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Replacement of pancreatic beta-cells is one of the most promising treatment options for treatment of type 1 diabetes (T1D), even though, toxic immunosuppressive drugs are required. In this study, we aim to deliver allogeneic beta-cell therapies without antirejection drugs using a bioengineered hybrid device that contains microencapsulated beta-cells inside 3D polycaprolactone (PCL) scaffolds printed using melt electrospin writing (MEW). Mouse beta-cell (MIN6) pseudoislets and QS mouse islets are encapsulated in alginate microcapsules, without affecting viability and insulin secretion. Microencapsulated MIN6 cells are then seeded within 3D MEW scaffolds, and these hybrid devices implanted subcutaneously in streptozotocin-treated diabetic NOD/SCID and BALB/c mice. Similar to NOD/SCID mice, blood glucose levels (BGL) are lowered from 30.1 to 4.8 mM in 25-41 days in BALB/c. In contrast, microencapsulated islets placed in prevascularized MEW scaffold 3 weeks after implantation in BALB/c mice normalize BGL (Impact statementThe retrievable 3D printed PCL scaffold we have produced promotes vascularization when implanted subcutaneously and allows seeded microencapsulated insulin-producing cells to normalize blood glucose of diabetic mice for at least 2 months, without the need for antirejection drugs to be administered. The scaffold is scalable for possible human use, but will require modification to ensure that normalization of blood glucose levels can be maintained long term.

Research evaluating hemostatic agents for the treatment of clinically significant bleeding has been hampered by inconsistency and lack of standardized primary clinical trial outcomes. Clinical trials of hemostatic agents in both cardiac surgery and mechanical circulatory support, such as extracorporeal membrane oxygenation and ventricular assist devices, are examples of studies that lack implementation of universally accepted outcomes.A subgroup of experts convened by the National Heart, Lung, and Blood Institute and the US Department of Defense developed consensus recommendations for primary outcomes in cardiac surgery and mechanical circulatory support.For cardiac surgery the primary efficacy endpoint of total allogeneic blood products (units vs mL/kg for pediatric patients) administered intraoperatively and postoperatively through day 5 or hospital discharge is recommended. For mechanical circulatory support outside the perioperative period the recommended primary outcome for extracorporeal membrane oxygenation is a 5-point ordinal score of thrombosis and bleeding severity adapted from the Common Terminology Criteria for Adverse Events version 5.0. The recommended primary endpoint for ventricular assist device is freedom from disabling stroke (Common Terminology Criteria for Adverse Events AE ≥ grade 3) through day 180.The proposed composite risk scores could impact the design of upcoming clinical trials and enable comparability of future investigations. Harmonizing and disseminating global consensus definitions and management guidelines can also reduce patient heterogeneity that would confound standardized primary outcomes in future research.

OBJECTIVE Schwann cells (SCs) have been shown to play an essential role in axon regeneration in both peripheral nerve injuries (PNIs) and spinal cord injuries (SCIs). The transplantation of SCs as an adjunctive therapy is currently under investigation in human clinical trials due to their regenerative capacity. Therefore, a reliable method for procuring large quantities of SCs from peripheral nerves is necessary. This paper presents a well-developed, validated, and optimized manufacturing protocol for clinical-grade SCs that are compliant with Current Good Manufacturing Practices (CGMPs). METHODS The authors evaluated the SC culture manufacturing data from 18 clinical trial participants who were recruited for autologous SC transplantation due to subacute SCI (n = 7), chronic SCI (n = 8), or PNIs (n = 3). To initiate autologous SC cultures, a mean nerve length of 11.8 ± 3.7 cm was harvested either from the sural nerve alone (n = 17) or with the sciatic nerve (n = 1). The nerves were digested with enzymes and SCs were isolated and further expanded in multiple passages to meet the dose requirements for transplantation. RESULTS An average yield of 87.2 ± 89.2 million cells at P2 and 150.9 ± 129.9 million cells at P3 with high viability and purity was produced. Cell counts and rates of expansion increased with each subsequent passage from P0 to P3, with the largest rate of expansion between P2 and P3. Larger harvest nerve lengths correlated significantly with greater yields at P0 and P1 (p < 0.05). In addition, a viability and purity above 90% was sustained throughout all passages in nearly all cell products. CONCLUSIONS This study presents reliable CGMP-compliant manufacturing methods for autologous SC products that are suitable for regenerative treatment of patients with SCI, PNI, or other conditions.

Background The COVID-19 pandemic has presented unique challenges for rapidly designing, initiating, and delivering therapeutic clinical trials. PRINCIPLE (Platform Randomised Trial of Treatments in the Community for Epidemic and Pandemic Illnesses) is the UK national platform investigating repurposed therapies for COVID-19 treatment of older people in the community at high risk of complications. Standard methods of patient recruitment were failing to meet the required pace and scale of enrolment. This paper describes the development and appraisal of a near real-time, data-driven, ethical approach for enhancing recruitment in community care by contacting people with a recent COVID-19 positive test result from the central NHS Test and Trace service within approximately 24–48 h of their test result. Methods A multi-disciplinary team was formed to solve the technical, ethical, public perception, logistical and information governance issues required to provide a near-real time (approximately within 24–48 h of receiving a positive test) feed of potential trial participants from test result data to the research team. PRINCIPLE was also given unique access to the Summary Care Record (SCR) to ensure safe prescribing, and to enable the trial team to quickly and safely bring consented patients into the trial. A survey of the public was used to understand public perceptions of the use of test data for this proposed methodology. Results Prior to establishing the data service, PRINCIPLE registered on average 87 participants per week. This increased by up to 87 additional people registered per week from the test data, contributing to an increase from 1013 recruits to PRINCIPLE at the start of October 2020 to 2802 recruits by 20 December 2020. Whilst procedural caveats were identified by the public consultation, out of 2639 people contacted by PRINCIPLE following a positive test result, no one raised a concern about being approached. Conclusions This paper describes a novel approach to using near-real time NHS operational data to recruit community-based patients within a few days of presentation with acute illness. This approach increased recruitment and reduced time between positive test and randomisation, allowing more rapid evaluation of treatments and increased safety for participants. End-to-end public and patient involvement in the design of the approach provided evidence to inform information governance decisions. Trial registration PRINCIPLE is funded by UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research. EudraCT number: 2020-001209-22. 26/03/2020 ISRCTN registry: ISRCTN86534580. 20/03/2020 REC number: 20/SC/058 IRAS number: 281958

The psychological consequences of losing a parent to cancer are unclear. We investigated whether experiencing parental death to cancer before 18 years of age increases the risk of psychotropic medication. We used register data of all children born in Denmark between 1 January 1987 and 31 December 2016 (N = 1,488,846). We assessed rate ratios (RRs) with 95% confidence intervals (CIs) for first redeemed prescription of antidepressants, anxiolytics and hypnotics according to parental death status using Poisson multi-state models. We further examined whether the associations differed according to the gender of the deceased parent, child's age at the time of death or the parental length of illness. Cancer-bereaved children had a significantly increased risk of first prescription of psychotropic medication (rate ratio, RR 1.22, 95% confidence interval, CI 1.10-1.34 for males; RR 1.18, 95% CI 1.09-1.28 for females). Associations were strongest if the parent had the same sex as the child and if the parent died within one year of diagnosis. The risk was highest during the first six months after the loss (RR 2.35, 95% confidence interval, CI 1.48-3.73 for males; RR 1.81, 95% CI 1.17-2.80 for females). Children who lose a parent to cancer, particularly in cases when the disease progressed quickly, may need extra psychological support, especially during the first six months after the death.

The number needed to treat (NNT) is a method of reporting outcomes from clinical trials.1 Treatment efficacy is determined by evaluating the outcome of one treatment relative to another treatment or to a control group when the only difference between the groups is the intervention of interest. The NNT can also be used to express the size of the outcome of one treatment relative to another. The NNT is expressed in terms designed to help decide whether the intervention might be valuable in clinical practice: the number of patients who need to be treated before a therapist can be sure that one patient improved who would not have improved without the intervention. For example, when comparing treatment X and treatment Y, an NNT score of 5 for treatment X indicates that, on average, after treating 5 patients, treatment X will have achieved one more positive outcome than if treatment Y had been used. The NNT does not tell the clinician which of those 5 patients will respond, only that 1 patient is likely to do so. The NNT was described in 1988 by Laupacis et al,2 and, although its use is becoming more popular, it is still not widely used. A search of MEDLINE back to 1991 using the search terms “number needed to treat” or “NNT” identified 121 citations reporting NNT information. Of these citations, only 3 concerned outcomes of physical therapy3–5 and, of these, only one5 described the use of NNT in a journal with content relevant to physical therapists. The NNT can be used to gauge the relative effectiveness of different treatments in restoring normal function or preventing future disability. If the treatment has a potentially harmful outcome (eg, stroke, headache, death from cervical manipulation), a similar calculation can be used …

Clinically relevant myopenia accompanies spinal cord injury (SCI), and compromises function, metabolism, body composition, and health. Myostatin, a transforming growth factor (TGF)β family member, is a key negative regulator of skeletal muscle mass. We investigated inhibition of myostatin signaling using systemic delivery of a highly selective monoclonal antibody - muSRK-015P (40 mg/kg) - that blocks release of active growth factor from the latent form of myostatin. Adult female mice (C57BL/6) were subjected to a severe SCI (65 kdyn) at T9 and were then immediately and 1 week later administered test articles: muSRK-015P (40 mg/kg) or control (vehicle or IgG). A sham control group (laminectomy only) was included. At euthanasia, (2 weeks post-SCI) muSRK-015P preserved whole body lean mass and sublesional gastrocnemius and soleus mass. muSRK-015P-treated mice with SCI also had significantly attenuated myofiber atrophy, lipid infiltration, and loss of slow-oxidative phenotype in soleus muscle. These outcomes were accompanied by significantly improved sublesional motor function and muscle force production at 1 and 2 weeks post-SCI. At 2 weeks post-SCI, lean mass was significantly decreased in SCI-IgG mice, but was not different in SCI-muSRK-015P mice than in sham controls. Total energy expenditure (kCal/day) at 2 weeks post-SCI was lower in SCI-immunoglobulin (Ig)G mice, but not different in SCI-muSRK-015P mice than in sham controls. We conclude that in a randomized, blinded, and controlled study in mice, myostatin inhibition using muSRK-015P had broad effects on physical, metabolic, and functional outcomes when compared with IgG control treated SCI animals. These findings may identify a useful, targeted therapeutic strategy for treating post-SCI myopenia and related sequelae in humans.

INTRODUCTION Coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with hypercoagulability which can predispose infected patients to both arterial and venous thromboembolic complications. Despite therapeutic anticoagulation, there remains a risk of ischemic strokes, which may lead to adverse patient outcomes. Only a few cases are described in the literature regarding SARS-CoV-2 positive patients developing thrombotic ischemic strokes despite therapeutic anticoagulation. CASE REPORT The following is a case discussion regarding a 71-year-old female with past medical history of hypertension, diabetes mellitus type 2, hyperlipidemia, and hypothyroidism who was admitted with severe SARS-CoV-2 infection to the intensive care unit and later developed acute left upper extremity weakness on the 5th day of her admission. Initial National Institutes of Health stroke scale (NIHSS) was 15. Subsequent brain imaging was significant for right middle cerebral artery ischemic stroke. The patient was therapeutically anticoagulated with 1.5 mg/kg subcutaneous dose of Enoxaparin since day 1 of her admission. D-dimer upon admission was 1.84 mg/L (

Fasciolosis caused by the liver flukes Fasciola hepatica and Fasciola gigantica is one of the most important neglected parasitic diseases of humans and animals. The ability of the parasites to infect and multiply in their intermediate snail hosts, and their adaptation to a wide variety of mammalian definitive hosts contribute to their high transmissibility and distribution. Within the mammalian host, the trauma caused by the immature flukes burrowing through the liver parenchyma is associated with most of the pathogenesis. Similarly, the feeding activity and the physical presence of large flukes in the bile ducts can lead to anaemia, inflammation, obstruction and cholangitis. The high frequency of non-synonymous polymorphisms found in Fasciola spp. genes allows for adaptation and invasion of a broad range of hosts. This is also facilitated by parasite's excretory-secretory (ES) molecules that mediate physiological changes that allows their establishment within the host. ES contains cathepsin peptidases that aid parasite invasion by degrading collagen and fibronectin. In the bile ducts, cathepsin-L is critical to haemoglobin digestion during feeding activities. Other molecules (peroxiredoxin, cathepsin-L and Kunitz-type inhibitor) stimulate a strong immune response polarised towards a Treg/Th2 phenotype that favours fluke's survival. Helminth defence molecule, fatty acid binding proteins, Fasciola-specific glycans and miRNAs modulate host pro-inflammatory responses, while antioxidant scavenger enzymes work in an orchestrated way to deter host oxidant-mediated damage. Combining these strategies Fasciola spp. survive for decades within their mammalian host, where they reproduce and spread to become one of the most widespread zoonotic worm parasites in the world.

This systematic review aimed to investigate timing, dose, and efficacy of upper limb intervention during the first 6 months poststroke. Three online databases were searched up to July 2020. Titles/abstracts/full-text were reviewed independently by 2 authors. Randomized and nonrandomized studies that enrolled people within the first 6 months poststroke, aimed to improve upper limb recovery, and completed preintervention and postintervention assessments were included. Risk of bias was assessed using Cochrane reporting tools. Studies were examined by timing (recovery epoch), dose, and intervention type. Two hundred and sixty-one studies were included, representing 228 (n=9704 participants) unique data sets. The number of studies completed increased from one (n=37 participants) between 1980 and 1984 to 91 (n=4417 participants) between 2015 and 2019. Timing of intervention start has not changed (median 38 days, interquartile range [IQR], 22–66) and study sample size remains small (median n=30, IQR 20–48). Most studies were rated high risk of bias (62%). Study participants were enrolled at different recovery epochs: 1 hyperacute (

PURPOSE Screening and prevention decisions for women at increased risk of developing breast cancer depend on genetic and clinical factors to estimate risk and select appropriate interventions. Integration of polygenic risk into clinical breast cancer risk estimators can improve discrimination. However, correlated genetic effects must be incorporated carefully to avoid overestimation of risk. MATERIALS AND METHODS A novel Fixed-Stratified method was developed that accounts for confounding when adding a new factor to an established risk model. A combined risk score (CRS) of an 86–single-nucleotide polymorphism polygenic risk score and the Tyrer-Cuzick v7.02 clinical risk estimator was generated with attenuation for confounding by family history. Calibration and discriminatory accuracy of the CRS were evaluated in two independent validation cohorts of women of European ancestry (N = 1,615 and N = 518). Discrimination for remaining lifetime risk was examined by age-adjusted logistic regression. Risk stratification with a 20% risk threshold was compared between CRS and Tyrer-Cuzick in an independent clinical cohort (N = 32,576). RESULTS Simulation studies confirmed that the Fixed-Stratified method produced accurate risk estimation across patients with different family history. In both validation studies, CRS and Tyrer-Cuzick were significantly associated with breast cancer. In an analysis with both CRS and Tyrer-Cuzick as predictors of breast cancer, CRS added significant discrimination independent of that captured by Tyrer-Cuzick ( P < 10−11 in validation 1; P < 10−7 in validation 2). In an independent cohort, 18% of women shifted breast cancer risk categories from their Tyrer-Cuzick–based risk compared with risk estimates by CRS. CONCLUSION Integrating clinical and polygenic factors into a risk model offers more effective risk stratification and supports a personalized genomic approach to breast cancer screening and prevention.

Objective To compare Prostate Health Index (PHI) and prostate‐specific antigen (PSA) density as secondary tests after multiparametric magnetic resonance imaging (mpMRI) in improving the detection accuracy of Gleason grade group (GG) 2‐5 prostate cancer (PCa) and in decreasing unnecessary biopsies in a multiethnic biopsy‐naïve population. Methods From February 2017 to February 2020, we recruited consecutive biopsy‐naïve men in participating urology clinics for elevated PSA levels. They all had a PHI score, mpMRI, and prostate biopsy. Experienced genitourinary radiologists read all mpMRI studies based on PIRADS version 2.0. Logistic regression models were used to generate receiver operating characteristic curves. Models were tested for effect modification between Race (Black vs White) and both PHI and PSA density, and Race and PIRADS to determine if race impacted their prediction accuracy. Sensitivity, specificity, and predictive values of PHI and PSA density thresholds were calculated by PIRADS scores. The primary outcome was GG2‐5 PCa, that is, Gleason score ≥3 + 4. Results The study included 143 men, of which 65 (45.5%) were self‐reported Black. Median age was 62.0 years and 55 men (38.4%) had GG2‐5 PCa. Overall, 18.1% had PIRADS 1‐2, 32.9% had PIRADS 3, and 49.0% had PIRADS 4‐5. For the binary logistic regressions, the interactions between PIRADS and Race (P = .08), Log (PHI) and Race (P = .17), and Log (PSA density) and Race (P = .42) were not statistically significant. Within PIRADS 3 lesions, a PHI ≥49 prevented unnecessary biopsies in 55% of men and missed no GG2‐5 PCa, yielding a negative predictive value of 100%. There was no reliable PHI or PSA density threshold to avoid PCa biopsies in PIRADS 1‐2 or 4‐5. Conclusions PHI and PSA density can be used after mpMRI to improve the detection of GG2‐5 PCa in a biopsy‐naïve cohort. PHI may be superior to PSA density in PIRADS 3 lesions by avoiding 55% of unnecessary biopsies. Using both PHI and PSA density in series may further increase specificity and lead to fewer unnecessary biopsies, but further larger studies are warranted to determine the optimal threshold of each biomarker.

Background Psychological distress may be present among patients who are considering enrollment in phase 1 cancer trials, as they have advanced cancer and no documented treatment options remain. However, the prevalence of psychological distress has not been previously investigated in larger cohorts. In complex phase 1 cancer trials, it is important to ensure adequate understanding of the study premises, such as the undocumented effects and the risk of adverse events. Materials and methods In a prospective study, patients completed questionnaires at two time points. We investigated psychological distress, measured as stress, anxiety, and depression, among patients at their first visit to the phase 1 unit (N = 229). Further, we investigated the understanding of trial information among patients who were enrolled in a phase 1 cancer trial (N = 57). Results We enrolled 75% of 307 eligible patients. We found a lower mean score of stress in our population compared to population norms, while the mean scores of anxiety and depression were higher. A total of 9% showed moderate to severe symptoms of anxiety and 11% showed moderate to severe symptoms of depression, which indicates higher levels than cancer patients in general. A total of 46 (81% of enrolled patients) completed questionnaires on trial information and consent. The understanding of the information on phase 1 cancer trials in these patients was slightly lower than the level reported for cancer trials in general. Some aspects relating to purpose, benefit, and additional risks were understood by fewer than half of the patients. Conclusion Our results suggest that distress is not as prevalent in the population of patients referred to phase 1 cancer trials as in the general cancer population. Although patients' understanding of trial information was reasonable, some aspects of complex phase 1 cancer trials were not easily understood by enrolled patients.

Coronavirus disease 2019 (COVID‐19) is characterized by dysregulated hyperimmune response and steroids have been shown to decrease mortality. However, whether higher dosing of steroids results in better outcomes has been debated. This was a retrospective observation of COVID‐19 admissions between March 1, 2020, and March 10, 2021. Adult patients (≥18 years) who received more than 10 mg daily methylprednisolone equivalent dosing (MED) within the first 14 days were included. We excluded patients who were discharged or died within 7 days of admission. We compared the standard dose of steroids (40 mg MED). Inverse probability weighted regression adjustment (IPWRA) was used to examine whether higher dose steroids resulted in improved outcomes. The outcomes studied were in‐hospital mortality, rate of acute kidney injury (AKI) requiring hemodialysis, invasive mechanical ventilation (IMV), hospital‐associated infections (HAI), and readmissions. Of the 1379 patients meeting study criteria, 506 received less than 40 mg of MED (median dose 30 mg MED) and 873 received more than or equal to 40 mg of MED (median dose 78 mg MED). Unadjusted in‐hospital mortality was higher in patients who received high‐dose corticosteroids (40.7% vs. 18.6%, p, Highlights In this observational study of 1379 patients, using Inverse probability weighted regression adjustment, those receiving 30 mg (IQR 24‐34 mg) methylprednisolone equivalent dose (MED) had lower in hospital mortality than those with 78 mg (IQR 59‐108 mg) MED.Higher dose steroids were not associated with better improvements in inflammatory markers, rates or duration of mechanical ventilation or readmissions.Higher dose steroids were however, associated with lower rates of acute kidney injury requiring hemodialysis.Dosage higher than 80 mg MED were associated with higher rates of hospital acquired infections.

OBJECTIVE Crouzon syndrome with acanthosis nigricans (CAN) is a rare and clinically complex subtype of Crouzon syndrome. At three craniofacial centers, this multicenter study was undertaken to assess clinical signs in relation to the required interventions and treatment course in patients with CAN. METHODS A retrospective cohort study of CAN was performed to obtain information about the clinical treatment course of these patients. Three centers participated: Erasmus Medical Centre, Rotterdam, the Netherlands; John Radcliffe Hospital, Oxford, United Kingdom; and Hôpital Necker-Enfants Malades, Paris, France. RESULTS Nineteen patients (5 males, 14 females) were included in the study. All children were operated on, with a mean of 2.2 surgeries per patient (range 1–6). Overall, the following procedures were performed: 23 vault expansions, 10 monobloc corrections, 6 midface surgeries, 11 foramen magnum decompressions, 29 CSF-diverting surgeries, 23 shunt-related interventions, and 6 endoscopic third ventriculostomies, 3 of which subsequently required a shunt. CONCLUSIONS This study demonstrates that patients with the mutation c.1172C>A (p.Ala391Glu) in the FGFR3 gene have a severe disease trajectory, requiring multiple surgical procedures. The timing and order of interventions have changed among patients and centers. It was not possible to differentiate the effect of a more severe clinical presentation from the effect of treatment order on outcome.

Reducing the rate of cesarean sections among women considered at low risk for delivery by that method is a goal of Healthy People 2030. Prior research suggests that perinatal mood and anxiety disorders increase the risk for cesarean section, but data are limited. This cross-sectional study of commercially insured women examined the relationship between perinatal depression and anxiety disorders and primary (first-time) cesarean section rates, using administrative claims data for US in-hospital deliveries from the period 2008-17. Of the 360,225 delivery hospitalizations among 317,802 unique women, 24.0 percent included a delivery by primary cesarean section, and 3.1 percent carried a diagnosis of depression, anxiety, or both made during the index pregnancy. Using an adjusted generalized estimating equation, we found that the predicted probability of primary cesarean section was 3.5 percentage points higher, on average, among women with these disorders compared with those without them. Our findings confirm the importance of pursuing research to identify mechanisms by which perinatal depression and anxiety disorders increase the risk for primary caesarean section among women otherwise considered at low risk for delivery by that method, as well as effective interventions.

Copyright © The Author(s) 2021. Anomalous perceptual experiences are relatively common in the general population. Evidence indicates that the key to distinguishing individuals with persistent psychotic experiences (PEs) with a need for care from those without is how they appraise their anomalous experiences. Here, we aimed to characterise the neural circuits underlying threatening and non-threatening appraisals in people with and without a need for care for PEs, respectively. A total of 48 participants, consisting of patients with psychosis spectrum disorder (clinical group, n = 16), non-need-for-care participants with PEs (non-clinical group, n = 16), and no-PE healthy control participants (n = 16), underwent functional magnetic resonance imaging while completing the Telepath task, designed to induce an anomalous perceptual experience. Appraisals of the anomalous perceptual experiences were examined, as well as functional brain responses during this window, for significant group differences. We also examined whether activation co-varied with the subjective threat appraisals reported in-task by participants. The clinical group reported elevated subjective threat appraisals compared to both the non-clinical and no-PE control groups, with no differences between the two non-clinical groups. This pattern of results was accompanied by reduced activation in the superior and inferior frontal gyri in the clinical group as compared to the non-clinical and control groups. Precuneus activation scaled with threat appraisals reported in-task. Resilience in the context of persistent anomalous experiences may be explained by intact functioning of fronto-parietal regions, and may correspond to the ability to contextualise and flexibly evaluate psychotic experiences. Medical Research Council; Institute of Psychiatry, Psychology, and Neuroscience, King’s College London; NIHR Maudsley Biomedical Research Centre.

Background Malingering is a common and challenging clinical presentation in emergency departments (EDs). Objective This study describes characteristics and outcomes among patients diagnosed as malingering in a psychiatric emergency service. Methods Index psychiatric ED encounters were identified for all adult patients seen during a 27-month period. Mortality data were obtained for patients from the state public health authority, and repeat ED visits for self-harm were obtained from the state hospital association. Patients with a diagnosis of malingering were compared with those without a malingering diagnosis using correlative statistics and multivariable analyses. Results Of 4710 encounters analyzed, 236 (5%) had a malingering diagnosis. No patients diagnosed as malingering died of suicide within 365 days of discharge, compared with 16 (0.4%) nonmalingering patients. Self-harm outcomes were available for 2689 encounters; 129 (5%) had a malingering diagnosis. Malingering was significantly associated with a repeat ED visit for self-harm within 365 days in multivariable analyses (adjusted odds ratio 2.52; 95% confidence interval 1.35–4.70); p Conclusions No psychiatric emergency service patients diagnosed as malingering died by suicide after discharge. New clinical approaches must balance malingering patients’ apparent low suicide risk with their other substantial comorbidities and risk for self-harm.

Preeclampsia (PE), the leading cause of maternal and fetal morbidity and mortality, is associated with poor fetal growth, intrauterine growth restriction (IUGR) and low birth weight (LBW). Offspring of women who had PE are at increased risk for cardiovascular (CV) disease later in life. However, the exact etiology of PE is unknown. Moreover, there are no effective interventions to treat PE or alleviate IUGR and the developmental origins of chronic disease in the offspring. The placenta is critical to fetal growth and development. Epigenetic regulatory processes such as histone modifications, microRNAs and DNA methylation play an important role in placental development including contributions to the regulation of trophoblast invasion and remodeling of the spiral arteries. Epigenetic processes that lead to changes in placental gene expression in PE mediate downstream effects that contribute to the development of placenta dysfunction, a critical mediator in the onset of PE, impaired fetal growth and IUGR. Therefore, this review will focus on epigenetic processes that contribute to the pathogenesis of PE and IUGR. Understanding the epigenetic mechanisms that contribute to normal placental development and the initiating events in PE may lead to novel therapeutic targets in PE that improve fetal growth and mitigate increased CV risk in the offspring.

To characterize patterns of cervical cancer screening among adolescents ages 14-20 years before and after the 2009 American College of Obstetrics and Gynecology recommendations.Retrospective cohort study.National Ambulatory Medical Care Survey 2005-2016 data.Female adolescents and young women ages 14-26 years.Multivariable logistic regression models identified independent predictors of unindicated cervical cancer screening at office-based visits among adolescents ages 14-20 years.Cervical cancer screening in women ages 14-20 and 21-26 years in 2 time periods: 2005-2008 and 2009-2016.Between 2005 and 2016, 11,768 office visits were among adolescents ages 14-20 years. Overall, the cervical cancer screening rate for young women ages 14-20 years was 4.0%, which decreased from 4.5% to 0.4% (P = .008) during the study period. Adolescents who received cervical cancer screening during an office visit were older (18-20 years: 24.1% vs 14-17 years: 8.2%; P.001), had a preventive care visit (preventive care: 79.7% vs other visit types: 20.3%; P.001), and saw an obstetrician/gynecologist (obstetrician/gynecologist: 74.81% vs other specialties: 25.1%; P.001). After adjusting for age, year, period, insurance status, region, and provider type, screening for cervical cancer was associated with living in the Southern region of the United States (adjusted odds ratio, 1.88; 95% confidence interval, 1.09-3.25; P = .02) and public insurance (adjusted odds ratio, 0.47, 95% confidence interval, 0.34-0.64; P.001).Despite recommendations, cervical cancer screening continued to occur in the adolescent population-especially older adolescents-creating unnecessary costs and potential harms. These findings show a slow uptake of guidelines nationally and the need for initiatives that encourage implementation of performance measures for providers, including ongoing provider and patient education.

Surgical oncology is cancer care that focuses on using surgery to diagnose, stage, and treat cancer and is one of the main treatments for malignancy. Patients older than 65 years are generally considered geriatric. The incidence of cancer in geriatric patients is increasing annually. Candidacy for surgical intervention depends on factors such as cancer type, size, location, grade and stage of the tumor, and the patient’s overall health status and age. Despite increasing agreement that age should not limit treatment options, geriatric patients tend to be undertreated. Cancer in geriatric patients has different features than in younger patients. As such, treatment options may be dissimilar in these 2 cohorts. Here, care of the geriatric patient undergoing surgical oncology interventions is discussed.

Assessing outcomes following surgery for single suture craniosynostosis is important to ensure minimum standards are being met, but also to compare results using different surgical techniques and treatment protocols. What constitutes an “outcome” and how this is measured remains a challenge, particularly when assessment should include consideration of aesthetic, functional, and psychological domains.The Oxford Craniofacial Unit has initiated routine collection of parents’ and patients’ ratings of 2 factors that are closely associated with psychological adjustment; how noticeable the child's headshape is and how much this bothers the parent and/or child. A brief Surgical Outcome Questionnaire is completed by parents and children (over 7 years) at their outpatient appointment; parents are also asked to rate the extent to which they feel surgery made a difference to their child's headshape.Data are presented for 519 parents and 248 children with single suture craniosynostosis who attended the Oxford Craniofacial Unit in 2018 and 2019; this represents over 80% of patients seen in the clinic indicating the questionnaire is acceptable for families and the potential for rapid, relevant data on a continuous basis. Analysis of the data is presented to demonstrate the utility of the Surgical Outcome Questionnaire in exploring the views of both parents and patients of the noticeability and level of concern about the child's headshape for different age groups and diagnoses.The Surgical Outcome Questionnaire provides a novel method of collecting routine data for patients across their craniofacial care pathway, using variables which are relevant and meaningful for patients and parents.

Background Development of depression in prostate cancer patients depends on multiple disease- and patient-related factors. Objective To investigate the risk of depression following radical prostatectomy focussing on the impact of surgery and subsequent treatment with salvage radiation or androgen deprivation therapy. Design, setting, and participants A population-based cohort study of 5570 men who underwent radical prostatectomy in Denmark from 1998 to 2011 was identified in the Danish Prostate Cancer Registry. Outcome measurements and statistical analysis Data on covariates and primary outcome defined as a hospital contact for depression or a redeemed antidepressant prescription were obtained from nationwide Danish registries. The risk of depression was evaluated using cumulative incidence functions and Cox models with time since surgery as an underlying time scale. Exposure to salvage procedures was included as time-varying covariates, and analyses were adjusted for confounders. Results and limitations The cumulative incidence of depression was increased in men who had undergone surgery compared with cancer-free men throughout follow-up of up to 18 yr, particularly among men on androgen deprivation therapy. Compared with no subsequent treatment, the risk of depression was increased with subsequent androgen deprivation therapy (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.4–2.3), salvage radiation (HR 1.3, 95% CI 1.0–1.6), and the treatments combined (HR 2.2, 95% CI 1.8–2.8) after adjustments for age, year of surgery, income, and cohabitation status. Further adjustment for comorbidity hardly changed the estimates. Conclusions Radical prostatectomy and subsequent salvage procedures increase the risk of depression, and men with subsequent androgen deprivation therapy are mainly at risk. Clinicians should thus be aware of depressive symptoms in patients receiving treatment for postsurgical relapse. Patient summary In a population-based study, we found that radical prostatectomy and subsequent treatments with either radiation or endocrine manipulation significantly increased the risk of developing clinical depression.

INTRODUCTION: During the Global War on Terrorism, many US Military service members sustained injuries with potentially long-lasting functional limitations and chronic pain. We sought to understand the patterns of prescription opioid use among service members injured in combat. METHODS: We queried the Military Health System Data Repository to identify service members injured in combat between 2007 and 2011. Sociodemographics, injury characteristics, treatment information, and costs of care were abstracted for all eligible patients. We surveyed for prescription opioid utilization subsequent to hospital discharge and through 2018. Negative binomial regression was used to identify factors associated with cumulative prescription opioid use. RESULTS: We identified 3,981 service members with combat-related injuries presenting during the study period. The median age was 24 years (interquartile range [IQR], 22-29 years), 98.5% were male, and the median follow-up was 3.3 years. During the study period, 98% (n = 3,910) of patients were prescribed opioids at least once and were prescribed opioids for a median of 29 days (IQR, 9-85 days) per patient-year of follow-up. While nearly all patients (96%; n = 3,157) discontinued use within 6 months, 91% (n = 2,882) were prescribed opioids again after initially discontinuing opioids. Following regression analysis, patients with preinjury opioid exposure, more severe injuries, blast injuries, and enlisted rank had higher cumulative opioid use. Patients who discontinued opioids within 6 months had an unadjusted median total health care cost of US $97,800 (IQR, US $42,364-237,135) compared with US $230,524 (IQR, US $134,387-370,102) among those who did not discontinue opioids within 6 months (p < 0.001). CONCLUSION: Nearly all service members injured in combat were prescribed opioids during treatment, and the vast majority experienced multiple episodes of prescription opioid use. Only 4% of the population met the criteria for sustained prescription opioid use at 6 months following discharge. Early discontinuation may not translate to long-term opioid cessation in this population. LEVEL OF EVIDENCE: Epidemiology study, level III.

Background: Coronavirus disease 2019 (COVID-19) is characterized by coagulopathy and thrombotic events. We examined factors associated with development of venous thromboembolism (VTE) in COVID-19 and to discern if higher dose of anticoagulation was beneficial in these patients. Methods: This study involves an observational study of prospectively collected data in the setting of a large community hospital in a rural setting in Northeast Georgia with COVID-19 between March 1, 2020 and February 5, 2021. Anticoagulation dose (none, standard, intermediate, and therapeutic dosages) was studied in adult patients ( >= 18 years). We constructed multivariable logistic regression model to examine the association of clinical characteristics with VTE. To examine the effect of dose of anticoagulation in preventing VTE, we used inverse probability weighted regression adjustment. Results: Of the 4,645 patients with COVID-19, 251 (5.4%) patients were found to have VTE. Of these, 91 had pulmonary embolism, 148 had deep venous thrombosis (DVT) and 12 had both. A total of 129 of VTE cases were diagnosed at admission. Of all admissions, 12.9% did not receive any DVT prophylaxis, 70.4% received prophylactic dose, 1.3% received intermediate dose and 15.5% received therapeutic dose. Male gender (odds ratio (OR): 1.55, 95% confidence interval (CI): 1.0 - 2.4, P = 0.04) and Black race (OR: 2.0, 95% CI: 1.2 - 3.4, P = 0.01), along with higher levels of lactate dehydrogenase (LDH) and D-dimer were associated with higher odds of developing VTE. Patients receiving steroids had lower rates of VTE (3.9% vs. 8.3%, P < 0.001). Use of intermediate or therapeutic anticoagulation was not associated with lower odds of developing VTE. However, patients on therapeutic anticoagulation had lower odds of in hospital mortality when compared to standard dose (OR: 0.47, 95% CI: 0.27 - 0.80, P = 0.006). Conclusions: In COVID-19, D-dimer and LDH can be useful in predicting VTE. Steroids appear to have some protective role in development of VTE. Therapeutic anticoagulation did not result in lower rates of VTE but was associated with in-hospital mortality. J Hematol. 2021;10(4):162-170 doi: https://doi.org/10.14740/jh836

The aim of this study was to assess the risks of psychiatric disorders in a large cohort of 905 individuals with NF1 and 7614 population comparisons matched on sex and year of birth. The cohort was linked to the Danish Psychiatric Central Research Register to ascertain information on hospital contacts for psychiatric disorders based on the International Classification of Diseases version 8 and 10. The hazard ratio (HR) for a first psychiatric hospital contact was higher in girls (4.19, 95% confidence interval [CI] 1.81–9.69) and boys with NF1 (5.02, 95% CI 3.27–7.69)

Background Cytomegalovirus (CMV) viremia is common in human immunodeficiency virus (HIV) infection and is associated with worse long-term outcomes. To date, no studies have assessed CMV viremia in children diagnosed with HIV in hospital. Methods We studied CMV viremia and clinical outcomes in 163 Kenyan children aged 2 months to 12 years, diagnosed with HIV in hospital. CMV DNA levels in plasma were measured using quantitative polymerase chain reaction (PCR). Regression models were used to assess associations between CMV viremia ≥1000 IU/mL and the risk of continued hospitalization or death at 15 days, duration of hospitalization, and 6-month mortality. Results At enrollment, 62/114 (54%) children had CMV viremia, and 20 (32%) were ≥1000 IU/mL. Eleven CMV reactivations were observed after admission. The prevalence and level of CMV viremia were highest in children −2 (P = .02). Adjusting for age and log10 HIV RNA, the relative risk of death or continued hospitalization at 15 days was 1.74 (95% confidence interval [CI] = 1.04, 2.90), and the hazard ratio of 6-month mortality was 1.97 (95% CI = .57, 5.07) for children with CMV DNA ≥1000 IU/mL compared to lower-level or undetectable CMV DNA. Children with CMV DNA ≥1000 IU/mL were hospitalized a median ~5 days longer than children with lower-level or undetectable CMV DNA (P = .002). Conclusions In this nested observational study, CMV viremia was common in hospitalized children with HIV, and levels ≥1000 IU/mL were associated with increased risk of mortality and longer hospitalization.

Diretrizes da Sociedade Brasileira de Cardiologia sobre Angina Instavel e Infarto Agudo do Miocardio sem Supradesnivel do Segmento ST – 2021

A 39-year-old woman presented with bleeding 4 months after a surgical termination of pregnancy. Persistent beta-human chorionic gonadotropin levels were suggestive of retained products of conception (RPOC). However, multimodal imaging revealed a concurrent uterine arteriovenous malformation (AVM). Although most stable AVMs can be managed conservatively, the need for surgical management of chronic RPOC and consequential hemorrhage risk complicates this approach. Patient-determined management prioritized blood conservation while minimizing risks to fertility. This case is discussed with respect to the rare concurrent existence of RPOC and AVM. Little is known regarding the optimal tandem therapeutic approach. As depicted, successful treatment requires careful diagnostic workup and a multidisciplinary approach.

Athletes exhibit better dynamic visual acuity (DVA) compared with nonathletes, whereas action video game players (VGPs) perform more similarly to controls despite having similar static visual acuity and refractive errors. The differences in DVA between groups were not related to differences in static visual acuity, refractive error, or smooth pursuit gain.The purpose of the study was to examine whether athletes and VGPs have superior DVA than controls (nonathletes, nongamers).Forty-six participants (15 athletes, 11 VGPs, 20 controls) aged 21.7 years (standard deviation, 2.8 years) were recruited. Participants were emmetropic with equivalent monocular and binocular static visual acuity between groups. Dynamic visual acuity was assessed using predictable (horizontal) and unpredictable (random) motion targets at velocities of 5, 10, 20, and 30°/s. Smooth pursuit eye movements were assessed using a horizontal motion step-ramp stimulus at the same speeds. This study was pre-registered with the Center for Open Science (https://osf.io/eu7qc).At 30°/s, there were significant main effects of group (F = 4.762, P = .01) and motion type (F = 9.538, P = .004). Tukey post hoc analysis for groups indicated that athletes performed better than did the control group (t = -2.919, P.02). An omnibus (group × motion type × speed) repeated measures ANOVA showed a main effect of speed (F = 110.137, P.001) and a speed × motion-type interaction (F = 27.825, P.001). Dynamic visual acuity decreased as speed increased, and the slope of the change was greater for random than for horizontal motion. Smooth pursuit gains were not significantly different between groups (P.05).Athletes have superior dynamic visual acuity performance compared with controls at 30°/s. This between-group difference cannot be fully explained by differences in smooth pursuit eye movements and therefore may reflect other differences between the groups.

BACKGROUND AND PURPOSE: Heart failure is associated with high morbidity and mortality, and new therapeutic targets are needed. Preclinical data suggest that pharmacological activation of protein kinase G (PKG) can reduce maladaptive ventricular remodeling and cardiac dysfunction in the stressed heart. However, clinical trial results have been mixed, and the effects of long-term PKG activation in the heart are unknown. EXPERIMENTAL APPROACH: We characterized the cardiac phenotype of mice carrying a heterozygous knock-in mutation of PKG1 (Prkg1(R177Q/+)), which causes constitutive, cGMP-independent activation of the kinase. We examined isolated cardiac myocytes and intact mice, the latter after stress induced by surgical transaortic constriction or angiotensin II infusion. KEY RESULTS: Cardiac myocytes from Prkg1(R177Q/+) mice showed altered phosphorylation of sarcomeric proteins and reduced contractility in response to electrical stimulation, compared to cells from wild type mice. Under basal conditions, young PKG1(R177Q/+) mice exhibited no obvious cardiac abnormalities, but aging animals developed mild increases in cardiac fibrosis. In response to angiotensin II infusion or fixed pressure overload induced by transaortic constriction, young PKG(R177Q/+) mice exhibited excessive hypertrophic remodeling with increased fibrosis and myocyte apoptosis, leading to increased left ventricular dilation and dysfunction compared to wild type litter mates. CONCLUSION AND IMPLICATIONS: Long-term PKG1 activation in mice may be harmful to the heart, especially in the presence of pressure overload and neurohumoral stress.

Traumatic brain injury (TBI) is a leading cause of death and disability. Yet, despite immense research efforts, treatment options remain elusive. Translational failures in TBI are often attributed to the heterogeneity of the TBI population and limited methods to capture these individual variabilities. Advances in machine learning (ML) have the potential to further personalized treatment strategies and better inform translational research. However, the use of ML has yet to be widely assessed in pre-clinical neurotrauma research, where data are strictly limited in subject number. To better establish ML's feasibility, we utilized the fluid percussion injury (FPI) portion of the rich, rat data set collected by Operation Brain Trauma Therapy (OBTT), which tested multiple pharmacological treatments. Previous work has provided confidence that both unsupervised and supervised ML techniques can uncover useful insights from this OBTT pre-clinical research data set. As a proof-of-concept, we aimed to better evaluate the multi-variate recovery profiles afforded by the administration of nine different experimental therapies. We assessed supervised pairwise classifiers trained on a pre-processed data set that incorporated metrics from four feature groups to determine their ability to correctly identify specific drug treatments. In all but one of the possible pairwise combinations of minocycline, levetiracetam, erythropoietin, nicotinamide, and amantadine, the baseline was outperformed by one or more supervised classifiers, the exception being nicotinamide versus amantadine. Further, when the same methods were employed to assess different doses of the same treatment, the ML classifiers had greater difficulty in understanding which treatment each sample received. Our data serve as a critical first step toward identifying optimal treatments for specific subgroups of samples that are dependent on factors such as types and severity of traumatic injuries, as well as informing the prediction of therapeutic combinations that may lead to greater treatment effects than individual therapies.

BACKGROUND Atrial fibrillation (AF) ablation is alternative treatment to medical therapy. Most feared complication is atrioesophageal fistula METHODS: Observational, retrospective analysis of consecutive 355 patients undergoing first AF ablation. Low-power long-duration (LPLD) group contained 158 patients, with 121 (76.58%) having paroxysmal AF who underwent ablation with power 20/30W (anterior and posterior left atrial wall), 17 mL/min flow, and a contact force of 10-30 g for 30 s. High-power short-duration group (HPSD) contained 197 patients, with 113 (57.36%) having paroxysmal AF who underwent ablation at 45/50W of power with a contact force of 8-15 g/10-20 g and a 35 mL/min flow rate for 6-8 s on the anterior and the posterior left atrial wall, respectively. Both groups had pulmonary veins isolated and atrial flutter was ablated when needed. For patients not in sinus rhythm, cardioversion was performed before ablation RESULTS: There were no complications. LPLD group: Left atrial time 118.74 min, total 145.32 min, radiofrequency time 4317.99s, X-ray 13.42 min, and elevation of luminal esophageal temperature (LET) in 132 (84.53%) patients. HPSD group: Left atrial time 72.16 min, total 93.76 min, radiofrequency time 1511.29s, X-ray 7.6 min, and LET elevation in only 75 (38.07%) patients. A markedly higher rate of first-pass isolation was observed in HPSD compared to LPLD, 77.16% versus 13.29%, respectively. Recurrence occurred in 64 (40.50%) and 32 (16.24%) in 28.45 and 22.35 months in LPLD and HPSD patients, respectively. In LPLD, 10 patients were submitted to endoscopy, and one (10%) had mild erythema and in HPSD, 13 performed the endoscopy, with two (15.38%) patients showing mild erythema CONCLUSION: HPSD technique compared to the LPLD technique showed significant reduced radiofrequency and fluoroscopy times, higher rate of first-pass isolation, lower recurrence rate, and esophageal temperature elevation and may also have a protective effect avoiding incidental esophageal injury due to these findings.

The diagnosis and treatment of head and neck cancer (HNC) can have substantial impact on swallowing function, nutritional balance, physical function and quality of life (QoL). Early initiated swallowing exercises are hypothesized to improve swallowing function in HNC patients. The aim was to investigate the effects of swallowing exercises and progressive resistance training (PRT) during radiotherapy on swallowing function, physical function and QoL in patients with pharynx-, larynx-, oral cavity cancer or unknown primary compared to usual care. In a multi-centre RCT participants were assigned to (a) twice-weekly PRT and daily swallowing exercises throughout treatment or (b) usual care. Outcomes were measured at end of treatment and 2, 6 and 12 months after. Primary outcome was penetration aspiration score (PAS). Data were analysed on an “intention-to-treat” basis by GEE logistic regression model, linear mixed effects model and cox regression. Of 371 invited HNC patients, 240 (65%) enrolled. Five participants were excluded. At 12 months follow-up, 59 (25%) participants were lost. Analyses showed significant effect on mouth opening, QoL, depression and anxiety at 12 months when comparing intervention to non-active controls. The trial found no effect on swallowing safety in HNC undergoing radiotherapy, but several positive effects were found on secondary outcomes when comparing to non-active controls. The intervention period may have been too short, and the real difference between groups is too small. Nevertheless, the need to identify long-lasting intervention to slow down or avoid functional deteriorations is ever more crucial as the surviving HNC population is growing.

Venetoclax is a small molecule inhibitor of the prosurvival protein BCL-2 that has gained market approval in BCL-2–dependent hematologic cancers including chronic lymphocytic leukemia and acute myeloid leukemia. Neuroblastoma is a heterogenous pediatric cancer with a 5-year survival rate of less than 50% for high-risk patients, which includes nearly all cases with amplified MYCN. We previously demonstrated that venetoclax is active in MYCN-amplified neuroblastoma but has limited single-agent activity in most models, presumably the result of other pro-survival BCL-2 family protein expression or insufficient prodeath protein mobilization. As the relative tolerability of venetoclax makes it amenable to combining with other therapies, we evaluated the sensitivity of MYCN-amplified neuroblastoma models to rational combinations of venetoclax with agents that have both mechanistic complementarity and active clinical programs. First, the MDM2 inhibitor NVP-CGM097 increases the prodeath BH3-only protein NOXA to sensitize p53-wild-type, MYCN-amplified neuroblastomas to venetoclax. Second, the MCL-1 inhibitor S63845 sensitizes MYCN-amplified neuroblastoma through neutralization of MCL-1, inducing synergistic cell killing when combined with venetoclax. Finally, the standard-of-care drug cocktail cyclophosphamide and topotecan reduces the apoptotic threshold of neuroblastoma, thus setting the stage for robust combination efficacy with venetoclax. In all cases, these rational combinations translated to in vivo tumor regressions in MYCN-amplified patient-derived xenograft models. Venetoclax is currently being evaluated in pediatric patients in the clinic, including neuroblastoma (NCT03236857). Although establishment of safety is still ongoing, the data disclosed herein indicate rational and clinically actionable combination strategies that could potentiate the activity of venetoclax in patients with amplified MYCN with neuroblastoma.

BACKGROUND: This study aimed to understand the prevalence of prediabetes and diabetes in patients with cancer overall, by tumor site, by cancer treatment, and by time point in the cancer continuum. METHODS: This cohort study has been conducted at the Huntsman Cancer Institute, Salt Lake City, Utah. Patients with a first primary invasive cancer enrolled in the Total Cancer Care protocol between July 2016 and July 2018 were eligible for this analysis. The prevalence of prediabetes and diabetes is based on ICD code, laboratory tests for HbA1c (%), fasting plasma glucose (mg/dl), non-fasting blood glucose (mg/dl), or insulin prescription. RESULTS: The final cohort comprised 3,512 patients with cancer, with a mean age of 57.8 years at cancer diagnosis. Of all patients, 49.1% (n=1,724) were female. At cancer diagnosis, the prevalence of prediabetes was 6.0% (95% CI: 5.3–6.8) and of diabetes 12.2% (95% CI: 11.2–13.3). One year after diagnosis the prevalences were 16.6% for prediabetes (95% CI: 15.4–17.9) and 25.0% for diabetes (95% CI: 23.6–26.4). At the end of the observation period, the prevalence of prediabetes was 21.2% (95% CI: 20.4–23.0) and of diabetes was 32.6% (95% CI: 29.2–32.1). Patients with myeloma (39.2%; 95% CI: 32.6–46.2) had the highest prevalence of prediabetes and patients with pancreatic cancer the highest prevalence of diabetes (65.1%; 95% CI: 57.0–72.3). In patients who underwent chemotherapy (prediabetes: 29.1% vs 15.6%; diabetes: 37.6% vs 29.0%), radiation therapy (prediabetes: 24.3% vs. 19.9%; diabetes: 33.7% vs 32.1%), or immunotherapy (diabetes: 29.2% vs 20.4; prediabetes: 36.0% vs 32.2%), the prevalence of prediabetes and diabetes was higher compared to patients not undergoing those therapies. CONCLUSIONS: Every second patient with cancer suffers from prediabetes or diabetes. It is essential to foster interprofessional collaboration and to develop evidence-based practice guidelines. A better understanding of the impact of cancer treatment on the development of prediabetes and diabetes remains critical.

Background Black hip fracture patients experience worse health outcomes than otherwise similar White patients, but causes of these disparities are not known. We sought to determine if delays in hip fracture surgery and/or hospital structures contribute to racial disparities in hip fracture outcomes. Methods Using 2006 to 2016 Trauma Quality Program Public Use Files, we identified hip fracture patients with primary mechanisms of fall from standing and determined surgical treatment category (no surgery, surgery within 24 hours after arrival, surgery 24-48 hours after arrival, surgery more than 48 hours after arrival) as well as hospital structure characteristics (trauma center designation, teaching status, profit status, bed size). We used generalized structural equation models to conduct path analyses and determine if hip fracture treatment and hospital characteristics mediated the relationship between race (non-Hispanic Black/non-Hispanic White) and outcomes (complications, length of stay, disposition). Results Non-Hispanic Black patients were more likely than non-Hispanic White patients to receive treatment at an academic medical center (49.1% vs. 28.0%), at a hospital with >600 inpatient beds (39.5% vs. 25.3%), and at a level I or II trauma center (86.8% vs. 77.7%); were more likely to go without hip fracture repair surgery (22.8% vs. 21.4%); and were more likely to have delayed surgery >48 hours after hospital arrival (15.5% vs. 10.6%). Path analysis suggests hip fracture treatment group and hospital characteristics mediate the relationship with complications, length of stay, and disposition. Conclusion Non-Hispanic Black patients with fall-related hip fracture are more likely to experience delays in care, complications, and longer inpatient stays. Hospital characteristics contribute to increased risk of complications and longer length of stay, both as independent determinants of outcomes and as determinants of delays in hip fracture surgery. Level of evidence Prognostic and epidemiologic, level III.

Severe intra-abdominal infection commonly requires intensive care. Mortality is high and is mainly determined by disease-specific characteristics, i.e. setting of infection onset, anatomical barrier disruption, and severity of disease expression. Recent observations revealed that antimicrobial resistance appears equally common in community-acquired and late-onset hospital-acquired infection. This challenges basic principles in anti-infective therapy guidelines, including the paradigm that pathogens involved in community-acquired infection are covered by standard empiric antimicrobial regimens, and second, the concept of nosocomial acquisition as the main driver for resistance involvement. In this study, we report on resistance profiles of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecalis and Enterococcus faecium in distinct European geographic regions based on an observational cohort study on intra-abdominal infections in intensive care unit (ICU) patients. Resistance against aminopenicillins, fluoroquinolones, and third-generation cephalosporins in E. coli, K. pneumoniae and P. aeruginosa is problematic, as is carbapenem-resistance in the latter pathogen. For E. coli and K. pneumoniae, resistance is mainly an issue in Central Europe, Eastern and South-East Europe, and Southern Europe, while resistance in P. aeruginosa is additionally problematic in Western Europe. Vancomycin-resistance in E. faecalis is of lesser concern but requires vigilance in E. faecium in Central and Eastern and South-East Europe. In the subcohort of patients with secondary peritonitis presenting with either sepsis or septic shock, the appropriateness of empiric antimicrobial therapy was not associated with mortality. In contrast, failure of source control was strongly associated with mortality. The relevance of these new insights for future recommendations regarding empiric antimicrobial therapy in intra-abdominal infections is discussed.

Fear of cancer recurrence (FCR) is a significant problem for individuals diagnosed with a variety of different cancers. To date, FCR has not been studied in males with breast cancer. The objective of this study was to examine the severity of FCR in males with breast cancer. Males with breast cancer participated in an anonymous online survey and completed the Fear of Cancer Recurrence Inventory-Short Form scale (FCRI-SF). A frequency analysis was used to determine the percentage of participants that fell above or below the clinical cutoff for significant FCR. Regressions explored associations between FCR, age, cancer stage, time since diagnosis, and self-health rating. Fifty-nine participants completed the FCRI-SF. The mean age of the sample was 63.5 and 93% reported their race as white. The mean FCR score was 23.9 and 61% reported clinically significant FCR. More than 80% of the sample experienced at least problematic levels of FCR. Increasing age was associated with decreased FCR. Results of this study suggest that FCR is prevalent in men with breast cancer but larger studies with representative samples should be undertaken to better assess the prevalence of FCR in this population and compare it with other groups of patients. More attention is needed to understand the psychological distress experienced by men diagnosed and treated for breast cancer.

Introduction: Long-term freedom from atrial fibrillation (AF) after catheter ablation and, consequently, the potential for stroke reduction remain unpredictable. Recently, left atrial appendage closure (LAAC) became an effective mechanical alternative to oral anticoagulation (OAC) for stroke prevention in AF patients. Objective: This study aims to evaluate the feasibility and safety of combined treatment for AF with catheter ablation (CA) with the high-power short duration technique associated with LAAC in one single procedure. Methods: Patients with non-valvular AF who underwent combined CA and LAAC procedure were included in the retrospective observational study. Between April 2018 and October 2020, 13 patients with AF were included, eight (61,54%) males, eight (61.54%) with persistent AF (PersAF), mean age 68.54 (65–84) years old, mean time from AF diagnosis to treatment 13.08 (3–33) months, mean CHA2VASC2 5.08 (3–7), all patients with coronary or vascular disease, 12 (92.31%) with hypertension, five (38.46%) with left ventricular dysfunction, four (30.77%) prior strokes using OAC and four (30.77%) patients with diabetes. Indications for LAAC included history of contraindication to OAC because of severe bleeding in eight (61.54%), previous stroke in four (30.77%) and two (13.08%) patients with LAA thrombus, despite the use of two different OAC (one associated with bleeding). One patient had a pseudoaneurysm in femoral artery, and two patients died of non-procedure complications after 30 days. At six months, angiotomography showed successful complete sealing of the LAA in seven (77.72%) of nine patients evaluated, and the two patients without it had a leak of less than 2 mm. After mean follow-up of 14 months (five to 33), 10 (90.91%) of the 11 patients were in sinus rhythm. Three (27.27%) patients, one in blanking period, recovered sinus rhythm after amiodarone. No cardioembolic or bleeding events occurred. Conclusion: In this small observational study, we showed the feasibility and safety of the combined therapy with AF catheter ablation with LAAC with a high rate of sinus rhythm and no cardioembolic event.

Aims and methodMental health services have changed the way they operate during the COVID-19 pandemic. We investigated the challenges and innovations reported by staff working in services for people with intellectual disability and/or autism in National Health Service (NHS) and non-NHS sectors, and in in-patient and community settings.ResultsData were drawn from 648 staff who participated in a UK-wide online survey. Issues around infection risk and mitigation were more important to those working in the NHS and in-patient settings. Community staff were more likely to express concern about the practicalities of a rapid shift to remote working and engaging patients remotely. Qualitative data revealed support for maintaining remote staff working and remote service provision post-pandemic.Clinical implicationsGiven the current emphasis on community support for people with intellectual disability and/or autism, the focus of research and clinical practice should be the development of accessible and effective models of remote service provision.

This study documents sugar-sweetened beverage (SSB) consumption among overweight and obese Marshallese adults and examines the association between SSB consumption and body mass index. Data from 378...

Pancreatic cancer (PC) has high morbidity and mortality and is stressful for patients and their partners. We investigated the psychological symptom burden in partners of PC patients. We followed 5774 partners of PC patients diagnosed from 2000 to 2016 up for first redeemed prescriptions of antidepressants or hospital admission, anxiolytics, and hypnotics as proxies for clinical depression, anxiety, and insomnia and compared them with 59,099 partners of cancer-free spouses. Data were analysed using Cox regression and multistate Markov models. The cumulative incidence proportion of first depression was higher in partners of PC patients compared to comparisons. The highest adjusted HR of first depression was seen the first year after diagnosis (HR 3.2 (95% CI: 2.9; 3.7)). Educational level, chronic morbidity, and bereavement status were associated with an increased risk of first depression. There was a significantly higher first acute use (1 prescription only) of both anxiolytics and hypnotics and chronic use (3+ prescriptions) of hypnotics in partners of PC patients than in comparisons. Being a partner to a PC patient carries a substantial psychological symptom burden and increases the risk for first depression and anxiolytic use and long-term use of hypnotics. Attention should be given to the psychological symptom burden of partners of PC patients, as this may pose a barrier for the optimal informal care and support of the PC patient, as well as a risk for non-optimal management of symptoms in the partner.

Ciclopirox (CPX) is an FDA-approved topical antifungal agent that has demonstrated preclinical anticancer activity in a number of solid and hematologic malignancies. Its clinical utility as an oral anticancer agent, however, is limited by poor oral bioavailability and gastrointestinal toxicity. Fosciclopirox, the phosphoryloxymethyl ester of CPX (Ciclopirox Prodrug, CPX-POM), selectively delivers the active metabolite, CPX, to the entire urinary tract following parenteral administration. We characterized the activity of CPX-POM and its major metabolites in in vitro and in vivo preclinical models of high-grade urothelial cancer. CPX inhibited cell proliferation, clonogenicity and spheroid formation, and increased cell cycle arrest at S and G0/G1 phases. Mechanistically, CPX suppressed activation of Notch signaling. Molecular modeling and cellular thermal shift assays demonstrated CPX binding to γ-secretase complex proteins Presenilin 1 and Nicastrin, which are essential for Notch activation. To establish in vivo preclinical proof of principle, we tested fosciclopirox in the validated N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) mouse bladder cancer model. Once-daily intraperitoneal administration of CPX-POM for four weeks at doses of 235 mg/kg and 470 mg/kg significantly decreased bladder weight, a surrogate for tumor volume, and resulted in a migration to lower stage tumors in CPX-POM treated animals. This was coupled with a reduction in the proliferation index. Additionally, there was a reduction in Presenilin 1 and Hes-1 expression in the bladder tissues of CPX-POM treated animals. Following the completion of the first-in-human Phase 1 trial (NCT03348514), the pharmacologic activity of fosciclopirox is currently being characterized in a Phase 1 expansion cohort study of muscle-invasive bladder cancer patients scheduled for cystectomy (NCT04608045) as well as a Phase 2 trial of newly diagnosed and recurrent urothelial cancer patients scheduled for transurethral resection of bladder tumors (NCT04525131).

G protein-coupled receptor (GPR)35 is highly expressed in the gastro-intestinal tract, predominantly in colon epithelial cells (CEC), and has been associated with inflammatory bowel diseases (IBD), suggesting a role in gastrointestinal inflammation. The enterotoxigenic Bacteroides fragilis (ETBF) toxin (BFT) is an important virulence factor causing gut inflammation in humans and animal models. We identified that BFT signals through GPR35. Blocking GPR35 function in CECs using the GPR35 antagonist ML145, in conjunction with shRNA knock-down and CRISPRcas-mediated knock-out, resulted in reduced CEC-response to BFT as measured by E-cadherin cleavage, beta-arrestin recruitment and IL-8 secretion. Importantly, GPR35 is required for the rapid onset of ETBF-induced colitis in mouse models. GPR35-deficient mice showed reduced death and disease severity compared to wild-type C57Bl6 mice. Our data support a role for GPR35 in the CEC and mucosal response to BFT and underscore the importance of this molecule for sensing ETBF in the colon., Boleij et al. show that G protein-coupled receptor 35 (GPR35) regulates the responses to enterotoxigenic Bacteroides fragilis (ETBF) in colonic epithelial cells. They find that GPR35-deficiency nearly protected mice from ETBF-induced death, suggesting the importance of GPR35 in sensing ETBF in the colon.

Background: Shone syndrome is characterized by coincident mitral valve stenosis and left ventricular outflow tract obstruction. Although first described in 1963, little research has expounded surgical outcomes. We sought to evaluate our experience with this cohort, emphasizing outcomes including mortality, morbidity, and cardiac function. Methods: A retrospective chart review of 46 patients who underwent operation for Shone syndrome between 1990 and May 2018 was conducted. Index operations included 32 repairs of the left ventricular outflow tract, four mitral valve repair/replacements, nine combined repairs, and one non-Shone’s repair. Median age at index procedure was 22 days (2 days-10 years). Mean follow-up was 9.1 years (2 months-21 years), and 70 additional operations (51 reoperations) were required. Three patients were lost to follow-up. Results: Overall survival was 95.7% with two late deaths. Freedom from death or transplant was 93.5%. Thirteen (28.3%) patients remained free from reoperation. Thirty-three patients required 51 reoperations of the left ventricle outflow tract (n = 12), mitral valve (n = 16), combined repairs (n = 21), and transplant (n = 1). At most recent follow-up, patients exhibited mitral stenosis (n = 21), aortic stenosis (n = 7), and diminished LV function (n = 2). Conclusion: Surgical correction of Shone’s offers excellent survival benefit, but reoperation burden is high, with >70% of patients requiring reintervention in the follow-up period. A total of 65% of patients developed recurrent obstruction of left ventricular inflow or outflow, however, ventricular function is preserved in the majority of patients. All but one patient had no functional deficits, classified as New York Heart Association I with > 60% requiring no medication.

Cancer patients vary in their comfort with the label “survivor”. Here, we explore how comfortable males with breast cancer (BC) are about accepting the label cancer “survivor”. Separate univariate logistic regressions were performed to assess whether time since diagnosis, age, treatment status, and cancer stage were associated with comfort with the “survivor” label. Of the 70 males treated for BC who participated in the study, 58% moderately-to-strongly liked the term “survivor”, 26% were neutral, and 16% moderately-to-strongly disliked the term. Of the factors we explored, only a longer time since diagnosis was significantly associated with the men endorsing a survivor identity (OR = 1.02, p = 0.05). We discuss how our findings compare with literature reports on the comfort with the label “survivor” for women with BC and men with prostate cancer. Unlike males with prostate cancer, males with BC identify as “survivors” in line with women with BC. This suggests that survivor identity is more influenced by disease type and treatments received than with sex/gender identities.

We report a case of a patient with necrotizing infection of the conjunctiva and Tenon’s capsule caused by Streptococcus pyogenes, a rare and atypical ophthalmologic condition. A 50-years-old male patient with acute red-eye, purulent discharge, and pain diagnosed with post-septal cellulitis presented with a yellowish and dense membrane covering the ocular surface with necrotic Tenon’s capsule. Patient was hospitalized, and intravenous antibiotics were initiated (ceftriaxone and clindamycin). Topical antibiotics and corticosteroids were also administered, and the infection was eradicated in 2 weeks. Ancillary exams excluded rheumatologic involvement. Conjunctival culture confirmed Streptococcus pyogenes growth. Tenon’s biopsy revealed unspecific acute inflammatory necrosis. This is an uncommon condition in daily ophthalmological clinic. Literature review reported 3 cases associated with previous ocular surgery.