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Robot-assisted laparoscopic prostatectomy requires a pneumoperitoneum combined with steep Trendelenburg positioning, and these conditions can be associated with impairment of cerebral autoregulation. The objective of this study was to determine if choice of anaesthetic agent affects the preservation of cerebral autoregulation during robot-assisted laparoscopic prostatectomy. We randomly assigned 30 patients to maintenance of general anaesthesia with either propofol or sevoflurane. Cerebral autoregulation was tested by administration of intravenous phenylephrine to increase mean arterial pressure from approximately 80 mmHg to 100 mmHg while assessing cerebral blood flow using transcranial Doppler ultrasonography. Autoregulation was first tested in the supine position and then approximately once every hour after Trendelenburg positioning. The main outcome measure was the result of the final autoregulation test prior to completion of surgery. At that time, we found cerebral autoregulation to be significantly impaired in six of the 15 patients receiving sevoflurane and none of the 15 patients receiving propofol ( P = 0.02). However, it should be noted that some patients in the propofol group had impaired autoregulation on earlier tests. In conclusion, we found that autoregulation during robot-assisted laparoscopic prostatectomy is less likely to be impaired with propofol compared to sevoflurane anaesthesia, particularly towards the end of the surgery.

This document is a focused update to the 2017 colorectal cancer (CRC) screening recommendations from the U.S. Multi-Society Task Force on Colorectal Cancer, which represents the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy. This update is restricted to addressing the age to start and stop CRC screening in average-risk individuals and the recommended screening modalities. Although there is no literature demonstrating that CRC screening in individuals under age 50 improves health outcomes such as CRC incidence or CRC-related mortality, sufficient data support the U.S. Multi-Society Task Force to suggest average-risk CRC screening begin at age 45. This recommendation is based on the increasing disease burden among individuals under age 50, emerging data that the prevalence of advanced colorectal neoplasia in individuals ages 45 to 49 approaches rates in individuals 50 to 59, and modeling studies that demonstrate the benefits of screening outweigh the potential harms and costs. For individuals ages 76 to 85, the decision to start or continue screening should be individualized and based on prior screening history, life expectancy, CRC risk, and personal preference. Screening is not recommended after age 85.

Background and Purpose. Physical therapists are at risk for work-related musculoskeletal disorders (WMSDs). Little is known of how therapists respond to injury or of what actions they take to prevent injury. The purpose of this study was to investigate the prevalence and severity of WMSDs in physical therapists, contributing risk factors, and their responses to injury. Subjects. As part of a larger study, a systematic sample of 1 in 4 therapists on a state register (n=824) was surveyed. Methods. An 8-page questionnaire was mailed to each subject. Questions investigated musculoskeletal symptoms, specialty areas, tasks and job-related risk factors, injury prevention strategies, and responses to injury. Results. Lifetime prevalence of WMSDs was 91%, and 1 in 6 physical therapists moved within or left the profession as a result of WMSDs. Younger therapists reported a higher prevalence of WMSDs in most body areas. Use of mobilization and manipulation techniques was related to increased prevalence of thumb symptoms. Risk factors pertaining to workload were related to a higher prevalence of neck and upper-limb symptoms, and postural risk factors were related to a higher prevalence of spinal symptoms. Conclusion and Discussion. Strategies used to reduce work-related injury in industry may also apply to physical therapists. Increased risk of thumb symptoms associated with mobilization techniques suggests that further research is needed to establish recommendations for practice. The issues for therapists who move within or leave the profession are unknown, and further research is needed to better understand their needs and experiences.

The study examines the whole blood transcriptome profile before and after cardiopulmonary bypass (CPB) in neonates with hypoplastic left heart syndrome (HLHS), a severe form of congenital heart disease, that can develop low cardiac output syndrome (LCOS). Whole blood mRNA transcriptome profiles of 13 neonates with HLHS before and after their first palliative surgery were analyzed to determine differentially expressed genes and pathways. The median age and weight at surgery were 4 days and 3.2 kg, respectively. Of the 13 patients, 8 developed LCOS. There was no significant difference between CPB, aortic cross clamp, deep hypothermic cardiac arrest times between patients that develop LCOS and those that do not. Upon comparing differential gene expression profiles between patients that develop LCOS and those that do not in pre-operative samples, 1 gene was up-regulated and 13 were down regulated. In the post-operative samples, 4 genes were up-regulated, and 4 genes were down regulated when patients that develop LCOS were compared to those that do not. When comparing post-operative samples to pre-operative samples in the patients that do not develop LCOS, 1484 genes were up-regulated, and 1388 genes were down regulated; while patients that developed LCOS had 2423 up-regulated genes, and 2414 down regulated genes for the same pre to post-operative comparison. Pathway analysis revealed differential regulation of inflammatory pathways (IL signaling, PDGF, NOTCH1, NGF, GPCR) and metabolic pathways (heme metabolism, oxidative phosphorylation, protein metabolism including amino acid and derivatives, fatty acid metabolism, TCA cycle and respiratory electron transport chain). By identifying altered transcriptome profiles related to inflammation and metabolism in neonates with HLHS who develop LCOS after CPB, this study opens for exploration novel pathways and potential therapeutic targets to improve outcomes in this high-risk population.

BACKGROUND: Exposure to inflammation exacerbates injury in neonatal encephalopathy (NE). We hypothesized that brain biomarker mRNA, cytokine mRNA and microRNA differentiate inflammation (E. coli LPS), hypoxia (Hypoxia), and inflammation-sensitized hypoxia (LPS+Hypoxia) in an NE piglet model. METHODS: Sixteen piglets were randomized: (i) LPS 2 μg/kg bolus; 1 μg/kg infusion (LPS; n = 5), (ii) Saline with hypoxia (Hypoxia; n = 6), (iii) LPS commencing 4 h pre-hypoxia (LPS+Hypoxia; n = 5). Total RNA was acquired at baseline, 4 h after LPS and 1, 3, 6, 12, 24, 48 h post-insult (animals euthanized at 48 h). Quantitative PCR was performed for cytokines (IL1A, IL6, CXCL8, IL10, TNFA) and brain biomarkers (ENO2, UCHL1, S100B, GFAP, CRP, BDNF, MAPT). MicroRNA was detected using GeneChip (Affymetrix) microarrays. Fold changes from baseline were compared between groups and correlated with cell death (TUNEL) at 48 h. RESULTS: Within 6 h post-insult, we observed increased IL1A, CXCL8, CCL2 and ENO2 mRNA in LPS+Hypoxia and LPS compared to Hypoxia. IL10 mRNA differentiated all groups. Four microRNAs differentiated LPS+Hypoxia and Hypoxia: hsa-miR-23a, 27a, 31-5p, 193-5p. Cell death correlated with TNFA (R = 0.69; p

Prostate cancer (PCa) is dependent on the androgen receptor (AR). Advanced PCa is treated with an androgen deprivation therapy-based regimen; tumors develop resistance, although they typically remain AR-dependent. Expression of constitutively active AR variants lacking the ligand-binding domain including the variant AR-V7 contributes to this resistance. AR and AR-V7, as transcription factors, regulate many of the same genes, but also have unique activities. In this study, the capacity of the two AR isoforms to regulate splicing was examined. RNA-seq data from models that endogenously express AR and express AR-V7 in response to doxycycline were used. Both AR isoforms induced multiple changes in splicing and many changes were isoform-specific. Analyses of two endogenous genes, PGAP2 and TPD52, were performed to examine differential splicing. A novel exon that appears to be a novel transcription start site was preferentially induced by AR-V7 in PGAP2 although it is induced to a lesser extent by AR. The previously described AR induced promoter 2 usage that results in a novel protein derived from TPD52 (PrLZ) was not induced by AR-V7. AR, but not AR-V7, bound to a site proximal to promoter 2, and induction was found to depend on FOXA1.

Highlights • Higher power of cortical bursts after postnatal day 3 predicted worse cognitive, language and motor outcomes. • Association between cortical bursts and outcome was independent of structural MRI findings. • EEG may provide additional information by indexing persistent active mechanisms that support recovery or exacerbate damage., Objective Early prediction of neurological deficits following neonatal hypoxic-ischemic encephalopathy (HIE) may help to target support. Neonatal animal models suggest that recovery following hypoxia-ischemia depends upon cortical bursting. To test whether this holds in human neonates, we correlated the magnitude of cortical bursting during recovery (≥postnatal day 3) with neurodevelopmental outcomes. Methods We identified 41 surviving infants who received therapeutic hypothermia for HIE (classification at hospital discharge: 19 mild, 18 moderate, 4 severe) and had 9-channel electroencephalography (EEG) recordings as part of their routine care. We correlated burst power with Bayley-III cognitive, motor and language scores at median 24 months. To examine whether EEG offered additional prognostic information, we controlled for structural MRI findings. Results Higher power of central and occipital cortical bursts predicted worse cognitive and language outcomes, and higher power of central cortical bursts predicted worse motor outcome, all independently of structural MRI findings. Conclusions Clinical EEG after postnatal day 3 may provide additional prognostic information by indexing persistent active mechanisms that either support recovery or exacerbate brain damage, especially in infants with less severe encephalopathy. Significance These findings could allow for the effect of clinical interventions in the neonatal period to be studied instantaneously in the future.

Robertson, M.J., Kent, K., Tharp, N. et al. Large-scale discovery of male reproductive tract-specific genes through analysis of RNA-seq datasets. BMC Biol 18, 103 (2020). https://doi.org/10.1186/s12915-020-00826-z, Background: The development of a safe, effective, reversible, non-hormonal contraceptive method for men has been an ongoing effort for the past few decades. However, despite significant progress on elucidating the function of key proteins involved in reproduction, understanding male reproductive physiology is limited by incomplete information on the genes expressed in reproductive tissues, and no contraceptive targets have so far reached clinical trials. To advance product development, further identification of novel reproductive tract-specific genes leading to potentially druggable protein targets is imperative. Results: In this study, we expand on previous single tissue, single species studies by integrating analysis of publicly available human and mouse RNA-seq datasets whose initial published purpose was not focused on identifying male reproductive tract-specific targets. We also incorporate analysis of additional newly acquired human and mouse testis and epididymis samples to increase the number of targets identified. We detected a combined total of 1178 genes for which no previous evidence of male reproductive tract-specific expression was annotated, many of which are potentially druggable targets. Through RT-PCR, we confirmed the reproductive tract-specific expression of 51 novel orthologous human and mouse genes without a reported mouse model. Of these, we ablated four epididymis-specific genes (Spint3, Spint4, Spint5, and Ces5a) and two testis-specific genes (Pp2d1 and Saxo1) in individual or double knockout mice generated through the CRISPR/Cas9 system. Our results validate a functional requirement for Spint4/5 and Ces5a in male mouse fertility, while demonstrating that Spint3, Pp2d1, and Saxo1 are each individually dispensable for male mouse fertility. Conclusions: Our work provides a plethora of novel testis- and epididymis-specific genes and elucidates the functional requirement of several of these genes, which is essential towards understanding the etiology of male infertility and the development of male contraceptives.

Objective To define sepsis syndromes in high-HIV burden settings in the antiretroviral therapy (ART) era. Methods We characterized a prospective cohort of adults presenting to a tertiary emergency department in Harare, Zimbabwe with suspected community-acquired sepsis using blood and urine cultures, urine tuberculosis lipoarabinomannan (TB LAM), and serum cryptococcal antigen (CrAg) testing. The primary outcome was 30-day all-cause mortality. Results Of 142 patients enrolled 68% (n = 96/142, 95% confidence interval (CI) [60–75%]) were HIV-positive, 41% (n = 39/96, 95% CI [31–50%]) of whom were ART-naive. Among HIV-positive patients, both opportunistic pathogens (TB LAM-positivity, 36%, 95% CI [24–48%]; CrAg-positivity, 15%, 95% CI [7–23%]) and severe non-AIDS infections (S. pneumoniae urine antigen-positivity 12%, 95% CI [4–20%]; bacteraemia 17% (n = 16/96, 95% CI [9–24%]), of which 56% (n = 9/16, 95% CI [30–80%]) were gram-negative organisms) were common. Klebsiella pneumoniae recovered from blood and urine was uniformly resistant to ceftriaxone, as were most Escherichia coli isolates. Acknowledging the power limitations of our study, we conclude that relative to HIV-negative patients, HIV-positive patients had modestly higher 30-day mortality (adjusted hazard ratio (HR) 1.88, 95% CI [0.78–4.55]; p = 0.16, and 3.59, 95% CI [1.27–10.16], p = 0.02) among those with and without viral suppression, respectively. Conclusion Rapid point-of-care assays provide substantial clinically actionable information in the setting of suspected sepsis, even in areas with high ART coverage. Antimicrobial resistance to first-line antibiotics in high burden settings is a growing threat.

INTRODUCTION Limited data inform the current postpolypectomy surveillance guidelines, which suggest a shortened interval to third colonoscopy after a negative second examination if high-risk adenomas (HRA) were present on the initial screening colonoscopy. Therefore, we examined the risk of HRA at third colonoscopy stratified by findings on 2 previous examinations in a prospective screening colonoscopy cohort of US veterans. METHODS We identified participants who had 3 or more colonoscopies from CSP#380. We examined the risk of HRA on the third examination based on findings from the previous 2 examinations. Multivariate logistic regression was used to adjust for multiple covariates. RESULTS HRA were found at the third examination in 114 (12.8%) of 891 participants. Those with HRA on both previous examinations had the greatest incidence of HRA at third examination (14/56, 25.0%). Compared with those with no adenomas on both previous examinations, participants with HRA on the first examination remained at significantly increased risk for HRA at the third examination at 3 years after a negative second examination (odds ratio [OR] 3.41, 95% confidence interval [CI] 1.28-9.08), 5 years (OR 3.14, 95% CI 1.49-6.61), and 7 years (OR 2.89, 95% CI 1.08-7.74). DISCUSSION In a screening population, HRA on the first examination identified individuals who remained at increased risk for HRA at the third examination, even after a negative second examination. This finding supports current colorectal cancer surveillance guidelines, which suggest a shortened, 5-year time interval to third colonoscopy after a negative second examination if high-risk findings were present on the baseline examination.

Our early-life environment has a profound influence on developing organs that impacts metabolic function and determines disease susceptibility across the life-course. Using a rat model for exposure to an endocrine disrupting chemical (EDC), we show that early-life chemical exposure causes metabolic dysfunction in adulthood and reprograms histone marks in the developing liver to accelerate acquisition of an adult epigenomic signature. This epigenomic reprogramming persists long after the initial exposure, but many reprogrammed genes remain transcriptionally silent with their impact on metabolism not revealed until a later life exposure to a Western-style diet. Diet-dependent metabolic disruption was largely driven by reprogramming of the Early Growth Response 1 (EGR1) transcriptome and production of metabolites in pathways linked to cholesterol, lipid and one-carbon metabolism. These findings demonstrate the importance of epigenome:environment interactions, which early in life accelerate epigenomic aging, and later in adulthood unlock metabolically restricted epigenetic reprogramming to drive metabolic dysfunction., Early life exposure to environmental stressors, including endocrine disrupting chemicals (EDCs), can impact health later in life. Here, the authors show that neonatal EDC exposure in rats causes epigenetic reprogramming in the liver, which is transcriptionally silent until animals are placed on a Western-style diet.

During folliculogenesis, oocytes are dependent on metabolic and molecular support from surrounding somatic cells. Here, we examined the role of the dynamin (DNM) family of mechanoenzymes in mediating endocytotic uptake into growing follicular oocytes. We found DNM1 and DNM2 to be highly expressed in growing follicular oocytes as well as in mature germinal vesicle (GV) and metaphase II (MII) stage oocytes. Moreover, oocyte-specific conditional knockout (cKO) of DNM2 (DNM2Δ) led to complete sterility, with follicles arresting at the preantral stage of development. In addition, DNM2Δ ovaries were characterized by disrupted follicular growth as well as oocyte and follicle apoptosis. Further, the loss of DNM activity, either through DNM2 cKO or through pharmacological inhibition (Dyngo 6a) led to the impairment of endocytotic pathways in preantral oocytes as well as in mature GV and MII oocytes, respectively. Loss of DNM activity resulted in the redistribution of endosomes and the misslocalization of clathrin and actin, suggesting dysfunctional endocytosis. Notably, there was no observable effect on the fertility of DNM1Δ females. Our study has provided new insight into the complex and dynamic nature of oocyte growth during folliculogenesis, suggesting a role for DNM2 in mediating the endocytotic events that are essential for oocyte development.

The urgent need to scale up testing capacity during the COVID-19 pandemic has prompted the rapid development of point-of-care diagnostic tools such as lateral flow immunoassays (LFIA) for large-scale community-based rapid testing. However, studies of how the general public perform when using LFIA tests in different environmental settings are scarce. This user experience (UX) study of 264 participants in Northern Ireland aimed to gather a better understanding of how self-administered LFIA tests were performed by the general public at home. The UX performance was assessed via analysis of a post-test questionnaire including 30 polar questions and 11 7-point Likert scale questions, which covers the multidimensional aspects of UX in terms of ease of use, effectiveness, efficiency, accuracy and satisfaction. Results show that 96.6% of participants completed the test with an overall average UX score of 95.27% [95% confidence interval (CI) 92.71–97.83%], which suggests a good degree of user experience and effectiveness. Efficiency was assessed based on the use of physical resources and human support received, together with the mental effort of self-administering the test measured via NASA Task Load Index (TLX). The results for six TLX subscales show that the participants scored the test highest for mental demand and lowest for physical demand, but the average TLX score suggests that the general public have a relatively low level of mental workload when using LFIA self-testing at home. Five printed LFIA testing results (i.e. the ‘simulated’ results) were used as the ground truth to assess the participant’s performance in interpreting the test results. The overall agreement (accuracy) was 80.63% [95% CI 75.21–86.05%] with a Kappa score 0.67 [95% CI 0.58–0.75] indicating substantial agreement. The users scored lower in confidence when interpreting test results that were weak positive cases (due to the relatively low signal intensity in the test-line) compared to strong positive cases. The end-users also found that the kit was easier to use than they expected (p < 0.001) and 231 of 264 (87.5%) reported that the test kit would meet their requirements if they needed an antibody testing kit. The overall findings provide an insight into the opportunities for improving the design of self-administered SARS-CoV-2 antibody testing kits for the general public and to inform protocols for future UX studies of LFIA rapid test kits.

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, however our understanding of cell specific mechanisms underlying COPD pathobiology remains incomplete. Here, we analyze single-cell RNA sequencing profiles of explanted lung tissue from subjects with advanced COPD or control lungs, and we validate findings using single-cell RNA sequencing of lungs from mice exposed to 10 months of cigarette smoke, RNA sequencing of isolated human alveolar epithelial cells, functional in vitro models, and in situ hybridization and immunostaining of human lung tissue samples. We identify a subpopulation of alveolar epithelial type II cells with transcriptional evidence for aberrant cellular metabolism and reduced cellular stress tolerance in COPD. Using transcriptomic network analyses, we predict capillary endothelial cells are inflamed in COPD, particularly through increased CXCL-motif chemokine signaling. Finally, we detect a high-metallothionein expressing macrophage subpopulation enriched in advanced COPD. Collectively, these findings highlight cell-specific mechanisms involved in the pathobiology of advanced COPD., Chronic obstructive pulmonary disease is a leading cause of death worldwide, while our understanding of cell-specific mechanisms underlying its pathobiology remains incomplete. Here the authors perform scRNA-seq of human lung tissue to identify transcriptional changes in alveolar niche cells associated with the disease.

The constitutively active androgen receptor (AR) splice variant, AR-V7, plays an important role in resistance to androgen deprivation therapy in castration resistant prostate cancer (CRPC). Studies seeking to determine whether AR-V7 is a partial mimic of the AR, or also has unique activities, and whether the AR-V7 cistrome contains unique binding sites have yielded conflicting results. One limitation in many studies has been the low level of AR variant compared to AR. Here, LNCaP and VCaP cell lines in which AR-V7 expression can be induced to match the level of AR, were used to compare the activities of AR and AR-V7. The two AR isoforms shared many targets, but overall had distinct transcriptomes. Optimal induction of novel targets sometimes required more receptor isoform than classical targets such as PSA. The isoforms displayed remarkably different cistromes with numerous differential binding sites. Some of the unique AR-V7 sites were located proximal to the transcription start sites (TSS). A de novo binding motif similar to a half ARE was identified in many AR-V7 preferential sites and, in contrast to conventional half ARE sites that bind AR-V7, FOXA1 was not enriched at these sites. This supports the concept that the AR isoforms have unique actions with the potential to serve as biomarkers or novel therapeutic targets.

The Optilume® drug-coated balloon (DCB) is a urethral dilation balloon with a paclitaxel coating that combines mechanical dilation for immediate symptomatic relief with local drug delivery to maintain urethral patency. The ROBUST III study is a randomized, single-blind trial evaluating the safety and efficacy of the Optilume DCB against endoscopic management of recurrent anterior urethral strictures.Eligible patients were adult males with anterior strictures ≤12Fr in diameter and ≤3 cm in length, at least 2 prior endoscopic treatments, International Prostate Symptom Score ≥11 and maximum flow rate15 ml per second. A total of 127 subjects were enrolled at 22 sites. The primary study end point was anatomical success (≥14Fr by cystoscopy or calibration) at 6 months. Key secondary end points included freedom from repeat treatment, International Prostatic Symptom Score and peak flow rate. The primary safety end point included freedom from serious device- or procedure-related complications.Baseline characteristics were similar between groups, with subjects having an average of 3.6 prior treatments and average length of 1.7 cm. Anatomical success for Optilume DCB was significantly higher than control at 6 months (75% vs 27%, p0.001). Freedom from repeat intervention was significantly higher in the Optilume DCB arm. Immediate symptom and urinary flow rate improvement was significant in both groups, with the benefit being more durable in the Optilume DCB group. The most frequent adverse events included urinary tract infection, post-procedural hematuria and dysuria.The results of this randomized controlled trial support that Optilume is safe and superior to standard direct vision internal urethrotomy/dilation for the treatment of recurrent anterior urethral strictures3 cm in length. The Optilume DCB may serve as an important alternative for men who have had an unsuccessful direct vision internal urethrotomy/dilation but want to avoid or delay urethroplasty.

The aetiology of diarrhoea in a patient in Cuba with HIV was investigated. Although molecular diagnostics are still not used in many under-resourced settings, here traditional methods were supported by use of PCR. This approach enabled detection of a dual infection (Cystoisospora belli and Enterocytozoon bieneusi), the latter of which was not identified by microscopy with Didier's trichromic staining.

Background Incomplete resection of neoplastic polyps is considered an important reason for the development of colorectal cancer. However, there are no data on the natural history of polyps that were incompletely removed. Objective To examine the risk for metachronous neoplasia during surveillance colonoscopy after documented incomplete polyp resection. Design Observational cohort study of patients who participated in the CARE (Complete Adenoma REsection) study (2009 to 2012). Setting 2 academic medical centers. Patients Patients who had resection of a 5- to 20-mm neoplastic polyp, had a documented complete or incomplete resection, and had a surveillance examination. Measurements Segment metachronous neoplasia, defined as the proportion of colon segments with at least 1 neoplastic polyp at first surveillance examination, was measured. Segment metachronous neoplasia was compared between segments with a prior incomplete polyp resection (incomplete segments) and those with a prior complete resection (complete segments), accounting for clustering of segments within patients. Results Of 233 participants in the original study, 166 (71%) had at least 1 surveillance examination. Median time to surveillance was shorter after incomplete versus complete resection (median, 17 vs. 45 months). The risk for any metachronous neoplasia was greater in segments with incomplete versus complete resection (52% vs. 23%; risk difference [RD], 28% [95% CI, 9% to 47%]; P = 0.004). Incomplete segments also had a greater number of neoplastic polyps (mean, 0.8 vs. 0.3; RD, 0.50 [CI, 0.1 to 0.9]; P = 0.008) and greater risk for advanced neoplasia (18% vs. 3%; RD, 15% [CI, 1% to 29%]; P = 0.034). Incomplete resection was the strongest independent factor associated with metachronous neoplasia (odds ratio, 3.0 [CI, 1.12 to 8.17]). Limitation Potential patient selection bias due to incomplete follow-up. Conclusion This natural history study found a statistically significantly greater risk for future neoplasia and advanced neoplasia in colon segments after incomplete resection compared with segments with complete resection. Primary funding source None.

Introduction: Laparoscopic appendectomy is the gold standard for treatment of acute appendicitis. The single-incision laparoscopic surgery (SILS) approach has gained widespread acceptance. This study evaluates the learning curve of contemporarily trained surgeons adopting SILS appendectomy and, more specifically, the safety of the operation during the early phase of this learning curve. Methods: A retrospective review of 974 consecutive pediatric patients younger than 18 years of age, who underwent an appendectomy at a single institution from 2005 to 2018, was performed. Nonperforated and perforated appendicitis cases were included. A subgroup analysis was performed on SILS appendectomy. Outcomes measured included length of operating room and anesthesia time, as well as complication rate. A log-logistics and a Loess smoothing model were used. Results: A total of 438 single-incision laparoscopic appendectomies were reviewed. A trend toward faster operative times was observed for all surgeons as case numbers increased. The odds of still being operated on decreased by 0.997 for each additional case. Based on a 95% confidence band and this experienced time as the standard, we expect adopting surgeons to reach this experienced level after 51 cases. During the early SILS appendectomy learning curve, there was no significant difference in complication rate compared with multiport laparoscopy. Conclusion: As expected, the more single-incision cases were performed, the shorter the operative times. More importantly, there was no increase in complication rate during the learning stage of single-incision appendectomies in either perforated or nonperforated appendicitis.

Epidemiologic and preclinical data suggest a potential role for vitamin D in breast cancer treatment and prevention. However, results of prospective randomized trials are inconsistent. The objective of this study was to assess the effects of high-dose cholecalciferol (vitamin D3) on breast tumour proliferation and apoptosis. We conducted a prospective, randomized, phase 2, double-blinded pre-surgical window of opportunity trial. Newly diagnosed breast cancer patients were randomized to receive 40,000 IU of vitamin D3 per day or placebo for 2 to 6 weeks prior to breast surgery. The primary outcome was the relative change in proliferation (Ki67) and apoptosis (cleaved caspase 3 apoptotic assay [CC3]) in primary breast cancer cells pre and post treatment. Of 83 patients randomized, 80 completed the study (43 (53.8%) vitamin D and 37 (46.3%) placebo). Mean duration of drug intake was 19 days (range 9–28 days). There were no significant differences between the control arm and the vitamin D arm in percent changes of either Ki67 index (1.6% vs. 16.7%, p = 0.25) or CC3 (− 55.9% vs. − 45.9%, p = 0.28). Serum 25-hydroxyvitamin D (25-OHD) levels were 3 times higher in the vitamin D arm (62 nmol/L vs. 246 nmol/L, p

Neuroprotection from therapeutic hypothermia (HT) is incomplete, therefore additional strategies are necessary to improve long-term outcomes. We assessed the neuroprotective efficacy of magnesium sulfate (MgSO4) bolus and infusion over 48 h plus HT in a piglet model of term neonatal encephalopathy (NE). Fifteen newborn piglets were randomized following hypoxia–ischemia (HI) to: (i) MgSO4 180 mg/kg bolus and 8 mg/kg/h infusion with HT (Mg+HT) or (ii) HT and saline 0.5 ml/h (HT). Treatments were initiated 1 h post-HI; HT administered for 12 h (33.5 °C). HI was performed by transient carotid occlusion and inhalation of 6% O2 for 20–25 min. Primary outcomes included aEEG, magnetic resonance spectroscopy (MRS) at 24, and 48 h, and immunohistochemistry. MgSO4 bolus and infusion was well tolerated (no hypotension) and doubled serum magnesium (0.72 vs 1.52 mmol/L) with modest (16%) rise in CSF. In Mg+HT compared to HT, there was overall reduced cell death (p = 0.01) and increased oligodendrocytes (p = 0.002). No improvement was seen on aEEG recovery (p = 0.084) or MRS (Lac/NAA; PCr/Pi; NTP/epp) (p > 0.05) at 48 h. Doubling serum magnesium with HT was safe; however, the small incremental benefit of Mg+HT compared to HT is unlikely to translate into substantive long-term improvement. Such an incremental effect might justify further study of MgSO4 in combination with multiple therapies.

Objectives Provide normative values for cervical range of motion and describe trends in school age rugby union players. Design Cross-sectional study. Setting National 3 level club. Participants 59 school age rugby union players across under 8 (n = 8), under 9 (n = 9), under 10 (n = 15), under 13 (n = 13) and under 15 (n = 15) categories. Main outcome measures Cervical range of motion using a cervical range of motion device (CROM) to determine values for active range of motion. Results This study established mean ranges of motion for each age group. Pooled mean ranges with standard deviations for each direction were, flexion 66° (±11), extension 73° (±17), left rotation 69° (±9), right rotation 74° (±10), left lateral flexion 53° (±10) and right lateral flexion 49° (±12). No statistically significant differences were observed between the age groups, however, downward trends in lateral flexion were observed as age increased. School age rugby players had greater range of motion than senior playing counterparts. Conclusions No statistically significant differences in ranges of motion were observed between the age groups of under 8 through to under 15. However, downward trends in some ranges of motion highlight the need for age specific monitoring for potential adaptations to continued playing and comparison to age matched non-rugby players. Inclusion of other risk factors such as head re-positioning sense should also be evaluated to help guide injury risk reduction strategies.

Key points Therapeutic hypothermia (HT) to 33.0–34.0°C for 72 h provides optimal therapy for infants with neonatal encephalopathy (NE) in high‐resource settings. HT is not universally implemented in low‐ and middle‐income countries as a result of both limited resources and evidence.Facilitated passive cooling, comprising infants being allowed to passively lower their body temperature in the days after birth, is an emerging practice in some West African neonatal units.In this observational study, we demonstrate that infants undergoing facilitated passive cooling in a neonatal unit in Accra, Ghana, achieve temperatures within the HT target range ∼20% of the 72 h. Depth of HT fluctuates and can be excessive, as well as not maintained, especially after 24 h.Sustained and deeper passive cooling was evident for severe NE and for those that died.It is important to prevent excessive cooling, to understand that severe NE babies cool more and to be aware of facilitated passive cooling with respect to the design of clinical trials in low‐ and mid‐resource settings. Abstract Neonatal encephalopathy (NE) is a significant worldwide problem with the greatest burden in sub‐Saharan Africa. Therapeutic hypothermia (HT), comprising the standard of care for infants with moderate‐to‐severe NE in settings with sophisticated intensive care, is not available to infants in many sub‐Saharan African countries, including Ghana. We prospectively assessed the temperature response in relation to outcome in the 80 h after birth in a cohort of babies with NE undergoing ‘facilitated passive cooling’ at Korle Bu Teaching Hospital, Accra, Ghana. We hypothesized that NE infants demonstrate passive cooling. Thirteen infants (69% male) ≥36 weeks with moderate‐to‐severe NE were enrolled. Ambient mean ± SD temperature was 28.3 ± 0.7°C. Infant core temperature was 34.2 ± 1.2°C over the first 24 h and 35.0 ± 1.0°C over 80 h. Nadir mean temperature occurred at 15 h. Temperatures were within target range for HT with respect to 18 ± 14% of measurements within the first 72 h. Axillary temperature was 0.5 ± 0.2°C below core. Three infants died before discharge. Core temperature over 80 h for surviving infants was 35.3 ± 0.9°C and 33.96 ± 0.7°C for those that died (P = 0.043). Temperature profile negatively correlated with Thompson NE score on day 4 (r 2 = 0.66): infants with a Thompson score of 0–6 had higher temperatures than those with a score of 7–15 (P = 0.021) and a score of 16+/deceased (P = 0.007). More severe NE was associated with lower core temperatures. Passive cooling is a physiological response after hypoxia–ischaemia; however, the potential neuroprotective effect of facilitated passive cooling is unknown. An awareness of facilitated passive cooling in babies with NE is important for the design of clinical trials of neuroprotection in low and mid resource settings., Key points Therapeutic hypothermia (HT) to 33.0–34.0°C for 72 h provides optimal therapy for infants with neonatal encephalopathy (NE) in high‐resource settings. HT is not universally implemented in low‐ and middle‐income countries as a result of both limited resources and evidence.Facilitated passive cooling, comprising infants being allowed to passively lower their body temperature in the days after birth, is an emerging practice in some West African neonatal units.In this observational study, we demonstrate that infants undergoing facilitated passive cooling in a neonatal unit in Accra, Ghana, achieve temperatures within the HT target range ∼20% of the 72 h. Depth of HT fluctuates and can be excessive, as well as not maintained, especially after 24 h.Sustained and deeper passive cooling was evident for severe NE and for those that died.It is important to prevent excessive cooling, to understand that severe NE babies cool more and to be aware of facilitated passive cooling with respect to the design of clinical trials in low‐ and mid‐resource settings.

Self-selected intensity exercise has resulted in greater affective responses (AR) compared to prescribed exercise of similar intensity and many individuals self-select intensity at a moderate level identified by metabolic analysis. As such, self-selected intensity may be an effective alternative for exercise prescription designed to promote adherence and result in health and fitness benefits. Self-selected intensity has not been well described for many subject populations and exercise modes. Therefore, the purpose of this investigation was to measure affective and metabolic responses during self-selected intensity cycle exercise in college-aged men. Thirty-three men (22.4 ± 2.2 yr) performed a peak oxygen consumption test and a 20 min self-selected trial on a cycle ergometer on separate days. Oxygen consumption (VO2) was measured continuously throughout both exercise sessions. AR were measured using the Feeling Scale and ratings of perceived exertion (RPE) using the OMNI Scale every 5 min during the self-selected trial. χ2 analysis was used to determine if a significant proportion of subjects self-selected intensity above 50% VO2 reserve (VO2R), defined as a threshold for moderate-intensity exercise and potential cardiorespiratory fitness benefits by American College of Sports Medicine. Mean self-selected intensity was 57.6 ± 11.1%VO2peak and 89.3 ± 20.2% of ventilatory threshold. Twenty eight of 33 subjects self-selected intensity above 50% VO2R (p

Lateral flow immunoassays are low cost, rapid and highly efficacious point-of-care devices, which have been used for SARS-CoV-2 antibody testing by professionals. However, there is a lack of understanding about how self-administered tests are used by the general public for mass testing in different environmental settings. The purpose of this study was to assess the user experience (UX) (including usability) of a self-testing kit to identify COVID-19 antibodies used by a representative sample of the public in their cars, which included 1544 participants in Northern Ireland. The results based on 5-point Likert ratings from a post-test questionnaire achieved an average UX score of 96.03% [95% confidence interval (CI) 95.05–97.01%], suggesting a good degree of user experience. The results of the Wilcoxon rank sum tests suggest that UX scores were independent of the user’s age and education level although the confidence in this conclusion could be strengthened by including more participants aged younger than 18 and those with only primary or secondary education. The agreement between the test result as interpreted by the participant and the researcher was 95.85% [95% CI 94.85–96.85%], Kappa score 0.75 [95% CI 0.69–0.81] (indicating substantial agreement). Text analysis via the latent Dirichlet allocation model for the free text responses in the survey suggest that the user experience could be improved for blood-sample collection, by modifying the method of sample transfer to the test device and giving clearer instructions on how to interpret the test results. The overall findings provide an insight into the opportunities for improving the design of SARS-CoV-2 antibody testing kits to be used by the general public and therefore inform protocols for future user experience studies of point-of-care tests.

BACKGROUND Clinical follow-up in orthopaedic trauma is challenging, yet expectations exist that a 1-year follow-up is the minimum requirement for clinical trials and research publications. The primary purpose of our study was to evaluate the rate of follow-up after operative orthopaedic trauma care and the relationship to clinical care. Our secondary aim was to identify any independent risk factors regarding follow-up completion. METHODS A chart review of patients operatively treated for a traumatic injury during the months of January and July 2016 was conducted. Patient demographic characteristics, injury type, severity, and patient distance from the hospital were collected. The final clinical instructions and whether a return visit was requested or as needed were recorded. RESULTS There were 293 patients in this study, of whom 84 (29%) had follow-up of at least 1 year and 52 (18%) were instructed to follow up only as needed at their last visit prior to the 1-year mark. When removing the latter 52 patients, the 1-year follow-up rate was 35% (84 of 241 patients). Of these 241 patients, 157 (65%) were requested to return for additional clinical care but failed to return prior to 1 year. Logistic regression identified tobacco use (odds ratio [OR], 0.34 [95% confidence interval (CI), 0.15 to 0.77]; p = 0.010), final appointment status (OR, 6.3 [95% CI, 3.4 to 11.6]; p < 0.001), isolated compared with multiple fractures (OR, 2.2 [95% CI, 1.2 to 4.1]; p = 0.013), and distance from the trauma center per mile as a continuous variable (OR, 0.999 [95% CI, 0.998 to 1.0]; p = 0.03) as significant predictors. CONCLUSIONS Our data suggest that a 1-year clinic follow-up requirement may not be feasible. We observed a low rate of patients with a minimum 1-year clinical follow-up. Clinical care had been completed in 18% of patients prior to 1 year. Journal and grant reviewers may need to consider the feasibility and clinical relevance of these follow-up expectations.

Androgen receptor (AR) signaling continues to drive castration-resistant prostate cancer (CRPC) in spite of androgen deprivation therapy (ADT). Constitutively active shorter variants of AR, lacking the ligand binding domain, are frequently expressed in CRPC and have emerged as a potential mechanism for prostate cancer to escape ADT. ARv7 and ARv567es are 2 of the most commonly detected variants of AR in clinical samples of advanced, metastatic prostate cancer. It is not clear if variants of AR merely act as weaker substitutes for AR or can mediate unique isoform-specific activities different from AR. In this study, we employed LNCaP prostate cancer cell lines with inducible expression of ARv7 or ARv567es to delineate similarities and differences in transcriptomics, metabolomics, and lipidomics resulting from the activation of AR, ARv7, or ARv567es. While the majority of target genes were similarly regulated by the action of all 3 isoforms, we found a clear difference in transcriptomic activities of AR versus the variants, and a few differences between ARv7 and ARv567es. Some of the target gene regulation by AR isoforms was similar in the VCaP background as well. Differences in downstream activities of AR isoforms were also evident from comparison of the metabolome and lipidome in an LNCaP model. Overall our study implies that shorter variants of AR are capable of mediating unique downstream activities different from AR and some of these are isoform specific.

Extra-embryonic mesoderm (ExM)-composed of the earliest cells that traverse the primitive streak-gives rise to the endothelium as well as haematopoietic progenitors in the developing yolk sac. How a specific subset of ExM becomes committed to a haematopoietic fate remains unclear. Here we demonstrate using an embryonic stem cell model that transient expression of the T-box transcription factor Eomesodermin (Eomes) governs haemogenic competency of ExM. Eomes regulates the accessibility of enhancers that the transcription factor stem cell leukaemia (SCL) normally utilizes to specify primitive erythrocytes and is essential for the normal development of Runx1+ haemogenic endothelium. Single-cell RNA sequencing suggests that Eomes loss of function profoundly blocks the formation of blood progenitors but not specification of Flk-1+ haematoendothelial progenitors. Our findings place Eomes at the top of the transcriptional hierarchy regulating early blood formation and suggest that haemogenic competence is endowed earlier during embryonic development than was previously appreciated.

Microscopy is the gold standard for diagnosis of intestinal parasitic diseases in many countries, including Cuba, although molecular approaches often have higher sensitivity as well as other advantages. Fecal samples from 133 patients were analyzed by light microscopy and also real-time multiplex qPCR targeting Giardia duodenalis, Cryptosporidium spp., and Entamoeba histolytica, and, separately, Dientamoeba fragilis. Microscopy revealed G. duodenalis occurred most commonly (17 patients), followed by Blastocystis spp. (12 patients). In a few patients, Entamoeba histolytica/E. dispar, Cryptosporidium spp., and Cyclospora cayetanensis were identified. Molecular analysis identified 4 more G. duodenalis infections and 2 more Cryptosporidium spp. infections; concordance between microscopy and PCR showed almost perfect agreement for G. duodenalis (κ = 0.88) and substantial agreement for Cryptosporidium (κ = 0.74). PCR indicated that E. dispar, rather than E. histolytica, had been identified by microscopy. Additionally, 16 D. fragilis infections were detected using molecular methods. Although both microscopy and molecular techniques have a place in parasitology diagnostics, for parasites such as D. fragilis, where microscopy can underestimate occurrence, molecular techniques may be preferable, and also essential for distinguishing between morphologically similar microorganisms such as E. histolytica and E. dispar. Although in resource-constrained countries such as Cuba, microscopy is extremely important as a diagnostic tool for intestinal parasites, inclusion of molecular techniques could be invaluable for selected protozoa.

Summary Background Recognising that the immune suppressive microenvironment promotes tumour growth in Hodgkin lymphoma, we hypothesised that activating immunity might augment the activity of targeted chemotherapy. We evaluated the safety and activity of combinations of brentuximab vedotin with nivolumab or ipilimumab, or both in patients with relapsed or refractory Hodgkin lymphoma. Methods In this multicentre, open-label, phase 1/2 trial, patients with relapsed or refractory Hodgkin lymphoma aged 18 years or older who had relapsed after at least one line of therapy, with an Eastern Cooperative Oncology Group performance status of 2 or lower, and adequate organ and marrow function, with no pulmonary dysfunction were eligible for inclusion. Phase 1 primary objectives were to determine the maximum tolerated dose and dose limiting toxicities of brentuximab vedotin combined with ipilimumab (ipilimumab group), nivolumab (nivolumab group), or both (triplet therapy group) using a 3 + 3 dose escalation design with expansion cohorts. During the dose escalation phase, patients were enrolled sequentially into one of six cohorts: in the ipilimumab group fixed brentuximab vedotin 1·8 mg/kg with ipilimumab 1 mg/kg (cohort A) or 3 mg/kg (cohort B); in the nivolumab group fixed nivolumab 3 mg/kg with brentuximab vedotin 1·2 mg/kg (cohort D) or 1·8 mg/kg (cohort E); and in the triplet therapy group fixed nivolumab 3 mg/kg and ipilimumab 1 mg/kg with brentuximab vedotin 1·2 mg/kg (cohort G) or 1·8 mg/kg (cohort H). Additional patients were enrolled in the expansion phase at the same doses of cohorts B, E, and H. All drugs were given intravenously; brentuximab vedotin and nivolumab were given every 3 weeks, ipilimumab was given every 6 weeks in the ipilimumab group and every 12 weeks in the triplet therapy group. All eligible and treated patients were included in the analysis. This phase 1/2 study is registered with ClinicalTrials.gov , NCT01896999 . The phase 2, randomised portion of the trial is still enrolling. Findings Between March 7, 2014, and Dec 28, 2017, 64 patients were enrolled; two patients in the ipilimumab group and one patient in the nivolumab group were excluded due to ineligibility after enrolment and 61 were evaluable. A total of six dose limiting toxicities were reported in four patients, and the doses used in cohorts B, E, and H were established as maximum tolerated doses and patients were subsequently enrolled onto expansion cohorts (C, F, and I) with these schedules. There were ten (43%) grade 3–4 treatment related adverse events in the ipilimumab group, three (16%) in the nivolumab group, and 11 (50%) in the triplet therapy group including: eight (13%) of 64 patients reporting rash, and colitis, gastritis, pancreatitis and arthritis, and diabetic ketoacidosis each occurring in one (2%) patient. There were two (3%) treatment related deaths, one in the nivolumab group and one in the triplet therapy group. The overall response rate was 76% (95% CI 53–92) in the ipilimumab group, 89% (65–99) in the nivolumab group, and 82% (60–95) in the triplet therapy group, and the complete response rate was 57% (95% CI 34–78%) in the ipilimumab group, 61% (36–83%) in the nivolumab group, and 73% (50–89%) in the triplet therapy group. With a median follow-up of 2·6 years (IQR 1·8–2·9) in the ipilimumab group, 2·4 years (2·2–2·6) in the nivolumab group, and 1·7 years (1·6–1·9) in the triplet therapy group, median progression-free survival is 1·2 years (95% CI 1·7–not reached) in the ipilimumab group, but was not reached in the other two treatment groups. Median overall survival has not been reached in any of the groups. Interpretation There are clear differences in activity and toxicity of the three combination regimens. The tolerability and preliminary activity for the two most active regimens, brentuximab vedotin with nivolumab and the triplet therapy, are being compared in a randomised phase 2 trial ( NCT01896999 ). Funding Eastern Cooperative Oncology Group–American College of Radiology Imaging Network and the National Cancer Institute of the National Institutes of Health.

The transcriptional repressor Blimp1 controls cell fate decisions in the developing embryo and adult tissues. Here we describe Blimp1 expression and functional requirements within maternal uterine tissues during pregnancy. Expression is robustly up-regulated at early post-implantation stages in the primary decidual zone (PDZ) surrounding the embryo. Conditional inactivation results in defective formation of the PDZ barrier and abnormal trophectoderm invasion. RNA-Seq analysis demonstrates down-regulated expression of genes involved in cell adhesion and markers of decidualisation. In contrast, genes controlling immune responses including IFNγ are up-regulated. ChIP-Seq experiments identify candidate targets unique to the decidua as well as those shared across diverse cell types including a highly conserved peak at the Csf-1 gene promoter. Interestingly Blimp1 inactivation results in up-regulated Csf1 expression and macrophage recruitment into maternal decidual tissues. These results identify Blimp1 as a critical regulator of tissue remodelling and maternal tolerance during early stages of pregnancy., The transcriptional repressor Blimp1/PRDM1 regulates cell fate decisions in the developing embryo and adult tissues. Here the authors show that conditional inactivation within maternal uterine tissues results in a defective primary decidual zone barrier, increased expression of inflammatory cytokines IFN gamma and Csf1, and early embryonic lethality during pregnancy.

Goal We sought to quantify the independent effects of age, sex, and race/ethnicity on risk of colorectal cancer (CRC) and advanced neoplasia (AN) in Veterans. Study We conducted a retrospective, cross-sectional study of Veterans aged 40 to 80 years who had diagnostic or screening colonoscopy between 2002 and 2009 from 1 of 14 Veterans Affairs Medical Centers. Natural language processing identified the most advanced finding and location (proximal, distal). Logistic regression was used to examine the adjusted, independent effects of age, sex, and race, both overall and in screening and diagnostic subgroups. Results Among 90,598 Veterans [mean (SD) age 61.7 (9.4) y, 5.2% (n=4673) were women], CRC and AN prevalence was 1.3% (n=1171) and 8.9% (n=8081), respectively. Adjusted CRC risk was higher for diagnostic versus screening colonoscopy [odds ratio (OR)=3.79; 95% confidence interval (CI), 3.19-4.50], increased with age, was numerically (but not statistically) higher for men overall (OR=1.53; 95% CI, 0.97-2.39) and in the screening subgroup (OR=2.24; 95% CI, 0.71-7.05), and was higher overall for Blacks and Hispanics, but not in screening. AN prevalence increased with age, and was present in 9.2% of men and 3.9% of women [adjusted OR=1.90; 95% CI, 1.60-2.25]. AN risk was 11% higher in Blacks than in Whites overall (OR=1.11; 95% CI, 1.04-1.20), was no different in screening, and was lower in Hispanics (OR=0.74; 95% CI, 0.55-0.98). Women had more proximal CRC (63% vs. 39% for men; P=0.03), but there was no difference in proximal AN (38.3% for both genders). Conclusions Age and race were associated with AN and CRC prevalence. Blacks had a higher overall prevalence of both CRC and AN, but not among screenings. Men had increased risk for AN, while women had a higher proportion of proximal CRC. These findings may be used to tailor when and how Veterans are screened for CRC.

Hyper-realistic face masks have been used as disguises in at least one border crossing and in numerous criminal cases. Experimental tests using these masks have shown that viewers accept them as real faces under a range of conditions. Here, we tested mask detection in a live identity verification task. Fifty-four visitors at the London Science Museum viewed a mask wearer at close range (2 m) as part of a mock passport check. They then answered a series of questions designed to assess mask detection, while the masked traveller was still in view. In the identity matching task, 8% of viewers accepted the mask as matching a real photo of someone else, and 82% accepted the match between masked person and masked photo. When asked if there was any reason to detain the traveller, only 13% of viewers mentioned a mask. A further 11% picked disguise from a list of suggested reasons. Even after reading about mask-related fraud, 10% of viewers judged that the traveller was not wearing a mask. Overall, mask detection was poor and was not predicted by unfamiliar face matching performance. We conclude that hyper-realistic face masks could go undetected during live identity checks.

A mortality analysis of the Life Esidimeni tragedy was precluded during the investigation by the Health Ombud by the lack of data integrity. Information on the mental healthcare users (MHCUs) transferred out of Life Esidimeni hospitals between October 2015 and June 2016 was subsequently collected by the Gauteng Department of Health, permitting statistical analysis. Survival rates were calculated according to gender and transfer destination and adjusted for patient age. Mortality was compared with that of the general population for the calendar year of 2016. Of the 1 442 MHCUs, 15% were transferred to specialised psychiatric hospitals and 85% to a rehabilitation centre or non-governmental residential facility. By the end of August 2017, 9% (n=131) of the cohort had died. Significant predictors of survival were younger age (p

BACKGROUND Recent data suggest that adenoma size and number are more important predictors of metachronous colorectal neoplasia than advanced histology. Furthermore, there is poor reproducibility in diagnosing advanced histology; high-grade dysplasia and villous histology. Therefore we developed a new metric, adenoma bulk, the sum of diameters of all baseline adenomas, regardless of advanced features. GOAL Compare the predictive value for metachronous advanced neoplasia of adenoma bulk to conventional paradigm. STUDY Data were collected prospectively in a multicenter adenoma-chemoprevention trial (2004 to 2013). For the conventional paradigm, high-risk baseline findings were defined as ≥3 adenomas, large adenomas (≥1 cm) or adenomas with villous components or high-grade dysplasia. Adenoma bulk was examined across quartiles and as a continuous variable. Predictive characteristics (sensitivities, specificities, c-statistics) for metachronous advanced neoplasia using conventional criteria and adenoma bulk were calculated. receiver operator characteristic curves were computed using logistic regression. RESULTS In total, 1948 adults had index and follow-up colonoscopies (mean follow-up, 45.2 mo). Those with an adenoma bulk ≥10 mm (4th quartile) had a higher metachronous advanced neoplasia risk (14.4% vs. 6.9-8.2% in lower 3 quartiles; P=0.0002). The c-statistics and sensitivities (specificity fixed at 0.73) for the adenoma bulk and conventional models were 0.587 and 0.563 (P=0.17) and 0.396 and 0.390, respectively. CONCLUSIONS Categorizing sporadic adenoma patients as high versus low risk for metachronous advanced neoplasia by adenoma bulk of

Objective: This study compares the change in midface position following Le Fort III advancement using either rigid external distraction (group 1) or internal distraction (group 2). We hypothesized that, with reference to right-facing cephalometry, internal distraction would result in increased clockwise rotation and inferior displacement of the midface. Design: Le Fort III osteotomies and standardized distraction protocols were performed on 10 cadaveric specimens per group. Right-facing lateral cephalograms were traced and compared across time points to determine change in position at points orbitale, anterior nasal spine (ANS), A-point, and angle ANB. Setting: Institutional. Patients, Participants: Twenty cadaveric head specimens. Interventions: Standard subcranial Le Fort III osteotomies were performed from a coronal approach and adequately mobilized. The specified distraction mechanism was applied and advanced by 15 mm. Main Outcome Measure(s): Changes of position were calculated at various skeletal landmarks: orbitale, ANS, A-point, and ANB. Results: Group 1 demonstrated relatively uniform x-axis advancement with minimal inferior repositioning at the A-point, ANS, and orbitale. Group 2 demonstrated marked variation in x-axis advancement among the 3 points, along with a significant inferior repositioning and clockwise rotation of the midface ( P < .0001). Conclusion: External distraction resulted in more uniform advancement of the midface, whereas internal distraction resulted in greater clockwise rotation and inferior displacement. External distraction appears to provide increased vector control of the midface, which is important in creating a customized distraction plan based on the patient’s individual occlusal and skeletal needs.

We assessed Gleason pattern 5 (GP5) and other prostatic adenocarcinoma (PCa) morphologies to determine their association with biochemical recurrence (BCR). A search for grade group 5 PCa with radical prostatectomy (RP) yielded 49 patients. RPs were reviewed for %GP5 and morphologies (sheets, single cells, cords, small solid cylinders, solid medium to large nests with rosette-like spaces [SMLNRS], comedonecrosis, cribriform glands, glomerulations, intraductal carcinoma of the prostate [IDC-P], and prostatic ductal adenocarcinoma [PDCa]). Prevalence of morphologies was as follows: single cells 100%, cribriform glands 98.7%, cords 85.7%, IDC-P 77.6%, comedonecrosis 53.1%, sheets 49.0%, small solid cylinders 49.0%, PDCa 44.9%, glomerulations 34.7%, and SMLNRS 14.3%. From 28 patients who were treated with RP as monotherapy, 64.3% (18/28) had BCR. Comedonecrosis, sheets, small solid cylinders, IDC-P, and PDCa were significantly associated with BCR. Number of morphologies on RP and %GP5 were higher in patients with BCR (6.8 ± 2.1 versus 3.7 ± 2.9%; P

Purpose Handheld ultrasound technology is increasingly used in health care. Its use for fracture care has not been adequately evaluated. The purpose of this study was to evaluate handheld, pocket-sized ultrasound in the diagnosis and assessment of reductions in distal radius fractures. Methods A total of 23 patients with distal radius fractures (average age, 53 years; 13 women) and 20 control patients (average age, 53 years; 10 women) were prospectively enrolled. All patients with distal radius fractures underwent standard, 3-view radiographic and ultrasonographic examinations of the wrist before and after closed reduction. Control patients had a one-time standard radiographic and ultrasonographic examination of the wrist. Radiographs were used as the reference standard. All images were assessed for the presence or absence of a fracture by a board-certified, hand fellowship–trained orthopedic surgeon and musculoskeletal fellowship–trained radiologist who were blinded to the study protocol. If a fracture was detected, the adequacy of reduction was assessed. Results The sensitivity of distal radius fracture diagnosis on ultrasound was 100% and specificity ranged from 90% to 95%. The sensitivity of identifying a satisfactory reduction ranged from 76% to 93% and specificity was 93% to 94%. Interrater reliability between the musculoskeletal radiologist and hand surgeon was κ = 0.86 for diagnosing the fracture and κ = 0.82 for identifying a satisfactory reduction. Intrarater reliability ranged from κ = 0.82 to 0.86. Conclusions A pocket-sized, handheld diagnostic ultrasound device demonstrates the ability to diagnose distal radius fractures and assess fracture reductions. Type of study/level of evidence Diagnostic II.

This review discusses an approach to determining the cause of neonatal encephalopathy, as well as current evidence on resuscitation and subsequent management of hypoxic-ischaemic encephalopathy (HIE). Encephalopathy in neonates can be due to varied aetiologies in addition to hypoxic-ischaemia. A combination of careful history, examination and the judicious use of investigations can help determine the cause. Over the last 7 years, infants with moderate to severe HIE have benefited from the introduction of routine therapeutic hypothermia; the number needed to treat for an additional beneficial outcome is 7 (95% CI 5 to 10). More recent research has focused on optimal resuscitation practices for babies with cardiorespiratory depression, such as delayed cord clamping after establishment of ventilation and resuscitation in air. Around a quarter of infants with asystole at 10 min after birth who are subsequently cooled have normal outcomes, suggesting that individualised decision making on stopping resuscitation is needed, based on access to intensive treatment unit and early cooling. The full benefit of cooling appears to have been exploited in our current treatment protocols of 72 hours at 33.5°C; deeper and longer cooling showed adverse outcome. The challenge over the next 5–10 years will be to assess which adjunct therapies are safe and optimise hypothermic brain protection in phase I and phase II trials. Optimal care may require tailoring treatments according to gender, genetic risk, injury severity and inflammatory status.

Inflammation plays a major role in colon carcinogenesis. Endogenously produced specialized proresolving lipid mediators (SPMs) play a central role in inflammation and tissue homeostasis, and have been implicated in carcinogenesis. We studied the associations of plasma levels of two SPMs [lipoxin A4 (LXA4 ) and resolvin D1(RvD1)] with risk for recurrent adenoma. In this pilot study, we used data and biosamples from an adenoma chemoprevention study investigating the effects of aspirin and/or folic acid on the occurrence of colorectal adenomas. In the parent study, 1121 participants with a recent adenoma were randomized to study agents to be taken until the next surveillance colonoscopy about 3 years later. In this pilot study, LXA4 and RvD1 from samples taken near the end of study treatment were measured in a randomly selected sub-set of 200 participants. Commercially available ELISA kits to assay the analytes were validated using a metabololipidomic LC-MS/MS assay. Poisson regression with a robust error variance was used to calculate risk ratios and 95% confidence intervals. Plasma LXA4 and RvD1 were not associated with the risk of adenoma occurrence. LXA4 at the end of study follow-up was 32% (P = 0.01) proportionately higher in women compared to men. A similar non-significant trend toward higher levels among women was observed for RvD1. Our preliminary findings provided no evidence that plasma LXA4 or RvD1 are associated with reduced risk of colorectal adenoma occurrence, but suggest LXA4 may differ among men and women. Future studies focusing on SPM's local effects and levels in the colon are needed.

Bulgaria is one of European countries where trichinellosis continues to be regularly diagnosed and registered. The clinical and epidemiological features of 72 cases of trichinellosis associated with five outbreaks caused by Trichinella spiralis and Trichinella britovi between 2009 and 2011, are described. At hospital admission, patients were often initially treated with antibiotics, without any improvement. A range of signs and symptoms were recorded, including: myalgia, elevated temperature, arthralgia, difficulty with movement, facial oedema, conjunctival hyperaemia, ocular haemorrhages, diarrhoea, skin rash, headache, and fatigue. Due to the variable clinical course of the disease, the diagnostic process for trichinellosis is often complex and difficult. This means the diagnosis may be established late for an appropriate treatment, potentially leading to a severe course of the disease with complications. Laboratory abnormalities were expressed by marked eosinophilia (97.2%), leucocytosis (70.8%), elevated serum creatine phosphokinase levels (82%), and antibody-positive results by ELISA and indirect hemagglutination. Patients were treated with albendazole (Zentel) 10 mg/kg for 7–10 days. In two outbreaks, the aetiological agent was T. spiralis, in one outbreak T. britovi, and an unknown Trichinella species in the fourth outbreak. The sources of infection were domestic pigs, probably fed with scraps and offal of wild game. In one outbreak, T. spiralis was also detected in brown rats trapped close to where the pig had been raised in the backyard. These epidemiological factors are relevant in considering implementation of targeted control programmes.

Immunocompromised individuals often become symptomatic with infections which are normally fairly asymptomatic in healthy individuals. The particular mechanisms that underlie susceptibility to coinfections in human immunodeficiency virus (HIV)-infected individuals are multifaceted. ZIKV and other flaviviruses are sensitive to neutralizing antibodies, whose production can be limited in HIV-infected individuals but are also sensitive to type I interferons, which are expressed at high levels in HIV-infected individuals. Data in this study highlight how individual components of the innate and adaptive immune responses which become perturbed in HIV-infected individuals influence ZIKV infection., Flaviviruses are controlled by adaptive immune responses but are exquisitely sensitive to interferon-stimulated genes (ISGs). How coinfections, particularly simian immunodeficiency viruses (SIVs), that induce robust ISG signatures influence flavivirus clearance and pathogenesis is unclear. Here, we studied how Zika virus (ZIKV) infection is modulated in SIV-infected nonhuman primates. We measured ZIKV replication, cellular ZIKV RNA levels, and immune responses in non-SIV-infected and SIV-infected rhesus macaques (RMs), which we infected with ZIKV. Coinfected animals had a 1- to 2-day delay in peak ZIKV viremia, which was 30% of that in non-SIV-infected animals. However, ZIKV viremia was significantly prolonged in SIV-positive (SIV+) RMs. ISG levels at the time of ZIKV infection were predictive for lower ZIKV viremia in the SIV+ RMs, while prolonged ZIKV viremia was associated with muted and delayed adaptive responses in SIV+ RMs.

Background: According to Slade’s Personal Recovery Framework, mental health recovery involves developing a positive identity, reframing experiences, developing self-management and valued social roles.Aim: This study explored how developing a personal narrative can support mental health recovery through reframing and developing a more positive identity. This paper provides an overview of the study’s three phases and the resultant Personal Narrative Workshop Programme.Method: Phase 1 involved developing and analysing my own recovery narrative using autoethnography. Phase 2 used Participatory Action Research (PAR) to explore the experience of other service users, with co-researchers recruited to two focus groups. Six co-researchers continued into Phase 3 (three cycles of PAR) to develop the workshop programme.Results: An eight-session workshop programme was co-produced and fully documented.Conclusions: Developing a narrative is not benign: it can involve reliving trauma; and dealing with the ‘voice of others’ in our narratives can be difficult. As a result, the workshop programme aimed to provide a supportive environment, promoting collaboration and validation. Methodological issues resulted from the complexities of using a PAR approach, and on the multiplicity of roles for the researcher.

OBJECTIVES There is little guidance regarding when to stop surveillance colonoscopy in individuals with a history of adenomas or colorectal cancer (CRC). We evaluated both yield and recommendations for follow-up colonoscopy in a large cohort of older individuals undergoing colonoscopy, using the GI Quality Improvement Consortium registry. METHODS We analyzed the yield of colonoscopy in adults aged ≥75 years, comparing those who had an indication of surveillance as opposed to an indication of diagnostic or screening, stratified by 5-year age groups. Our primary outcome was CRC and advanced lesions. We also evaluated recommended follow-up intervals by age and findings. RESULTS Between 2010 and 2017, 376,686 colonoscopies were performed by 3,976 endoscopists at 628 sites, of which 43.2% were for surveillance. Detection of CRC among surveillance patients increased with age from 0.51% (age 75-79 years) to 1.8% (age ≥ 90 years); however, these risks were lower when compared with both the diagnostic and screening for the same age band (P < 0.0001). Yield of advanced lesions also increased by every 5-year interval of age across all groups by indication. Even at the most advanced ages and in those with nonadvanced findings, only a minority of patients were recommended for no further colonoscopy. For example, in patients aged 90 years and older with only low risk findings, 62.9% were recommended to repeat colonoscopy. DISCUSSION Surveillance colonoscopy is frequently recommended at advanced ages even when recent findings may be clinically insignificant. Further work is needed to develop guidelines to inform best practice around when to stop surveillance in older adults.

The purpose of this analysis was to determine if a correlation exists between socioeconomic status (SES) and pyloric stenosis (PS) as well as between PS and feeding method.Data was collected retrospectively from the electronic medical record. Patients were included if they resided in a county in Illinois where our institution maintains10% visit share, were 1 year in age, and received a pyloromyotomy from January 2011 to May 2018. Patient addresses were geocoded and merged with county and tract-level census data. A control group was matched on gender, race, tract level, median household income (MHI), and age. Feeding method for each group was collected. Univariate analysis and multivariate analyses were employed.SES was explored using MHI. After controlling for gender, age, race, and institution adjusted tract size, the association between MHI and pyloromyotomy remained significant. As MHI decreased, the odds of having a PS case increased. Additionally, the PS incidence rate increased as MHI decreased. Patients who were exclusively formula fed were more likely to have PS.Pyloric stenosis had a direct correlation with SES as defined by MHI. As MHI decreased, the rates of PS increased. In addition, breastfeeding was protective, independent of MHI.Prognosis study.Level II.

High-throughput transcriptomics and proteomics approaches have recently identified a large number of germ cell–specific genes with many that remain to be studied through functional genetics approaches. Serine proteases (PRSS) constitute nearly one-third of all proteases, and, in our bioinformatics screens, we identified many that are testis specific. In this study, we chose to focus on Prss44, Prss46, and Prss54, which we confirmed as testis specific in mouse and human. Based on the analysis of developmental expression in the mouse, expression of all four genes is restricted to the late stage of spermatogenesis concomitant with a potential functional role in spermiogenesis, spermiation, or sperm function. To best understand the male reproductive requirement and functional roles of these serine proteases, each gene was individually ablated by CRISPR/Cas9-mediated ES cell or zygote approach. Homozygous deletion mutants for each gene were obtained and analyzed for phenotypic changes. Analyses of testis weights, testis and epididymis histology, sperm morphology, and fertility revealed no significant differences in Prss44, Prss46, and Prss54 knockout mice in comparison to controls. Our results thereby demonstrate that these genes are not required for normal fertility in mice, although do not preclude the possibility that these genes may function in a redundant manner. Elucidating the individual functional requirement or lack thereof of these novel genes is necessary to build a better understanding of the factors underlying spermatogenesis and sperm maturation, which has implications in understanding the etiology of male infertility and the development of male contraceptives., Summary Sentence The testis-specific serine proteases Prss44, Prss46, and Prss54 are dispensable for male fertility based on phenotype analyses of knockout mice produced using the CRISPR/Cas9 system.

Aims Arrhythmogenic cardiomyopathy (ACM) is a myocardial disease caused mainly by mutations in genes encoding desmosome proteins ACM patients present with ventricular arrhythmias, cardiac dysfunction, sudden cardiac death, and a subset with fibro-fatty infiltration of the right ventricle predominantly. Endurance exercise is thought to exacerbate cardiac dysfunction and arrhythmias in ACM. The objective was to determine the effects of treadmill exercise on cardiac phenotype, including myocyte gene expression in myocyte-specific desmoplakin (Dsp) haplo-insufficient (Myh6-Cre:DspW/F) mice. Methods and results Three months old sex-matched wild-type (WT) and Myh6-Cre:DspW/F mice with normal cardiac function, as assessed by echocardiography, were randomized to regular activity or 60 min of daily treadmill exercise (5.5 kJ work per run). Cardiac myocyte gene expression, cardiac function, arrhythmias, and myocardial histology, including apoptosis, were analysed prior to and after 3 months of routine activity or treadmill exercise. Fifty-seven and 781 genes were differentially expressed in 3- and 6-month-old Myh6-Cre:DspW/F cardiac myocytes, compared to the corresponding WT myocytes, respectively. Genes encoding secreted proteins (secretome), including inhibitors of the canonical WNT pathway, were among the most up-regulated genes. The differentially expressed genes (DEGs) predicted activation of epithelial–mesenchymal transition (EMT) and inflammation, and suppression of oxidative phosphorylation pathways in the Myh6-Cre:DspW/F myocytes. Treadmill exercise restored transcript levels of two-third (492/781) of the DEGs and the corresponding dysregulated transcriptional and biological pathways, including EMT, inflammation, and secreted inhibitors of the canonical WNT. The changes were associated with reduced myocardial apoptosis and eccentric cardiac hypertrophy without changes in cardiac function. Conclusion Treadmill exercise restored transcript levels of the majority of dysregulated genes in cardiac myocytes, reduced myocardial apoptosis, and induced eccentric cardiac hypertrophy without affecting cardiac dysfunction in a mouse model of ACM. The findings suggest that treadmill exercise has potential beneficial effects in a subset of cardiac phenotypes in ACM.

Co-existing infection/inflammation and birth asphyxia potentiate the risk of developing neonatal encephalopathy (NE) and adverse outcome. In a newborn piglet model we assessed the effect of E. coli lipopolysaccharide (LPS) infusion started 4 h prior to and continued for 48 h after hypoxia on brain cell death and systemic haematological changes compared to LPS and hypoxia alone. LPS sensitized hypoxia resulted in an increase in mortality and in brain cell death (TUNEL positive cells) throughout the whole brain, and in the internal capsule, periventricular white matter and sensorimotor cortex. LPS alone did not increase brain cell death at 48 h, despite evidence of neuroinflammation, including the greatest increases in microglial proliferation, reactive astrocytosis and cleavage of caspase-3. LPS exposure caused splenic hypertrophy and platelet count suppression. The combination of LPS and hypoxia resulted in the highest and most sustained systemic white cell count increase. These findings highlight the significant contribution of acute inflammation sensitization prior to an asphyxial insult on NE illness severity.

Prostaglandin E2 receptor EP1 (PGE

More than 1000 genes are predicted to be predominantly expressed in mouse testis, yet many of them remain unstudied in terms of their roles in spermatogenesis and sperm function and their essentiality in male reproduction. Since individually indispensable factors can provide important implications for the diagnosis of genetically related idiopathic male infertility and may serve as candidate targets for the development of nonhormonal male contraceptives, our laboratories continuously analyze the functions of testis-enriched genes in vivo by generating knockout mouse lines using the CRISPR/Cas9 system. The dispensability of genes in male reproduction is easily determined by examining the fecundity of knockout males. During our large-scale screening of essential factors, we knocked out 30 genes that have a strong bias of expression in the testis and are mostly conserved in mammalian species including human. Fertility tests reveal that the mutant males exhibited normal fecundity, suggesting these genes are individually dispensable for male reproduction. Since such functionally redundant genes are of diminished biological and clinical significance, we believe that it is crucial to disseminate this list of genes, along with their phenotypic information, to the scientific community to avoid unnecessary expenditure of time and research funds and duplication of efforts by other laboratories., Thirty testis-enriched genes are dispensable for male fertility based on phenotypic analyses of knockout mice produced by the CRISPR/Cas9 system.