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Purpose: To assess the statistical fragility of randomized controlled trials that assess the use of platelet-rich plasma (PRP) for the treatment of knee osteoarthritis (OA) and report a continuous primary outcome measure with statistical significance., Methods: A systematic electronic search of MEDLINE, EMBASE, and Cochrane database was performed on August 10, 2024. All randomized controlled trials addressing the use of PRP for the treatment of symptomatic knee osteoarthritis were included that reported statistically significant primary continuous outcomes. The continuous fragility index (CFI) and continuous fragility quotient (CFQ) were calculated using approximative method, as previously described using the mean and standard deviation of the outcomes of interest., Results: There were a total of 34 eligible outcomes available for analysis. The overall median CFI across all included studies was 5.7 (IQR: 4.8-9.9). The overall median CFQ across all included studies was 0.131 (IQR: 0.055-0.243). Loss to follow-up was greater than the CFI in only 3 of 34 eligible outcomes (8.8%). The most analyzed outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score (n = 9) with a median CFI of 6.6 and median CFQ of 0.250. The outcome with the highest median CFI was the WOMAC stiffness subscale at 93. Spearman correlation analysis demonstrated a nonstatistically significant trend toward decreasing CFI (-0.497) and a statistically significant decrease in CFQ (-0.681; p = 0.03) with increasing grades of osteoarthritis., Conclusions: There was an overall median CFI of 5.7 and CFQ of 0.131 for RCTs that report statistically significant continuous outcomes for the use of PRP in treating symptomatic knee OA. Although there are no current guidelines regarding statistical fragility of continuous outcomes, these results can be considered fragile given statistical significance may be reversed with only a few changes in patient outcomes., Level of Evidence: II; systematic review of Level I and II studies., Competing Interests: Disclosures The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Valvular heart disease, including calcific or degenerative aortic stenosis (AS), is increasingly prevalent among the older adult population. Over the last few decades, treatment of severe AS has been revolutionised following the development of transcatheter aortic valve replacement (TAVR). Despite improvements in outcomes, older adults with competing comorbidities and geriatric syndromes have suboptimal quality of life outcomes, highlighting the cumulative vulnerability that persists despite valve replacement. Sarcopenia, characterised by loss of muscle strength, mass and function, affects 21%-70% of older adults with AS. Sarcopenia is an independent predictor of short-term and long-term outcomes after TAVR and should be incorporated as a prognostic marker in preprocedural planning. Early diagnosis and treatment of sarcopenia may reduce morbidity and mortality and improve quality of life following TAVR. The adverse effects of sarcopenia can be mitigated through resistance training and optimisation of nutritional status. This is most efficacious when administered before sarcopenia has progressed to advanced stages. Management should be individualised based on the patient's wishes/preferences, care goals and physical capability. Exercise during the preoperative waiting period may be safe and effective in most patients with severe AS. However, future studies are needed to establish the benefits of prehabilitation in improving quality of life outcomes after TAVR procedures., Competing Interests: Competing interests: AAD receives research funding from the Pepper Scholars Program of the Johns Hopkins University Claude D Pepper Older Americans Independence Center funded by the National Institute on Aging (P30-AG021334), mentored patient-oriented research career development award from the National Heart, Lung, and Blood Institute (K23-HL153771), the NIH National Institute on Aging (R01-AG078153) and the Patient-Centered Outcomes Research Institute (PCORI)., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cryptococcosis is an invasive, opportunistic fungal infection seen especially in human immunodeficiency virus (HIV) infected patients. Cryptococcal meningitis (CM) is the second leading cause of mortality in HIV patients. We report a case of disseminated cryptococcosis presenting with altered mental status in a newly diagnosed HIV infection., Methods and Results: A 50-year-old with a short history of altered mental sensorium and a history of low-grade fever and weight loss for few months presented at a tertiary care hospital in North India. He was detected positive for HIV-1. Cryptococcal antigen (CRAG) was positive in Cerebrospinal fluid (CSF), and negative in serum. The fungal culture in CSF was sterile while the fungal blood culture grew Cryptococcus neoformans. The patient was treated with single high-dose Liposomal Amphotericin B (LAmB) therapy followed by Fluconazole and Flucytosine for the next two weeks followed by fluconazole daily for consolidation and maintenance therapy. Antiretroviral therapy (ART) was started 4 weeks after induction therapy. After 6 months, the patient is doing fine., Conclusion: Single dose LAmB along with the backbone of fluconazole and flucytosine appears promising in disseminated cryptococcal infection in HIV-infected individuals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Environmental enteric dysfunction (EED) is a subclinical enteropathy challenging to diagnose due to an overlap of tissue features with other inflammatory enteropathies. EED subjects ( n  = 52) from Pakistan, controls ( n  = 25), and a validation EED cohort ( n  = 30) from Zambia were used to develop a machine-learning-based image analysis classification model. We extracted histologic feature representations from the Pakistan EED model and correlated them to transcriptomics and clinical biomarkers. In-silico metabolic network modeling was used to characterize alterations in metabolic flux between EED and controls and validated using untargeted lipidomics. Genes encoding beta-ureidopropionase, CYP4F3, and epoxide hydrolase 1 correlated to numerous tissue feature representations. Fatty acid and glycerophospholipid metabolism-related reactions showed altered flux. Increased phosphatidylcholine, lysophosphatidylcholine (LPC), and ether-linked LPCs, and decreased ester-linked LPCs were observed in the duodenal lipidome of Pakistan EED subjects, while plasma levels of glycine-conjugated bile acids were significantly increased. Together, these findings elucidate a multi-omic signature of EED., Competing Interests: KDRS has equity in Asklepion Pharmaceuticals and is a consultant to Travere Therapeutics and Mirum Pharmaceuticals. All the other authors have no conflicts of interest to disclose., (© 2024 The Authors.)

Introduction and Importance: Pneumocystis jirovecii (PJP) pneumonia is a serious life-threatening condition in immunocompromised individuals and is often associated with human immunodeficiency virus (HIV) + patients. We describe a case of PJP pneumonia which provided a diagnostic challenge in a patient who presented with no known risk factors leading to a delay in initiation of appropriate antibiotic therapy., Case Presentation: A 71-year-old previously healthy white/Caucasian male presented with subacute hypoxic respiratory failure due to multifocal pneumonia with diffuse bilateral ground glass opacities with consolidations despite prior treatment with antibiotics and steroids. He was admitted and started on intravenous broad-spectrum antibiotics but continued to deteriorate, eventually requiring intubation and transfer to the ICU. Bronchoscopy revealed PJP and treatment was initiated, but the patient developed refractory shock and multiorgan failure, and ultimately died. It was later discovered that he was HIV-1 positive., Clinical Discussion: PJP, as a potential cause of his presentation, was not considered given that our patient lacked any overt risk factors for PJP pneumonia. He continued to worsen despite broad spectrum antibiotic therapy and hence bronchoscopy was pursued. His clinical profile, in hindsight, was suspicious for PJP pneumonia and early PJP-directed antibiotic therapy may have prevented a fatal outcome, as in this case. There was an element of cognitive bias across multiple providers which may have contributed to the delay in treatment despite his rapid clinical decline while on conventional pneumonia treatment protocol. His diagnosis was later evident when his BAL-DFA grew PJP in addition to his low levels of CD4 and CD8 cells. He was found to be HIV-1 positive five days after his death; there was a delay in this diagnosis since all positive HIV tests from the hospital are reported as 'pending' until the presumptive positive sample goes to the Connecticut Department of Public Health State laboratory for the confirmatory test. PJP-targeted therapies were initiated later in our patient's hospital course when the infection had progressed to refractory septic shock with multiorgan failure and eventual death., Conclusion: PJP pneumonia is a fatal disease if not recognized early in the course of illness, and the patient usually undergoes multiple antibiotic regimens before they are diagnosed and receive appropriate clinical care. The gold standard of diagnostic testing for PJP is by obtaining bronchial washings through a flexible bronchoscopy and the turnaround time for such results may take a few days to result. A significant proportion of patients may not have any overt risk factors of immunosuppression and early empiric treatment for PJP may be clinically appropriate as the delay in diagnosis may be associated with significant morbidity and mortality risk., (© 2024. The Author(s).)

Background: Roussy-Lévy syndrome (RLS) is characterized by postural hand tremor seen in patients with familial autosomal dominant Charcot-Marie-Tooth (CMT) neuropathy., Phenomenology Shown: This video demonstrates irregular, jerky bilateral kinetic, postural, rest tremor affecting the right > left hand, along with pes cavus and gait ataxia in a patient with CMT disease., Educational Value: Pes cavus, tendon areflexia, sensory ataxia, and upper limb tremor should prompt consideration of CMT neuropathy., Highlights: This video abstract depicts a bilateral hand tremor characteristic of Roussy-Lévy syndrome seen in patients with Charcot-Marie-Tooth disease neuropathy. The significance of the abstract lies in the phenomenology and the physiology of the tremor seen in patients with genetically confirmed duplication of PMP22 gene., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Background: Resistance training has been consistently shown to have multiple health benefits, especially for patients who have undergone bariatric surgery. Patients who have undergone bariatric surgery are recommended to participate in resistance exercise; however, protocols and guidelines for resistance training remain poorly implemented., Objective: This is a protocol for a systematic review and possibly a meta-analysis that will synthesize evidence of the effects of resistance exercise on changes in body composition, muscular strength, overall weight loss or maintenance of weight loss, and quality of life in patients after metabolic and bariatric surgery (MBS). The findings of this study may provide practice recommendations for resistance training among patients who have undergone MBS., Methods: We registered this systematic review on PROSPERO (CRD42023464928) on September 18, 2023. A systematic search of electronic databases (Embase, PubMed, Scopus, Web of Science, and CINAHL) was conducted on studies published from January 1, 1991, to May 15, 2023, to identify English-language human studies on adult patients who have undergone MBS that include a resistance training intervention and describe outcome measurements of body composition or strength. Screening will be performed using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, and relevant data elements will be extracted., Results: Searches and screenings commenced in May 2023. Data extraction and analyses will be completed by the end of December 2023, after which findings will be synthesized and reported by the end of March 2024., Conclusions: This systematic review will summarize the evidence regarding resistance training in patients after MBS. The findings from this systematic review and possible meta-analysis may provide practice recommendations for resistance training protocols in this patient population and identify characteristics of protocols with the best adherence and outcomes. With these results, we anticipate that we will gain a deeper understanding of the role of resistance training after MBS., Trial Registration: PROSPERO CRD42023464928; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=464928., International Registered Report Identifier (irrid): PRR1-10.2196/49513., (©Whitney Elks, Adam Rooks, Spencer Schulte, Kavita Batra, Jocelyn Burke, Varun Jain. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 23.11.2023.)

Progressive multifocal leukoencephalopathy (PML) is a central nervous system disease caused by the human polyomavirus 2 that usually occurs in a setting of immunodeficiency. PML without overt immunosuppression is considered a rare occurrence but has been described in multiple previous case reports and series. Its prevalence, overall frequency, and prognosis are largely unknown. This is a single-center retrospective review of all University of Florida cases with the ICD10 PML diagnosis code (A81.2). PML without overt immunosuppression was defined as absence of human immunodeficiency virus (HIV) infection, hematological malignancy, immunomodulatory/-suppressive medications, autoimmune conditions with a propensity for PML (sarcoidosis, systemic lupus erythematosus). Cases that did not fulfill criteria for clinically or histologically definite PML were excluded. Of 52 patients with the ICD10 code A 81.2, 17 fulfilled definite diagnostic criteria for PML. Overt immunosuppression was identified in 15/17 (88.2%) cases (10/17 (58.8%): human immunodeficiency virus; 5/17 (29.4%): immunomodulatory/-suppressive medication). Two/seventeen (11.8%) cases were consistent with PML without overt immunosuppression. Possible contributing factors were a preceding dog bite and mild hypogammaglobulinemia M (39 mg/dL) in case 1 and significant alcohol use without evidence for liver disease in case 2. Both cases were fatal within 6 (case 1) and 2 (case 2) months. The results suggest that PML without overt immunosuppression may be more common than previously described. Therefore, PML should be considered even in the absence of overt immunosuppression if clinical and radiographic findings are suggestive of the diagnosis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Diagnosing and treating oral cavity lesions is a challenging task for most of the clinicians due to similar symptoms and clinical appearances. Frequently, histopathology and immunohistochemistry aid in making the diagnosis., Objectives: The objectives were to describe the clinical features, and histopathological features and systemic association in patients with oral mucosal lesions (OML)., Materials and Methods: A cross-sectional descriptive study was undertaken at a tertiary care centre in patients with OML. A total of 369 cases with OML were included in the study., Results: Males constituted 61.78% of the cases. History of habits such as tobacco, gutka chewing, smoking, and alcohol was given by 32.25%, 29.81%, 26.56%, and 11.38% of cases, respectively. Common symptoms were soreness, burning sensation, oral pain and ulcers. Both oral and cutaneous involvement was seen in 17.89% of cases. Oral lichen planus (oral LP) constituted largest group of patients (21.96%) wherein reticulate type was the most frequent type and buccal mucosa was the commonest site. Oral carcinomas constituted 20.33% of cases followed by infective etiology (11.92%), vesiculobullous group of diseases (10.30%), aphthous stomatitis (8.94%), premalignant lesions (7.05%) such as leukoplakia (3.80%) and submucous fibrosis (2.44%). Histopathology was done in 209 cases. Clinico-histopathological correlation was seen in oral LP (90.27%), oral pemphigus (82.35%), and malignancies (98.66%)., Conclusion: Oral LP formed the largest group of cases followed by Oral squamous cell carcinoma (SCC). Several rare conditions, such as Melkersson-Rosenthal syndrome and blue rubber bleb nevus syndrome were also a part of the study. Thorough clinical and histopathological examination in this diverse group of diseases clinches the diagnosis., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Indian Dermatology Online Journal.)

Background: Mild stroke has variable outcomes, and there is an ongoing debate regarding whether the administration of thrombolytics improves outcomes in this subgroup of stroke patients. Having a better understanding of the features of mild stroke may help identify patients who are at risk of poor outcomes., Objective: The objective of this study is to evaluate the association of clinical and imaging-based small vessel disease features (white matter hyperintensities and cerebral microbleeds) with stroke severity and clinical outcomes in patients with mild stroke., Methods: In this retrospective study, mild stroke was defined as a National Institute of Health stroke scale (NIHSS) score <5. Clinical, laboratory and imaging data were compared between patients with mild stroke versus non-mild stroke (NIHSS≥5). Multivariate logistic regression analysis was performed to identify predictors of mild stroke and poor discharge outcome., Results: Among 296 patients included in the study, 131 patients (44%) had mild stroke. On multivariate analysis, patients with mild stroke were three times more likely to have sensory symptoms [odds ratio (OR) = 2.9; 95% confidence interval (CI) = (1.2-6.8)] and four times more likely to have stroke due to small vessel disease (OR = 3.7; 95%CI = 1.4-9.9). Among patients with mild stroke, higher age (OR = 1.1; 95%CI = 1.02-1.1), presence of cerebral microbleed (OR = 4.5; 95%CI = 1.5-13.8), vertigo (OR = 7.3; 95%CI = 1.2-45.1) and weakness (OR = 5.0; 95%CI = 1.2-20.3) as presenting symptoms were more likely to have poor discharge outcome., Conclusion: Sensory symptoms and stroke due to small vessel disease are more common in mild stroke than non-mild stroke. Among patients with mild stroke, presence of cerebral microbleeds on imaging and symptoms of muscle weakness are associated with poor discharge outcome. Larger studies are needed to assess the impact of cerebral microbleed on mild stroke outcomes and risk stratify the benefit of thrombolytics in this group., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Mucormycosis is a fast-spreading angioinvasive fungal infection with a very high mortality rate. It is associated with immunodeficiency, diabetes mellitus, iron overload, stem cell transplantation and the use of steroids. As cultures and histopathological biopsy may have low yield in invasive fungal infections, new generation sequencing of cfDNA (cell free deoxyribonucleic acid) has become a cornerstone for diagnosis. Over the past 18 months, increasing reports of COVID-19 associated Mucormycosis have emerged, most specifically in India and other nearby developing countries. Awareness and knowledge of this newly discovered association is of high importance and clinical relevance as the global COVID-19 pandemic continues. Herein, we present a case of a patient who was treated with steroids for COVID-19 in the outpatient setting and presented with unilateral periorbital pain and blurry vision. She progressively developed bilateral vision loss, fixed bilateral mydriasis, ophthalmoplegia and coma. Imaging findings included leptomeningeal, vascular, and subcortical enhancement accompanied with multifocal infarction. Subsequent biopsy of the paranasal sinuses revealed broad type fungal elements and cfDNA sequencing identified the pathogen as Rhizopus species. She was treated with intravenous amphotericin B, but succumbed to the infection., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

The precisionFDA Truth Challenge V2 aimed to assess the state of the art of variant calling in challenging genomic regions. Starting with FASTQs, 20 challenge participants applied their variant-calling pipelines and submitted 64 variant call sets for one or more sequencing technologies (Illumina, PacBio HiFi, and Oxford Nanopore Technologies). Submissions were evaluated following best practices for benchmarking small variants with updated Genome in a Bottle benchmark sets and genome stratifications. Challenge submissions included numerous innovative methods, with graph-based and machine learning methods scoring best for short-read and long-read datasets, respectively. With machine learning approaches, combining multiple sequencing technologies performed particularly well. Recent developments in sequencing and variant calling have enabled benchmarking variants in challenging genomic regions, paving the way for the identification of previously unknown clinically relevant variants., Competing Interests: DECLARATION OF INTERESTS C.B. is an employee and shareholder of SAGA Diagnostics AB. A.C., P.-C.C., A.K., M.N., G.B., S.G., and H.Y. are employees of Google, and A.C. is a shareholder. S.D.-B., D.K.-Z., D.T., Ö.K., G.B., K.N., E.A., R.B., I.J.J., A.D., V.S., A.J., and H.S.T. are employees of Seven Bridges Genomics. O.S. and S. T.W. are employees of DNAnexus. G.L., C.M., L.T.F., Y.D., and S.Z. are employees of Genetalks. V.J., M.R., B.L., C.R., S.C., and R.M. are employees of Illumina. S.M.E.S. and M.M. are employees of Roche. C.H. is an employee of Wasai Technology. H.F., Z.L., and L.C. are employees of Sentieon.

Objectives: Up to 10% of acute ischemic stroke (AIS) patients can die in the first 30 days. Older age and a higher National Institutes of Health Stroke Scale (NIHSS) score are associated with transition to comfort measures only (CMO) in AIS. There are insufficient data on specific stroke etiology, infarct location, or vascular territory for the association of AIS with the use of CMO. We therefore evaluated the clinical and imaging factors associated with utilization of CMO and their outcomes. Methods: AIS patients seen in an academic comprehensive stroke center in the United States between July 1, 2015, and June 30, 2016, were subgrouped based on the use of CMO orders (CMO vs. non-CMO) during hospitalization. Clinical, laboratory, and imaging data were analyzed. Multivariable logistic regression analysis was performed, adjusting for pertinent covariates. Results: The study consisted of 296 patients, 27 (9%) patients were transitioned to CMO. Compared with non-CMO patients, those with CMO were older (mean ± standard deviation: 66 ± 15 vs. 75 ± 11 years, p  = 0.002). Hemorrhagic transformation of AIS was more likely in CMO (17% vs. 41%, p  = 0.0030) compared with non-CMO patients. On multivariate analysis, severe stroke measured by the NIHSS score (odds ratio [OR] = 1.2; 95% confidence interval [CI] = 1.1-1.4), infarction of the insular cortex (OR = 12.9; 95% CI = 1.4-118.4), and presence of cerebral edema with herniation (OR = 9.4; 95% CI = 2.5-35.5) were associated with transition to CMO. Conclusions: The presence of severe stroke, infarction of the insular cortex, and cerebral edema with herniation were associated with utilization of CMO in AIS. Impairment of multiple neurological functions served by the insular cortex could play a role in transition to CMO.

Background: Consolidation of physician practices is well-documented in recent years, yet minimal data exist regarding consolidation in general surgery. This study evaluates current trends in general surgery practice consolidation., Methods: Data were obtained through the CMS Physician Compare database. Surgeons and practices were categorized by size, and trends were analyzed using the Cochran-Armitage test. Data were stratified by US region., Results: From 2012 to 2020, practicing general surgeons increased from 20,044 to 20,637 (+3%). Unique general surgery practices declined from 8178 to 6489 (-21%). The percentage of surgeons in practices of 1 or 2 declined from 19% to 12%, while surgeons in groups of 500 or more grew from 20% to 31%. Tests for trends towards consolidation at both the individual surgeon and unique practice levels were significant (p < .001). The Midwest region demonstrated the highest degree of consolidation., Conclusion: Consistent with trends in medicine overall, general surgery is experiencing substantial practice consolidation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Primary sclerosing cholangitis (PSC) is associated with inflammatory bowel disease (IBD). Patients with concomitant PSC-IBD are at higher risk for IBD-related complications including dysplasia and malignancy, however the typical clinical IBD course is less severe. The aim of this study was to identify the prevalence of biologic use and therapeutic drug monitoring (TDM) in a cohort of PSC-IBD patients., Methods: Retrospective analysis of patients with PSC-IBD on biologic therapy who underwent TDM from Jan. 2018 to Aug. 2020 at the University of Virginia. Demographic data including age, disease duration, and comorbidities were recorded. IBD categorizations were recorded according to the Montreal Classification. Treatment outcomes including therapy changes after TDM were obtained., Results: A total of 157 patients with PSC-IBD were identified. Of these, 29 patients (19%) were treated with biologic therapy during the study period. 13 patients underwent reactive TDM due to primary or secondary loss of response and one patient underwent proactive TDM during the study period. Median duration of IBD in this group was 9 years, and the median duration of concomitant PSC-IBD was 5.8 years. 20 TDM tests were obtained in these 14 total patients. Sub-therapeutic drug levels were found in 12 tests among 8 patients, and 3 showed detectable anti-drug antibodies. 8 showed appropriate trough levels. TDM resulted in a change to IBD therapy (i.e., dose escalation, change in biologic therapy used, or addition of IBD medication) in 17 out of 20 tests., Conclusion: Herein we describe epidemiologic data of biologic use in PSC-IBD patients at an academic center. PSC-IBD classically follows a less severe clinical presentation and course. However, our study demonstrates that a subset of PSC-IBD patients exist which require biologic therapy and follow a more refractory clinical trajectory. In this subset, TDM showed a high incidence of sub-therapeutic trough levels and anti-drug antibodies, leading to a change in therapy in 85% of TDM instances. Larger studies are recommended to better understand this unique subset of PSC-IBD patients., (Copyright © 2021 by The American College of Gastroenterology.)

Background: Hypertrophic cardiomyopathy (HCM) accounts for significant morbidity and mortality worldwide. Arrhythmias are considered the main cause of mortality, however, there is paucity of data relating to trends of arrhythmia and associated outcomes in HCM patients., Methods: Nationwide Inpatient Sample from 2003 to 2014 was analyzed. HCM related hospitalizations were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD9-CM) code 425.1 and 425.11 in all diagnosis fields., Results: Overall, there was an increase in number of hospitalizations related to arrhythmias among HCM patients from 7784 in 2003 to 8380 in 2014 (relative increase 10.5%, P  < 0.001). The increase was most significant in patients ≥ 80 years and those with higher comorbidity burden. Atrial fibrillation (AF) was the most frequently occurring arrhythmia however atrial flutter (AFL) witnessed the highest rise during the study period. In general, there was a down trend in mortality with the greatest reduction occurring in patients with ventricular fibrillation/flutter (VF/VFL). The mean length of stay was higher if patients had arrhythmia, which led to increased cost of care from $16105 in 2003 to $19310 in 2014 (relative increase 22.9%, P  < 0.001)., Conclusion: There is overall decline in HCM related hospitalizations but rise in hospitalization among HCM patients with arrhythmias. HCM with arrhythmia accounts for significant inpatient mortality coupled with prolonged hospital stay and increased cost of care. However, there is an encouraging downtrend in the mortality most likely because of improved clinical practice, cardiac screening and primary and secondary prevention strategies., Competing Interests: Authors declare no conflict of interests for this article.

Background and Aim: Smooth and rapid emergence and extubation, with minimal coughing, is desirable after cervical spine surgery to facilitate early neurological examination. The present study investigated the effect of dexmedetomidine as an intraoperative anesthetic adjuvant on postoperative extubation and recovery profile in patients undergoing anterior cervical discectomy and fusion (ACDF) surgery., Material and Methods: Sixty-four, American Society of Anesthesiologist I or II adult patients (age 18-60 years) were randomized in this placebo-controlled, double-blind study. In group D, dexmedetomidine was started at 0.2 μg/kg/h after a loading dose of 1 μg/kg before induction and in group P, volume and infusion rate-matched normal saline was used. Perioperative hemodynamics, intraoperative anesthetic consumption, and postoperative recovery profile were observed., Results: Thirty-one patients in each group successfully completed the study. Time to emergence (6.9 min vs 10 min, P < 0.001), time to extubation (8.5 min vs 12.2 min, P = 0.002), and time to achieve modified Aldrete score ≥9 (5 min vs 10 min, P < 0.001) were earlier in group D compared to group P, respectively. Pain score at extubation was lower (0 vs 20) and time for first analgesic was longer (50 min vs 15 min) in group D compared to group P. Coughing at extubation was comparable in both the groups. One patient in group D had severe postextubation bradycardia., Conclusions: Intraoperative use of dexmedetomidine at the lowest recommended dosage in adults undergoing ACDF surgery results in a favorable recovery profile with reduced emergence/extubation time and postoperative pain, but similar incidence of coughing., Competing Interests: There are no conflicts of interest.

Silicon oxide substrates underwent gas-phase functionalization with various aminosilanes, and the resulting surfaces were evaluated for their suitability as a solid support for solid phase peptide synthesis (SPPS). APTES (3-aminopropyltriethoxysilane), APDEMS (3-aminopropyldiethoxymethylsilane), and APDIPES (3-aminopropyldiisopropylethoxysilane) were individually applied to thermal oxide-terminated silicon substrates via gas-phase deposition. Coated surfaces were characterized by spectroscopic ellipsometry (SE), contact angle goniometry, X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), and spectrophotometry. Model oligopeptides with 16 residues were synthesized on the amino surfaces, and the chemical stabilities of the resulting surfaces were evaluated against a stringent side chain deprotection (SCD) step, which contained trifluoroacetic acid (TFA) and trifluoromethanesulfonic acid (TFMSA). Functionalized surface thickness loss during SCD was most acute for APDIPES and the observed relative stability order was APTES > APDEMS > APDIPES. Amino surfaces were evaluated for compatibility with stepwise peptide synthesis where complete deprotection and coupling cycles are paramount. Model trimer syntheses indicated that routine capping of unreacted amines with acetic anhydride significantly increased purity as measured by MALDI-MS. An inverse correlation between the amine loading density and peptide purity was observed. In general, peptide purity was highest for the lowest amine density APDIPES surface.

The immune checkpoint inhibitors have brought about a paradigm shift in the treatment of many cancers and are being used as the first line therapy in increasing number of aggressive malignancies, including metastatic melanoma. Their adverse effects, mostly mediated by an uncontrolled overactivation of the immune system, may compromise the therapeutic benefit. Combination immune checkpoint therapies in particular, have higher therapeutic efficacy, but have also been associated with a higher incidence of severe immune-related adverse effects including autoimmune lymphocytic myocarditis. Recent clinical reports of this rare and life threatening condition indicated rapid progression of severe hemodynamic and electrical instability, with or without acute decompensated heart failure, reduced ejection fraction and shock, pointing to the need for early recognition, diagnosis and prompt management. Current guidelines for management of other immune-related adverse effects recommend high-dose glucocorticoids, with consideration of immunomodulators, such as infliximab in patients with severe colitis. However, knowledge about the treatment approaches in immune-related myocarditis remains extremely scarce. Here we report a case of severe, steroid refractory, lymphocytic myocarditis that occurred after the first cycle of combination immunotherapy with the programmed cell death protein-1 inhibitor, nivolumab, and the cytotoxic T-lymphocyte-associated protein 4 blocker, ipilimumab, for metastatic melanoma. We discuss treatment approaches including the role for transvenous pacemaker, advanced heart failure support, and interdisciplinary decision making.

Background: Endonasal endoscopic approach for transsphenoidal excision of pituitary adenoma has undergone remarkable evolution in the last two decades. It is considered less invasive and less stressful, with results comparable to the previous "gold standard" technique of microscopic transsphenoidal excision of pituitary adenoma. The aim of this study was to compare the various perioperative anesthetic and surgical factors which differ in the two approaches (endoscopic vs. microscopic) for pituitary adenoma excision, during the period when surgeons increasingly started using endoscope at our center., Materials and Methods: Data of 307 patients from January 2011 to December 2013 were reviewed in this retrospective study. Various parameters were divided and compared on the basis of the type of approach for pituitary tumor resection vis-à-vis microscope-assisted sublabial transsphenoidal (MSLTS) resection or microscope-assisted transnasal transsphenoidal (MTNTS) resection or endoscope-assisted endonasal transsphenoidal (ETSS) resection., Results: Demographic variables (except age); tumor type, dimensions, and invasiveness; patients' comorbidities; postoperative nausea/vomiting, electrolyte imbalance, respiratory, and cardiovascular problems were comparable among three groups. Duration of surgery and anesthesia were shortest for MTNTS group and longest for ETSS group ( P < 0.001). Blood loss was higher in ETSS technique (median 300 mL) and least in MTNTS (median 100 mL), and the difference was significant across all three groups ( P = 0.0003). Postoperative cerebrospinal fluid rhinorrhea was 17% in the MSLTS group compared to 6.5% in MTNTS and 7.9% in ETSS ( P = 0.047)., Conclusion: ETSS with the expected advantage of being less invasive offers a better chance for complete resection of adenoma. Neuroanesthesiologist must be prepared for longer surgical time and more blood loss as compared to previous microscopic approach, at least till the surgeons expertise in this newer technique., Competing Interests: There are no conflicts of interest.

Background: The study aimed to evaluate and compare the stress distribution and 3-dimensional displacements along the craniofacial sutures in between the Rapid maxillary Expansion (RME) and Implant supported RME (I-RME). METHODS: Finite element model of the skull and the implants were created using ANSYS software. The finite element model thus built composed of 537692 elements and 115694 nodes in RME model & 543078 elements and 117948 nodes with implants model. The forces were applied on the palatal surface of the posterior teeth to cause 5mm of transverse displacement on either side of the palatal halves, making it a total of 10mm. The stresses and the displacement values were obtained and interpreted., Results: Varying pattern of stress and the displacements with both positive and negative values were seen. The maximum displacement was seen in the case of plain RME model and that too at Pterygomaxillary suture and Mid-palatal suture in descending order. In the case of I-RME maximum displacement was seen at Zygomaticomaxillary suture followed by Pterygomaxillary suture. The displacements produced in all the three planes of space for the plain RME model were greater in comparison to the Implant Supported RME model. And the stresses remained high for all the sutures in case of an I-RME., Conclusions: There is a definite difference in the stress and the displacement pattern produced by RME and I-RME model and each can be used according to the need of the patient. The stresses generated in case of conventional RME were considerably less than that of the I-RME for all the sutures.

A key operational decision faced by a multi-facility health care diagnostic centre serving different patient categories (for example: Health Check-up Patient ( HCP ), Out-Patient ( OP ), Emergency Patient ( EP ), or In-Patient) is whom to serve next at a particular facility. In this paper, we model random arrival of these patients belonging to different categories and priorities at multiple diagnostic facilities over a finite planning horizon. We formulate a mathematical model for sequential decision-making under uncertainty using Markov Decision Process (MDP) with the objective of maximising net revenue and use dynamic programming (DP) to solve it. To address dimensionality and scalability issue of MDP, we provide a decentralised MDP (D&#95;MDP) formulation. We develop simulation-based neighbourhood search algorithm to improve DP solution for D&#95;MDP. We compare these solutions with three other rule-based heuristics using simulation., Competing Interests: No potential conflict of interest was reported by the authors.

Opinion Statement: Immune therapies represent a quantum leap in the fight against cancer. Recently approved immune checkpoint inhibitors that target receptors involved in immune escape of cancer cells (including cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death protein ligand-1 (PD-L1) are increasingly being used for therapeutic benefit in a number of cancers. The robust anti-cancer activity of these agents has been accompanied by the recognition of new adverse effects, often due to the over activation of immune system, that may limit their therapeutic benefit and adversely impact outcomes. Combination treatments in particular, such as approaches using two targeted immunotherapy agents, have higher risk of adverse effects. Our review focuses on the approved checkpoint inhibitor therapies and their potential for cardiovascular toxicity. While very few cases of autoimmune cardiotoxicity and myocarditis have been reported in clinical trials, severe, life-threatening episodes of heart failure and hemodynamic compromise associated with the use of immune checkpoint inhibitors have recently been reported in the literature. Early recognition, diagnosis, and management of autoimmune myocarditis represent an important clinical challenge with no current guidelines available for prevention, identification, and treatment of this serious condition. This area of cardio-oncology is evolving rapidly as more drugs in this class are being discovered and pending approval. There is a need for future studies focused on prospective identification of biomarkers and clinical standards for treatment and long-term follow-up of cardiovascular toxicity to successfully continue the treatment of cancer while preventing the adverse outcomes with novel immune therapies.

Cancer therapy targeting the epidermal growth factor receptor (EGFR)/erythroblastic leukemia viral oncogene B (ErbB)/human EGFR receptor (HER) family of tyrosine kinases has been successfully used in treatment of several malignancies. The ErbB pathways play a role in the maintenance of cardiac homeostasis. This article summarizes current knowledge about EGFR/ErbB/HER receptor-targeted cancer therapeutics focusing on their cardiotoxicity profiles, molecular mechanisms, and implications in clinical cardio-oncology. The article discusses challenges in predicting, monitoring, and treating cardiac dysfunction and heart failure associated with ErbB-targeted cancer therapeutics and highlights opportunities for researchers and clinical investigators., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: No Gut Syndrome refers to a condition which results after a near total enterectomy (NTE) has been performed. These patients are unable to sustain life without life-long parenteral nutrition (PN). Re-establishment of bowel continuity, complications, quality of life (QoL), and overall outcomes are important aspects to be considered in patients who might need a NTE. We have previously reported two similar cases as well as a literature review in patients with No Gut Syndrome. In the present report, we present an additional case and an update of the literature., Presentation of the Case: A 62-year old man with multiple co-morbidities presented with features of acute small bowel obstruction. Exploratory laparotomy revealed severe mesenteric ischemia and extensive small bowel necrosis. Patient eventually underwent a NTE and was discharged on parenteral nutrition., Discussion: Near total enterectomy (NTE) is a clinical condition in which a patient is left without or with minimal length of small bowel along with either gastrointestinal continuity or exteriorization of the proximal end. This condition has remained a dilemma for surgeons worldwide chiefly as a result of its perceived incompatibility with life. There are only a few available options for proceeding with treatment, however maintenance on long term parenteral nutrition has shown promising results., Conclusion: Long term parenteral nutrition serves as a viable treatment option for managing patients after a NTE., (Published by Elsevier Ltd.)

The primary objective of the study was to develop a pH and transit time controlled sigmoidal release polymeric matrix for colon-specific delivery of indomethacin. Tablet matrices were prepared using a combination of hydrophilic polymers (polycarbophil or carbopol) having pH-sensitive swelling properties with hydrophobic polymer ethyl cellulose. The prepared matrices were characterized for physical properties and in vitro release kinetics. The presence of ethyl cellulose in a hydrophilic polymer matrix resulted in a sigmoidal in vitro drug release pattern with negligible-to-very low drug release in the initial phase (0-6 h) followed by controlled release for 14-16 h. The retardation in initial release can be attributed to the presence of ethyl cellulose that reduced swelling of hydrophilic polymer(s), while in the later portion, polymer relaxation at alkaline pH due to the ionization of acrylic acid units on carbopol and polycarbophil resulted in enhanced drug release. Thus, a sigmoidal release pattern was obtained that could be ideal for colonic delivery of indomethacin in the potential treatment of colon cancer.

The primary objective of the study was to develop a pH and transit time controlled sigmoidal release polymeric matrix for colon-specific delivery of indomethacin. Tablet matrices were prepared using a combination of hydrophilic polymers (polycarbophil or carbopol) having pH sensitive swelling properties with hydrophobic polymer ethyl cellulose. The prepared matrices were characterized for physical properties and in vitro release kinetics. The presence of ethyl cellulose in a hydrophilic polymer matrix resulted in a sigmoidal in vitro drug release pattern with negligible to very low drug release in the initial phase (0-6 h) followed by controlled release for 14-16 h. The retardation in initial release can be attributed to the presence of ethyl cellulose that reduced swelling of hydrophilic polymer(s) while in the later portion, polymer relaxation at alkaline pH due to the ionization of acrylic acid units on carbopol and polycarbophil resulted in enhanced drug release. Thus, a sigmoidal release pattern was obtained that could be ideal for colonic delivery of indomethacin in the potential treatment of colon cancer.