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Background & Aims Older adults with colorectal polyps undergo frequent surveillance colonoscopy. There is no specific guidance regarding when to stop surveillance. We aimed to characterize endoscopist recommendations regarding surveillance colonoscopy in older adults and identify patient, procedure, and endoscopist characteristics associated with recommendations to stop. Methods This was a retrospective cohort study at a single academic medical center of adults aged ≥75 years who underwent colonoscopy for polyp surveillance or screening during which polyps were found. The primary outcome was a recommendation to stop surveillance. Predictors examined included patient age, sex, family history of colorectal cancer, polyp findings, and endoscopist sex and years in practice. Associations were evaluated using multilevel logistic regression. Results Among 1426 colonoscopies performed by 17 endoscopists, 34.6% contained a recommendation to stop and 52.3% to continue. Older patients were more likely to receive a recommendation to stop, including those 80–84 years (odds ratio [OR], 7.7; 95% confidence interval [CI], 4.8–12.3) and ≥85 years (OR, 9.0; 95% CI, 3.3–24.6), compared with those 75–79 years. Family history of colorectal cancer (OR, 0.42; 95% CI, 0.24–0.74) and a history of low-risk (OR, 0.17; 95% CI, 0.11–0.24) or high-risk (OR, 0.02; 95% CI, 0.01–0.04) polyps were inversely associated with recommendations to stop. The likelihood of a recommendation to stop varied significantly across endoscopists. Conclusions Only 35% of adults ≥75 years of age are recommended to stop surveillance colonoscopy. The presence of polyps was strongly associated with fewer recommendations to stop. The variation in endoscopist recommendations highlights an opportunity to better standardize recommendations following colonoscopy in older adults.

Summary Background The rare inversa subtype of recessive dystrophic epidermolysis bullosa (RDEB-I) is characterized by predominant intertriginous skin blistering and marked mucosal involvement. Specific recessive missense mutations in the collagen VII triple helix are implicated in the disease. To date, otological complications have been reported infrequently in this patient group. Methods We conducted an observational, retrospective, double institution case record review of patients with RDEB-I who presented with otological complications between January 2000 and June 2020. Diagnosis was established on the basis of clinical features, family history and mutation analysis of the COL7A1 gene. Results In total, 11 (44%) of 25 patients with RDEB-I in our database (2 paediatric, 9 adult; mean age 40.9 years, range 8–72 years) experienced otological complications. Of these 11 patients, 10 (90.9%) had recurrent otitis externa, 7 (63.6%) had meatal stenosis and 7 (63.6%) had recurrent blistering of the external auditory canals. All 11 patients reported hearing difficulties, with conductive hearing loss confirmed by audiology testing in 6 (54.5%) of these. Of the 11 patients, 3 (27.3%) went on to have implantable hearing aids [2 bone-anchored hearing aids (BAHA) and 1 middle ear implant (MEI)] fitted with favourable outcome, while a fourth paediatric patient presented with a cholesteatoma that was surgically managed. Discussion We observed a higher prevalence of otological morbidity in RDEB-I than previously reported, and present the first case of cholesteatoma in epidermolysis bullosa (EB). Our data indicate that BAHA and MEI are safe and effective treatment options for hearing loss in EB. Clinicians should be vigilant in screening for ear symptoms in RDEB-I and consider early referral to an Ear, Nose and Throat specialist.

To compare deep infection rate and causative organisms in open fractures of the lower extremity from agricultural trauma with similar injuries in nonagricultural trauma.Retrospective.Two tertiary care institutions.Open lower extremity fractures sustained between 2003 and 2018 caused by agriculture-related trauma in adult patients were reviewed. A nonagriculture open fracture control group (NAG) was identified for comparison. Patient demographics and injury characteristics were assessed. Outcomes included occurrence of deep infection and causative organisms.One hundred seventy-eight patients were identified in the agriculture (AG) (n = 89) and control (NAG) (n = 89) groups. Among patients with agricultural injury, farm machinery was the most common mechanism in 69 (77.5%) of them. Open injuries of the foot (38.2%) and tibial shaft injuries (25.8%) were the most common in the AG and NAG groups, respectively. Deep infection was seen in 21% of patients in the AG group compared with 10% in the NAG group (P0.05). In the AG group, anaerobic infection occurred in 44% of patients with deep infection compared with 9.1% in the NAG group (P0.05). The most common anaerobic organisms included enterococci, Pseudomonas aeruginosa, and Clostridium perfringens.This study supports that open fractures due to agricultural trauma have a high infection rate, with anaerobic infection occurring at higher rates than in injuries due to nonagricultural trauma. Prophylactic treatment with antibiotics directed against anaerobes is indicated in these injuries.Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

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.

Background and Purpose. Although most physical therapists experience work-related musculoskeletal disorders (WMSDs) at some time, only a small minority claim workers' compensation. This article describes the experiences of a group of therapists with WMSDs who made compensation claims. Methods. Interviews were used to document the experiences of physical therapists who reported that they had changed their career because of WMSDs. Results and Discussion. Therapists described their experiences in negative terms and found dealing with the workers' compensation system frustrating and unpleasant. They encountered attitudes that labeled them as malingerers and felt their credibility was questioned. Conclusions. Physical therapists' experiences of the workers' compensation system were negative, and they were keen to become independent of it. Those who claimed workers' compensation perceived that a compensable claim could limit their employment opportunities, making confidentiality an important issue when treating other health care professionals.

Introduction Open tibial fractures are the most common open long bone fracture, despite this, the management of these complex injuries still remains a topic of discussion amongst orthopaedic surgeons. Sources of data We searched the EMBASE, MEDLINE and Google Scholar and a systematic review of 7500 articles, leaving 23 after exclusion criteria were applied, in order to analyse the management of open tibial fractures. Areas of agreement and controversy Infection was noted to be the most significant concern amongst authors, with definitive external fixation having a high rate of superficial pin-site infection and internal fixation having a high deep infection rate. Growing points It is essential to have a combined ortho-plastic approach to the management of these fractures as muscle flaps were the most common form of soft tissue coverage. Areas timely for developing research A national pragmatic trial into the management of open tibial fractures is required looking at fixation methods and soft tissue coverage, with at least a 2-year follow-up in order to ascertain the most appropriate management of these fractures and patient-related outcomes.

ObjectiveIncreases in incidence of collagenous colitis (CC) have been documented across Europe; however, previous data from NHS Lothian (1998–2003) demonstrated this to be a low-prevalence area. We aimed to assess incidence of CC in NHS Lothian over time by comparing a more recent cohort (2013–2018) with our existing cohort.MethodsAll histologically confirmed diagnoses of CC between 2013 and 2018 were obtained from the NHS Lothian colorectal pathology department (Western General Hospital, Edinburgh). Case record review was performed to obtain relevant demographic and clinical data. Data were also collected regarding the availability of colonoscopy in NHS Lothian.Results224 cases of CC were diagnosed between 2013 and 2018, compared with 25 between 1998 and 2003. Mean annual incidence rose from 0.5/100 000 population to 4.3/100 000 population. Incidence in females ≥60 years old rose from 2.3/100 000 population to 22.4/100 000 population (pConclusionWe describe the increasing incidence of CC in Southeast Scotland, with temporal trends comparable to other European countries. The increase is particularly marked in older females and parallels increasing numbers of colonoscopies being performed.

ST-segment elevation myocardial infarction (STEMI) is characterized by ST-segment elevation in at least 2 contiguous leads, chest discomfort, and the release of biomarkers requiring emergent revascularization. In 2013, the American College of Cardiology Foundation/American Heart Association revised STEMI guidelines to include augmented vector right (aVR) ST-segment elevation to be treated as a STEMI equivalent. However, aVR ST-segment elevation with multilead ST depression can occur in presentations other than occlusive myocardial infarctions. The purpose of this clinical feature is to provide a brief review of aVR ST-segment elevation, explore approaches to clinical decision making, and provide tools to support nurse practitioners caring for patients with cardiac issues.

Background Cancer therapy-related cardiac dysfunction may occur in pediatric cancer survivors. Identification of early markers of myocardial damage secondary to anthracycline exposure is crucial to develop strategies that may ameliorate this complication. Objectives The purpose of this study was to identify early myocardial changes induced by doxorubicin with and without cardioprotection using dexrazoxane detected by serial cardiac magnetic resonance imaging (CMR) in a pre-clinical mouse model. Methods Serial CMR examinations were performed in 90 mice distributed in 3 groups: 45 received doxorubicin (DOX group), 30 mice received doxorubicin with dexrazoxane (DOX/DEX group) and 15 mice received saline injections (control group). We obtained the following CMR parameters in all mice: T2, extracellular volume quantification (ECV), myocardial deformation, and functional quantification. Results Myocardial edema assessed by T2 time was the earliest parameter demonstrating evidence of myocardial injury, most notable in the DOX group at week 4 and 8 compared with DOX/DEX group. Similarly, global longitudinal strain was abnormal in both the DOX and DOX/DEX groups. However, this change persisted only in the DOX group. The ECV was significantly elevated in the DOX group at the final CMR, while only minimally elevated in the DOX/DEX group. The right and left ejection fraction was decreased, along with the mass to volume ratio in the DOX group. The T2 time, ECV, and deformation correlated with ejection fraction and left ventricular volume. Conclusions T2 time and deformation by CMR identifies early myocardial injury from anthracyclines. Dexrazoxne did not prevent the initial edema, but the inflammatory changes were not sustained. CMR may be useful for early detection of cardiac dysfunction. Serial CMR demonstrates dexrazoxane minimizes cardiac dysfunction and aids recovery in a mouse model.

Advances in neonatal–perinatal medicine have resulted in increased survival at lower gestations. Although the incidence of germinal matrix haemorrhage-intraventricular haemorrhage and cystic periventricular leucomalacia is reducing, a new phenotype of preterm brain injury has emerged consisting of a combination of destructive and dysmaturational effects. Consequently, severe neurological disability is reported at a lower rate than previously, but the overall morbidity associated with premature birth continues to present a large global burden and contributes significantly to increased financial costs to health systems and families. In this review, we examine the developmental milestones of fetal brain development and how preterm birth can disrupt this trajectory. We review common morbidities associated with premature birth today. Although drug-based and cell-based neuroprotective therapies for the preterm brain are under intense study, we outline basic, sustainable and effective non-medical, family-centred and developmental care strategies which have the potential to improve neurodevelopmental outcomes for this population and need to be considered part of the future neuroprotection care bundle.

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 The success of clinical trials in Epidermolysis Bullosa (EB) is dependent upon the availability of a valid and reliable scoring tool that can accurately assess and monitor disease severity. The Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) and Instrument for Scoring Clinical Outcomes of Research for Epidermolysis Bullosa (iscorEB) were independently developed and validated against the Birmingham Epidermolysis Bullosa Severity Score but have never been directly compared. Objective To compare the reliability, convergent validity, and discriminant validity of the EBDASI and iscorEB scoring tools. Methods An observational cohort study was conducted in 15 patients with EB. Each patient was evaluated using the EBDASI and iscorEB-clinician scoring tools by 6 dermatologists with expertise in EB. Quality of life was assessed using the iscorEB-patient and Quality of Life in EB measures. Results The intraclass correlation coefficients for interrater reliability were 0.942 for the EBDASI and 0.852 for the iscorEB-clinician. The intraclass correlation coefficients for intrarater reliability was 0.99 for both scores. The two tools demonstrated strong convergent validity with each other. Conclusion Both scoring tools demonstrate excellent reliability. The EBDASI appears to better discriminate between EB types and disease severities.

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

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.

Background Posterior fossa abnormalities (PFAs) are commonly identified within routine screening and are a frequent indication for fetal magnetic resonance imaging (MRI). Although biometric measurements of the posterior fossa (PF) are established on fetal ultrasound and MRI, qualitative visual assessments are predominantly used to differentiate PFAs. Objectives This systematic review aimed to assess 2-dimensional (2D) biometric measurements currently in use for assessing the PF on fetal MRI to delineate different PFAs. Methods The protocol was registered (PROSPERO ID CRD42019142162). Eligible studies included T2-weighted MRI PF measurements in fetuses with and without PFAs, including measurements of the PF, or other brain areas relevant to PFAs. Results 59 studies were included - 6859 fetuses had 62 2D PF and related measurements. These included linear, area and angular measurements, representing measures of PF size, cerebellum/vermis, brainstem, and supratentorial measurements. 11 measurements were used in 10 or more studies and at least 1200 fetuses. These dimensions were used to characterise normal for gestational age, diagnose a range of pathologies, and predict outcome. Conclusion A selection of validated 2D biometric measurements of the PF on fetal MRI may be useful for identification of PFA in different clinical settings. Consistent use of these measures, both clinically and for research, is recommended.

Sinusoidal obstruction syndrome (SOS) is a serious complication of hematopoietic stem cell transplantation (HSCT). Sirolimus plus tacrolimus is an accepted regimen for graft-versus-host disease (GVHD) prophylaxis, with both agents implicated as risk factors for SOS. We analyzed 260 consecutive patients who underwent allogeneic HSCT following myeloablative conditioning using total body irradiation (TBI)-based (n = 151) or chemotherapy only (n = 109) regimens, with sirolimus plus tacrolimus for GVHD prophylaxis. SOS occurred in 28 patients at a median of 22 (range, 12–58) days. Mean sirolimus trough levels were higher between days 11 and 20 following transplant in patients who developed SOS (10.3 vs. 8.5 ng/ml, P = 0.008), with no significant difference in mean trough levels between days 0 and 10 (P = 0.67) and days 21–30 (P = 0.37). No differences in mean tacrolimus trough levels during the same time intervals were observed between those developing SOS and others. On multivariable analysis, a mean sirolimus trough level ≥ 9 ng/ml between days 11 and 20 increased the risk of SOS (hazard ratio 3.68, 95% CI: 1.57–8.67, P = 0.003), together with a longer time from diagnosis to transplant (P = 0.004) and use of TBI (P = 0.006). Our results suggest that mean trough sirolimus levels ≥ 9 ng/mL between days 11 and 20 post transplant may increase the risk of SOS and should be avoided.

The fecal immunochemical test (FIT) is a tool used for colorectal cancer screening and its use is growing rapidly. FIT, applied as a qualitative or quantitative test, has far better sensitivity for hemoglobin than older, guaiac fecal occult blood tests. This translates into several advantages of FIT, including ability to screen using only 1 stool sample per cycle. This article reviews current understanding of FIT performance as a 1-time test and when applied programmatically. It outlines how to apply the test at the patient level and track performance at the program level. Future prospects for FIT application are highlighted.

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.

Prostaglandin E2 receptor EP1 (PGE2/EP1) promotes diabetic renal injury, and EP1 receptor deletion improves hyperfiltration, albuminuria, and fibrosis. The role of EP1 receptors in hypertensive kidney disease (HKD) remains controversial. We examined the contribution of EP1 receptors to HKD. EP1 null (EP1-/-) mice were bred with hypertensive TTRhRen mice (Htn) to evaluate kidney function and injury at 24 weeks. EP1 deletion had no effect on elevation of systolic blood pressure in Htn mice (HtnEP1-/-) but resulted in pronounced albuminuria and reduced FITC-inulin clearance, compared with Htn or wild-type (WT) mice. Ultrastructural injury to podocytes and glomerular endothelium was prominent in HtnEP1-/- mice; including widened subendothelial space, subendothelial lucent zones and focal lifting of endothelium from basement membrane, with focal subendothelial cell debris. Cortex COX2 mRNA was increased by EP1 deletion. Glomerular EP3 mRNA was reduced by EP1 deletion, and EP4 by Htn and EP1 deletion. In WT mice, PGE2 increased chloride reabsorption via EP1 in isolated perfused thick ascending limb (TAL), but PGE2 or EP1 deletion did not affect vasopressin-mediated chloride reabsorption. In WT and Htn mouse inner medullary collecting duct (IMCD), PGE2 inhibited vasopressin-water transport, but not in EP1-/- or HtnEP1-/- mice. Overall, EP1 mediated TAL and IMCD transport in response to PGE2 is unaltered in Htn, and EP1 is protective in HKD.

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.

An infant girl developed a hemangioma affecting her left iris concurrently with diffuse cutaneous infantile hemangiomas from day 2 of life. Intraocular hemangiomas are rarely reported and are usually associated with neonatal hemangiomatosis, the presence of which indicates a high risk for visceral lesions. This striking case highlights the unusual clinical presentation of iris hemangioma and demonstrates the importance of conducting visceral screening when faced with these lesions. Oral propranolol was commenced and resulted in rapid improvement of all lesions without complication.

Taeniosis is a neglected disease, particularly in developing countries, and is caused by infection with the adult tapeworm of either Taenia solium, Taenia saginata, and Taenia asiatica. Of these, T. solium is of primary concern due to the potential for cysticercosis should T. solium eggs be ingested. In Cuba, all cases of taeniosis are assumed to be caused by T. saginata, although some cases of cysticercosis have been documented. It is therefore important to gain further insights regarding the species causing taeniosis in Cuba, especially as diagnostic records indicate an increasing incidence, with the highest number of cases reported in 2020. In this study, we analysed 37 Taenia-positive faecal samples (or proglottids isolated from faecal samples) from the period 2001 until 2020 from all regions of the country. Genomic DNA was extracted from the samples, which had been stored in 10% formalin, using the QIAamp Tissue Kit. Species identification was carried out by duplex real-time PCR targeting the mitochondrial DNA. All cases were found to be T. saginata, and sequence analysis of three isolates confirmed the identification of this species. Our data do not provide any evidence that T. solium currently occurs in Cuba. However, given the relatively low number of samples analysed here, that the parasite may be imported with visitors or travellers who have been in endemic countries, and that taeniosis has relatively mild symptoms and thus infected patients may not seek medical attention, we recommend species determination for all taeniosis cases reported in Cuba., Highlights • The incidence of taeniosis cases in Cuba is rising, with 2020 being a peak year • Although assumed to be Taenia saginata, this has not been confirmed • We investigated 37 samples from 2001 until 2020 that had been stored in formalin • Duplex real-time PCR indicated T. saginata; 3 cases were confirmed by sequencing

Inflammation in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection drives severity of coronavirus disease 2019 (COVID-19) and is influenced by host genetics. To understand mechanisms of inflammation, animal models that reflect genetic diversity and clinical outcomes observed in humans are needed. We report a mouse panel comprising the genetically diverse Collaborative Cross (CC) founder strains crossed to human ACE2 transgenic mice (K18-hACE2) that confers susceptibility to SARS-CoV-2. Infection of CC x K18- hACE2 resulted in a spectrum of survival, viral replication kinetics, and immune profiles. Importantly, in contrast to the K18-hACE2 model, early type I interferon (IFN-I) and regulated proinflammatory responses were required for control of SARS-CoV-2 replication in PWK x K18-hACE2 mice that were highly resistant to disease. Thus, virus dynamics and inflammation observed in COVID-19 can be modeled in diverse mouse strains that provide a genetically tractable platform for understanding anti-coronavirus immunity.One Sentence SummaryGenetically diverse mice model a spectrum of clinically relevant innate immune responses to SARS-CoV-2 infection.

Author(s): Langbroek, GB; Wolkerstorfer, A; Horbach, SER; Spuls, PI; Kelly, KM; Robertson, SJ; van Raath, MI; Al-Niaimi, F; Kono, T; Boixeda, P; Laubach, HJ; Badawi, AM; Troilius Rubin, A; Haedersdal, M; Manuskiatti, W; van der Horst, CMAM; Ubbink, DT; COSCAM study group | Abstract: BackgroundDue to a large variety in treatment outcomes reported in therapeutic trials and lacking patient-relevant outcomes, it is hard to adequately compare and improve current therapies for patients with capillary malformations (CMs). The Core Outcome Set for Capillary Malformations (COSCAM) project aims to develop a core outcome set (COS) for use in future CM trials, in which we will first develop a core outcome (sub)domain set (CDS). Here, we describe the methods for the development of a CDS and present the results of the first development stage.MethodsThe COSCAM project is carried out according to the recommendations of the Cochrane Skin Core OUtcomes Set INitiative (CS-COUSIN) and the Core Outcome Measures in Effectiveness Trials (COMET) initiative. During the first stage, we identified all potentially relevant outcome subdomains based on a systematic review, two focus group sessions and input from patient representatives of Dutch patient organizations and the COSCAM-founding group. In stage two, we will present the subdomains in a three-round e-Delphi study and online consensus meeting, in which CM patients, parents/caregivers and CM experts worldwide rate the importance of the proposed subdomains, hereby finalizing the core outcome (sub)domains of the CDS.ResultsA total of 67 potential outcome subdomains were included; sixteen were previously used in the literature, 20 were proposed by Dutch patients and their parents/caregivers (nn=n13) in focus group sessions and 38 were suggested by the experts of the COSCAM-founding group. Seven were excluded because of overlap.ConclusionThe final CDS may serve as a minimum standard in future CM trials, thereby facilitating adequate comparison of treatment outcomes. After this CDS development, we will select appropriate outcome measurement instruments to measure the core outcome subdomains.

Indiscriminate ordering of Oncotype DX (ODX) is expensive and of poor value to patients, physicians, and health care providers. The 3 Magee equations, Gage Algorithm, and University of Tennessee predictive algorithm all use standard clinicopathologic data to provide surrogate ODX scores. In this hypothesis-generating study, we evaluated whether these prognostic scores could be used to identify patients unlikely to benefit from additional ODX testing.Retrospective data was collected from 302 patients with invasive ductal breast cancer and available ODX scores. Additional data was available for: Magee equations 1 (212 patients), 2 (299 patients), 3 (212 patients), Gage Algorithm (299 patients), and University of Tennessee predictive algorithm (286 patients). ODX scores were banded according to the TAILORx results.Correlation with ODX scores was between 0.7 and 0.8 (Gage), 0.8 and 0.9 (Magee 2, University of Tennessee predictive algorithm), and0.9 (Magee 1 and 3). Magee 3 was the most robust and is proposed as a screening tool: for patients aged ≤ 50 years, ODX testing would be not required if the Magee 3 score was 14 or ≥ 20; for those aged50 years, ODX would not be required if the Magee 3 score was 18 or ≥ 26. Using these cut-offs, 110 (51.9%) of 212 patients would be deemed as not requiring ODX testing, and 109 (99.1%) of110 patients would be appropriately managed.Use of all formulae, and the Magee 3 equation in particular, are proposed as possible screening tools for ODX testing, resulting in significantly reduced frequency of ODX testing. This requires validation in other populations.

Inactivating mutations in the copper transporter Atp7b result in Wilson’s disease. The Atp7b −/− mouse develops hallmarks of Wilson’s disease. The activity of several nuclear receptors decreased in Atp7b −/− mice, and nuclear receptors are critical for maintaining metabolic homeostasis. Therefore, we anticipated that Atp7b −/− mice would exhibit altered progression of diet-induced obesity, fatty liver, and insulin resistance. Following 10 wk on a chow or Western-type diet (40% kcal fat), parameters of glucose and lipid homeostasis were measured. Hepatic metabolites were measured by liquid chromatography–mass spectrometry and correlated with transcriptomic data. Atp7b −/− mice fed a chow diet presented with blunted body-weight gain over time, had lower fat mass, and were more glucose tolerant than wild type (WT) littermate controls. On the Western diet, Atp7b −/− mice exhibited reduced body weight, adiposity, and hepatic steatosis compared with WT controls. Atp7b −/− mice fed either diet were more insulin sensitive than WT controls; however, fasted Atp7b −/− mice exhibited hypoglycemia after administration of insulin due to an impaired glucose counterregulatory response, as evidenced by reduced hepatic glucose production. Coupling gene expression with metabolomic analyses, we observed striking changes in hepatic metabolic profiles in Atp7b −/− mice, including increases in glycolytic intermediates and components of the tricarboxylic acid cycle. In addition, the active phosphorylated form of AMP kinase was significantly increased in Atp7b −/− mice relative to WT controls. Alterations in hepatic metabolic profiles and nuclear receptor signaling were associated with improved glucose tolerance and insulin sensitivity as well as with impaired fasting glucose production in Atp7b −/− mice.

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.

BACKGROUND: The TOBY-Xe proof of concept randomised trial found no effect of xenon combined with hypothermia after birth asphyxia on the lactate to N-acetyl aspartate ratio (Lac/NAA) in the thalamus and fractional anisotropy (FA) in white matter tracts measured within 15 days of birth. To confirm that these biomarkers are qualified to predict long-term outcome after neural rescue therapy we assessed surviving participants at 2-3 years of age.METHODS: Of the 92 infants in TOBY-Xe, one was omitted from the study, 69 survived and we assessed 62 participants, 32 in the hypothermia and xenon and 30 in the hypothermia only groups. We examined the relation between Lac/NAA and FA and the scores of the Bayley Scales of Infant and Toddler Development III and calculated their predictive accuracy for moderate or severe disability or death.RESULTS: Fifteen of 62 participants (24%) developed moderate/severe disability, and 22/92 (24%) died. The Lac/NAA ratio (difference in medians 0.628, 95% CI -0.392 to 4.684) and FA (difference in means -0.055, 95% CI -0.033 to -0.077) differed significantly between participants with or without moderate or severe disability or death and were significantly related with development scores in both groups. Adverse outcomes were correctly identified in 95.65% of cases by Lac/NAA and 78.79% by FA, with adequate mean calibration of the model.INTERPRETATION: The results confirm the qualification of the cerebral magnetic resonance biomarkers employed in the TOBY-Xe study as predictors of outcome after neuroprotective therapy. FUND: The Centre for the Developing Brain, King's College London, UK.

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

The preterm birth (PTB) rate in Harris County, Texas, exceeds the U.S. rate (11.4% vs.9.6%), and there are 15 active Superfund sites in Harris County. Polycyclic aromatic hydrocarbons (PAHs) are contaminants of concern (COC) at Superfund sites across the nation. In this investigation, we tested the hypothesis that higher levels of exposure to PAHs and PAH-DNA adducts in placenta of women living near Superfund sites contribute to the increased rate of PTBs. Levels of benzo[a]pyene (BP), benzo[b]fluorene (BbF) and dibenz[a,h]anthracene (DBA), were higher in placentae from preterm deliveries compared with term deliveries in women living near Superfund sites, whereas this was not the case for women living in non-Superfund site areas. Among the PAHs, DBA levels were significantly higher than BP or BbF, and DBA levels were inversely correlated with gestational age at delivery and birth weight. Bulky PAH-DNA adducts are more prevalent in placental tissue from individuals residing near Superfund sites. Expression of Ah receptor (AHR) and NF-E2-related factor 2 (NRF2) was decreased in preterm deliveries in subjects residing near Superfund sites. Unbiased metabolomics revealed alterations in pathways involved in pentose phosphate, inositol phosphate and starch and sucrose metabolism in preterm subjects in Superfund site areas. In summary, this is the first report showing an association between PAH levels, DNA adducts, and modulation of endogenous metabolic pathways with PTBs in subjects residing near Superfund sites, and further studies could lead to novel strategies in the understanding of the mechanisms by which PAHs contribute to PTBs in women.

The Norwegian Food Safety Authority (Mattilsynet, NFSA) and the Norwegian Environment Agency (Miljødirektoratet, NEA) requested the Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) for a scientific opinion on Chronic wasting disease (CWD) in cervids. The project was divided into two phases, and VKM published the scientific opinion from phase I “CWD in Norway” in June 2016. The current report is the result of phase II. VKM was asked to provide updated information on food safety, aspects important for transmission of CWD within and between populations and species, and the potential origin of the disease in Norway. Moreover, VKM was asked to highlight important risk factors with regard to disease transmission, and how these risk factors might affect choice of management strategy. Finally, VKM was asked to highlight relevant management strategies from North America or elsewhere. VKM appointed a working group consisting of one member of the Panel on Microbial Ecology, one member of the Panel on Biological Hazards, and five external experts, as well as VKM`s secretariat to answer the questions from NEA and NFSA. One member of the Panel on Alien Organisms and Trade in Endangered Species (CITES), one member of the Panel on Animal Health and Welfare, as well as one member of the Panel on Biological Hazards commented on the draft report. The Panel on Biological Hazards assessed and approved the final report. Background: Chronic wasting disease (CWD) is a prion disease that affects deer, moose, reindeer, and related species (cervids). Prion diseases are chronic neurodegenerative diseases that occur naturally in humans and ruminants, and are invariably fatal. Some prion diseases, such as classical scrapie in sheep and goats and chronic wasting disease (CWD) in cervids, are contagious, spreading directly between animals or via environmental contamination. In contrast, prion diseases known to affect humans are not known to be contagious. Prions are extraordinary agents consisting of misfolded protein aggregates that are remarkably stable and can remain infectious for years in the environment. Prion proteins are present in most animals, but the misfolding makes them very hard to break down. Consequently, misfolded prion proteins accumulate in the brain and eventually in other tissues, causing damage to those tissues. Until recently, CWD was only known from North America and South Korea. During a routine marking event in April 2016, a female reindeer (Rangifer tarandus) of the Nordfjella wild reindeer herd in Norway exhibited unusual behaviour, and died shortly afterwards. This unusual death was routinely investigated, and the animal was diagnosed with CWD. This was the first time CWD had been diagnosed outside North America and South Korea and the first case of natural CWD in reindeer. In addition, two moose (Alces alces) in Selbu, Norway were diagnosed with CWD in May 2016. Selbu is located approximately 300 km northeast of the Nordfjella mountain range. Currently there is considerable uncertainty regarding the nature of the CWD diagnosed in the two moose. Some of the characteristics of these cases indicate consistency with atypical prion disease, as described in domestic animals, but a final conclusion depends on the results from ongoing investigations. Following the diagnosis in reindeer, Norwegian authorities initiated a screening programme in which hunters were requested to collect tissue and the heads of dead cervids during the 2016 hunting season. Animals that had died from causes other than hunting were also tested for CWD. Since March 2016, 4629 samples of moose, 2550 samples of red deer, 627 samples of roe deer, 860 samples of reindeer, 2494 semi-domesticated reindeer, 163 farmed deer and 104 samples of unidentified species were tested for CWD. Two additional cases of CWD were diagnosed in wild reindeer in the Nordfjella population. Together with a clinical, pathological and epidemiological picture consistent with contagious CWD, as described from North America, this indicated that there is an ongoing outbreak of CWD in the wild reindeer population of the northern part of Nordfjella wild reindeer range. Results: An increase in the distribution and prevalence of CWD will increase exposure of other species, including domestic animals and humans, to this infectious agent. There is currently no evidence indicating transmission of CWD to domestic animals or humans, either by direct contact with cervids, cervid meat, or other products from cervids, or through the environment. VKM continues to support the conclusion from phase I concerning food safety of meat from cervids, that the zoonotic risk of CWD (transmission to humans) is very low. Preliminary results from characterisation of the moose cases and the agent involved indicate that important features deviate significantly from those found in the reindeer and in North American cervids, raising uncertainty with regards to the zoonotic potential. Therefore, based on the data currently available, VKM is not able to reach an evidence-based conclusion regarding the food safety of meat from moose and other cervids infected with this potentially new variant of CWD. Whereas direct transmission (animal-to-animal) seems most important in the early phases of a CWD epizootic, the role of indirect transmission (from the environment) increases as the prevalence increases. Once contagious CWD is established, it is very likely that the disease will increase in prevalence within the affected population and spread to contact populations. The rate of increase in prevalence, the resulting impact in a given population, and the efficacy of spread will depend on a range of environmental factors, and the characteristics of the species and population in question. For example, in affected populations of a gregarious species like reindeer, CWD is likely to lead to population decline in the long-term. Experiences from North America indicate that prions aggregate in the environment, making eradication of the disease extremely difficult once it has been allowed to develop and become endemic. It is therefore important that efficient measures are implemented at the VKM Report 2017:9 9 earliest opportunity in order to have a realistic chance of eradicating local occurrence of CWD and preventing further spread. Contagious CWD found in a confinable population, such as many wild reindeer herds, should be managed by eradication of the host population, fallowing of the area (> 5 years), and restocking from a healthy population. The report explains that culling of the Nordfjella reindeer herd is a necessary, immediate response to the current situation. However, as part of an adaptive management strategy, this measure should be under active review and may be revised in the event that new cases of CWD are discovered. In contrast, in continuous populations, such as most red deer, moose, and roe deer populations, spatially targeted culling within a defined containment zone should be used to control a CWD outbreak. Confinement of CWD-infected populations should be increased where possible and contact with other populations of cervids restricted, for example by fencing, herding, enhancing natural or man-made obstacles, or decreasing the densities of the relevant cervid populations. Potential “hotspots” for disease transmission (supplementary salt-licks, supplementary feeding sites etc.) should be eliminated in areas with CWD as well as the surrounding areas, and should further be considered for other parts of the country. Precautionary measures should be implemented to prevent anthropogenic spread of the disease. Finally, increasing the national surveillance of CWD in cervids is essential to ensure that there is a comprehensive basis for future evidence-based management. This is required to ensure that cases and spread of disease are identified as soon as possible, as late discovery will limit the chances for successful eradication of CWD in Norway.

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

BACKGROUND: Surveillance recommendations for patients with low-risk non-muscle-invasive bladder cancer (NMIBC) are based on limited evidence. Our objective was to add to the evidence by assessing outcomes after frequent versus recommended cystoscopic surveillance. METHODS: This is a retrospective cohort study of patients diagnosed with low-risk (low grade Ta) NMIBC from 2005 – 2011 with follow-up through 2014 from the Department of Veterans Affairs. Patients were classified as having undergone frequent versus recommended cystoscopic surveillance (>3 versus 1–3 cystoscopies in the first 2 years after diagnosis). Using propensity score adjusted models, we estimated the impact of frequent cystoscopy on the number of transurethral resections, the number of resections without cancer in the specimen, and on risk of progression to muscle-invasive cancer or bladder cancer death. RESULTS: Among 1,042 patients, 798 (77%) had more frequent cystoscopy than recommended. In adjusted analyses, the frequent cystoscopy group had twice as many transurethral resections (55 versus 26 per 100 person years; p

INTRODUCTION This review aims to provide information on return rates and times to return to sport following surgical management of triangular fibrocartilage (TFC) tears. SOURCES OF DATA A systematic search of CINAHAL, Cochrane, EMBASE, Google Scholar, Medline, PEDro, Scopus, SPORTDiscus and Web of Science was performed using the keywords 'triangular', 'fibro-cartilage', 'complex', 'tear', 'distal radio-ulnar joint', 'athletes', 'sports', 'non-operative', 'conservative', 'operative' and 'return to sport'. AREAS OF AGREEMENT In all of the 10 studies included, conservative management for 6 weeks to 6 months was the first-line treatment. If symptoms persisted following this period, surgical management was advised. Arthroscopic debridement was recommended for central tears, and arthroscopic repair was recommended for peripheral tears. AREAS OF CONTROVERSY The optimal treatment modalities for TFC tears remain to be defined. GROWING POINTS Traumatic central tears can be treated with arthroscopic debridement alone. Arthroscopic repair with an all-inside repair can improve return rates to sport over an outside-in technique for ulna-sided tears. AREAS TIMELY FOR DEVELOPING RESEARCH Future prospective studies should aim to establish the optimal treatment modalities for TFC tears.

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.

Epidermolysis bullosa (EB), notably severe recessive dystrophic EB (RDEB-S), is associated with increased risk of aggressive mucocutaneous squamous cell carcinomas, the major cause of mortality in early adulthood. This observational, retrospective case review describes a series of EB patients with cutaneous squamous cell carcinomas over a 28-year period. Forty-four EB patients with squamous cell carcinomas were identified with a total of 221 primary tumours. They comprised: 31 (70%) with RDEB-S, 4 (9%) with other RDEB subtypes, 5 (11.4%) with dominant dystrophic EB, 3 (6.8%) with intermediate junctional EB and 1 (2.3%) with Kindler EB. Squamous cell carcinomas occurred earlier in RDEB-S (median age 29.5 years; age range 13-52 years) than other groups collectively (median age 47.1 years; age range 30-89 years) and most had multiple tumours (mean 5.8; range 1-44). Squamous cell carcinoma-associated mortality was high in RDEB-S (64.5%), with median survival after first squamous cell carcinoma of 2.4 years (range 0.5-12.6 years), significantly lower than previous reports, highlighting the need for early surveillance and better treatments.

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.

OBJECTIVES Determine the rate of perioperative complications between morbidly obese (body mass index greater than 40 kg/m2) and non-morbidly obese patients undergoing operative treatment of acetabular fractures across two time periods (2000-2005 and 2012-2019). DESIGN Retrospective, case-control study. SETTING Level I academic trauma center. PATIENTS 435 consecutive patients from 2000 to 2005 and 216 consecutive patients from 2012 to 2019 with acetabular fractures treated by a single surgeon. INTERVENTION Operative fixation of acetabular fracture. MAIN OUTCOME MEASUREMENTS Outcome variables include positioning time, operative time, estimated blood loss, hospital stay, wound complications, and perioperative complications. RESULTS Twenty-eight morbidly obese and 188 non-morbidly obese patients from 2012-19, as well as 41 morbidly obese patients and 394 non-morbidly obese patients from 2000-05 were included in the study. The relative risk (RR) of wound complications between 2012-19 groups was significantly higher for morbidly obese patients (RR=5.31, p=0.009), but has decreased significantly for morbidly obese patients between 2000-05 and 2012-19 (RR=0.31 p=0.017). The rate of total perioperative complications was similar between morbidly obese and non-morbidly obese groups from 2012-19 (21% v. 8%, p=0.230). For morbidly obese patients, the rate of total perioperative complications decreased significantly between 2000-05 and 2012-19 (63% v. 21% p=0.010). CONCLUSION Acetabular fracture surgery can be safely performed in morbidly obese patients. Although obesity remains a significant risk factor for wound complications, the risk for morbidly obese patients has decreased significantly since our initial investigation as a result of adaptations to surgical techniques and surgeon experience. LEVEL OF EVIDENCE Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Importance Spitz nevi are benign melanocytic neoplasms that classically present in childhood. Isolated Spitz nevi have been associated with oncogenic gene fusions in approximately 50% of cases. The rare agminated variant of Spitz nevi, thought to arise from cutaneous genetic mosaicism, is characterized by development of clusters of multiple lesions in a segmental distribution, which can complicate surgical removal. Somatic single-nucleotide variants in the HRAS oncogene have been described in agminated Spitz nevi, most of which were associated with an underlying nevus spilus. The use of targeted medical therapy for agminated Spitz nevi is not well understood. Observations A girl aged 30 months presented with facial agminated Spitz nevi that recurred rapidly and extensively after surgery. Owing to the morbidity of further surgery, referral was made to a molecular tumor board. The patient’s archival nevus tissue was submitted for extended immunohistochemical analysis and genetic sequencing. Strong ROS1 protein expression was identified by immunohistochemistry. Consistent with this, analysis of whole-genome sequencing data revealed GOPC-ROS1 fusions. These results indicated likely benefit from the oral tyrosine kinase inhibitor crizotinib, which was administered at a dosage of 280 mg/m2 twice daily. An excellent response was observed in all lesions within 5 weeks, with complete flattening after 20 weeks. Conclusions and Relevance Given the response following crizotinib treatment observed in this case, the kinase fusion was believed to be functionally consequential in the patient’s agminated Spitz nevi and likely the driver mutational event for growth of her nevi. The repurposing of crizotinib for GOPC-ROS1 Spitz nevi defines a new treatment option for these lesions, particularly in cases for which surgery is relatively contraindicated.

Heterozygous missense mutations in the human COL7A1 gene – coding for collagen VII – lead to the rare, dominantly inherited skin disorder dominant dystrophic epidermolysis bullosa (DDEB), which is characterised by skin fragility, blistering, scarring and nail dystrophy. To better understand the pathophysiology of DDEB and develop more effective treatments, suitable mouse models for DDEB are required but to date none have existed. We identified the two most common COL7A1 mutations in DDEB patients (p.G2034R and p.G2043R) and used CRISPR-Cas9 to introduce the corresponding mutations into mouse Col7a1 (p.G2028R and p.G2037R). Dominant inheritance of either of these two alleles results in a phenotype that closely resembles that seen in DDEB patients. Specifically, mice carrying these alleles show recurrent blistering that is first observed transiently around the mouth and paws in the early neonatal period and then again around the digits from 5-10 weeks of age. Histologically, the mice show micro-blistering and reduced collagen VII immunostaining. Biochemically, collagen VII from these mice displays reduced thermal stability, which we also observed to be the case for DDEB patients carrying the analogous mutations. Unlike previous rodent models of epidermolysis bullosa, which frequently show early lethality and severe disease, these mouse models, which to our knowledge are the first for DDEB, show no reduction in growth and survival, and – together with a relatively mild phenotype – represent a practically and ethically tractable tool for better understanding and treating epidermolysis bullosa. This article has an associated First Person interview with the first author of the paper., Summary: We developed mouse models for the blistering genetic skin disorder dominant dystrophic epidermolysis bullosa (DDEB) by introducing mutations into mouse Col7a1. These models should help to improve the understanding and treatment of DDEB.

Neonatal encephalopathy is a leading cause of morbidity and mortality worldwide. Although therapeutic hypothermia (HT) is now standard practice in most neonatal intensive care units in high resource settings, some infants still develop long-term adverse neurological sequelae. In low resource settings, HT may not be safe or efficacious. Therefore, additional neuroprotective interventions are urgently needed. Melatonin’s diverse neuroprotective properties include antioxidant, anti-inflammatory, and anti-apoptotic effects. Its strong safety profile and compelling preclinical data suggests that melatonin is a promising agent to improve the outcomes of infants with NE. Over the past decade, the safety and efficacy of melatonin to augment HT has been studied in the neonatal piglet model of perinatal asphyxia. From this model, we have observed that the neuroprotective effects of melatonin are time-critical and dose dependent. Therapeutic melatonin levels are likely to be 15–30 mg/L and for optimal effect, these need to be achieved within the first 2–3 h after birth. This review summarises the neuroprotective properties of melatonin, the key findings from the piglet and other animal studies to date, and the challenges we face to translate melatonin from bench to bedside.