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Aims: Predicting medication adherence in post myocardial infarction (MI) patients has the potential to improve patient outcomes. Most adherence prediction models dichotomize adherence metrics and status. This study aims to develop medication adherence prediction models that avoid dichotomizing adherence metrics and to test whether a simplified model including only 90-days adherence data would perform similarly to a full multivariable model., Methods: Post MI adult patients were followed for 1-year post the event. Data from pharmacy records were used to calculate proportion of days covered (PDC). We used Bayesian beta-regression to model PDC as a proportion, avoiding dichotomization. For each medication group, statins, P2Y12 inhibitors and aspirin, two prediction models were developed, a full and a simplified model., Results: 3692 patients were included for model development. The median (Inter quartile range) PDC at 1-year for statins, P2Y12 inhibitors and aspirin was 0.8 (0.33, 1.00), 0.79 (0.23, 0.99) and 0.79 (0.23, 0.99), respectively. All models showed good fit to the data by visual predictive checks. Bayesian R2 for statins, P2Y12 inhibitors and aspirin models were 61.4%,71.2% and 55.2%, respectively. The simplified models showed similar performance compared with full complex models as evaluated by cross validation., Conclusions: We developed Bayesian multilevel models for statins, P2Y12 inhibitors and aspirin in post MI patients that handled 1-year PDC as a proportion using the beta-distribution. In addition, simplified models, with 90-days adherence as single predictor, had similar performance compared with full complex models., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Context: About 30% of patients with active acromegaly experience paradoxically increased growth hormone (GH) secretion during the diagnostic oral glucose tolerance test (OGTT). Endogenous glucose-dependent insulinotropic polypeptide (GIP) is implicated in this paradoxical secretion., Objective: We used the GIP receptor (GIPR) antagonist GIP(3-30)NH2 to test the hypothesis that GIP mediates this paradoxical response when GIPR is abundantly expressed in somatotropinomas., Design, Patients, Setting, Interventions: 25 treatment-naïve patients with acromegaly were enrolled. Each patient underwent one OGTT during simultaneous placebo infusion and one OGTT during a GIP(3-30)NH2 infusion. Blood samples were drawn at baseline and regularly after infusions to measure GH. We assessed pituitary adenoma size by magnetic resonance imaging and GIPR expression by immunohistochemistry on resected somatotropinomas. For mechanistic confirmation, we applied in vitro and ex vivo approaches., Main Outcome Measure: The effect of GIP(3-30)NH2 on paradoxical GH secretion during OGTT as a measure of GIP involvement., Results: In four of seven patients with paradoxical GH secretion, GIP(3-30)NH2 infusion completely abolished the paradoxical response (P = 0.0003). Somatotrophs were available from three of four of these patients, all showing abundant GIPR expression. Adenoma size did not differ between patients with and without paradoxical GH secretion., Conclusions: Of 25 patients with acromegaly, seven had paradoxical GH secretion during OGTT, and pharmaceutical GIPR blockade abolished this secretion in four. Corresponding somatotroph adenomas abundantly expressed GIPR, suggesting a therapeutic target in this subpopulation of patients. In vitro and ex vivo analyses confirmed the role of GIP and the effects of the antagonist., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Central congenital hypothyroidism (CCH) is a thyroid hormone deficiency at birth caused by inadequate pituitary stimulation of the thyroid gland. Although primary CH has been studied extensively, studies on CCH are sparse., Objectives: To assess the prevalence of CCH in Israel and describe its clinical features, neonatal screening results, and outcomes., Design: Multicenter cross-sectional retrospective chart review., Setting: Nine pediatric endocrine units throughout Israel., Patients: Patients diagnosed with CCH in 1987-2021 were categorized into early (within 14 days of life) and late (after 14 days) diagnosis groups. Newborn screening (NBS) results were retrospectively retrieved from the national NBS program dataset., Results: CCH prevalence in Israel was about 1:42,800 live births. Subjects were 94 patients (54 males), of these, 84% had multiple pituitary hormone deficiencies and 16% had isolated CCH. The median age at diagnosis was 50 days (range, 1-8760), with 66% having moderate to severe hypothyroidism. NBS detected only three infants. Early diagnosis occurred in 34% due to hypopituitarism, while 66% were diagnosed later due to growth and developmental delays. Neurodevelopmental sequelae included mental retardation (12%), learning difficulties (18%), delayed speech (27%), and motor clumsiness (19%), with no significant differences in outcomes between early and late diagnosis., Conclusions: Despite high rates of neurodevelopmental sequelae, no differences were found between early and late diagnosis groups. Further research is needed to assess the impact of delayed diagnosis on neurological outcomes in newborns with CCH. Improved strategies for detecting CHH in newborns are also necessary., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background and Hypothesis: Recent studies show that, despite providing some relief, feedback about being at risk for psychosis often triggers negative emotional reactions. Inspired by Tversky and Kahneman's (1981) work on the framing effect and medical framings that favors positive framing like "life-threatening" over "high-risk for death," this study tested the hypothesis that positive reframing of psychosis risk (PR) could alleviate these concerns. To establish the justifiability and feasibility of testing this hypothesis with patients and their families, the study first sought to test whether mental health professionals (MHPs) view positive framing as superior to present state-of-the-art approaches., Study Design: The study used an experimental design utilizing a simulated feedback session, recorded with professional actors, featuring a clinician, an adolescent, and his mother. One hundred forty-eight MHPs were randomly assigned to view either negatively or positively framed feedback and were asked about its induced impact on the adolescent and mother., Study Results: The study results supported our main hypothesis, indicating significant benefits of positive framing over negative in areas like empathy, stress reduction, stigma, help-seeking, and hope. Contrary to our second hypothesis, familiarity with PR did not affect these results., Conclusions: These findings suggest that MHPs view positive reframing of PR as more beneficial and less harmful than present negative framing approaches. This sets the stage for subsequent phases that will assess the perceptions and preferences of individuals at risk and their families. The discussion highlights possible misconceptions of positive framing, such as labeling, positive psychology, and de-medicalization., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: During the COVID-19 pandemic, the majority of patients received ambulatory treatment, highlighting the importance of primary health care (PHC). However, there is limited knowledge regarding PHC workload in Europe during this period. The utilization of COVID-19 PHC indicators could facilitate the efficient monitoring and coordination of the pandemic response. The objective of this study is to describe PHC indicators for disease surveillance and monitoring of COVID-19's impact in Europe., Methods: Descriptive, cross-sectional study employing data obtained through a semi-structured ad hoc questionnaire, which was collectively agreed upon by all participants. The study encompasses PHC settings in 31 European countries from March 2020 to August 2021. Key-informants from each country answered the questionnaire. Main outcome: the identification of any indicator used to describe PHC COVID-19 activity., Results: Out of the 31 countries surveyed, data on PHC information were obtained from 14. The principal indicators were: total number of cases within PHC (Belarus, Cyprus, Italy, Romania and Spain), number of follow-up cases (Croatia, Cyprus, Finland, Spain and Turkey), GP's COVID-19 tests referrals (Poland), proportion of COVID-19 cases among respiratory illnesses consultations (Norway and France), sick leaves issued by GPs (Romania and Spain) and examination and complementary tests (Cyprus). All COVID-19 cases were attended in PHC in Belarus and Italy., Conclusions: The COVID-19 pandemic exposes a crucial deficiency in preparedness for infectious diseases in European health systems highlighting the inconsistent recording of indicators within PHC organizations. PHC standardized indicators and public data accessibility are urgently needed, conforming the foundation for an effective European-level health services response framework against future pandemics., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Public Health Association.)

The effect of natural rapid cooling and oven slow cooling on the precision of thermoluminescence measurements of LiF:Mg,Ti is investigated. Three separate series of measurements resulted in average precisions of 5.1 and 5.0%, respectively. However, the highest precision of 1.7% (1 SD) was achieved for an oven-cooled material., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Context: Pseudohypoparathyroidism type IA (PHPIA) is a rare genetic disorder characterized by hormone resistance and a typical phenotype named Albright hereditary osteodystrophy. Unawareness of this rare disease leads to delays in diagnosis., Objective: The aims of this study were to describe the clinical and molecular characteristics of patients with genetically confirmed GNAS mutations and to evaluate their long-term outcomes., Methods: A retrospective search for all patients diagnosed with PHPIA in 2 referral centers in Israel was conducted., Results: Nine children (8 females) belonging to 6 families were included in the study. Five patients had GNAS missense mutations, 2 had deletions, and 2 had frameshift mutations. Four mutations were novel. Patients were referred at a mean age of 2.4 years due to congenital hypothyroidism (5 patients), short stature (2 patients), or obesity (2 patients), with a follow-up duration of up to 20 years. Early obesity was observed in the majority of patients. Elevated parathyroid hormone was documented at a mean age of 3 years; however, hypocalcemia became evident at a mean age of 5.9 years, about 3 years later. All subjects were diagnosed with mild to moderate mental retardation. Female adult height was very short (mean -2.5 SD) and 5 females had primary or secondary amenorrhea., Conclusion: Long-term follow-up of newborns with a combination of congenital hypothyroidism, early-onset obesity, and minor dysmorphic features associated with PHPIA is warranted and molecular analysis is recommended since the complete clinical phenotype may develop a long time after initial presentation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: This study aims to summarize the research literature evaluating machine learning (ML)-based clinical decision support (CDS) systems in healthcare settings., Materials and Methods: We conducted a review in accordance with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta Analyses extension for Scoping Review). Four databases, including PubMed, Medline, Embase, and Scopus were searched for studies published from January 2016 to April 2021 evaluating the use of ML-based CDS in clinical settings. We extracted the study design, care setting, clinical task, CDS task, and ML method. The level of CDS autonomy was examined using a previously published 3-level classification based on the division of clinical tasks between the clinician and CDS; effects on decision-making, care delivery, and patient outcomes were summarized., Results: Thirty-two studies evaluating the use of ML-based CDS in clinical settings were identified. All were undertaken in developed countries and largely in secondary and tertiary care settings. The most common clinical tasks supported by ML-based CDS were image recognition and interpretation (n = 12) and risk assessment (n = 9). The majority of studies examined assistive CDS (n = 23) which required clinicians to confirm or approve CDS recommendations for risk assessment in sepsis and for interpreting cancerous lesions in colonoscopy. Effects on decision-making, care delivery, and patient outcomes were mixed., Conclusion: ML-based CDS are being evaluated in many clinical areas. There remain many opportunities to apply and evaluate effects of ML-based CDS on decision-making, care delivery, and patient outcomes, particularly in resource-constrained settings., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In this cohort study conducted in a national healthcare organization in Israel, we found that individuals with glucose-6-phosphate dehydrogenase deficiency had an increased risk of coronavirus disease 2019 (COVID-19) infection and severity, with higher rates of hospitalization and diagnosed long COVID., Competing Interests: Potential conflicts of interest . E. R. reports financial interests as a cofounder of MedAware and Metabomed, Ltd, and is a divested cofounder and unpaid scientific consultant of Pangea Biomed. E. M. reports honoraria for lectures from Teva, Medisone, and Astra Zeneca; participation on advisory boards for Merck and SK-Pharma; roles as a board member of the Israeli National Diabetes Council and the Israeli Society of ADHD; and a role as a committee member of the Israeli National Dementia Prevention Program. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: This study evaluated the impact of serum uric acid (sUA) on the accuracy of pooled cohort equations (PCE) model, Systematic COronary Risk Evaluation 2 (SCORE2), and SCORE2-older persons., Methods and Results: We evaluated 19 769 asymptomatic self-referred adults aged 40-79 years free of cardiovascular disease and diabetes who were screened annually in a preventive healthcare setting. sUA levels were expressed as a continuous as well as a dichotomous variable (upper sex-specific tertiles defined as high sUA). The primary endpoint was the composite of death, acute coronary syndrome, or stroke, after excluding subjects diagnosed with metastatic cancer during follow-up. Mean age was 50 ± 8 years and 69% were men. During the median follow-up of 6 years, 1658 (8%) subjects reached the study endpoint. PCE, SCORE2, and high sUA were independently associated with the study endpoint in a multivariable model (P < 0.001 for all). Continuous net reclassification improvement analysis showed a 13% improvement in the accuracy of classification when high sUA was added to either PCE or SCORE2 model (P < 0.001 for both). sUA remained independently associated with the study endpoint among normal-weight subjects in the SCORE2 model (HR 1.3, 95% CI 1.1-1.6) but not among overweight individuals (P for interaction = 0.01). Subgroup analysis resulted in a significant 16-20% improvement in the model performance among normal-weight and low-risk subjects (P < 0.001 for PCE; P = 0.026 and P < 0.001 for SCORE2, respectively)., Conclusion: sUA significantly improves the classification accuracy of PCE and SCORE2 models. This effect is especially pronounced among normal-weight and low-risk subjects., Competing Interests: Conflict of interest: None declared, (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

A seeming contradiction in the prediction of the spatially correlated trapping center/luminescent center model applied to LiF:Mg,Ti has been the linear/supralinear behavior of the dose response of glow peak 5a. In the TC/LC model, the localised electron-hole recombination, giving rise to glow peak 5a, is expected to result in an extended region of linear dose response. Deconvolution of the glow curves based on first order kinetic peak shapes results, however, in a dose response of peak 5a, which closely resembles the linear/supralinear dose response of peak 5. It is demonstrated herein that when general-order kinetics peak shapes are used for peak 5a, the analysis can result in a linear dose response of glow peak 5a up to dose levels as high as 30 Gy, well beyond the 1-Gy onset of supralinearity of peak 5. The extended linearity suggests a resolution of the contradiction., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Context: Preclinical studies show seliciclib (R-roscovitine) suppresses neoplastic corticotroph proliferation and pituitary adrenocorticotrophic hormone (ACTH) production., Objective: To evaluate seliciclib as an effective pituitary-targeting treatment for patients with Cushing disease (CD)., Methods: Two prospective, open-label, phase 2 trials, conducted at a tertiary referral pituitary center, included adult patients with de novo, persistent, or recurrent CD who received oral seliciclib 400 mg twice daily for 4 consecutive days each week for 4 weeks. The primary endpoint in the proof-of-concept single-center study was normalization of 24-hour urinary free cortisol (UFC; ≤ 50 µg/24 hours) at study end; in the pilot multicenter study, primary endpoint was UFC normalization or ≥ 50% reduction in UFC from baseline to study end., Results: Sixteen patients were consented and 9 were treated. Mean UFC decreased by 42%, from 226.4 ± 140.3 µg/24 hours at baseline to 131.3 ± 114.3 µg/24 hours by study end. Longitudinal model showed significant UFC reductions from baseline to each treatment week. Three patients achieved ≥ 50% UFC reduction (range, 55%-75%), and 2 patients exhibited 48% reduction; none achieved UFC normalization. Plasma ACTH decreased by 19% (P = 0.01) in patients who achieved ≥ 48% UFC reduction. Three patients developed grade ≤ 2 elevated liver enzymes, anemia, and/or elevated creatinine, which resolved with dose interruption/reduction. Two patients developed grade 4 liver-related serious adverse events that resolved within 4 weeks of seliciclib discontinuation., Conclusion: Seliciclib may directly target pituitary corticotrophs in CD and reverse hypercortisolism. Potential liver toxicity of seliciclib resolves with treatment withdrawal. The lowest effective dose requires further determination., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

All endocrine glands are susceptible to neoplastic growth, yet the health consequences of these neoplasms differ between endocrine tissues. Pituitary neoplasms are highly prevalent and overwhelmingly benign, exhibiting a spectrum of diverse behaviors and impact on health. To understand the clinical biology of these common yet often innocuous neoplasms, we review pituitary physiology and adenoma epidemiology, pathophysiology, behavior, and clinical consequences. The anterior pituitary develops in response to a range of complex brain signals integrating with intrinsic ectodermal cell transcriptional events that together determine gland growth, cell type differentiation, and hormonal production, in turn maintaining optimal endocrine health. Pituitary adenomas occur in 10% of the population; however, the overwhelming majority remain harmless during life. Triggered by somatic or germline mutations, disease-causing adenomas manifest pathogenic mechanisms that disrupt intrapituitary signaling to promote benign cell proliferation associated with chromosomal instability. Cellular senescence acts as a mechanistic buffer protecting against malignant transformation, an extremely rare event. It is estimated that fewer than one-thousandth of all pituitary adenomas cause clinically significant disease. Adenomas variably and adversely affect morbidity and mortality depending on cell type, hormone secretory activity, and growth behavior. For most clinically apparent adenomas, multimodal therapy controlling hormone secretion and adenoma growth lead to improved quality of life and normalized mortality. The clinical biology of pituitary adenomas, and particularly their benign nature, stands in marked contrast to other tumors of the endocrine system, such as thyroid and neuroendocrine tumors., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: The objective of this study is to report results from the open-label extension (OLE) of the OPTIMAL trial of oral octreotide capsules (OOC) in adults with acromegaly, evaluating the long-term durability of therapeutic response., Design: The study design is an OLE of a double-blind placebo-controlled (DPC) trial., Methods: Patients completing the 36-week DPC period on the study drug (OOC or placebo) or meeting predefined withdrawal criteria were eligible for OLE enrollment at 60 mg/day OOC dose, with the option to titrate to 40 or 80 mg/day. The OLE is ongoing; week 48 results are reported., Results: Forty patients were enrolled in the OLE, 20 each having received OOC or placebo, with 14 and 5 patients completing the DPC period as responders, respectively. Ninety percent of patients completing the DPC period on OOC and 70% of those completing on placebo completed 48 weeks of the OLE. Maintenance of response in the OLE (i.e. insulin-like growth factor I (IGF1) ≤ 1.0 × upper limit of normal (ULN)) was achieved by 92.6% of patients who responded to OOC during the DPC period. Mean IGF1 levels were maintained between the end of the DPC period (0.91 × ULN; 95% CI: 0.784, 1.045) and week 48 of the OLE (0.90 × ULN; 95% CI: 0.750, 1.044) for those completing the DPC period on OOC. OOC safety was consistent with previous findings, with no increased adverse events (AEs) associated with the higher dose and improved gastrointestinal tolerability observed over time., Conclusions: Patients with acromegaly maintained long-term biochemical response while receiving OOC, with no new AEs observed with prolonged OOC exposure.

Objective: People are increasingly encouraged to self-manage their chronic conditions; however, many struggle to practise it effectively. Most studies that investigate patient work (ie, tasks involved in self-management and contexts influencing such tasks) rely on self-reports, which are subject to recall and other biases. Few studies use wearable cameras and deep learning to capture and classify patient work activities automatically., Materials and Methods: We propose a deep learning approach to classify activities of patient work collected from wearable cameras, thereby studying self-management routines more effectively. Twenty-six people with type 2 diabetes and comorbidities wore a wearable camera for a day, generating more than 400 h of video across 12 daily activities. To classify these video images, a weighted ensemble network that combines Linear Discriminant Analysis, Deep Convolutional Neural Networks, and Object Detection algorithms is developed. Performance of our model is assessed using Top-1 and Top-5 metrics, compared against manual classification conducted by 2 independent researchers., Results: Across 12 daily activities, our model achieved on average the best Top-1 and Top-5 scores of 81.9 and 86.8, respectively. Our model also outperformed other non-ensemble techniques in terms of Top-1 and Top-5 scores for most activity classes, demonstrating the superiority of leveraging weighted ensemble techniques., Conclusions: Deep learning can be used to automatically classify daily activities of patient work collected from wearable cameras with high levels of accuracy. Using wearable cameras and a deep learning approach can offer an alternative approach to investigate patient work, one not subjected to biases commonly associated with self-report methods., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Context: Incidence and awareness of endocrine-related adverse events (ERAE) associated with use of immune checkpoint inhibitors (ICI) has grown with increased ICI use, yet mechanisms for ERAE prediction, surveillance, and development are not well established., Objective: We prospectively evaluated the impact of endocrine autoimmunity on ERAE development and overall survival (OS)., Methods: Adults ≥ 18 years of age prescribed ICI treatment for advanced or metastatic solid tumors and no known active/past endocrine disorders were eligible for enrollment. Thyroid, adrenal, and pancreatic antibodies as well as hormone levels were assessed prior to ICI treatment and at 8 to 9 weeks and 36 weeks after treatment for ERAE in relation to presence and changes in endocrine-specific antibodies, hormone levels, and OS., Results: Sixty patients were enrolled and ERAE were detected in 14 (23.3%), with a median onset of 52 days (IQR, 38.5-71.5) after first ICI dose. Hypothyroidism occurred in 12 (20%) patients, and 2 (3.33%) patients developed hypophysitis. Diabetes and primary adrenal insufficiency were not observed. Antibodies were detected in 14 patients (11 at baseline, 3 developed during follow-up) and their presence was significantly associated with ERAE (R2 59.3%, P < 0.001). Thyroid peroxidase antibody (20%) and thyroid-stimulating immunoglobulin (3.3%) were most common, and anti-GAD was present in 1 patient. The presence of ERAE was associated with a more favorable OS (P = 0.001)., Conclusion: Endocrine-specific autoantibodies play an important role in ERAE pathogenesis and may serve as predictive markers for early identification and treatment of ICI-induced endocrinopathies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.

Background: Patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs) are increasingly recognized as important ways for patients to be more actively involved in their treatment and enhance shared decision-making., Objective: The current study investigated the associations between PROMs, PREMs and various symptoms measures reported by clinicians and psychiatric patients., Method: One hundred and twenty people admitted to a psychiatric hospital completed two PREMs, one PROM (the shortened version of the Manchester Short Assessment of Quality of Life scale) and Effects of Symptoms on Daily Functioning (the Sheehan Disability Scale), the Patient Clinical Global Impression and the Modified Colorado Symptom Index. Their psychiatrists rated them using the Global Assessment of Functioning scale, the Health of the Nation Outcome Scales and the Therapist Clinical Global Impression., Results: There was a strong correlation between patient's evaluation of their quality of life (PROM), experience of their care (PREM) and the overall severity of their condition and their progress. The pattern of correlation between patients' and clinicians' measures revealed a three-layer structure representing a continuum from inner experience to external presentation of experiences., Conclusion: Together these findings help identify and emphasize various domains of subjective experiences and their relation to external ratings., (© The Author(s) 2022. Published by Oxford University Press on behalf of International Society for Quality in Health Care. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

An experimental investigation into the possibility of dose-rate effects and wall scatter in the thermoluminescent response of LiF:Mg,Ti (TLD-100) was carried out. The investigation was motivated by theoretical simulations predicting the possible presence of dose-rate effects coupled with the lack of detailed experimental studies. The dose rate was varied by changing the source to sample distance, by the use of attenuators, sources of 137Cs of various activities, filtration and the construction of identical geometrical irradiators of Teflon and stainless steel. Four levels of dose in the linear dose response region were studied at 10-2 Gy, 1.5 × 10-2 Gy, 0.1 Gy and 0.5 Gy to avoid complications in interpretation due to supralinearity above 1 Gy. At the dose of 1.5 × 10-2 Gy, the dose rate was varied by five orders of magnitude from 4.9 × 10-3 Gy s-1 to 4.9 × 10-8 Gy s-1. At the other levels of dose, a one to two orders of magnitude in dose rate was achieved. Within the measurement uncertainty of 5-10%, no dose-rate effects were observed in any of the experimental measurements and no changes in the shape of the glow curve were observed. The maximum wall scatter effect (Teflon to stainless steel) was measured at ~8% within the experimental uncertainty and well below expectations. The results are encouraging with respect to the accurate and reproducible use of LiF:Mg,Ti under various experimental conditions of irradiation., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

This commentary highlights three important findings in the study by Vijayvargiya et al, published in this journal, involving 9554 oropharyngeal cancer patients from the SEER database. Firstly, there is improved performance in outcome prediction with TNM-8 in HPV+ OPC. However, heterogeneity exists, especially in TNM-8 stage I disease, and there is need for ongoing improvement in risk stratification. Several anatomical and non-anatomical prognostic factors have been proposed. Among them, radiologic extranodal extension has emerged as one of the promising parameters to be considered for future staging. These baseline prognostic factors should address sensitivity, specificity, and diagnostic accuracy to serve different clinical needs. Secondly, cure is possible for some patients presenting with M1 disease. Optimal management of such patients remains to be explored, and clinical trials targeting de novo M1 disease should be encouraged to optimize outcomes for this subset. Finally, methodologies to address missing tumor HPV status in historical cohorts have been discussed, including using baseline demographics and clinical characteristics, as well as statistical procedures such as multiple imputation., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Use of medical cannabis (MC) in Israel has increased since its regulatory approval in 2016. Currently, more than 1% of Israeli adults are treated with MC; this requires primary care physicians (PCPs) to be familiar with this treatment option., Objectives: We assessed the attitudes and knowledge of Israeli PCPs toward MC and evaluated their willingness to prescribe it for different medical conditions., Methods: A cross-sectional survey which was distributed to PCPs in Israel. Physicians were asked about their opinions, knowledge, and willingness to prescribe MC., Results: Two hundred and one PCPs answered the questionnaire. Their average age was 47 years (±11.2), 71% were specialists. 51% of the respondents thought that MC is an effective treatment. 63% replied that they had little knowledge and 75% indicated that they would like to deepen it. 61% of the respondents were willing to initiate an MC treatment for a dying patient, while less than 50% were willing to initiate MC treatment for various other conditions. Most respondents indicated that they were willing to renew a prescription for any approved medical condition. Willingness to prescribe MC increased for physicians who agreed that MC was effective (odds ratio [OR] 21.9, 95% confidence interval [CI] 2.40-200.85), for physicians who strongly agreed with the statement that they had sufficient knowledge (OR 5.0, 95% CI 1.58-15.83) and for residents compared with specialists (OR 4.0, 95% CI 1.52-10.73)., Conclusions: Our survey revealed PCPs' differing opinions and insufficient knowledge regarding treatment with MC. These findings suggest that continuing medical education regarding MC is needed., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.)

Context: The identification and biological actions of pituitary-derived exosomes remain elusive., Objective: This work aimed to validate production of exosomes derived from human and rat pituitary and elucidate their actions., Methods: Isolated extracellular vesicles (EVs) were analyzed by Nanoparticle Tracking Analysis (NTA) and expressed exosomal markers detected by Western blot, using nonpituitary fibroblast FR and myoblast H9C2 cells as controls. Exosome inhibitor GW4869 was employed to detect attenuated EV release. Exosomal RNA contents were characterized by RNA sequencing. In vitro and in vivo hepatocyte signaling alterations responding to GH1-derived exosomes (GH1-exo) were delineated by mRNA sequencing. GH1-exo actions on protein synthesis, cAMP (3',5'-cyclic adenosine 5'-monophosphate) response, cell motility, and metastases were assessed., Results: NTA, exosomal marker detection, and GW4869 attenuated EV release, confirming the exosomal identity of pituitary EVs. Hydrocortisone increased exosome secretion in GH1 and GH3 cells, suggesting a stress-associated response. Exosomal RNA contents showed profiles distinct for pituitary cells, and rat primary hepatocytes exposed to GH1-exo exhibited transcriptomic alterations distinct from those elicited by growth hormone or prolactin. Intravenous GH1-exo injection into rats attenuated hepatic Eif2ak2 and Atf4 mRNA expression, both involved in cAMP responses and amino acid biosynthesis. GH1-exo suppressed protein synthesis and forskolin-induced cAMP levels in hepatocytes. GH1-exo-treated HCT116 cells showed dysregulated p53 and mitogen-activated protein kinase (MAPK) pathways and attenuated motility of malignant HCT116 cells, and decreased tumor metastases in nude mice harboring splenic HCT116 implants., Conclusion: Our findings elucidate biological actions of somatotroph-derived exosomes and implicate exosomes as nonhormonal pituitary-derived messengers., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: The SAGIT® instrument (SAGIT) has been developed to enable accurate characterization of acromegaly disease activity., Objective: We evaluated the ability of SAGIT to discriminate acromegaly disease control status., Methods: This multicenter, noninterventional, prospective and retrospective, longitudinal study, conducted at academic and private clinical practice sites, included patients aged ≥ 18 years with a diagnosis of controlled (n = 109) or non-controlled (n = 105) acromegaly, assessed by clinical global evaluation of disease control (CGE-DC) questionnaire, investigator therapeutic decision, and international guidelines. Control status was not determined at baseline for 13 patients. Since 9 patients were enrolled retrospectively, all presented analyses are based on the prospective population (N = 227). Patients were assessed over a 2-year follow-up period. Classification and regression tree (CART) analyses were performed to investigate how SAGIT components at baseline (signs/symptoms [S], associated comorbidities [A], growth hormone levels [G], insulin-like growth factor 1 levels [I], tumor features [T]) discriminate between controlled and non-controlled acromegaly., Results: Baseline mean subscores S, G, I, and T were significantly lower in patients with CGE-DC controlled vs CGE-DC non-controlled acromegaly. SAGIT components I and G for CGE-DC and S, A, G, I, and T for the clinician's therapeutic decision were retained by CART analyses. For international guidelines, only SAGIT component I was retained. The risk for undergoing ≥ 1 treatment change during the study was 3.44 times greater for CGE-DC non-controlled acromegaly relative to CGE-DC controlled acromegaly., Conclusion: The SAGIT instrument is a valid and sensitive tool to comprehensively and accurately assess acromegaly severity., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Aims: Despite reports that medical cannabis improves symptoms in Crohn's disease [CD], controlled studies evaluating disease response are lacking. This study assessed the effect of cannabidiol [CBD]-rich cannabis oil for induction of remission in CD., Methods: In a double-blind, randomised, placebo-controlled, single-centre trial, patients received orally either cannabis oil containing160/40 mg/ml cannabidiol/tetrahydrocannabinol [CBD/THC] or placebo for 8 weeks. Disease parameters, including the CD activity index [CDAI], and simple endoscopic score for CD [SES-CD], were assessed before and after treatment. In a subgroup of patients, blood samples were collected for CBD and THC plasma levels., Results: The study included 56 patients, age 34.5 ± 11 years, men/women 30/26 [54/46%],30 in cannabis and 26 in placebo groups. CDAI at recruitment and after 8 weeks was 282 (interquartile range [IQR] 243-342) and 166 [IQR 82-226], and 264 [IQR 234-320] and 237 [IQR 121-271] [p <0.05] in the cannabis and placebo groups, respectively. Median quality of life [QOL] score improved from 74 for both groups at baseline to 91 [IQR 85-102] and 75 [IQR 69-88] after 8 weeks in the cannabis and placebo groups, respectively [p = 0.004]. SES-CD was 10 [IQR 7-14] and 11 [IQR7-14], and 7 [4-14] and 8 [IQR 4-12] [p = 0.75] before and after treatment, in the cannabis and placebo groups, respectively. Inflammatory markers (C-reactive protein [CRP], calprotectin) remained unchanged., Conclusions: Eight weeks of CBD-rich cannabis treatment induced significant clinical and QOL improvement without significant changes in inflammatory parameters or endoscopic scores. The oral CBD-rich cannabis extract was well absorbed. Until further studies are available, cannabis treatment in Crohn's disease should be used only in the context of clinical trials., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The cooling rate to room temperature following the 400°C pre-irradiation anneal is known to affect the thermoluminescent properties of LiF:Mg,Ti (TLD-100) as a result of migration and clustering of defects during the cooling down process. In this investigation the dose response over an extended dose range from 0.01 to 7000 Gy in both naturally cooled and the much slower furnace-cooled samples has been measured. Glow curve deconvolution based on first-order kinetics is employed to extract the dose response of the various glow peaks. Of especial interest is the behaviour of glow peaks 4, 5a and 5 as a function of dose. The idea is to modify the supralinear dose response of peak 5 from 1 to 30 Gy to a linear behaviour. This dose range is important for clinical therapy and a linear dose response is of substantial advantage leading to both improved accuracy and precision., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aims: Data on the association of cardiorespiratory fitness with survival of cancer patients are limited. This study aimed to evaluate the association between midlife cardiorespiratory fitness and survival after a subsequent cancer diagnosis., Methods: We evaluated 19,134 asymptomatic self-referred adults who were screened in preventive healthcare settings. All subjects were free of cardiovascular disease and cancer at baseline and completed a maximal exercise stress test. Fitness was categorised into age-specific and sex-specific quintiles according to the treadmill time and dichotomised to low (quintiles 1-2) and high fitness groups., Results: The mean age was 50 ± 8 years and 72% were men. During a median follow-up of 13 years (interquartile range 7-16) 517 (3%) died. Overall, 1455 (7.6%) subjects developed cancer with a median time to cancer diagnosis of 6.4 years (interquartile range 3-10). Death from the time of cancer diagnosis was significantly lower among the high fitness group (Plog rank = 0.03). Time-dependent analysis showed that subjects who developed cancer during follow-up were more likely to die (P < 0.001). The association of cancer with survival was fitness dependent such that in the lower fitness group cancer was associated with a higher risk of death, whereas among the high fitness group the risk of death was lower (hazard ratio 20 vs. 15; Pfor interaction = 0.047). The effect modification persisted after applying a 4-year blanking period between fitness assessment and cancer diagnosis (Pfor interaction = 0.003)., Conclusion: Higher midlife cardiorespiratory fitness is associated with better survival among cancer patients. Our findings support fitness assessment in preventive healthcare settings., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Objective: We conduct a first large-scale analysis of mobile health (mHealth) apps available on Google Play with the goal of providing a comprehensive view of mHealth apps' security features and gauging the associated risks for mHealth users and their data., Materials and Methods: We designed an app collection platform that discovered and downloaded more than 20 000 mHealth apps from the Medical and Health & Fitness categories on Google Play. We performed a suite of app code and traffic measurements to highlight a range of app security flaws: certificate security, sensitive or unnecessary permission requests, malware presence, communication security, and security-related concerns raised in user reviews., Results: Compared to baseline non-mHealth apps, mHealth apps generally adopt more reliable signing mechanisms and request fewer dangerous permissions. However, significant fractions of mHealth apps expose users to serious security risks. Specifically, 1.8% of mHealth apps package suspicious codes (eg, trojans), 45.0% rely on unencrypted communication, and as much as 23.0% of personal data (eg, location information and passwords) is sent on unsecured traffic. An analysis of the app reviews reveals that mHealth app users are largely unaware of the surfaced security issues., Conclusion: Despite being better aligned with security best practices than non-mHealth apps, mHealth apps are still far from ensuring robust security guarantees. App users, clinicians, technology developers, and policy makers alike should be cognizant of the uncovered security issues and weigh them carefully against the benefits of mHealth apps., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Context: Mechanisms underlying pituitary corticotroph adenoma adrenocorticotropin (ACTH) production are poorly understood, yet circulating ACTH levels closely correlate with adenoma phenotype and clinical outcomes., Objective: We characterized the 5' ends of proopiomelanocortin (POMC) gene transcripts, which encode the precursor polypeptide for ACTH, in order to investigate additional regulatory mechanisms of POMC gene transcription and ACTH production., Methods: We examined 11 normal human pituitary tissues, 32 ACTH-secreting tumors, as well as 6 silent corticotroph adenomas (SCAs) that immunostain for but do not secrete ACTH., Results: We identified a novel regulatory region located near the intron 2/exon 3 junction in the human POMC gene, which functions as a second promoter and an enhancer. In vitro experiments demonstrated that CREB binds the second promoter and regulates its transcriptional activity. The second promoter is highly methylated in SCAs, partially demethylated in normal pituitary tissue, and highly demethylated in pituitary and ectopic ACTH-secreting tumors. In contrast, the first promoter is demethylated in all POMC-expressing cells and is highly demethylated only in pituitary ACTH-secreting tumors harboring the ubiquitin-specific protease 8 (USP8) mutation. Demethylation patterns of the second promoter correlate with clinical phenotypes of Cushing disease., Conclusion: We identified a second POMC promoter regulated by methylation status in ACTH-secreting pituitary tumors. Our findings open new avenues for elucidating subcellular regulation of the hypothalamic-pituitary-adrenal axis and suggest the second POMC promoter may be a target for therapeutic intervention to suppress excess ACTH production., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Previously, we identified a Chlamydia trachomatis lymphogranuloma venereum (LGV) recombinant strain possessing a non-LGV ompA genotype. Here, culture-independent genome sequencing confirms its circulation in Europe, Middle East, and North America, and unveils emergence of antibiotic resistance. Broad surveillance is needed., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

The nonidentity problem (NIP) is a deep puzzle challenging the moral intuition that what is bad must be bad for someone. The first part of the paper constructs a new theory of harming, whereas the second part builds on the conclusions of the first to offer a new solution to the NIP. The first part discusses the neglected question of when a burden inflicted in the context of overall benefitting can be discretized as a separate entity-only when it can, is it possible to identify the burden as harm, and only then is it possible to harm in bringing into overall good existence. The second part explains how, in those cases where creating is indeed harming, we can use the logic of concept expansion to construct a concept of wronging that applies to creation cases., (© The Author(s) 2021. Published by Oxford University Press, on behalf of the Journal of Medicine and Philosophy Inc. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Enhancer demethylation in leukemia has been shown to lead to overexpression of genes which promote cancer characteristics. The vascular endothelial growth factor A (VEGFA) enhancer, located 157 Kb downstream of its promoter, is demethylated in chronic myeloid leukemia (CML). VEGFA has several alternative splicing isoforms with different roles in cancer progression. Since transcription and splicing are coupled, we wondered whether VEGFA enhancer activity can also regulate the gene's alternative splicing to contribute to the pathology of CML. Our results show that mutating the VEGFA +157 enhancer promotes exclusion of exons 6a and 7 and activating the enhancer by tethering a chromatin activator has the opposite effect. In line with these results, CML patients present with high expression of +157 eRNA and inclusion of VEGFA exons 6a and 7. In addition, our results show that the positive regulator of RNAPII transcription elongation, CCNT2, binds VEGFA's promoter and enhancer, and its silencing promotes exclusion of exons 6a and 7 as it slows down RNAPII elongation rate. Thus our results suggest that VEGFA's +157 enhancer regulates its alternative splicing by increasing RNAPII elongation rate via CCNT2. Our work demonstrates for the first time a connection between an endogenous enhancer and alternative splicing regulation of its target gene., (© The Author(s) 2021. Published by Oxford University Press on behalf of NAR Cancer.)

Background: While it is clear that first trimester congenital cytomegalovirus (CMV) infection can lead to serious neonatal and childhood adverse outcome, the extent of the effect of second and third trimester congenital CMV infection is still unclear. Our aim was to study the short- and long-term outcomes following second and third trimester infection and to evaluate the contribution of prenatal imaging in a prospective cohort., Methods: We studied pregnant women with primary CMV infection in the second and third trimesters, as diagnosed by well-dated seroconversion, and proof of vertical CMV transmission. All patients underwent serial prenatal ultrasound (US) and most of them fetal magnetic resonance imaging (MRI). Follow-up information was obtained from hospital charts and by telephone interviews with parents., Results: Primary CMV infection occurred in 135 patients, 107 and 28 with second and third trimester infection, respectively. The incidence proportion of composite outcome (hearing loss or neurodevelopmental impairment) following second trimester infection was 7% (7/100, after excluding cases that were terminated) with a 3% incidence of partial unilateral sensory neural hearing loss and a 5% incidence of minor neurodevelopmental abnormalities, including slight verbal and motor delay. Following third trimester infection, there was one case of a very mild motor delay. The incidence proportion of abnormal prenatal findings on US or MRI was not significantly correlated to hearing loss or neurodevelopmental abnormalities., Conclusions: Second trimester infection is associated with a slight risk of developing mild childhood sequelae, mostly partial unilateral hearing loss, which may develop late in childhood. Prenatal imaging failed to predict the development of childhood adverse outcome., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Insulin secretion from pancreatic beta cells is tightly regulated by glucose and paracrine signals within the microenvironment of islets of Langerhans. Extracellular matrix from islet microcapillary endothelial cells (IMEC) affect beta-cell spreading and amplify insulin secretion. This study was aimed at investigating the hypothesis that contact-independent paracrine signals generated from IMEC may also modulate beta-cell insulin secretory functions. For this purpose, conditioned medium (CMp) preparations were prepared from primary cultures of rat IMEC and were used to simulate contact-independent beta cell-endothelial cell communication. Glucose-stimulated insulin secretion (GSIS) assays were then performed on freshly isolated rat islets and the INS-1E insulinoma cell line, followed by fractionation of the CMp, mass spectroscopic identification of the factor, and characterization of the mechanism of action. The IMEC-derived CMp markedly attenuated first- and second-phase GSIS in a time- and dose-dependent manner without altering cellular insulin content and cell viability. Size exclusion fractionation, chromatographic and mass-spectroscopic analyses of the CMp identified the attenuating factor as the enzyme triosephosphate isomerase (TPI). An antibody against TPI abrogated the attenuating activity of the CMp while recombinant human TPI (hTPI) attenuated GSIS from beta cells. This effect was reversed in the presence of tolbutamide in the GSIS assay. In silico docking simulation identified regions on the TPI dimer that were important for potential interactions with the extracellular epitopes of the sulfonylurea receptor in the complex. This study supports the hypothesis that an effective paracrine interaction exists between IMEC and beta cells and modulates glucose-induced insulin secretion via TPI-sulfonylurea receptor-KATP channel (SUR1-Kir6.2) complex attenuating interactions., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Approximately 10% to 20% of prolactinomas are resistant to dopamine agonist therapy. The ErbB signaling pathway may drive aggressive prolactinoma behavior., Objective: We evaluated lapatinib, an ErbB1-epidermal growth factor receptor (EGFR)/ErbB2 or human EGFR2 (HER2) tyrosine kinase inhibitor (TKI), in aggressive prolactinomas., Design: A prospective, phase 2a multicenter trial was conducted., Setting: This study took place at a tertiary referral pituitary center., Patients: Study participants included adults with aggressive prolactinomas showing continued tumor growth despite maximally tolerated dopamine agonist therapy., Intervention: Intervention included oral lapatinib 1250 mg/day for 6 months., Main Outcome Measures: The primary end point was 40% reduction in any tumor dimension assessed by magnetic resonance imaging at study end; tumor response was assessed by Response Evaluation Criteria in Solid Tumors criteria. Secondary end points included prolactin (PRL) reduction, correlation of response with EGFR/HER2 expression, and safety., Results: Owing to rigorous inclusion criteria, of 24 planned participants, only 7 consented and 4 were treated. None achieved the primary end point but 3 showed stable disease, including 2 with a 6% increase and 1 with a 16.8% decrease in tumor diameter. PRL response was not always concordant with tumor response, as 2 showed 28% and 59% increases in PRL. The fourth participant had a PRL-secreting carcinoma and withdrew after 3 months of lapatinib because of imaging and PRL progression. EGFR/HER2 expression did not correlate with treatment response. Lapatinib was well tolerated overall, with reversible grade 1 transaminitis in 2 patients, grade 2 rash in 2 patients, and grade 1 asymptomatic bradycardia in 2 patients., Conclusions: An oral TKI such as lapatinib may be an effective option for a difficult-to-treat patient with an aggressive prolactinoma., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The Unified Interaction Model (UNIM) simulates the linear/supralinear dose response of the glow peaks of LiF:Mg,Ti (TLD-100) and other thermoluminescent materials and the dependence of the supralinearity on photon/electron energy. The UNIM is based on the radiation action of spatially correlated trapping centres (TCs) and luminescent centres (LCs), which results in localised (geminate) electron/hole recombination by quantum mechanical tunnelling. The linear dose response is mainly attributed to geminate recombination. UNIM simulations of the dose response of glow peak 5 in LiF:Mg,Ti following 500 and 8 keV electron/photon irradiation are discussed. In addition, simulations of postirradiation photo-excitation that redistribute the electrons and holes in the various TCs and LCs are demonstrated to extend the region of linear dose response and reduce the supralinearity. Experimental verification of dose-response linearity for levels of dose ≤30 Gy following both 3.65 and 5 eV photon excitation is presented., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: The study sought to understand the potential roles of a future artificial intelligence (AI) documentation assistant in primary care consultations and to identify implications for doctors, patients, healthcare system, and technology design from the perspective of general practitioners., Materials and Methods: Co-design workshops with general practitioners were conducted. The workshops focused on (1) understanding the current consultation context and identifying existing problems, (2) ideating future solutions to these problems, and (3) discussing future roles for AI in primary care. The workshop activities included affinity diagramming, brainwriting, and video prototyping methods. The workshops were audio-recorded and transcribed verbatim. Inductive thematic analysis of the transcripts of conversations was performed., Results: Two researchers facilitated 3 co-design workshops with 16 general practitioners. Three main themes emerged: professional autonomy, human-AI collaboration, and new models of care. Major implications identified within these themes included (1) concerns with medico-legal aspects arising from constant recording and accessibility of full consultation records, (2) future consultations taking place out of the exam rooms in a distributed system involving empowered patients, (3) human conversation and empathy remaining the core tasks of doctors in any future AI-enabled consultations, and (4) questioning the current focus of AI initiatives on improved efficiency as opposed to patient care., Conclusions: AI documentation assistants will likely to be integral to the future primary care consultations. However, these technologies will still need to be supervised by a human until strong evidence for reliable autonomous performance is available. Therefore, different human-AI collaboration models will need to be designed and evaluated to ensure patient safety, quality of care, doctor safety, and doctor autonomy., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Purpose: The phase 3 CHIASMA OPTIMAL trial (NCT03252353) evaluated efficacy and safety of oral octreotide capsules (OOCs) in patients with acromegaly who previously demonstrated biochemical control while receiving injectable somatostatin receptor ligands (SRLs)., Methods: In this double-blind study, patients (N = 56) stratified by prior SRL dose were randomly assigned 1:1 to OOC or placebo for 36 weeks. The primary end point was maintenance of biochemical control at the end of treatment (mean insulin-like growth factor 1 [IGF-1] ≤ 1.0 × upper limit of normal [ULN]; weeks 34 and 36). Time to loss of IGF-1 response and proportion requiring reversion to injectable SRLs were assessed as broader control measures., Results: Mean IGF-1 measurements were 0.80 and 0.97 × ULN for OOC and 0.84 and 1.69 × ULN for placebo, at baseline and end of treatment, respectively. Mean growth hormone (GH) changed from 0.66 to 0.60 ng/mL for OOCs and 0.90 to 2.57 ng/mL for placebo. Normalization of IGF-1 levels (≤ 1.0 × ULN) was maintained in 58.2% for OOCs vs 19.4% for placebo (P = .008); GH levels were maintained (< 2.5 ng/mL) in 77.7% for OOC vs 30.4% for placebo (P = .0007). Median time to loss of response (IGF-1 > 1.0 or ≥ 1.3 × ULN definitions) for patients receiving placebo was 16 weeks; for patients receiving OOCs, it was not reached for both definitions during the 36-week trial (P < .0001). Of the patients in the OOC group, 75% completed the trial on oral therapy. The OOC safety profile was consistent with previous SRL experience., Conclusions: OOCs may be an effective therapy for patients with acromegaly who previously were treated with injectable SRLs., (© Endocrine Society 2020.)

Context: Combination therapy with somatostatin receptor ligand (SRL) plus pegvisomant for patients with acromegaly is recommended after a maximizing dose on monotherapy. Lower-dose combination regimens are not well studied., Objective: To compare cost-effectiveness and efficacy of 3 lower-dose combination regimens in controlled and uncontrolled acromegaly., Design and Setting: Prospective, randomized, open-label, parallel arm study at a tertiary referral pituitary center., Patients: Adults with acromegaly regardless of response to prior SRL and biochemical control status at baseline, stratified by an SRL dose required for insulin-like growth factor (IGF)-I normalization during any 3-month period within 12 months preceding enrollment., Intervention: Combination therapy for 24 to 32 weeks on arm A, high-dose SRL (lanreotide 120 mg/octreotide long-acting release [LAR] 30 mg) plus weekly pegvisomant (40-160 mg/week); arm B, low-dose SRL (lanreotide 60 mg/octreotide LAR 10 mg) plus weekly pegvisomant; or arm C, low-dose SRL plus daily pegvisomant (15-60 mg/day)., Main Outcome Measure: Monthly treatment cost in each arm in participants completing ≥ 24 weeks of therapy., Results: Sixty patients were enrolled and 52 were evaluable. Fifty of 52 (96%) demonstrated IGF-I control regardless of prior SRL responsiveness (arm A, 14/15 [93.3%]; arm B, 22/23 [95.7%]; arm C, 14/14 [100%]). Arm B was least costly (mean, $9837 ± 1375 per month), arm C was most expensive (mean, $22543 ± 11158 per month), and arm A had an intermediate cost (mean, $14261 ± 1645 per month). Approximately 30% of patients required pegvisomant dose uptitration. Rates of adverse events were all < 10%., Conclusions: Low-dose SRL plus weekly pegvisomant represents a novel dosing option for achieving cost-effective, optimal biochemical control in patients with uncontrolled acromegaly requiring combination therapy., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

DNA damage response (DDR) and DNA repair pathways determine neoplastic cell transformation and therapeutic responses, as well as the aging process. Altered DDR functioning results in accumulation of unrepaired DNA damage, increased frequency of tumorigenic mutations, and premature aging. Recent evidence suggests that polypeptide hormones play a role in modulating DDR and DNA damage repair, while DNA damage accumulation may also affect hormonal status. We review the available reports elucidating involvement of insulin-like growth factor 1 (IGF1), growth hormone (GH), α-melanocyte stimulating hormone (αMSH), and gonadotropin-releasing hormone (GnRH)/gonadotropins in DDR and DNA repair as well as the current understanding of pathways enabling these actions. We discuss effects of DNA damage pathway mutations, including Fanconi anemia, on endocrine function and consider mechanisms underlying these phenotypes. (Endocrine Reviews 41: 1 - 19, 2020)., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Previously, we showed that contamination of SH-SY5Y neuroblastoma cells by Mycoplasma hyorhinis strains NDMh and MCLD leads to increased levels of calpastatin (the endogenous, specific inhibitor of the Ca2+-dependent protease calpain), resulting in inhibition of calpain activation. We have found that the increased calpastatin level is promoted by the lipoprotein fraction (MhLpp) of the mycoplasmal membrane. Here, we present MhLpp-based novel synthetic lipopeptides that induce upregulation of calpastatin in SH-SY5Y neuroblastoma cells, leading to protection of the treated cells against Ca2+/amyloid-β-peptide toxicity. These lipopeptides present a new class of promising agents against calpain-induced cell toxicity., (© FEMS 2020.)

Objective: The aim of the Acromegaly Consensus Group was to revise and update the consensus on diagnosis and treatment of acromegaly comorbidities last published in 2013., Participants: The Consensus Group, convened by 11 Steering Committee members, consisted of 45 experts in the medical and surgical management of acromegaly. The authors received no corporate funding or remuneration., Evidence: This evidence-based consensus was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence following critical discussion of the current literature on the diagnosis and treatment of acromegaly comorbidities., Consensus Process: Acromegaly Consensus Group participants conducted comprehensive literature searches for English-language papers on selected topics, reviewed brief presentations on each topic, and discussed current practice and recommendations in breakout groups. Consensus recommendations were developed based on all presentations and discussions. Members of the Scientific Committee graded the quality of the supporting evidence and the consensus recommendations using the GRADE system., Conclusions: Evidence-based approach consensus recommendations address important clinical issues regarding multidisciplinary management of acromegaly-related cardiovascular, endocrine, metabolic, and oncologic comorbidities, sleep apnea, and bone and joint disorders and their sequelae, as well as their effects on quality of life and mortality., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: To demonstrate the association between small left atria (LA) and outcome in a relatively large heterogeneous population of hospitalized patients., Methods and Results: In a single-centre retrospective study, all inpatients that underwent an echocardiographic assessment between 2011 and 2016 and had an available left atrial volume index (LAVI) measurement were included. The cohort consisted of 17 343 inpatients who had an available LAVI measurement, 288 with small LA (LAVI <16 mL/m2), 7531 patients had LAVI within normal limits (16-34 mL/m2) divided into low normal (16-24.9 mL/m2; n = 2636) and high normal (25-34 mL/m2; n = 4895), 4720 patients had large LAVI (34.1-45 mL/m2) and 4804 had very large LAVI (>45 mL/m2). Median follow-up time was 2.4 years. After adjustments for age, gender, and baseline characteristics with a P-value <0.2 in univariable analyses (body mass index, haemoglobin, ischaemic heart disease, valvulopathy, atrial fibrillation, diabetes mellitus, hypertension, hyperlipidaemia, smoking, renal dysfunction, lung disease, and malignancy) small LA was associated with a higher risk for in-hospital mortality (odds ratio 2.9, 95% confidence interval (CI) 1.4-5.7; P = 0.002] and all-cause mortality [hazard ratio (HR) 2.1, 95% CI 1.6-2.8; P < 0.001] compared with high normal LA. For every mL/m2 decrease below high normal LA size the risk for in-hospital and long-term all-cause mortality increased by 10% (HR 1.1, 95% CI 1.02-1.18; P = 0.005) and 8% (HR 1.08, 95% CI 1.05-1.12; P < 0.001), respectively., Conclusion: Small LA are independently associated poorer short- and long-term mortality. LA volume should be referred to as J-shaped in terms of mortality., Helsinki Committee Approval Number: 0170-17-TLV., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Context: Congenital adrenal hyperplasia (CAH) was among the first genetic disorders included in newborn screening (NBS) programs worldwide, based on 17α-hydroxyprogesterone (17-OHP) levels in dried blood spots. However, the success of NBS for CAH is hampered by high false positive (FP) rates, especially in preterm and low-birthweight infants., Objective: To establish a set of cutoff values adjusting for both gestational age (GA) and birthweight (BW), with the aim of reducing FP rates., Design: This cross-sectional, population-based study summarizes 10 years of experience of the Israeli NBS program for diagnosis of CAH. Multitiered 17-OHP cutoff values were stratified according to both BW and GA., Participants: A total of 1,378,132 newborns born between 2008 and 2017 were included in the NBS program., Results: Eighty-eight newborns were ultimately diagnosed with CAH; in 84 of these, CAH was detected upon NBS. The combined parameters-adjusted approach significantly reduced the recall FP rate (0.03%) and increased the positive predictive value (PPV) (16.5%). Sensitivity among those referred for immediate attention increased significantly (94%). There were four false negative cases (sensitivity, 95.4%), all ultimately diagnosed as simple-virilizing. Sensitivity and specificity were 95.4% and 99.9%, respectively, and the percentage of true-positive cases from all newborns referred for evaluation following a positive NBS result was 96%., Conclusions: The use of cutoff values adjusted for both GA and BW significantly reduced FP rates (0.03%) and increased overall PPV (16.5%). Based on our 10 years of experience, we recommend the implementation of this two parameter-adjusted approach for NBS of classic CAH in NBS programs worldwide., (Copyright © 2019 Endocrine Society.)

DNA damage occurs as a result of environmental insults and aging and, if unrepaired, may lead to chromosomal instability and tumorigenesis. Because GH suppresses ataxia-telangiectasia mutated kinase phosphorylation, decreases DNA repair, and increases DNA damage accumulation, we elucidated whether GH effects on DNA damage are mediated through induced IGF-1. In nontumorous human colon cells, GH, but not IGF-1, increased DNA damage. Stably disrupted IGF-1 receptor (IGF-1R) by lentivirus-expressing short hairpin RNA in vitro or treatment with the IGF-1R phosphorylation inhibitor picropodophyllotoxin (PPP) in vitro and in vivo led to markedly induced GH receptor (GHR) abundance, rendering cells more responsive to GH actions. Suppressing IGF-1R triggered DNA damage in both normal human colon cells and three-dimensional human intestinal organoids. DNA damage was further increased when cells with disrupted IGF-1R were treated with GH. Because GH induction of DNA damage accumulation appeared to be mediated not by IGF-1R but probably by more abundant GH receptor expression, we injected athymic mice with GH-secreting xenografts and then treated them with PPP. In these mice, high circulating GH levels were associated with increased colon DNA damage despite disrupted IGF-1R activity (P < 0.01), whereas GHR levels were also induced. Further confirming that GH effects on DNA damage are directly mediated by GHR signaling, GHR-/- mice injected with PPP did not show increased DNA damage, whereas wild-type mice with intact GHR exhibited increased colon DNA damage in the face of IGF-1 signaling suppression. The results indicate that GH directly induces DNA damage independent of IGF-1., (Copyright © 2019 Endocrine Society.)

Because an acidic cellular microenvironment is engendered by inflammation and may determine cell differentiation, we elucidated the impact of acidic conditions on induction of proopiomelanocortin (POMC) expression. Here, we demonstrate mechanisms for proton sensitivity of CRH receptor 1 (CRHR1) signaling to POMC and ACTH production. Low pH (6.8) resulted in doubling of POMC expression and ACTH production in pituitary cell line AtT-20 and in primary mouse pituitary cells. Using CRISPR knockout, we show that CRHR1 is necessary for acid-induced POMC expression, and this induction is mediated by CRHR1 histidine residues and calmodulin-dependent protein kinase II in both pituitary corticotroph cells and in nonpituitary cell lines expressing ectopic ACTH. In contrast, CRH ligand binding affinity to CRHR1 was decreased with acidic pH, implying that proton-induced POMC expression prevails in acidic conditions independently of CRH ligand binding. The results indicate that proton-induced CRHR1 signaling regulates ACTH production in response to an acidic microenvironment.

This article addresses the development of attitudes toward the other and otherness in light of the classical psychoanalytical approach of Freud. Through this approach, the authors attempt to surmount the criticism that was raised in the literature in connection with the difficulty faced by students and professionals in the field of social work in achieving cultural competence. Based on this approach the authors suggest that cultural competence can develop provided two conditions exist: (1) interpersonal contact between lecturer and student, and (2) using the bond to help the student connect with the inner stranger within himself or herself, or as Freud put it, connecting with the "unconscious parts of the mind." With the help of two examples presented, the authors demonstrate how every meeting with strangeness is first and foremost a meeting with a concrete stranger-in the first case the meeting of Jewish students with an Arab student, and in the second case the meeting of a secular student with an ultra-Orthodox boy. Implications for social work practice and education are discussed., (© 2017 National Association of Social Workers.)

Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (>80%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2-4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to secondary progressive disease and treatment discontinuation. We conclude that demographic, clinical and paraclinical information helps predict individual response to disease-modifying therapies at the time of their commencement., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)