Notes

Mentor Endrenyi's Legacy of music: An exam in the Regulation Requirement "Fixed Consequences, As opposed to Haphazard Results, Should Be Used for Just about all Terms".
Collectively, these data define a YAP-dependent mechanism of pancreatic cancer cell development and suggest that inhibition of AP-1 can suppress this development. SIGNIFICANCE A pancreatic ductal cell-specific knockout mouse model featuring constitutively active YAP allows for the study of YAP-dependent transformation of the pancreas and for screening pharmacologically active inhibitors.Following chemotherapy and relapse, high-risk neuroblastoma tumors harbor more genomic alterations than at diagnosis, including increased transcriptional activity of the Yes-associated protein (YAP), a key downstream component of the Hippo signaling network. Although YAP has been implicated in many cancer types, its functional role in the aggressive pediatric cancer neuroblastoma is not well-characterized. In this study, we performed genetic manipulation of YAP in human-derived neuroblastoma cell lines to investigate YAP function in key aspects of the malignant phenotype, including mesenchymal properties, tumor growth, chemotherapy response, and MEK inhibitor response. Standard cytotoxic therapy induced YAP expression and transcriptional activity in patient-derived xenografts treated in vivo, which may contribute to neuroblastoma recurrence. Moreover, YAP promoted a mesenchymal phenotype in high-risk neuroblastoma that modulated tumor growth and therapy resistance in vivo. Finally, the BH3-only protein, Harakiri (HRK), was identified as a novel target inhibited by YAP, which, when suppressed, prevented apoptosis in response to nutrient deprivation in vitro and promoted tumor aggression, chemotherapy resistance, and MEK inhibitor resistance in vivo. Collectively, these findings suggest that YAP inhibition may improve chemotherapy response in patients with neuroblastoma via its regulation of HRK, thus providing a critical strategic complement to MEK inhibitor therapy. SIGNIFICANCE This study identifies HRK as a novel tumor suppressor in neuroblastoma and suggests dual MEK and YAP inhibition as a potential therapeutic strategy in RAS-hyperactivated neuroblastomas.Graft-versus-host disease (GvHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT), mediated primarily by donor T cells that become activated and attack host tissues. Noninvasive strategies detecting T-cell activation would allow for early diagnosis and possibly more effective management of HCT recipients. PET imaging is a sensitive and clinically relevant modality ideal for GvHD diagnosis, and there is a strong rationale for the use of PET tracers that can monitor T-cell activation and expansion with high specificity. The TNF receptor superfamily member OX40 (CD134) is a cell surface marker that is highly specific for activated T cells, is upregulated during GvHD, and mediates disease pathogenesis. We recently reported the development of an antibody-based activated T-cell imaging agent targeting OX40. selleck In the present study, we visualize the dynamics of OX40 expression in an MHC-mismatch mouse model of acute GvHD using OX40-immunoPET. This approach enabled visualization of T-cell activation at early stages of disease, prior to overt clinical symptoms with high sensitivity and specificity. This study highlights the potential utility of the OX40 PET imaging as a new strategy for GvHD diagnosis and therapy monitoring. SIGNIFICANCE OX40-immunoPET imaging is a promising noninvasive strategy for early detection of GvHD, capable of detecting signs of GvHD pathology even prior to the development of overt clinical symptoms.
Different primary care delivery models exist for mothers and their infants. We examined whether primary care system performance measures differed when mother-infant dyads received primary care from the same or different providers.

We conducted a population-based cohort study using Ontario health administrative data from 2004 to 2016. We included primiparous women and their singleton term infants and classified the primary care practitioners who provided the majority of care to the infant and the mother as concordant (same family physician for both; reference group), discordant (a different family physician for each) or pediatrician (pediatrician for the child, family physician for the mother). The primary outcome was nonobstetric maternal hospital admissions between 42 days and 2 years after delivery.

Among 481 721 mother-child pairs, 239 033 (49.6%) received concordant care, 114 006 (23.7%) received discordant care, and 128 682 (26.7%) received pediatrician care. Mothers in the pediatrician group were ance. link2 The reason that pediatric primary care is associated with better maternal and child outcomes remains to be determined.
Concordant care provided to a new mother and her infant by the same family physician was not associated with better primary care health system performance. The reason that pediatric primary care is associated with better maternal and child outcomes remains to be determined.
Although frequent emergency department (ED) use is a global issue, little research has been conducted in a country like Japan where universal health insurance is available. The study aims to (1) document the proportion of ED visits that are by frequent users and (2) describe the differences in characteristics of frequent ED users and other ED users including expenditures between a secondary and a tertiary hospital.

A prevalence study for a period of 1 year.

A secondary hospital and a tertiary hospital in central Japan.

All patients who presented to the EDs.

We defined frequent ED user as a patient who visited the ED≥5 times/year. The main outcome measures were the proportion of frequent ED users among all ED users and the proportion of healthcare expenditures by the frequent ED users among all ED expenditures.

Of 25 231 ED visits over 1 year, 134 frequent ED users accounted for 1043 visits-0.66% of all ED users, comprised 4.1% of all ED visits, and accounted for 1.9% of total healthcare expenditures. Median ED visits per one frequent ED user was 7.9. At the patient level, after adjusting for age, gender and receiving public assistance, older age (OR 1.01, 95% CI 1.00 to 1.02) and receiving public assistance (OR 7.19, 95% CI 2.87 to 18.07) had an association with frequent ED visits. At the visit-level analysis, evaluation by internal medicine (OR 1.27, 95% CI 1.02 to 1.57), psychiatry (OR 124.69, 95% CI 85.89 to 181.01) and obstetrics/gynaecology (OR 2.77, 95% CI 2.09 to 3.67) were associated with frequent ED visits.

The proportion of frequent ED users, of total visits, and of expenditures attributable to them-while still in the low end of the distribution of published ranges-are lower in this study from Japan than in reports from many other countries.
The proportion of frequent ED users, of total visits, and of expenditures attributable to them-while still in the low end of the distribution of published ranges-are lower in this study from Japan than in reports from many other countries.
Ovarian cancer is the eighth most common cancer in women worldwide, and about 1 in 5 women with ovarian cancer do not receive treatment, because they are too unwell by the time they are diagnosed. Symptoms of ovarian cancer are non-specific or can be associated with other common conditions, and women experiencing these symptoms have been shown to self-manage them using over-the-counter medication. Results from a recent proof-of-concept study suggest there may be an increase in the purchases of painkillers and indigestion medication 10-12 months before ovarian cancer diagnosis. We propose a case-control study, as part of a larger project called the Cancer Loyalty Card Study (CLOCS), to investigate whether a significant change in medication purchases could be an indication for early signs of ovarian cancer, using data already collected through store loyalty cards.

Using a retrospective case-control design, we aim to recruit 500 women diagnosed with ovarian cancer (cases) and 500 women without ovarian cancer (controls) in the UK who hold a loyalty card with at least one participating high street retailer. We will use pre-existing loyalty card data to compare past purchase patterns of cases with those of controls. In order to assess ovarian cancer risk in participants and their purchase patterns, we will collect information from participants on ovarian cancer risk factors and clinical data including symptoms experienced before diagnosis from recruited women with ovarian cancer.

CLOCS was reviewed and approved by the North West-Greater Manchester South Research Ethics Committee (19/NW/0427). Study outcomes will be disseminated through academic publications, the study website, social media and a report to the research sites that support the study once results are published.

ISRCTN 14897082, CPMS 43323, NCT03994653.
ISRCTN 14897082, CPMS 43323, NCT03994653.Transoral drainage of peritonsillar abscess during the COVID-19 pandemic is a high-risk procedure due to potential aerosolisation of SARS-CoV-2. This case describes conservative management of peritonsillar abscess in a 21-year-old male with COVID-19.Two 59-year-old male patients with COVID-19 pneumonia developed pulmonary cavitation with air-fluid level, accompanied by right-sided chest pain several weeks after first onset of symptoms. Considering a possible bacterial abscess formation, both patients were started on antibiotics. No microbiological pathogen was detected in further investigations (sputum analysis, bronchoscopy with bronchoalveolar lavage and CT-guided drainage of the cavitation). Histopathological analysis of the drained fluid was non-specific, and the aetiology remained not fully understood. We report pulmonary cavitation as a rare finding in late stage COVID-19 pneumonia. As both our patients presented with localised chest pain prior to detection of the lesions, new onset of this symptom should warrant further investigation.Coronavirus is a severe infectious disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has led to increased mortality worldwide. Multiple reports have been published citing that gastrointestinal symptoms are common in patients with COVID-19 infection. It has also been found that the ACE2 receptor of SARS-CoV-2 is expressed more in the pancreas than the lungs. link3 Despite this, little attention has been paid to the extent and details of pancreatic injury caused by COVID-19. Lack of awareness regarding the COVID-19 status of patients presenting with pancreatitis may expose healthcare workers to SARS-CoV-2 while performing interventions to manage complications of pancreatitis such as necrosis. We report a case of COVID-19-induced acute necrotising pancreatitis in the absence of any known risk factors.A 73-year-old man with significant medical history including renal transplantation and chronic immunosuppression presented to the hospital with acute respiratory failure. His initial treatment included steroids for concern for Pneumocystis jiroveci pneumonia, although this was later excluded as the diagnosis. The patient's illness was consistent with COVID-19; however, he was not diagnosed with the virus until late in his course. The patient was found to have pneumatosis intestinalis that was successfully managed conservatively. Despite his multiple medical comorbidities, the patient had a positive outcome following COVID-19 infection. We discuss the association of pneumatosis intestinalis and COVID-19, and we investigate the various factors, including immunosuppression, that could play a role in this patient's successful recovery from the virus.
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