality of older patients (≥ 75 yr old) admitted to ICU. Data Extraction: General characteristics, mortality rate, and factors independently associated with mortality were extracted independently by two reviewers. Disagreements were solved by discussion within the study team. Data Synthesis: Because of expected heterogeneity, no meta-analysis was performed. We selected 129 studies (median year of publication, 2015; interquartile range, 2012–2017) including 17 based on a national registry. Most were conducted in Europe and North America. The median number of included patients was 278 (interquartile range, 124–1,068). ICU and in-hospital mortality were most frequently reported with considerable heterogeneity observed across studies that was not explained by study design or location. ICU mortality ranged from 1% to 51%, in-hospital mortality from 10% to 76%, 6-month mortality from 21% to 58%, and 1-year mortality from 33% to 72%. Factors addressed in multivariate analyses were also heterogeneous across studies. Severity score, diagnosis at admission, and use of mechanical ventilation were the independent factors most frequently associated with ICU mortality, whereas age, comorbidities, functional status, and severity score at admission were the independent factors most frequently associated with 3– 6 and 12 months mortality. Conclusions: In this systematic review of older patients admitted to intensive care, we have documented substantial variation in short- and long-term mortality as well as in prognostic factors evaluated. To better understand this variation, we need consistent, high-quality data on pre-ICU conditions, ICU physiology and treatments, structure and system factors, and post-ICU trajectories. These data could inform geriatric care bundles as well as a core data set of prognostic factors to inform patient-centered decision-making. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). Supported, in part, by institutional sources. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: helene.vallet@aphp.fr Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Surrogate Humane Endpoints in Small Animal Models of Acute Lung Injury: A Modified Delphi Consensus Study of Researchers and Laboratory Animal Veterinarians Objectives: In many jurisdictions, ethical concerns require surrogate humane endpoints to replace death in small animal models of acute lung injury. Heterogenous selection and reporting of surrogate endpoints render interpretation and generalizability of findings between studies difficult. We aimed to establish expert-guided consensus among preclinical scientists and laboratory animal veterinarians on selection and reporting of surrogate endpoints, monitoring of these models, and the use of analgesia. Design: A three-round consensus process, using modified Delphi methodology, with researchers who use small animal models of acute lung injury and laboratory animal veterinarians who provide care for these animals. Statements on the selection and reporting of surrogate endpoints, monitoring, and analgesia were generated through a systematic search of MEDLINE and Embase. Participants were asked to suggest any additional potential statements for evaluation. Setting: A web-based survey of participants representing the two stakeholder groups (researchers, laboratory animal veterinarians). Statements were rated on level of evidence and strength of support by participants. A final face-to-face meeting was then held to discuss results. Subjects: None. Interventions: None. Measurements and Main Results: Forty-two statements were evaluated, and 29 were rated as important, with varying strength of evidence. The majority of evidence was based on rodent models of acute lung injury. Endpoints with strong support and evidence included temperature changes and body weight loss. Behavioral signs and respiratory distress also received support but were associated with lower levels of evidence. Participants strongly agreed that analgesia affects outcomes in these models and that none may be necessary following nonsurgical induction of acute lung injury. Finally, participants strongly supported transparent reporting of surrogate endpoints. A prototype composite score was also developed based on participant feedback. Conclusions: We provide a preliminary framework that researchers and animal welfare committees may adapt for their needs. We have identified knowledge gaps that future research should address. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). Drs. Fergusson, Stewart, McIntyre, and Lalu contributed to conceptualization. Drs. Fergusson, Stewart, McIntyre, Stacey, and Lalu contributed to methodology. Drs. McGinn, MacNeil, and Lalu contributed to formal analysis. Drs. McGinn, Fergusson, Stewart, MacNeil, and Lalu contributed to investigation. Drs. McGinn and Lalu contributed to data curation. Drs. McGinn, Barron, and Lalu contributed to writing—original draft. Drs. McGinn, MacNeil, and Lalu contributed to visualization. Drs. Fergusson, Stewart, and Lalu contributed to supervision. Drs. McGinn, Barron, MacNeil, and Lalu contributed to project administration. Drs. Fergusson, Stewart, McIntyre, and Lalu contributed to funding acquisition. All coauthors contributed to writing, review, and editing. Supported, in part, by a planning and dissemination grant from the Canadian Institutes for Health Research (no 345325), a New Ideas Grant from the Ontario Institutes for Regenerative Medicine, and a Grant-in-Aid from the Ontario Lung Association (Drs. Stewart, McIntyre, and Lalu). Drs. McGinn, Fergusson, Barron, Liu, and Lalu institutions received funding from Canadian Institutes of Health Research (CIHR). Dr. Kristof received funding from Ottawa Hospital Research Institute (travel costs). Dr. Downey received support for article research from the National Institutes of Health. Dr. Brown received support for article research from CIHR. Dr. dos Santos disclosed that she is funded by CIHR. Dr. Lalu is supported by The Ottawa Hospital Anesthesia Alternate Funds Association and the University of Ottawa Junior Research Chair in Innovative Translational Research. All of work was completed at the Ottawa Hospital Research Institute in Ottawa, ON, Canada. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: mlalu@toh.ca or manojlalu@gmail.com Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Effectiveness of Bundle Interventions on ICU Delirium: A Meta-Analysis Objective: To evaluate the impact of bundle interventions on ICU delirium prevalence, duration, and other patients' adverse outcomes. Data Sources: The Cochrane Library, PubMed, CINAHL, EMBASE, PsychINFO, and MEDLINE from January 2000 to July 2020. The protocol of the study was registered in International prospective register of systematic reviews (CRD42020163147). Study Selection: Randomized clinical trials or cohort studies that examined the following outcomes were included in the current study: ICU delirium prevalence and duration, proportion of patient-days with coma, ventilator-free days, mechanical ventilation days, ICU or hospital length of stay, and ICU or inhospital or 28-day mortality. Data Extraction: Using a standardized data-collection form, two authors screened the studies and extracted the data independently, and assessed the studies' quality using the Modified Jadad Score Scale for randomized clinical trials and the Newcastle-Ottawa Scale for cohort studies. Data Synthesis: Eleven studies with a total of 26,384 adult participants were included in the meta-analysis. Five studies (three randomized clinical trials and two cohort studies) involving 18,638 patients demonstrated that ICU delirium prevalence was not reduced (risk ratio = 0.92; 95% CI, 0.68–1.24). Meta-analysis showed that the use of bundle interventions was not associated with shortening the duration of ICU delirium (mean difference = –1.42 d; 95% CI, –3.06 to 0.22; two randomized clinical trials and one cohort study), increasing ventilator-free days (mean difference = 1.56 d; 95% CI, –1.56 to 4.68; three randomized clinical trials), decreasing mechanical ventilation days (mean difference = –0.83 d; 95% CI, –1.80 to 0.14; four randomized clinical trials and two cohort studies), ICU length of stay (mean difference = –1.08 d; 95% CI, –2.16 to 0.00; seven randomized clinical trials and two cohort studies), and inhospital mortality (risk ratio = 0.86; 95% CI, 0.70–1.06; five randomized clinical trials and four cohort studies). However, bundle interventions are effective in reducing the proportion of patient-days experiencing coma (risk ratio = 0.47; 95% CI, 0.39–0.57; two cohort studies), hospital length of stay (mean difference = –1.47 d; 95% CI, –2.80 to –0.15; four randomized clinical trials and one cohort study), and 28-day mortality by 18% (risk ratio = 0.82; 95% CI, 0.69–0.99; three randomized clinical trials). Conclusions: This meta-analysis fails to support that bundle interventions are effective in reducing ICU delirium prevalence and duration, but supports that bundle interventions are effective in reducing the proportion of patient-days with coma, hospital length of stay, and 28-day mortality. Larger randomized clinical trials are needed to evaluate the impact of bundle interventions on ICU delirium and other clinical outcomes. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). The funding source had no role in the study design, data collection, data analysis, data explanation, or article writing. Dr. Wu is receiving a grant (#71661167008) from "the National Natural Science Foundation of China." The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: helenywu@vip.163.com This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Inspiratory Muscle Training With an Electronic Resistive Loading Device Improves Prolonged Weaning Outcomes in a Randomized Controlled Trial Objectives: To test if the use of an inspiratory muscle training program with an electronic resistive loading device is associated with benefits as to muscle strength, weaning, and survival in the ICU. Design: Prospective randomized controlled trial. Settings: Study conducted at the ICU of a Navy's hospital, Rio de Janeiro, Brazil, from January 2016 to September 2018. Patients: Tracheostomized patients (18–86 yr) on prolonged weaning. Interventions: Participants were assigned to inspiratory muscle training (intervention group) or a traditional T-piece protocol (control group). In the inspiratory muscle training group, participants underwent training with an electronic inspiratory training device (POWERbreathe K-5; Technologies Ltd, Birmingham, United Kingdom). MEASUREMENTS AND MAIN RESULTS: Changes in respiratory muscle strength and rates of ICU survival and weaning success were compared between groups. Forty-eight participants in the inspiratory muscle training group and 53 ones in the control group were included in the final analysis. The inspiratory muscle training was associated with a substantially higher gain on muscle strength as assessed by the maximal inspiratory pressure (70.5 [51.0–82.5] vs –48.0 cm H2O [36.0–72.0 cm H2O]; p = 0.003) and the timed inspiratory effort index (1.56 [1.25–2.08] vs 0.99 cm H2O/s [0.65–1.71 cm H2O/s]; p = 0.001). Outcomes at the 60th day of ICU were significantly better in the intervention group regarding both survival (71.1% vs 48.9%; p = 0.030) and weaning success (74.8% vs 44.5%; p = 0.001). Conclusions: The use of an inspiratory muscle training program with an electronic resistive loading device was associated with substantial muscle strength gain and positive impacts in two very relevant clinical outcomes: the rates of ICU survival and successful weaning. This work was performed at Hospital Naval Marcilio Dias, Rio de Janiero, Brazil (Brazil's Navy). This study was approved by the local Research Ethics Committee and was registered in a publicly accessible clinical trial database (ClinicalTrials.gov ID: NCT02932189). Approved by the institution's ethics committee under the number 45060215.3.0000.0065. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. All authors contributed substantially to the study design, data analysis and interpretation, and the writing of the article. All authors read and approved the final article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). Dr. de Souza disclosed that this study was partially supported by Universidade Estácio de Sá by a research productivity program and disclosed off-label product use of the digital vacuometer MVD 300 (Globalmed, Porto Alegre, Brazil) and the device POWERbreathe K-5 and the software (BreatheLink; Power Breathe International, Warwickshire, United Kingdom). Dr. Alvim disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: brunoguimaraespneumo@yahoo.com.br Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Timing, Outcome, and Risk Factors of Intracranial Hemorrhage in Acute Respiratory Distress Syndrome Patients During Venovenous Extracorporeal Membrane Oxygenation Objectives: Intracranial hemorrhage is a serious complication in patients receiving venovenous extracorporeal membrane oxygenation during treatment of the acute respiratory distress syndrome. We analyzed timing, outcome, and risk factors of intracranial hemorrhage in patients on venovenous extracorporeal membrane oxygenation. Design: Retrospective cohort study. Setting: Single acute respiratory distress syndrome referral center. Patients: Patients receiving venovenous extracorporeal membrane oxygenation were identified from a cohort of 1,044 patients with acute respiratory distress syndrome. Patients developing an intracranial hemorrhage during venovenous extracorporeal membrane oxygenation therapy were compared with patients without evidence for intracranial hemorrhage. The primary objective was to assess the association of intracranial hemorrhage with 60-day mortality. Further objectives included the identification of risk factors for intracranial hemorrhage and the evaluation of clinical cutoff values. Interventions: None. Measurements and Main Results: Among 444 patients treated with venovenous extracorporeal membrane oxygenation, 49 patients (11.0% [95% CI, 8.3–14.4%]) developed an intracranial hemorrhage. The median time to intracranial hemorrhage occurrence was 4 days (95% CI, 2–7 d). Patients who developed an intracranial hemorrhage had a higher 60-day mortality compared with patients without intracranial hemorrhage (69.4% [54.4–81.3%] vs 44.6% [39.6–49.6%]; odds ratio 3.05 [95% CI, 1.54–6.32%]; p = 0.001). A low platelet count, a high positive end expiratory pressure, and a major initial decrease of PaCO2 were identified as independent risk factors for the occurrence of intracranial hemorrhage. A platelet count greater than 100/nL and a positive end expiratory pressure less than or equal to 14 cm H2O during the first 7 days of venovenous extracorporeal membrane oxygenation therapy as well as a decrease of PaCO2 less than 24 mm Hg during venovenous extracorporeal membrane oxygenation initiation were identified as clinical cutoff values to prevent intracranial hemorrhage (sensitivity 91% [95% CI, 82–99%], 94% [85–99%], and 67% [48–81%], respectively). Conclusions: Intracranial hemorrhage occurs early during venovenous extracorporeal membrane oxygenation and is a determinant for 60-day mortality. Appropriate adjustment of identified modifiable risk factors might lower the prevalence of intracranial hemorrhage during venovenous extracorporeal membrane oxygenation therapy. The study was approved by the Medical Ethics Committee of Charité-Universitätsmedizin Berlin (No. EA1/007/19). Data are available from the corresponding author. Drs. Graw and Menk are co-senior authors. Dr. Menk contributed to conception and design and study supervision. Drs. Hunsicker, Beck, Graw, and Menk contributed to acquisition of data. Drs. Hunsicker, Beck, Weber-Carstens, Graw, and Menk contributed to interpretation of data. Drs. Hunsicker, Krannich, and Menk contributed to statistical analysis. Drs. Hunsicker, Graw, and Menk contributed to drafting of the article. All authors contributed to critical revision of the article for important intellectual content. Drs. Hunsicker, Weber-Carstens, Spies, Graw, and Menk contributed to final revision of article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). Supported, in part, by institutional sources only. Dr. Graw received funding from CSL Behring, and he is a participant in the BIH-Charité Clinician Scientist Program funded by the Charité – Universitätsmedizin Berlin and the Berlin Institute of Health. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Mario Menk, MD, PhD, Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail: mario.menk@charite.de Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Procalcitonin Is Useful for Antibiotic Deescalation in Sepsis No abstract available

Determining Thresholds for Three Indices of Autoregulation to Identify the Lower Limit of Autoregulation During Cardiac Surgery Objectives: Monitoring cerebral autoregulation may help identify the lower limit of autoregulation in individual patients. Mean arterial blood pressure below lower limit of autoregulation appears to be a risk factor for postoperative acute kidney injury. Cerebral autoregulation can be monitored in real time using correlation approaches. However, the precise thresholds for different cerebral autoregulation indexes that identify the lower limit of autoregulation are unknown. We identified thresholds for intact autoregulation in patients during cardiopulmonary bypass surgery and examined the relevance of these thresholds to postoperative acute kidney injury. Design: A single-center retrospective analysis. Setting: Tertiary academic medical center. Patients: Data from 59 patients was used to determine precise cerebral autoregulation thresholds for identification of the lower limit of autoregulation. These thresholds were validated in a larger cohort of 226 patients. Methods and Main Results: Invasive mean arterial blood pressure, cerebral blood flow velocities, regional cortical oxygen saturation, and total hemoglobin were recorded simultaneously. Three cerebral autoregulation indices were calculated, including mean flow index, cerebral oximetry index, and hemoglobin volume index. Cerebral autoregulation curves for the three indices were plotted, and thresholds for each index were used to generate threshold- and index-specific lower limit of autoregulations. A reference lower limit of autoregulation could be identified in 59 patients by plotting cerebral blood flow velocity against mean arterial blood pressure to generate gold-standard Lassen curves. The lower limit of autoregulations defined at each threshold were compared with the gold-standard lower limit of autoregulation determined from Lassen curves. The results identified the following thresholds: mean flow index (0.45), cerebral oximetry index (0.35), and hemoglobin volume index (0.3). We then calculated the product of magnitude and duration of mean arterial blood pressure less than lower limit of autoregulation in a larger cohort of 226 patients. When using the lower limit of autoregulations identified by the optimal thresholds above, mean arterial blood pressure less than lower limit of autoregulation was greater in patients with acute kidney injury than in those without acute kidney injury. Conclusions: This study identified thresholds of intact and impaired cerebral autoregulation for three indices and showed that mean arterial blood pressure below lower limit of autoregulation is a risk factor for acute kidney injury after cardiac surgery. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). Supported, in part, by the National Institutes of Health (NIH) K76 AG057020 (to Dr. Brown) and by NIH R01 NS107417 and the American Heart Association Transformational Project Award (cofunded by the Lawrence J. and Florence A. DeGeorge Charitable Trust) (to Dr. Lee). Drs. Lee, Hogue, and Brown received support for article research from the National Institutes of Health (NIH). Dr. Lee has received support from and been a paid consultant for Medtronic, and she received research support from Edwards Life Sciences. Dr. Lee's arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Some methods used to measure and monitor autoregulation as described in this article were patented by The Johns Hopkins University, listing Dr. Brady as a coinventor. These patents are exclusively licensed to Medtronic. Dr. Brown reported receiving grants from the NIH during the conduct of the study, and consulting for and participating in a data share with Medtronic. Dr. Brady is listed as inventor on patents awarded and assigned to the Johns Hopkins University. These patents are related to the monitoring technology described in this article and are exclusively licensed to Medtronic, and Dr. Brady received a portion of the licensing fee. Dr. Venkataraman received funding from Vixiar Medical (consulting) and from universities for speaker honorariums, and she was supported by the National Science Foundation CAREER award 1845430. Dr. Hogue reported receiving grants and personal fees for being a consultant and providing lectures for Medtronic/Covidien, being a consultant to Merck, and receiving grants from the NIH outside of the submitted work, and he disclosed off-label product use of autoregulation monitoring is investigational. Drs. Czosnyka and Smielewski received funding from licensing ICM+ through Cambridge Enterprise Ltd, United Kingdom. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: liuxiuyun1@gmail.com Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Stability of Do-Not-Resuscitate Orders in Hospitalized Adults: A Population-Based Cohort Study Objectives: Prior work has shown substantial between-hospital variation in do-not-resuscitate orders, but stability of do-not-resuscitate preferences between hospitalizations and the institutional influence on do-not-resuscitate reversals are unclear. We determined the extent of do-not-resuscitate reversals between hospitalizations and the association of the readmission hospital with do-not-resuscitate reversal. Design: Retrospective cohort study. Setting: California Patient Discharge Database, 2016–2018. Patients: Nonsurgical patients admitted to an acute care hospital with an early do-not-resuscitate order (within 24 hr of admission). Interventions: None. Measurements and Main Results: We identified nonsurgical adult patients who survived an initial hospitalization with an early-do-not-resuscitate order and were readmitted within 30 days. The primary outcome was the association of do-not-resuscitate reversal with readmission to the same or different hospital from the initial hospital. Secondary outcomes included association of readmission to a low versus high do-not-resuscitate-rate hospital with do-not-resuscitate reversal. Among 49,336 patients readmitted within 30 days following a first do-not-resuscitate hospitalization, 22,251 (45.1%) experienced do-not-resuscitate reversal upon readmission. Patients readmitted to a different hospital versus the same hospital were at higher risk of do-not-resuscitate reversal (59.5% vs 38.5%; p < 0.001; adjusted odds ratio = 2.4; 95% CI, 2.3–2.5). Patients readmitted to low versus high do-not-resuscitate-rate hospitals were more likely to have do-not-resuscitate reversals (do-not-resuscitate-rate quartile 1 77.0% vs quartile 4 27.2%; p < 0.001; adjusted odds ratio = 11.9; 95% CI, 10.7–13.2). When readmitted to a different versus the same hospital, patients with do-not-resuscitate reversal had higher rates of mechanical ventilation (adjusted odds ratio = 1.9; 95% CI, 1.6–2.1) and hospital death (adjusted odds ratio = 1.2; 95% CI, 1.1–1.3). Conclusions: Do-not-resuscitate reversals at the time of readmission are more common than previously reported. Although changes in patient preferences may partially explain between-hospital differences, we observed a strong hospital effect contributing to high do-not-resuscitate-reversal rates with significant implications for patient outcomes and resource. Drs. Mehta, Walkey, and Douglas conceived the study. Dr. Mehta was responsible for data collection. Drs. Mehta, Walkey, Curran-Everett, and Douglas were responsible for data analysis and interpretation. Drs. Mehta drafted the article. All the authors were responsible for critical revisions of article and provided final approval for the manuscript. Dr. Mehta had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr. Mehta conducted all aspects of data analysis. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). Supported, in part, by the National Institutes of Health (NIH) K23HL141704 (to Dr. Mehta; primary funding source), NIH R01HL136660 and R01HL139751 (to Dr. Walkey), NIH R01HL136403 (to Dr. Matlock), and NIH R01NR016459 (to Dr. Douglas). Drs. Mehta and Walkey's institutions received funding from the National Institutes of Health (NIH). Drs. Mehta and Matlock received support for article research from the NIH. Dr. Walkey received funding from UptoDate. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Anuj B. Mehta, MD, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, 1400 Jackson Street J209, Denver, CO. E-mail: mehtaa@njhealth.org Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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