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Takayasu arteritis is a rare inflammatory disease of large arteries. We performed a genetic study in Takayasu arteritis comprising 6,670 individuals (1,226 affected individuals) from five different populations. We discovered HLA risk factors and four non-HLA susceptibility loci in VPS8, SVEP1, CFL2, and chr13q21 and reinforced IL12B, PTK2B, and chr21q22 as robust susceptibility loci shared across ancestries. Functional analysis proposed plausible underlying disease mechanisms and pinpointed ETS2 as a potential causal gene for chr21q22 association. We also identified >60 candidate loci with suggestive association (p < 5 x 10(-s)) and devised a genetic risk score for Takayasu arteritis. Takayasu arteritis was compared to hundreds of other traits, revealing the closest genetic relatedness to inflammatory bowel disease. Epigenetic patterns within risk loci suggest roles for monocytes and B cells in Takayasu arteritis. This work enhances understanding of the genetic basis and pathophysiology of Takayasu arteritis and provides clues for potential new therapeutic targets., National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) [R01 AR070148]; National Institute of Arthritis and Musculoskeletal and Skin DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) [U54 AR057319, U01 AR51874 04]; National Center for Research ResourcesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [U54 RR019497]; Office of Rare Diseases Research of the National Center for Advancing Translational Sciences; Imperial College, National Institute for Health Research, Biomedical Research Centre; Wellcome TrustWellcome TrustEuropean Commission [WT107881]; Medical Research CouncilUK Research & Innovation (UKRI)Medical Research Council UK (MRC)European Commission [MC_UU_00002/4], This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health grant R01 AR070148 to A.H.S. The Vasculitis Clinical Research Consortium has received support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54 AR057319 and U01 AR51874 04), the National Center for Research Resources (U54 RR019497), and the Office of Rare Diseases Research of the National Center for Advancing Translational Sciences. J.C.M., A.P.K., and R.M.M. acknowledge support from the Imperial College, National Institute for Health Research, Biomedical Research Centre. C.W. and G.R. acknowledge support from The Wellcome Trust (WT107881) and the Medical Research Council (MC_UU_00002/4). This work was supported by the use of study data downloaded from the dbGaP website, under dbGaP: phs000272.v1.p1, phs000431.v2.p1, phs000583.v1.p1, and phs000444.v1.p1.

Background: Unmet need for mental health services remains high in the United States and is disproportionately concentrated in some groups. The scale and nature of these disparities have not been fully elucidated and bear further scrutiny. As such, in this study, we examine the demographic, socioeconomic, and health correlates of unmet need for mental health treatment as well as the reasons for unmet need. Methods: We draw upon the National Survey for Drug Use and Health (NSDUH) from 2002 to 16 for adults aged 18 and over in the United States (n = 579,017). Using multivariable logistic regression, we simultaneously model the demographic, socioeconomic, and health correlates of unmet need for mental health treatment from 2002 to 16. We also analyse the reasons for unmet need expressed by these populations, reasons which include cost, perceived stigma, minimisation of symptoms, low perceived effectiveness of treatment, and structural barriers. Results: Major characteristics associated with increased odds of unmet need include past year substance abuse or dependence (other than hallucinogens and sedatives), fair, poor, or very poor health, being female, and an educational attainment of college or higher. With respect to reasons for unmet need, cost was most often cited, followed by perceived stigma, structural barriers, and minimisation. Characteristics associated with increased odds of indicating cost as a reason for unmet need include: being uninsured or aged 26–35. Minimisation and low perceived effectiveness are mentioned by high-income persons as reasons for unmet need. College-educated persons and women had higher odds of citing structural barriers as a reason for unmet need. Conclusions: The correlates and causes of unmet need highlight the intersectionality of individual health needs with implications on addressing inequities in mental health policy and practice.

Rationale: Human herpesviruses Epstein-Barr virus and cytomegalovirus are frequently detectable in the lungs of patients with idiopathic pulmonary fibrosis (IPF) and could contribute to disease pat...

Although the expression of the putative cannabinoid receptor GPR55 has been shown to be involved in the growth of various tumours and is increased in a number of cancers, its expression has not been examined in patients with endometrial cancer (EC). Quantitative RT-PCR (for mRNA levels) and immunohistochemistry (for protein levels) were used to measure GPR55 expression in patients with Type 1 and Type 2 EC and correlated against cannabinoid receptor (CB1 and CB2) protein levels using non-cancerous endometrium as the control tissue. The data indicated that GPR55 transcript and GPR55 protein levels were significantly (p

Background : Memory control (MC) ability is critical for people's mental and physical health. Previous research had conceptually demonstrated that MC ability has close relationship with reappraisal. However, experimental evidence supporting the relationship was limited. Thus, in the present study, we investigated how MC and reappraisal are linked, both in behavior and in the brain. Methods : The habitual use of reappraisal was assessed by Emotion Regulation Questionnaire, and memory control ability was measured through directed forgetting task. Resting-state functional magnetic resonance imaging was used to test the seed-based functional connectivity in 181 healthy subjects. Results : Behavioral results revealed that more frequent reappraisal was associated with an enhanced ability to control negative memories. Resting-state seed-based functional connectivity showed that habitual use of reappraisal was positively related to the strength of functional connectivity between the right ventrolateral prefrontal cortex (VLPFC) and right insula. Most importantly, this functional connectivity mediated the effect of habitual use of reappraisal on control over negative memories. Limitations : Present results mainly showed the habitual use of reappraisal was related with MC ability in negative items. Future study could further explore the relationship between MC ability of different categories of negative emotional memories and other kinds of ER strategies. Conclusions : Our results support the notion that reappraisal provides opportunities for individuals to practice and enhance inhibitory control—a relationship underpinned by connectivity between the right VLPFC and right insula.

Background Chinese medicine (CM) modalities, including acupuncture and Chinese herbal medicine (CHM), are popular palliative interventions among patients with cancer, but further clinical research is required to assess their effectiveness and safety. Objective To prioritize top ten important CM clinical research questions from patients with cancer, cancer survivors and caregivers' perspectives via a face-to-face prioritization workshop in Hong Kong. Methods A list of 25 CM clinical research questions for cancer palliative care, which were identified from existing systematic reviews (SRs) and overview of SRs, was presented to 17 participants (patients with cancer [n = 5], cancer survivors [n = 6] and caregivers [n = 6]). The participants were then invited to establish consensus on prioritizing top ten research questions. Results Among the top ten priorities, five (50%) focused on acupuncture and related therapies, while five (50%) were on CHM. The three most important research priorities were (i) manual acupuncture plus opioids for relieving pain; (ii) CHM for improving quality of life among patients receiving chemotherapy; and (iii) concurrent use of CHM plus loperamide for reducing stomatitis. Conclusion The top ten participant-endorsed CM clinical research priorities for cancer palliative care can guide local researchers on future direction. They can also inform local research funders on patient-centred allocation of limited funding. Under limited research funding, the most important co-prioritized research question from professional and patient perspectives may be addressed first. Patient or public contribution Patients with cancer, cancer survivors and caregivers participated in conduct of the study to prioritize CM clinical research questions.

PURPOSE: Obesity increases the risk of cancer recurrence and death in survivors of breast cancer. This study tested the hypothesis that exercise alone, diet alone, and the combination of exercise plus diet reduce body weight and improve body composition in survivors of breast cancer. METHODS: In this 2×2 factorial trial, 351 survivors of breast cancer with overweight or obesity were randomized to one of four treatment groups for 52 weeks: control, exercise alone, diet alone, or exercise plus diet. Endpoints included body weight and body composition measured by dual-energy x-ray absorptiometry. RESULTS: After 52 weeks, compared with control, diet alone [−5.39 kg (95% CI: −7.24, −3.55); −6.0% (95% CI: −8.0, −3.9)] and exercise plus diet [−6.68 kg (95% CI: −8.46, −4.90); −7.4% (95% CI: −9.4, −5.4)] reduced body weight; exercise alone did not change body weight. Compared with control, diet alone [−3.59 kg (95% CI: −5.00, −2.17)] and exercise plus diet [−4.28 kg (95% CI: −5.71, −2.84)] reduced fat mass; exercise alone did not change fat mass. Compared with control, diet alone [−0.82 kg (95% CI: −1.50, −0.15)] and exercise plus diet [−1.24 kg (95% CI: −1.92, −0.56)] reduced lean mass; exercise alone did not change lean mass. Compared with control, exercise alone, diet alone, and exercise plus diet did not change bone mineral density. CONCLUSION: In survivors of breast cancer with overweight or obesity, diet alone or diet plus exercise produced clinically meaningful weight loss at week 52. The majority of weight loss was fat mass.

Background There is an emerging viewpoint that change in body weight is not sufficiently sensitive to promptly identify clinically meaningful change in body composition, such as skeletal muscle depletion. Objectives We aimed to determine whether body weight stability is associated with skeletal muscle depletion and whether skeletal muscle depletion is prognostic of death independently of change in body weight. Methods This retrospective cohort included 1921 patients with stage I-III colorectal cancer. Computed tomography (CT)-based skeletal muscle characteristics and body weight were measured at diagnosis and after a mean 15.0-mo follow-up. Body weight stability was defined as weight change less than ±5% during follow-up. Sarcopenia and myosteatosis were defined using established thresholds for patients with cancer. Multivariable-adjusted logistic and flexible parametric proportional hazards survival models were used to quantify statistical associations. Results At follow-up, 1026 (53.3%) patients were weight stable. Among patients with weight stability, incident sarcopenia and myosteatosis occurred in 8.5% (95% CI: 6.3%, 10.6%) and 13.5% (95% CI: 11.1%, 15.9%), respectively. Men were more likely to be weight stable than were women (56.7% compared with 49.9%; P = 0.04). Weight-stable men were less likely to develop incident sarcopenia (5.4% compared with 15.4%; P = 0.003) and myosteatosis (9.3% compared with 20.8%; P = 0.001) than weight-stable women. Among all patients, the development of incident sarcopenia (HR: 1.40; 95% CI: 1.02, 1.91) and of myosteatosis (HR: 1.41; 95% CI: 1.05, 1.90) were associated with a higher risk of death, independently of change in body weight. Patient sex did not modify the relation between skeletal muscle depletion and death. Conclusions Body weight stability masks clinically meaningful skeletal muscle depletion. Body composition quantified using clinically acquired CT images may provide a vital sign to identify patients at increased risk of death. These data may inform the design of future cachexia trials.

This study determined the effect of pelvic organ decentralization and reinnervation 1 yr later on the contribution of muscarinic and purinergic receptors to ex vivo, nerve-evoked, bladder smooth muscle contractions. Nineteen canines underwent decentralization by bilateral transection of all coccygeal and sacral (S) spinal roots, dorsal roots of lumbar (L)7, and hypogastric nerves. After exclusions, 8 were reinnervated 12 mo postdecentralization with obturator-to-pelvic and sciatic-to-pudendal nerve transfers then euthanized 8-12 mo later. Four served as long-term decentralized only animals. Controls included six sham-operated and three unoperated animals. Detrusor muscle was assessed for contractile responses to potassium chloride (KCl) and electric field stimulation (EFS) before and after purinergic receptor desensitization with α, β-methylene adenosine triphosphate (α,β-mATP), muscarinic receptor antagonism with atropine, or sodium channel blockade with tetrodotoxin. Atropine inhibition of EFS-induced contractions increased in decentralized and reinnervated animals compared with controls. Maximal contractile responses to α,β-mATP did not differ between groups. In strips from decentralized and reinnervated animals, the contractile response to EFS was enhanced at lower frequencies compared with normal controls. The observation of increased blockade of nerve-evoked contractions by muscarinic antagonist with no change in responsiveness to purinergic agonist suggests either decreased ATP release or increased ecto-ATPase activity in detrusor muscle as a consequence of the long-term decentralization. The reduction in the frequency required to produce maximum contraction following decentralization may be due to enhanced nerve sensitivity to EFS or a change in the effectiveness of the neurotransmission.

Objective Anthropometric measures of obesity, including BMI and waist circumference (WC), do not quantify excess adiposity and metabolic abnormalities consistently across racial populations. This study tested the hypothesis that participant race modifies the association of anthropometric measures of obesity and cancer risk. Methods This prospective cohort (The Pennington Center Longitudinal Study) included 18,296 adults, 6,405 (35.0%) male sex and 6,273 (34.3%) Black race. The primary exposures were BMI (weight in kilograms/height in meters squared) and WC (centimeters). The primary end point was the time from study enrollment to diagnosis of histologically confirmed invasive cancer. Results During a median follow-up of 14.0 years (interquartile range: 9.8-19.0 years), invasive cancer occurred in 1,350 participants. Among men, race modified the association of BMI (Pinteraction = 0.02) and WC (Pinteraction = 0.01) with cancer incidence; compared with a BMI of 22 kg/m2 , a BMI of 35 kg/m2 in White men was associated with a hazard ratio of 1.83 (95% CI: 1.58-2.12), whereas in Black men, the hazard ratio was 0.89 (95% CI: 0.72-1.11). Among women, race did not modify the association of BMI (Pinteraction = 0.41) or WC (Pinteraction = 0.36) with cancer incidence. Conclusions In this diverse cohort of adults, participant race and sex modified the prognostic associations of anthropometric measures of obesity and cancer risk.

ObjectiveThe primary objective of this study was to evaluate the correlation of large mitochondrial DNA (mtDNA) deletions in skin samples of people with HIV (PWH) with measures of neuropathy and prior exposure to therapy. We hypothesized that deletions would be associated with neuropathy. As secondary objectives, we determined the correlation of deletion burden with demographic data and neuropathy measures.MethodsIn this retrospective cohort study, we measured the accumulation of large mtDNA deletions in skin biopsies from PWH recruited as part of the AIDS Clinical Trials Group (ACTG). Our cohort includes individuals with and without sensory neuropathy, as well as individuals with normal or abnormal skin biopsies. Skin biopsies, sural and peroneal nerve conduction studies, total neuropathy score, and deletion burden scores were measured, along with baseline demographic data such as age, CD4+ cell count, viral counts, and prior nucleoside reverse transcriptase inhibitor exposures.ResultsSixty-seven PWH were enrolled in the study. The mean age of the cohort (n = 67) was 44 years (SD 6.8, range 32–65 years), and 9 participants were female. The mean CD4+ T-cell count was 168 cells/mm3(SD 97 cells/mm3, range 1–416 cells/mm3) and mean viral load was 51,129 copies/mL (SD 114,586 copies/mL, range 147–657,775 copies/mL). We determined that there was a correlation between the total mtDNA deletion and intraepidermal nerve fiber density (IENFD) (r= −0.344,p= 0.04) and sural nerve amplitude (r= −0.359,p= 0.004).ConclusionsBoth IENFD and sural nerve amplitude statistically correlate with mitochondrial mutation burden in PWH, specifically in those with HIV-associated sensory neuropathy as assessed by skin biopsy.

Herpes Simplex virus (HSV) infection is one of the most common sexually transmitted infections among women of the reproductive age. It is estimated to affect about 2−3% of pregnant women. Vertical transmission during pregnancy is rare occurring in less than 1% of cases but for those with active lesions or shedding the virus asymptomatically the risk of vertical transmission intrapartum is high. Neonates with HSV may develop severe consequences such as disseminated, central nervous system and skin, eye mouth/mucous disease or suffer mortality. A high index of suspicion, timely diagnosis and institution of appropriate treatment during acute and recurrent episodes will reduce the risk of vertical transmission and therefore neonatal consequences. Routine screening for HSV in pregnancy is not recommended. This review provides an overview of HSV in pregnancy, diagnosis and management especially around unique scenarios such as prelabour preterm rupture of fetal membranes and presentation with active disease in labour.

The anterolateral soft tissue envelope of the knee is frequently injured at the time of ACL rupture. This study aims to investigate the MRI injury patterns to the Anterolateral complex and their associations in patients with acute 'isolated ligament' ACL ruptures. Professional athletes who underwent ACL reconstruction for complete ACL rupture between 2015 and 2019 were included in this study. Patients' characteristics and intraoperative findings were retrieved from clinical and surgical documentation. Preoperative MRIs were evaluated and the injuries to respective structures of the Anterolateral complex and their associations were recorded. Anterolateral complex injuries were noted in 63% of cases. The majority of injuries were to Kaplan Fibre (39% isolated injury and 19% combined with Anterolateral ligament injury). There was a very low incidence of isolated Anterolateral ligament injuries (2%). Kaplan Fibre injuries are associated with the presence of lateral femoral condyle bone oedema, and injuries to the superficial MCL, deep MCL, and ramp lesions. High grade pivot shift test was not associated with the presence of Kaplan Fibre or Anterolateral ligament injuries. Patients with an intact Anterolateral complex sustained injury to other knee structures (13% to medial ligament complex, 14% to medial meniscus, and 16% to lateral meniscus). There is a high incidence of concomitant Anterolateral complex injuries in combination with ACL ruptures, with Kaplan Fibre (and therefore the deep capsulo-osseous layer of the iliotibial band) being the most commonly injured structure. Anterolateral ligament injuries occur much less frequently. These findings reinforce the importance of considering the presence of, and if necessary, treating injuries to structures other than the ACL, as a truly isolated ACL injury is rare.

Syphilis remains a common congenital infection over the globe. There has been a tremendous rise in the number of congenital syphilis cases worldwide in the last 20 years. It affects large numbers of pregnant mothers in high burden regions causing a significantly high perinatal mortality and morbidity, which can be easily prevented by early antenatal screening and treatment. Diagnosis of maternal syphilis in pregnancy mainly based on clinical symptoms, serological tests and direct identification of treponemes in clinical samples. However, the diagnosis can be challenging due to the relapsing-remitting nature of the disease. The early stage of the infection is usually symptomatic which is commonly followed by an asymptomatic latent phase but infectious and as a result serological tests will be positive. The risk of transplacental transmission is high during the second and third trimester. Obstetric complications of syphilis include spontaneous miscarriage, non-immune hydrops, stillbirth, preterm labour, low birth weight, increased neonatal mortality and congenital syphilis among neonates. Penicillin is the drug of choice for treatment and should be commenced immediately. Babies born to mothers with syphilis should also be treated with penicillin. Early detection and prompt intervention are the key to the prevention and successful control of congenital syphilis. The aim of this review is to highlight the impact of syphilis infection on pregnancy and discuss the current trends in diagnosis and management of maternal and congenital syphilis.

This study examined overall and gender-specific associations between place-based characteristics and opposite-sex exchange sex among people who inject drugs (PWID) in the U.S. PWID were recruited from 19 metropolitan statistical areas (MSAs) for the Centers for Disease Control and Prevention’s 2012 National HIV Behavioral Surveillance. Administrative data were used to describe the economic, social, and political features of the ZIP codes, MSAs, counties, and states where PWID lived. Multilevel modeling estimated associations of place characteristics and exchange sex. We found that 52% of women and 23% of men reported past-year opposite-sex exchange sex (N = 7599). Female PWID living in states with stronger policies supporting working caregivers had lower odds of exchange sex (aOR = 0.80; 95% CI 0.69, 0.94). PWID living in ZIP codes with greater economic deprivation had higher odds of exchange sex (aOR = 1.10; 95% CI 1.03, 1.17). We found that a high percentage of male PWID exchanged sex with women; determinants and risks of this group merit exploration. If future research establishes that the relationships identified here are causal, interventions to reduce exchange sex among PWID should include policies supporting working caregivers and reducing poverty rates.

Toxoplasma gondii is an important zoonotic protozoan parasite that can infect all warm-blooded animals including mammals and birds. Raptors can be intermediate hosts for T. gondii and the infection may be dependent on their feeding habits. In this study, we investigated the seroprevalence of T. gondii in ten raptor species from Florida, Pennsylvania, and Tennessee followed by a parasite bioassay on select seropositive samples. From a total of 155 raptors, we detected T. gondii antibodies using a modified agglutination test (cutoff 1:25) in 32 (20.6%) birds. The T. gondii seroprevalence was 44.8% in Falconiformes (13/29), 75% in Strigiformes (15/20), and 3.8% in Ciconiiformes (4/106). All Ciconiiformes samples (hearts and sera) were collected from Pennsylvania during nuisance wildlife removal projects and all birds were apparently healthy. Falconiform and Strigiform samples were collected from an exotics clinic in Tennessee and a rehabilitation center in Florida. All sampled birds were dead or euthanatized due to failure of rehabilitation or treatment. There was no statistically significant difference in T. gondii seroprevalence between Tennessee and Florida in the tested raptors. There was also no statistically significant difference in T. gondii exposure between males and females or adults and subadults. Mice bioassay attempts using fresh brain and/or heart tissue were performed on four seropositive birds. We isolated viable T. gondii tachyzoites from one red-shouldered hawk (Buteo lineatus) and genotyped the isolate using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) of ten genetic markers. The isolated strain was designated as TgHawkFL1, which is ToxoDB PCR-RFLP genotype #28. Further research is needed to investigate the prevalence of T. gondii in raptors in the United States to obtain a better understanding of the life cycle, wildlife population impacts, and transmission dynamics of the parasite., Graphical abstract Image 1, Highlights • The overall seroprevalence was 20.6% (N = 155). • We isolated ToxoDB PCR-RFLP genotype #28 from one Red-shouldered hawk. • Raptors can be good indicators of environmental contamination with T. gondii.

Characterize the population PK and exposure–response (ER) relationships of selinexor in patients with diffuse large B-cell lymphoma (DLBCL) (efficacy endpoints) or other non-Hodgkin’s lymphoma (NHL) patients (safety endpoints) to determine the optimal dose in patients with DLBCL. This work included patients from seven clinical studies, with 800 patients for PK, 175 patients for efficacy and 322 patients for safety analyses. Logistic regression models and Cox-regression models were used for binary and time-to-event endpoints, respectively. Model-based simulations were performed to justify dose based on balance between efficacy and safety outcome. Selinexor pharmacokinetics were well-described by a two-compartment model with body weight as a significant covariate on clearance and central volume of distribution and gender on clearance. Overall response rate (ORR) in patients with DLBCL increased with day 1 Cmax and decreased in patients with higher baseline tumor size (p

A new Ebola outbreak is currently ongoing in the Democratic Republic of Congo, after the most severe outbreak in West Africa in 2014-2016 was controlled. Ebola outbreaks are usually a significant cause of death among pregnant women. The clinical presentation of Ebola Virus infection in pregnancy often mimics common pregnancy related bleeding complications or febrile conditions common in pregnancy. The large amount of body fluids discharged during the management of these conditions make pregnancy a highly risky intervention for nosocomial infection transmission, especially to health workers. In this review, we discuss the Ebola virus, its pathogenesis, clinical features, diagnosis and the current supportive intensive medical and obstetric- specific practices to ensure safe management of Ebola positive pregnant women. We present how Ebola may be managed in highly resourced settings where experience is limited in the management of pregnancy complicated by Ebola infection and how wherever these patients are managed, postpartum contraceptive support is necessary because of lingering concerns about sexual transmission. Wider issues highlighted by the Ebola outbreaks included the demonstration of how weak health systems from prolonged lack of investment, in the face of highly infectious diseases like Ebola Virus infection, can pose a risk to the global community, bringing sharply into focus the need for essential collaboration between national health departments and international health organizations such as the World Health Organization.

Cytomegalovirus (CMV) is a ubiquitous DNA virus with a global seroprevalence of 83 %. It is the most common pathogen causing teratogenic congenital infection. It is therefore a major public health concern. Maternal infection is associated with congenital CMV (cCMV), the leading cause of non-genetic sensorineural hearing loss. cCMV also causes impairment of cognitive development and cerebral palsy. Transmission of CMV occurs through direct contact with bodily fluids such as saliva, urine or semen from someone who is actively shedding the virus. Transmission rates are higher after primary infection with the rate of transmission increasing with gestational age. Severe fetal effects are however more common when infection occurs before 20weeks. Past infection does not confer immunity to mother or protect the fetus. cCMV may present with cerebral or extracerebral abnormalities on ultrasound, fetal growth restriction and fetal loss. Diagnosis of primary maternal CMV in pregnancy should be based on seroconversion in pregnancy (de novo appearance of virus-specific immunoglobulin G (IgG) in the serum of pregnant women who were previously seronegative) or on detection of specific immunoglobulin M (IgM) and IgG antibodies in association with low IgG avidity. Prenatal diagnosis of fetal CMV is imperfect and based on amniocentesis performed at least 8 weeks after presumed maternal infection and after 17 weeks of gestation. Hygiene information and education of pregnant women is currently the most effective strategy for prevention of CMV infection. The role of vaccines, antiviral drugs and immunoglobulins remains unproven.

The US Food and Drug Administration has approved 3 chimeric antigen receptor (CAR) T-cell therapies. For continued breakthroughs, novel CAR designs are needed. This includes different antigen-binding domains such as antigen-ligand binding partners and variable lymphocyte receptors. Another recent advancement in CAR design is Boolean logic gates that can minimize on-target, off-tumor toxicities. Recent studies on the optimization of costimulatory signaling have also shown how CAR design can impact function. By using specific signaling pathways and transcription factors, CARs can impact T-cell gene expression to enhance function. By using these techniques, the promise of CAR T-cell therapies for solid tumors can be fulfilled.

Immature fetal lung is associated with many adverse outcomes including respiratory distress syndrome and transient tachypnoea of the newborn. Several methods/tools have been used over several decades to assess fetal lung maturity prior to delivery. Some of the methods that have been used to assess fetal lung maturity include amniocentesis for the biochemical markers, lecithin and sphingomyelin, lamellar body counts, gray scale ultrasound scan and magnetic resonance imaging. Amniocentesis an invasive procedure which carries a small risk of miscarriage has almost become obsolete. Magnetic resonance imaging on the other hand is expensive and not very practical. Quantitative ultrasound fetal lung maturity (quantusFLM) assessment is a new technique aimed at assessing fetal lung texture using ultrasound. The technique depends on visualization of fetal lungs at the level of the 4- chamber view. Images obtained are then uploaded via a web page application and these are analyzed remotely and results generated in minutes. The analysis depends on studying changes in the texture of lung images that depend on changes at histological level especially of collagen, fat and water. These changes are undetectable to the human eye. Randomized clinical trials have shown this technique to be accurate, reproducible, and completely non - invasive. The aim of this review was to take a historic look at methods/tools for assessing fetal lug maturity and discuss further advances and a potential non-invasive tool/method especially the non-invasive assessment that combines ultrasound scan and machine learning to accurately assess lung maturity.

Sexual and gender minority adolescents are at increased risk of mental health disorders; yet. little is known about how they cope with minority stressors using social support from adults. The present study examined adolescent reports of adult social support. Using a semistructured life history calendar approach, ethnically diverse sexual and gender minority adolescents (N = 52, aged 14–20 years old, M age = 16.56, SD = 1.66) and conducted a thematic analysis of their responses. A thematic analysis was conducted. The interviews were transcribed and double-coded using a model of social support as a sensitizing framework. Qualitative analyses revealed three themes centered on (a) support from the presence of nonparental adults in schools, (b) validation from adults’ use of proper gender pronouns, and (c) encountering adults who demonstrate a lack of knowledge about sexual and gender minority issues. The present study demonstrates that coping with minority stress can take more subtle forms, both outside the home (or parental context) and in family relationships. These implications are useful for adults working with sexual or gender minority adolescents in social service and educational settings.

Background Sexual minorities (SM) have specific substance use patterns and show elevated rates of substance use and substance use disorders. We investigated the potential association between substance use - including chemsex drug use - among SM adults in the United States (US) and social inequality, with an additional focus on disparities in unmet need for mental health treatment. Methods A secondary cross-sectional data analysis was performed using National Survey on Drug Use and Health (NSDUH) data from 2015 to 2017 and including 126,463 individuals with 8241 identifying as SM. Multivariable logistic regression models were implemented to quantify disparities in substance use, to calculate the effect of sociodemographic variables on substance use, and to examine associations with socioeconomic vulnerability. Findings SM showed higher odds of past-year substance use and lifetime chemsex drug use. All SM except for bisexual men exhibited higher odds of past-month binge drinking relative to heterosexuals. Bisexual women had higher odds for use of all analysed substances relative to heterosexual women. Being older and being a woman were shown to be protective factors. Urbanity, being uninsured, and unmet need for mental health treatment were associated with significantly higher odds of substance use, chemsex drug use and binge drinking. A link was established between drug use and health indicators, with higher odds of drug use for lower health ratings. SM experienced significantly higher levels of socioeconomic vulnerability. Higher vulnerability indices were associated with increased odds for drug use. Interpretation This study is among the first nationally representative samples that analysed the link between sociodemographic factors and unmet need for mental health treatment and substance use in SM. It emphasises the multifactorial aetiology of substance use exposure, highlights the underlying mechanisms for substance use among SM while underscoring disparities among them. Approaches tailored to SM subgroups may be needed to address comorbidities and negative health outcomes of substance use in the long-term. However, critical gaps in the literature remain and large-scale studies inclusive of SM individuals are needed to present causal links. Funding: Gillings Fellowship SYOG054 to ARU.

Vagus nerve stimulation (VNS) is thought to affect neural activity by recruiting brain-wide release of neuromodulators. VNS is used in treatment-resistant epilepsy, and is increasingly being explored for other disorders, such as depression, and as a cognitive enhancer. However, the promise of VNS is only partially fulfilled due to a lack of mechanistic understanding of the transfer function between stimulation parameters and neuromodulatory response, together with a lack of biosensors for assaying stimulation efficacy in real time. We here develop an approach to VNS in head-fixed mice on a treadmill and show that pupil dilation is a reliable and convenient biosensor for VNS-evoked cortical neuromodulation. In an ‘optimal’ zone of stimulation parameters, current leakage and off-target effects are minimized and the extent of pupil dilation tracks VNS-evoked basal-forebrain cholinergic axon activity in neocortex. Thus, pupil dilation is a sensitive readout of the moment-by-moment, titratable effects of VNS on brain state., Despite its wide and growing use, the mechanisms by which in vivo vagus nerve stimulation (VNS) exerts its therapeutic benefits are still largely unknown. Here, the authors show in mice that pupil dilation is a reliable and noninvasive biosensor for titratable VNS-evoked cortical neuromodulation by acetylcholine.

For treatment of severe malaria, the World Health Organization recommends 3 mg/kg intravenous artesunate in pediatric patients weighing less than 20 kg. Here we describe the Food and Drug Administration’s rationale for selecting 2.4 mg/kg in pediatric patients weighing less than 20 kg based on literature review and independent analyses.

Bloodstream infections (BSI) are significant causes of morbidity and mortality in cancer patients. These patients often receive 10 to 14 days of intravenous (IV) antibiotics. The objective of this study was to compare the outcomes of cancer patients transitioned from IV to oral (PO) therapy compared to continuation of IV treatment. This was a single-center, retrospective cohort study of hospitalized adult cancer patients with gram-negative bacteremia. Patients transitioned to a PO fluoroquinolone (FQ) within 5 days were allocated to the IV-to-PO group, while the remaining patients comprised the IV group. The primary outcome was the composite of treatment failure, defined as infection-related readmission, infection recurrence, or inpatient mortality. A multivariable logistic regression model was constructed to account for confounding variables. Secondary outcomes assessed included infection-related length of stay (LOS), hospital LOS, and adverse events, such as Clostridioides difficile infection and catheter-related complications. The IV-to-PO group included 78 patients, while the remaining 133 patients were allocated to the IV group. Differences at baseline included more hematologic malignancy, neutropenia, ICU admissions, and higher Pitt bacteremia scores in the IV group. The rate of treatment failure was significantly higher in the IV group (24% vs 9%; p < 0.01), which persisted in the logistic regression (aOR 3.5, 95% CI 1.3–9.1). The IV-to-PO group had decreased infection-related and hospital length of stay, as well as fewer catheter-related complications. The use of PO FQ may be considered for the definitive treatment of uncomplicated Enterobacterales BSI in cancer patients.

Our understanding of the interactions between the nuclear and mitochondrial genomes is becoming increasingly important as they are extensively involved in establishing early development and developmental progression. Evidence from various biological systems indicates the interdependency between the genomes, which requires a high degree of compatibility and synchrony to ensure effective cellular function throughout development and in the resultant offspring. During development, waves of DNA demethylation, de novo methylation, and maintenance methylation act on the nuclear genome and typify oogenesis and pre- and postimplantation development. At the same time, significant changes in mitochondrial DNA copy number influence the metabolic status of the developing organism in a typically cell-type-specific manner. Collectively, at any given stage in development, these actions establish genomic balance that ensures each developmental milestone is met and that the organism's program for life is established.

Background The prevalence of burnout and depressive symptoms is high among physician trainees. Research Question What is the burden of burnout and depressive symptoms among fellows training in pulmonary and critical care medicine (PCCM) and what are associated individual fellow, program, and institutional characteristics? Study Design and Methods We conducted a cross-sectional electronic survey of fellows enrolled in pulmonary, PCCM, and critical care medicine training programs in the United States to assess burnout and depressive symptoms. Burnout symptoms were measured using the Maslach Burnout Index two-item measure. The two-item Primary Care Evaluation of Mental Disorders Procedure was used to screen for depressive symptoms. For each of the two outcomes (burnout and depressive symptoms), we constructed three multivariate logistic regression models to assess individual fellow characteristics, program structure, and institutional polices associated with either burnout or depressive symptoms. Results Five hundred two of the 976 fellows who received the survey completed it—including both outcome measures—giving a response rate of 51%. Fifty percent of fellows showed positive results for either burnout or depressive symptoms, with 41% showing positive results for depressive symptoms, 32% showing positive results for burnout, and 23% showing positive results for both. Reporting a coverage system in the case of personal illness or emergency (adjusted OR [aOR], 0.44; 95% CI, 0.26-0.73) and access to mental health services (aOR, 0.14; 95% CI, 0.04-0.47) were associated with lower odds of burnout. Financial concern was associated with higher odds of depressive symptoms (aOR, 1.13; 95% CI, 1.05-1.22). Working more than 70 hours in an average clinical week and the burdens of electronic health record (EHR) documentation were associated with a higher odds of both burnout and depressive symptoms. Interpretation Given the high prevalence of burnout and depressive symptoms among fellows training in PCCM, an urgent need exists to identify solutions that address this public health crisis. Strategies such as providing an easily accessible coverage system, access to mental health resources, reducing EHR burden, addressing work hours, and addressing financial concerns among trainees may help to reduce burnout or depressive symptoms and should be studied further by the graduate medical education community.

Objective To identify the geographic, organisational, and payment correlates of buprenorphine and methadone treatment among substance abuse treatment (SAT) providers. Methods Secondary analyses of the National Survey of Substance Abuse Treatment Services (NSSATS) from 2007–16 were conducted. We provide bivariate descriptive statistics regarding substance abuse treatment services which offered buprenorphine and methadone treatment from 2007–16. Using multiple logistic regression, we regressed geographic, organisational, and payment correlates on buprenorphine and methadone treatment. Results Buprenorphine is increasingly offered at SAT facilities though uptake remains comparatively low outside of the northeast. SAT facilities run by tribal governments or Indian Health Service which offer buprenorphine remain low compared to privately operated SAT facilities (AOR = 0.528). The odds of offering buprenorphine among facilities offering free or no charge treatment (AOR = 0.838) or a sliding fee scale (AOR = 0.464) was lower. SAT facilities accepting Medicaid payments showed higher odds of offering methadone treatment (AOR = 2.035). Conclusions Greater attention towards the disparities in provision of opioid agonist therapies is warranted, especially towards the reasons why uptake has been moderate among civilian providers. Additionally, the care needs of Native Americans facing opioid-related use disorders bears further scrutiny.

Summary Background Few large projects have evaluated the factors that influence the HIV RNA concentrations (viral load) in cerebrospinal fluid (CSF) during antiretroviral therapy (ART) over time. We aimed to determine the correlates of HIV RNA in CSF in a large cohort. Methods We analysed longitudinal data from adults living with HIV in the US CHARTER cohort. Participants in the CHARTER study were recruited from six US academic medical centres—in Baltimore (MD), Galveston (TX), New York (NY), St Louis (MO), San Diego (C92A), and Seattle (WA). Participants in this study had been assessed at least three times between Sept 4, 2003, and Sept 14, 2010, and were taking ART and underwent venous and lumbar puncture with measurement of HIV RNA concentration at all assessments. The lower limit of quantification of the HIV RNA assays was 50 copies per mL. Data were analysed with longitudinal mixed effects logistic regression to identify correlates of HIV RNA concentration (as a binary [detectable or not] and as a continuous variable) in CSF over time. We tested demographic characteristics, plasma HIV RNA, nadir and current CD4 cell count in blood, current CD8 cell count in blood, estimated duration of HIV infection, AIDS diagnosis, duration of ART, adherence to ART, ART characteristics, and CSF characteristics as potential correlates. Findings At the time of analysis, 2207 assessments from 401 participants met the criteria for inclusion in this study. Mean duration of observation was 33·7 months (range 12–84). HIV RNA concentrations in 710 (32·2%) plasma specimens and in 255 (11·6%) CSF specimens were greater than the lower limit of quantification. The best multivariate model of HIV RNA concentration in CSF greater than the lower limit of quantification over time included increased plasma HIV RNA concentration (odds ratio 18·0 per 1 log10 copy per mL, 95% CI 11·3 to 28·8; p Interpretation The identified correlates of HIV RNA concentration in CSF during ART could strengthen clinical prediction of risk for failure to achieve or maintain HIV RNA suppression in CSF. Because most participants in this analysis were ART-experienced and were taking a three-drug regimen that did not include an integrase inhibitor, future research should focus on participants who are taking their first ART regimens or regimens that include integrase inhibitors or two drugs. Funding The work was supported by the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke.

Over the past century, psychologists have discussed whether forgetting might arise from active mechanisms that promote memory loss to achieve various functions, such as minimizing errors, facilitating learning, or regulating one's emotional state. The past decade has witnessed a great expansion in knowledge about the brain mechanisms underlying active forgetting in its varying forms. A core discovery concerns the role of the prefrontal cortex in exerting top-down control over mnemonic activity in the hippocampus and other brain structures, often via inhibitory control. New findings reveal that such processes not only induce forgetting of specific memories but also can suppress the operation of mnemonic processes more broadly, triggering windows of anterograde and retrograde amnesia in healthy people. Recent work extends active forgetting to nonhuman animals, presaging the development of a multilevel mechanistic account that spans the cognitive, systems, network, and even cellular levels. This work reveals how organisms adapt their memories to their cognitive and emotional goals and has implications for understanding vulnerability to psychiatric disorders.

Aims Within the TeleCheck-AF project, numerous centres in Europe used on-demand photoplethysmography (PPG) technology to remotely assess heart rate and rhythm in conjunction with teleconsultations. Based on the TeleCheck-AF investigator experiences, we aimed to develop an educational structured stepwise practical guide on how to interpret PPG signals and to introduce typical clinical scenarios how on-demand PPG was used. Methods and results During an online conference, the structured stepwise practical guide on how to interpret PPG signals was discussed and further refined during an internal review process. We provide the number of respective PPG recordings (FibriCheck®) and number of patients managed within a clinical scenario during the TeleCheck-AF project. To interpret PPG recordings, we introduce a structured stepwise practical guide and provide representative PPG recordings. In the TeleCheck-AF project, 2522 subjects collected 90 616 recordings in total. The majority of these recordings were classified by the PPG algorithm as sinus rhythm (57.6%), followed by AF (23.6%). In 9.7% of recordings, the quality was too low to interpret. The most frequent clinical scenarios where PPG technology was used in the TeleCheck-AF project was a follow-up after AF ablation (1110 patients) followed by heart rate and rhythm assessment around (tele)consultation (966 patients). Conclusion We introduce a newly developed structured stepwise practical guide on PPG signal interpretation developed based on presented experiences from TeleCheck-AF. The present clinical scenarios for the use of on-demand PPG technology derived from the TeleCheck-AF project will help to implement PPG technology in the management of AF patients.

Three classes of ion-driven protein motors have been identified to date: ATP synthase, the bacterial flagellar motor and a proton-driven motor that powers gliding motility and the type 9 protein secretion system in Bacteroidetes bacteria. Here, we present cryo-electron microscopy structures of the gliding motility/type 9 protein secretion system motors GldLM from Flavobacterium johnsoniae and PorLM from Porphyromonas gingivalis. The motor is an asymmetric inner membrane protein complex in which the single transmembrane helices of two periplasm-spanning GldM/PorM proteins are positioned inside a ring of five GldL/PorL proteins. Mutagenesis and single-molecule tracking identify protonatable amino acid residues in the transmembrane domain of the complex that are important for motor function. Our data provide evidence for a mechanism in which proton flow results in rotation of the periplasm-spanning GldM/PorM dimer inside the intra-membrane GldL/PorL ring to drive processes at the bacterial outer membrane. Using cryo-electron microscopy, the authors describe the structure and function of a molecular motor powering both the Bacteroidetes type 9 protein secretion system and the associated gliding motility apparatus.

Intestinal parasitic infections are widespread worldwide and with increased global travel and transport of food, these are not entirely limited to traditionally endemic areas. The prevalence of parasitic infections in endemic areas among pregnant women ranges from 24 to 70 % with approximately 10 % of women having multiple parasites. Pregnancy with its increased nutritional demands and altered immunological defenses is an especially vulnerable time for acquiring parasitic infections, which may be associated with adverse outcomes such as anaemia, which in some cases may even contribute to mortality. The presence of a helminthic infections during pregnancy may also cause immunological effects that can contribute to maternal morbidity and mortality as well as affecting the maternal immune response and immune system function in the baby after birth. Mass administration of anthelminthic drug therapy has been applied in endemic areas but there is inconclusive evidence of its benefit in improving pregnancy outcomes, however, no safety concerns have been highlighted with the use of the recommended drugs for parasitic infections.

Introduction Recurrent multidirectional shoulder instability after failed capsular repair/plication, is a challenging treatment problem. The long head of the biceps has been identified as a structure that may be utilized as a checkrein to stop abnormal anterior and inferior translation of the humeral head. The purpose of this study is to analyse the outcomes of biceps suspensionplasty (BS) in the treatment of recurrent shoulder instability. Methods A retrospective review identified patients with recurrent multidirectional instability that underwent BS as part of a revision shoulder stabilization procedure. Clinical records were reviewed for demographics, pain, complications, recurrent instability, reoperations, and range of motion. Patients were also administered ASES/SST/SANE/Rowe and Oxford instability questionnaire at minimum of 2-year clinical follow-up. Results Five patients (7 shoulders) were included with a mean follow-up of 3.2 years (2–7 years). Patients had an average of 1.6 prior procedures (1–3). Average patient age was 24.2 years (18.7–32.4 years) and all were female. Four shoulders were treated open while 3 were treated arthroscopically with a capsular shift and biceps suspension. Four shoulders also underwent capsular reconstruction with allograft. At final follow-up three shoulders had recurrent inferior subluxation, although all patients considered their shoulders to be much better (4) or somewhat better (3) and none have undergone repeat surgery. Conclusion In our series of patients, we found BS may be useful as an adjunct to a revision capsular shift or reconstruction. While 42.8% of patients experienced recurrent subluxations, this high-risk population demonstrated encouraging subjective results and avoiding joint arthrodesis in the short-term.

Purpose of Review To evaluate the critical studies published so far on the most promising antiviral therapies for COVID-19, with particular emphasis on any solid organ transplant–specific information. Recent Findings Although the literature is increasing exponentially, most clinical trials have been preliminary, thus lacking robust evidence to support many of the drugs discussed here. The main exception is remdesivir, for which several trials have been published supporting its use for patients with severe COVID-19. No solid organ transplant–specific data on remdesivir or other antiviral therapies have been published so far. Summary While further studies are urgently needed, in particular those specific to solid organ transplant recipients, the evidence so far only supports the use of remdesivir for patients with severe COVID-19.

Untreated gastroesophageal reflux disease (GERD) can lead to Barrett’s esophagus and an increased risk for esophageal adenocarcinoma. Magnetic sphincter augmentation (MSA) is a safe and effective modality for the treatment of GERD. Preliminary research on short-term outcomes after MSA demonstrated significant regression of Barrett’s. Further investigation is required to evaluate the long-term effect of this treatment. A retrospective review of patients was conducted with biopsy-proven Barrett’s esophagus who underwent MSA between 2007 and 2019. As a part of their preoperative evaluation, patients underwent esophagogastroduodenoscopy (EGD) with biopsies of the distal esophagus and gastroesophageal junction including any abnormal-appearing segments, pH testing, and a videoesophagram. Patients were categorized according to the length of Barrett’s identified (ultrashort 3 cm). Improvement was defined as a decrease in length (e.g. long to short). There were 87 patients identified for study inclusion. 55 patients were male. The median body mass index was 26.95. The median age was 61.81 (49.79–68.29). Mean follow-up time was 2.35 ± (1.57) years. 7 (8.0%) of these patients began with long segment Barrett’s, 58 (66.7%) began with short segment disease, and 22 (25.3%) began with an ultrashort segment. Within this cohort, 74 (85.06%) had undergone postoperative biopsy. 7 out of 74 patients (9.46%) showed improvement in their intestinal metaplasia and 45/74 (60.81%) showed complete regression. Fisher’s exact test showed a significant decrease in Barrett’s length following MSA (p = 0.002). No patients progressed to dysplasia or neoplasia. There was a statistically significant decrease in the median Demeester score from 34.00 to 13.70 after surgery (p

We conducted a longitidinal assessment of 806 respondents in March, 2020 in the US to examine the trustworthiness of sources of information about COVID-19. Respondents were recontacted after four months. Information sources included mainstream media, state health departments, the CDC, the White House, and a well-known university. We also examined how demographics, political partisanship, and skepticism about COVID-19 were associated with the perceived trustworthiness of information sources and decreased trustworthiness over time. At baseline, the majority of respondants reported high trust in COVID-19 information from state health departments (75.6%), the CDC (80.9%), and a university (Johns Hopkins, 81.1%). Mainstream media was trusted by less than half the respondents (41.2%), and the White House was the least trusted source (30.9%). At the 4-month follow-up, a significant decrease in trustworthiness in all five sources of COVID-19 information was observed. The most pronounced reductions were from the CDC and the White House. In multivariate analyses, factors associated with rating the CDC, state health department, and a university as trustworthy sources of COVID-19 information were political party affiliation, level of education, and skepticism about COVID-19. The most consistent predictor of decreased trust was political party affiliation, with Democrats as compared to Republicans less likely to report decreased trust across all sources.

Aims: Recently, a novel isoform of anaplastic lymphoma kinase, with alternative transcription initiation (ALKATI ), has been described in melanoma and is susceptible to targeted ALK-inhibitor therapy. Clinical outcomes of patients with ALKATI mutated melanoma as well as correlation with immunohistochemical (IHC) methods has not yet been described. Methods and results: Clinicopathologic characteristics were abstracted for 324 patients with metastatic melanoma (MM). IHC, fluorescence in situ hybridization, and RNA based digital molecular analysis (NanoString Technologies) assays were performed on archival tissue from 173 stage III and 192 stage IV tumors. ALKATI was identified in 12.7% and 4.8% stage III and IV tumors, respectively. Discrete presentations of the ALKATI are seen: isolated ALKATI (N=20) and mixed ALKATI (combined ALKATI and ALKWT ; N=7). Isolated ALKWT expression (N=4) was seen with no ALK fusions. Stage III patients showed improved survival with ALKATI expression as compared to those with ALKWT or no expression [5-year survival 80% (95% CI: 57%-100%) versus 43% (95% CI: 34%-55%), p=0.013]. Clinicopathologic characteristics were not statistically significant. Strong diffuse cytoplasmic staining of ALK IHC (N=12), has a sensitivity of 52.2%, specificity 100%, PPV of 100% and NPV of 92.5% of detecting isolated ALKATI . Conclusion: Presence of ALKATI is a good prognostic indicator in MM. ALK IHC and digital molecular analysis can be incorporated into MM evaluation to identify patients with ALKATI for targeted therapy.

To present a tumor motion control system during free breathing using direct tumor visual feedback to patients in 0.35 T magnetic resonance‐guided radiotherapy (MRgRT). We present direct tumor visualization to patients by projecting real‐time cine MR images on an MR‐compatible display system inside a 0.35 T MRgRT bore. The direct tumor visualization included anatomical images with a target contour and an auto‐segmented gating contour. In addition, a beam‐status sign was added for patient guidance. The feasibility was investigated with a six‐patient clinical evaluation of the system in terms of tumor motion range and beam‐on time. Seven patients without visual guidance were used for comparison. Positions of the tumor and the auto‐segmented gating contour from the cine MR images were used in probability analysis to evaluate tumor motion control. In addition, beam‐on time was recorded to assess the efficacy of the visual feedback system. The direct tumor visualization system was developed and implemented in our clinic. The target contour extended 3 mm outside of the gating contour for 33.6 ± 24.9% of the time without visual guidance, and 37.2 ± 26.4% of the time with visual guidance. The average maximum motion outside of the gating contour was 14.4 ± 11.1 mm without and 13.0 ± 7.9 mm with visual guidance. Beam‐on time as a percentage was 43.9 ± 15.3% without visual guidance, and 48.0 ± 21.2% with visual guidance, but was not significantly different (P = 0.34). We demonstrated the clinical feasibility and potential benefits of presenting direct tumor visual feedback to patients in MRgRT. The visual feedback allows patients to visualize and attempt to minimize tumor motion in free breathing. The proposed system and associated clinical workflow can be easily adapted for any type of MRgRT.

Background: Many of the painful, disabling features of early diffuse cutaneous systemic sclerosis have an inflammatory component and are potentially treatable with corticosteroid therapy. These features include painful and itchy skin, fatigue and musculoskeletal involvement. Yet many clinicians are understandably reluctant to prescribe corticosteroids because of the concern that these are a risk factor for scleroderma renal crisis. The aim of PRedSS (PRednisolone in early diffuse cutaneous Systemic Sclerosis) is to evaluate the efficacy and safety of moderate dose prednisolone in patients with early diffuse cutaneous systemic sclerosis, specifically whether moderate dose prednisolone is (a) effective in terms of reducing pain and disability, and improving skin score and (b) safe, with particular reference to renal function. Methods: PRedSS is a Phase II, multicentre, double-blind randomised controlled trial which aims to recruit 72 patients with early diffuse cutaneous systemic sclerosis. Patients are randomised to receive either prednisolone (dosage approximately 0.3 mg/kg) or placebo therapy for 6 months. The two co-primary outcome measures are the difference in mean Health Assessment Questionnaire Disability Index at 3 months and the difference in modified Rodnan skin score at 3 months. Secondary outcome measures include patient reported outcome measures of itch, hand function, anxiety and depression, and helplessness. Results: Recruitment commenced in December 2017 and after a slow start (due to delays in opening centres) 25 patients have now been recruited. Conclusion: PRedSS should help to answer the question as to whether clinicians should or should not prescribe prednisolone in early diffuse cutaneous systemic sclerosis.

More than a million cases of cutaneous squamous cell carcinoma are diagnosed in the USA each year, and its incidence is increasing. Most of these malignancies arise from premalignant lesions, providing an opportunity for intervention before malignant progression. We previously documented how cytoplasmic mislocalization of CDC25A in premalignant and malignant skin cancers confers resistance to apoptotic cell death via a mechanism that depends on its interaction with 14-3-3ε. From these data, we hypothesized that 14-3-3ε overexpression drives skin tumor development and progression, such that targeting 14-3-3ε may be a useful strategy for skin cancer treatment. Like CDC25A, 14-3-3ε was overexpressed and mislocalized to the cytoplasm of both benign and malignant human skin cancer. Skin-targeted deletion of the 14-3-3ε gene reduced skin tumor development by 75% and blocked malignant progression. 14-3-3ε suppressed apoptosis through activation of Akt, leading to inhibition of BCL2 associated agonist of cell death and upregulation of Survivin. Using virtual tetrapeptide libraries, we developed a novel peptide that specifically blocked 14-3-3ε heterodimerization and thereby prevented its interaction with CDC25A. The peptide reduced prosurvival signaling, killed skin cancer cells and reduced skin tumor growth in xenograft. Normal skin keratinocytes were unaffected by inhibition or deletion of 14-3-3ε. Thus, targeting of 14-3-3ε dimerization is a promising strategy for the treatment of premalignant skin lesions.

Takayasu arteritis is a large vessel vasculitis which commonly affects the aorta and its major branches. Active arterial inflammation is characterised by the presence of T and B lymphocytes, natural killer cells, macrophages and occasional multinucleate giant cells. Uncontrolled vascular inflammation can progress to cause arterial stenosis, occlusion or aneurysmal dilatation. Medical treatment involves combination immunosuppression and more recently biologic therapies targeting TNF-α and IL-6. Due to the typical delays in diagnosis and accumulation of arterial injury, open and endovascular surgical intervention are important and potentially life-saving treatment options for Takayasu arteritis. Common indications for surgery include aortic coarctation and ascending aortic dilatation ± aortic valve regurgitation, renal artery stenosis, ischaemic heart disease, supra-aortic disease, mesenteric ischaemia, severe limb-threatening claudication and aneurysm repair. Surgical outcomes are markedly improved in patients with clinically inactive disease and those who receive adequate periprocedural immunosuppression. Decisions regarding surgical approaches are best made as part of a multi-disciplinary team.

We introduce laser cavitation rheology (LCR) as a minimally-invasive optical method to characterize mechanical properties within the interior of biological and synthetic aqueous soft materials at high strain-rates. We utilized time-resolved photography to measure cavitation bubble dynamics generated by the delivery of focused 500 ps duration laser radiation at λ = 532 nm within fibrin hydrogels at pulse energies of Ep = 12, 18 µJ and within polyethylene glycol (600) diacrylate (PEG (600) DA) hydrogels at Ep = 2, 5, 12 µJ. Elastic moduli and failure strains of fibrin and PEG (600) DA hydrogels were calculated from these measurements by determining parameter values which provide the best fit of the measured data to a theoretical model of cavitation bubble dynamics in a Neo-Hookean viscoelastic medium subject to material failure. We demonstrate the use of this method to retrieve the local, interior elastic modulus of these hydrogels and both the radial and circumferential failure strains.

Graft-versus-host disease (GVHD) remains an important cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). For decades, GVHD prophylaxis has included calcineurin inhibitors, despite their incomplete efficacy and impairment of graft-versus-leukemia (GVL). Distinct from pharmacologic immune suppression, we have developed what we believe is a novel, human CD83-targeted chimeric antigen receptor (CAR) T cell for GVHD prevention. CD83 is expressed on allo-activated conventional CD4(+) T cells (Tconvs) and proinflammatory dendritic cells (DCs), which are both implicated in GVHD pathogenesis. Human CD83 CAR T cells eradicate pathogenic CD83(+) target cells, substantially increase the ratio of regulatory T cells (Tregs) to allo-activated Tconvs, and provide durable prevention of xenogeneic GVHD. CD83 CAR T cells are also capable of treating xenogeneic GVHD. We show that human acute myeloid leukemia (AML) expresses CD83 and that myeloid leukemia cell lines are readily killed by CD83 CAR T cells. Human CD83 CAR T cells are a promising cell-based approach to preventing 2 critical complications of allo-HCT — GVHD and relapse. Thus, the use of human CD83 CAR T cells for GVHD prevention and treatment, as well as for targeting CD83(+) AML, warrants clinical investigation.

Background and aim Secondary prophylaxis (SP) of variceal rebleeding was reported to improve outcomes of hepatocellular carcinoma (HCC) patients, but the optimal endoscopic approach is not well defined. We compared outcomes in HCC patients who underwent SP by endoscopic ultrasound-guided cyanoacrylate obturation (EUS-CYA) versus no SP. Methods Between 2014 and 2018, 30 consecutive patients with inoperable HCC and recent endoscopically controlled variceal bleeding were prospectively recruited. Twenty-seven patients with persistent varices ≥ 3 mm on endoscopic ultrasound underwent EUS-CYA for SP. Thirty-three HCC patients treated by esophagogastroduodenoscopy-guided CYA obturation (EGD-CYA) alone for acute variceal bleeding between 2009 and 2013 were identified from a prospective gastrointestinal bleed registry as standard of care controls for comparison. Outcome measures were death-adjusted cumulative incidence of rebleeding, bleeding-free survival, technical success, and procedure-related adverse events of EUS-CYA. Results The majority of patients in both groups had advanced HCC, portal vein thrombosis, and Child-Pugh B cirrhosis. EUS-CYA was successful in all 27 patients with no radiographic evidence of cyanoacrylate-lipiodol embolization. Significantly lower 30- and 90-day death-adjusted cumulative incidence of rebleeding (14.8% vs 42.4%, P = 0.023 and 18.5% vs 60.6%, P = 0.002, respectively) and significantly higher variceal bleeding-free survival at 3 and 6 months (51.9% vs 21.2%, P = 0.009, 40.7% vs 15.2%, P = 0.010, respectively) were observed in the EUS-CYA group when compared with standard of care group. Conclusions Secondary prophylaxis by EUS-CYA reduced rebleeding rate and improved variceal bleeding-free survival in patients with inoperable HCC and variceal bleeding when compared with no SP. Randomized studies are needed to confirm the benefits of EUS-CYA for this difficult-to-treat population.

Background Observational studies suggest that regular physical activity may reduce cardiovascular morbidity and cancer recurrence in survivors of breast cancer. The association between physical activity and cardiac function with breast cancer therapy is unknown. Methods Self‐reported physical activity was assessed using the Godin Leisure‐Time Exercise Questionnaire at repeated intervals in a longitudinal cohort study of 603 breast cancer participants treated with doxorubicin and/or trastuzumab. Multivariable regression models estimated associations between clinical variables and physical activity. Generalized estimating equations adjusted for prespecified variables estimated associations between baseline physical activity and longitudinal echocardiographic measures of systolic and diastolic function. Results Physical activity was low at baseline, prior to cancer therapy initiation. More than half of participants reported no moderate‐strenuous physical activity, and only 12.1% met guideline recommended levels of physical activity. Physical activity increased after chemotherapy completion; however, only 26.0% of individuals were sufficiently active 3 years after cancer diagnosis. Body mass index, hyperlipidemia and higher cancer stage were significantly associated with lower total physical activity at baseline. Higher baseline physical activity was very modestly associated with an attenuation in the absolute decline in left ventricular ejection fraction over time (β 0.4%, 95% CI 0.1, 0.7, P = .02 for each 10‐unit increase in total activity). There tended to be a cardioprotective association with cardiotoxicity risk, although this was not statistically significant (HR 0.83, 95% CI 0.66, 1.04, P = .097). Conclusions A small proportion of breast cancer patients and survivors are engaged in regular moderate‐strenuous physical activity. While only modest associations between self‐reported physical activity and left ventricular systolic function were observed, our findings do not exclude a cardioprotective benefit of exercise., Self‐reported physical activity was assessed using the Godin Leisure‐Time Exercise Questionnaire at repeated intervals in a longitudinal cohort study of 603 breast cancer participants treated with doxorubicin and/or trastuzumab. Physical activity was low at baseline and increased somewhat after chemotherapy completion however, only 26.0% of individuals were sufficiently active 3 years after cancer diagnosis. Higher baseline physical activity was very modestly associated with an attenuation in the absolute decline in left ventricular ejection fraction over time.

The peroneus quartus is one of a variety of described accessory peroneal muscles, most commonly an incidental finding on MRI or ultrasound of the ankle. We present the only described case in the literature of a peroneus quartus tendon rupture in a professional rugby player as well as the MRI findings.

Purpose Gastrointestinal symptoms in individuals with autism spectrum disorder may constitute a subgroup with complex gut-brain interactions underlying the pathogenesis. This study examined the prevalence of gastrointestinal symptoms in a sample of Chinese children with autism spectrum disorder, as well as the factors related to them. Participants and methods The participants included a clinic sample of 107 children with autism spectrum disorder and 249 gender- and age-matched typically developing community children. Results Results found children with autism spectrum disorder to be twice as likely to suffer from gastrointestinal symptoms, reporting increased rates of constipation, abdominal migraine and aerophagia. Autism spectrum disorder diagnosis remained a significant predictor of gastrointestinal symptoms after taking into account the potential confounders that included comorbid psychopathologies, diets, and parental anxiety and depression. Conclusion Our results suggest that autism spectrum disorder with gastrointestinal symptoms may constitute a subgroup within the autism spectrum disorder population that warrants further investigation.

Background Surgical resection is a mainstay of colorectal cancer treatment, and prior studies have shown improved outcomes in patients undergoing surgery for colorectal cancer by colorectal surgical specialists compared with nonspecialized surgeons. Here, we examine the geographic distribution of colorectal surgeons in the United States and its relationship with sociodemographic characteristics of the served population. Methods The Area Health Resource File from 2017 to 2018 was used to identify the number and location of colorectal surgeons practicing throughout the United States and sociodemographic characteristics at the county and hospital referral region (HRR) level. The main outcomes of interest were the density of colorectal surgeons per 100,000 population and associations with sociodemographic characteristics at the county and HRR level based on multivariable linear regression. Results In multivariable analysis, regions with higher proportion of nonwhite individuals and college-educated individuals had significantly more colorectal surgeons per 100,000 population, whereas regions with higher proportions of uninsured individuals had significantly fewer colorectal surgeons per 100,000 population at both the county and HRR levels. Conclusions Geographic and sociodemographic variability exists in the distribution of colorectal surgeons in the United States. Such variability may be contributing to disparities in access to specialized colorectal care.