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Background: Maccabi-RED is a new service developed in Israel that allows primary care staff to direct urgent cases to specialists in the community for evaluation in their local clinics on the same day as an alternative to an emergency department (ED) visit. A primary care physician or a nurse can activate the service, and all nearby specialists receive "a call" and can decide if they are willing to accept it, thus allowing the patient to avoid an unnecessary visit to the ED., Aim: To quantify and characterize the medical care provided by this service in a large national healthcare system., Design and Setting: Multicenter, community-based, retrospective cohort study., Methods: All Maccabi-RED visits recorded between September 2021 and August 2022 were included. Patient characteristics were compared to national demographics. Descriptive statistics were used to present data regarding recorded diagnoses, treating physicians, treatments or referrals provided, and subsequent emergency department admissions or hospitalizations., Results: 31831 visits were recorded. Most frequent diagnoses were musculoskeletal pain (12.1%), otitis or otalgia (7.8%), contusions (7.6%), fractures (7.1%), foreign body (6.7%), pregnancy-related symptoms (6.3%), and upper-respiratory or unspecified viral infection (6.3%). The most common treatments reported were foreign body removal (5%) and cast application (3.5%). Only 7.8% of visits resulted in emergency department admission within seven days (any cause). The average time from patient request to physician treatment was 91 min., Conclusions: Maccabi-RED is being widely used by patients nationwide. Additional studies are needed to investigate whether Maccabi-RED reduces emergency department visits and costs., (© The Author(s) 2024. Published by Oxford University Press. 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.)

NADPH, the primary source of reducing equivalents in the cytosol, is used in vertebrate rod photoreceptor outer segments to reduce the all-trans retinal released from photoactivated visual pigment to all-trans retinol. Light activation of the visual pigment isomerizes the 11-cis retinal chromophore to all-trans, thereby destroying it and necessitating its regeneration. Release and reduction of all-trans retinal are the first steps in the series of reactions that regenerate the visual pigment. Glucose and glutamine can both support the reduction of all-trans retinal to retinol, indicating that the NADPH used in rod photoreceptor outer segments can be generated by the pentose phosphate pathway as well as by mitochondria-linked pathways. We have used the conversion of all-trans retinal to all-trans retinol to examine whether amino acids other than glutamine can also support the generation of NADPH in rod photoreceptors. We have measured this conversion in single isolated mouse rod photoreceptors by imaging the fluorescence of the all-trans retinal and retinol generated after exposure of the cells to light. In agreement with previous work, we find that 5 mM glucose or 0.5 mM glutamine support the conversion of ∼70-80% of all-trans retinal to retinol, corresponding to a reduced NADP fraction of ∼10%. All other amino acids at 0.5 mM concentration support the conversion to a much lesser extent, indicating reduced NADP fractions of 1-2% at most. Taurine was also ineffective at supporting NADPH generation, while formic acid, the toxic metabolite of methanol, suppressed the generation of NADPH by either glucose or glutamine., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

With increased focus on antimicrobial stewardship in post-acute, long-term care (PALTC) settings, optimization of diagnostic testing is essential. Molecular diagnostics are currently being offered and used for the diagnosis of urinary tract infections (UTIs) in community and PALTC settings. Yet, no studies to date explore the role of rapid diagnostics such as polymerase chain reaction and other molecular methods in the stewardship efforts of PALTC settings, specifically compared with standard testing with urinalysis and culture with antimicrobial susceptibility testing. This article outlines a framework of diagnostic stewardship to critically evaluate the use of molecular diagnostics for the diagnosis of UTIs in PALTC and the impact on patient outcomes and antimicrobial stewardship. The authors suggest a 5-step process for evaluating the role of novel diagnostics in the PALTC setting. Understanding the shortcomings of newer diagnostic tests may identify needs for further investigation before their widespread use., Competing Interests: Disclosure The authors declare no conflicts of interest., (Copyright © 2024 Post-Acute and Long-Term Care Medical Association. All rights reserved.)

Objective: To compare the time to oral feeds in infants born to mothers with and without diabetes., Study Design: Retrospective study of infants born at or after 34 weeks gestational age and admitted between 1/1/2020 to 01/31/2022. Time to full oral feedings was compared between infants born to mothers with and without diabetes (267 versus 918) Continuous and binomial variables were analyzed with the Mann Whitney U test and the Chi-Square test respectively. Linear regression was then conducted to explore identified potential relationships from these analyses., Result: Comparison of groups via univariate analysis revealed a mean difference of two more days to establish full oral feedings (p = 0.0001). Maternal pregestational diabetes (PGDM) and obesity (Body mass index; BMI > 30 kg/m 2 ) were associated with longer time for infants to complete oral feeds (p 0.034 and 0.013 respectively)., Conclusion: Infants born to mothers with diabetes took longer to achieve full oral feedings., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Telemedicine has expanded rapidly in recent years, and many encounters that were conducted in person now take place remotely. This study aimed to assess primary care physicians' (PCPs) attitudes towards the different modalities of patient care., Methods: This is a cross-sectional nationwide descriptive study conducted in Israel. We asked PCPs to document an entire workday and answer a short questionnaire after each visit. The questions addressed the type of visit (face-to-face, remote synchronous [telephone/video], or remote asynchronous [online requests]), the perceived quality of the visit, and the physicians' feelings at the end of each visit. Before documenting their working day, we asked the participants to answer a questionnaire about their general attitudes toward different modalities of medical visits and how they affect their well-being and burnout., Results: Sixty physicians documented 2,025 visits, of which 39% took place in person, 36% stemmed from online patient requests, 18% were telephone meetings, < 1% were video meetings, and 6% consisted of other types of contact. Mixed effects logistic regressions were used to model the visits' evaluation. The odds ratios (ORs) for perceived medical quality of visits focused on medical tasks were lower for non-face-to-face visits: OR = 0.39, 95% CI 0.25-0.59 for remote synchronous, and OR = 0.14, 95% CI 0.09-0.23 for remote asynchronous. The perceived medical quality of visits focused on administrative tasks was lower for remote asynchronous than for face-to-face visits (OR = 0.31, 95% CI 0.14-0.65). We found no association between medical quality and patients, physicians, or clinic characteristics. The inappropriateness of the visit modality was also associated with lower medical quality (OR = 0.13, 95% CI 0.09-0.18). We found a correlation between perception of medical quality and physicians' feelings at the end of the visits, Spearman's r = 0.82 (p < 0.001)., Conclusions: A substantial portion of the visits was dedicated to administrative tasks and remote medicine. In comparison, physicians rated face-to-face visits' quality higher than remote visits. Policymakers should intervene to minimize administrative work, reduce PCPs' administrative workload, and direct patients to the optimal visit modality for their complaints. These steps would increase medical quality, reduce burnout, and mitigate the shortage of PCPs., (© 2024. The Author(s).)

Background: The COVID-19 pandemic has necessitated changes in European healthcare systems, with a significant proportion of COVID-19 cases being managed on an outpatient basis in primary healthcare (PHC). To alleviate the burden on healthcare facilities, many European countries developed contact-tracing apps and symptom checkers to identify potential cases. As the pandemic evolved, the European Union introduced the Digital COVID-19 Certificate for travel, which relies on vaccination, recent recovery, or negative test results. However, the integration between these apps and PHC has not been thoroughly explored in Europe., Objective: To describe if governmental COVID-19 apps allowed COVID-19 patients to connect with PHC through their apps in Europe and to examine how the Digital COVID-19 Certificate was obtained., Methodology: Design and setting: Retrospective descriptive study in PHC in 30 European countries. An ad hoc, semi-structured questionnaire was developed to collect country-specific data on primary healthcare activity during the COVID-19 pandemic and the use of information technology tools to support medical care from 15 March 2020 to 31 August 2021. Key informants belong to the WONCA Europe network (World Organization of Family Doctors). The data were collected from relevant and reliable official sources, such as governmental websites and guidelines., Main Outcome Measures: Patient's first contact with health system, governmental COVID-19 app (name and function), Digital COVID-19 Certification, COVID-19 app connection with PHC., Results: Primary care was the first point of care for suspected COVID-19 patients in 28 countries, and 24 countries developed apps to complement classical medical care. The most frequently developed app was for tracing COVID-19 cases (24 countries), followed by the Digital COVID-19 Certificate app (17 countries). Bulgaria, Italy, Serbia, North Macedonia, and Romania had interoperability between PHC and COVID-19 apps, and Poland and Romania's apps considered social needs., Conclusions: COVID-19 apps were widely created during the first pandemic year. Contact tracing was the most frequent function found in the registered apps. Connection with PHC was scarcely developed. In future pandemics, connections between health system levels should be guaranteed to develop and implement effective strategies for managing diseases.

Competing Interests: Declaration of competing interest The authors have no competing interests to declare.

Downregulation of the urea cycle enzyme argininosuccinate synthase (ASS1) in multiple tumors is associated with a poor prognosis partly because of the metabolic diversion of cytosolic aspartate for pyrimidine synthesis, supporting proliferation and mutagenesis owing to nucleotide imbalance. Here, we find that prolonged loss of ASS1 promotes DNA damage in colon cancer cells and fibroblasts from subjects with citrullinemia type I. Following acute induction of DNA damage with doxorubicin, ASS1 expression is elevated in the cytosol and the nucleus with at least a partial dependency on p53; ASS1 metabolically restrains cell cycle progression in the cytosol by restricting nucleotide synthesis. In the nucleus, ASS1 and ASL generate fumarate for the succination of SMARCC1, destabilizing the chromatin-remodeling complex SMARCC1-SNF5 to decrease gene transcription, specifically in a subset of the p53-regulated cell cycle genes. Thus, following DNA damage, ASS1 is part of the p53 network that pauses cell cycle progression, enabling genome maintenance and survival. Loss of ASS1 contributes to DNA damage and promotes cell cycle progression, likely contributing to cancer mutagenesis and, hence, adaptability potential., (© 2024. The Author(s).)

Purpose: Light detection destroys the visual pigment. Its regeneration, necessary for the recovery of light sensitivity, is accomplished through the visual cycle. Release of all-trans retinal by the light-activated visual pigment and its reduction to all-trans retinol comprise the first steps of the visual cycle. In this study, we determined the kinetics of all-trans retinol formation in human rod and cone photoreceptors., Methods: Single living rod and cone photoreceptors were isolated from the retinas of human cadaver eyes (ages 21 to 90 years). Formation of all-trans retinol was measured by imaging its outer segment fluorescence (excitation, 360 nm; emission, >420 nm). The extent of conversion of released all-trans retinal to all-trans retinol was determined by measuring the fluorescence excited by 340 and 380 nm. Measurements were repeated with photoreceptors isolated from Macaca fascicularis retinas. Experiments were carried out at 37°C., Results: We found that ∼80% to 90% of all-trans retinal released by the light-activated pigment is converted to all-trans retinol, with a rate constant of 0.24 to 0.55 min-1 in human rods and ∼1.8 min-1 in human cones. In M. fascicularis rods and cones, the rate constants were 0.38 ± 0.08 min-1 and 4.0 ± 1.1 min-1, respectively. These kinetics are several times faster than those measured in other vertebrates. Interphotoreceptor retinoid-binding protein facilitated the removal of all-trans retinol from human rods., Conclusions: The first steps of the visual cycle in human photoreceptors are several times faster than in other vertebrates and in line with the rapid recovery of light sensitivity exhibited by the human visual system.

Background: Primary Health Care (PHC) plays a crucial role in managing the COVID-19 pandemic, with only 8% of cases requiring hospitalization. However, PHC COVID-19 data often goes unnoticed on European government dashboards and in media discussions. This project aims to examine official information on PHC patient care during the COVID-19 pandemic in Europe, with specific objectives: (1) Describe PHC's clinical pathways for acute COVID-19 cases, including long-term care facilities, (2) Describe PHC COVID-19 pandemic indicators, (3) Develop COVID-19 PHC activity indicators, (4) Explain PHC's role in vaccination strategies, and (5) Create a PHC contingency plan for future pandemics., Methods: A mixed-method study will employ two online questionnaires to gather retrospective PHC data on COVID-19 management and PHC involvement in vaccination strategies. Validation will occur through focus group discussions with medical and public health (PH) experts. A two-wave Delphi survey will establish a European PHC indicators dashboard for future pandemics. Additionally, a coordinated health system action plan involving PHC, secondary care, and PH will be devised to address future pandemic scenarios., Analysis: Quantitative data will be analysed using STATA v16.0 for descriptive and multivariate analyses. Qualitative data will be collected through peer-reviewed questionnaires and content analysis of focus group discussions. A Delphi survey and multiple focus groups will be employed to achieve consensus on PHC indicators and a common European health system response plan for future pandemics. The Eurodata research group involving researchers from 28 European countries support the development., Discussion: While PHC manages most COVID-19 acute cases, data remains limited in many European countries. This study collects data from numerous countries, offering a comprehensive perspective on PHC's role during the pandemic in Europe. It pioneers the development of a PHC dashboard and health system plan for pandemics in Europe. These results may prove invaluable in future pandemics. However, data may have biases due to key informants' involvement and may not fully represent all European GP practices. PHC has a significant role in the management of the COVID-19 pandemic, as most of the cases are mild or moderate and only 8% needed hospitalization. However, PHC COVID-19 activity data is invisible on governments' daily dashboards in Europe, often overlooked in media and public debates., (© 2024. The Author(s).)

Background: As populations age globally, effectively managing geriatric health poses challenges for primary care. Comprehensive geriatric assessments (CGAs) aim to address these challenges through multidisciplinary screening and coordinated care planning. However, most CGA tools and workflows have not been optimised for routine primary care delivery., Objective: This study aimed to evaluate the impact of a computerised CGA tool, called the Golden Age Visit, implemented in primary care in Israel., Methods: This study employed a quasiexperimental mixed-methods design to evaluate outcomes associated with the Golden Age electronic health assessment tool. Quantitative analysis used electronic medical records data from Maccabi Healthcare Services, the second largest health management organisation (HMO) in Israel. Patients aged 75 and older were included in analyses from January 2017 to December 2019 and January 2021 to December 2022. For patients, data were also collected on controls who did not participate in the Golden Age Visit programme during the same time period, to allow for comparison of outcomes. For physicians, qualitative data were collected via surveys and interviews with primary care physicians who used the Golden Age Visit SMARTEST e-assessment tool., Results: A total of 9022 community-dwelling adults aged 75 and older were included in the study: 1421 patients received a Golden Age Visit CGA (intervention group), and 7601 patients did not receive the assessment (control group). After CGAs, diagnosis rates increased significantly for neuropsychiatric conditions and falls. Referrals to physiotherapy, occupational therapy, dietetics and geriatric outpatient clinics also rose substantially. However, no differences were found in rates of hip fracture or relocation to long-term care between groups. Surveys among physicians (n=151) found high satisfaction with the programme., Conclusion: Implementation of a large-scale primary care CGA programme was associated with improved diagnosis and management of geriatric conditions. Physicians were also satisfied, suggesting good uptake and feasibility within usual care. Further high-quality studies are still needed but these results provide real-world support for proactively addressing geriatric health needs through structured screening models., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Some of the most common complaints addressed by primary care physicians (PCPs) require manual procedures, such as lacerations repair, abscesses drainage, ingrown toenails removal, dry needling for myofascial pain syndrome, and Epley maneuver for treating benign paroxysmal positional vertigo (BPPV). The aim of this study was to describe the procedural skills workshops program for PCPs implemented in Maccabi Healthcare Services and to investigate how many PCPs have participated and used the skills since the program's inception in 2017., Methods: In this observational study, we followed all participants in courses from 2017 to 2021. We extracted all procedures performed during these years by PCPs who learned the skill in MHS., Results: During the study period, 620 PCPs participated in workshops for dry needling, soft-tissue and joint injections, BPPV treatment, minor surgical procedures, and spirometry. Most procedures performed were dry needling (average annual number 3,537) and minor surgical procedures (average annual number 361). The average annual use per physician was highest for dry needling (annual average use per physician who used the learned skill was 50.9), followed by soft tissue and joint injections (16.8), minor surgical procedures (14.8), and BPPV treatment (7.5)., Conclusion: procedural skills workshops may expand PCPs' therapeutic arsenal, thus empowering PCPs and providing more comprehensive care for patients. Some manual skills, such as dry needling, soft tissue injections, and the Epley maneuver, were more likely to be used by participants than other skills, such as spirometry and soft tissue injections., (© 2024. The Author(s).)

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.)

Background: The use of medical health applications (mHealth apps) by patients, caregivers, and physicians is widespread. mHealth apps are often employed by physicians to quickly access professional knowledge, guide treatment, easily retrieve medical records, and monitor and manage patients. This study sought to characterize the use of mHealth apps among primary care physicians (PCPs) in Israel. The reasons for using apps and barriers to their use were also investigated., Methods: From all MHS' PCPs, we randomly selected 700 PCPs and invited them to complete a questionnaire regarding the use of mHealth apps and attitudes toward them., Results: From August 2020 to December 2020, 191 physicians completed the questionnaire (response rate 27.3%). 68.0% of PCPs reported using mHealth apps. Telemedicine service apps were the most frequently used. Medical calculators (used for clinical scoring) and differential diagnosis apps were the least frequently used. The most common reason for mHealth app use was accessibility, followed by time saved and a sense of information reliability. Among infrequent users of apps, the most common barriers reported were unfamiliarity with relevant apps and preference for using a computer. Concerns regarding information reliability were rarely reported by PCPs. Physician gender and seniority were not related to mHealth app use. Physician age was related to the use of mHealth apps., Conclusions: mHealth apps are widely used by PCPs in this study, regardless of physician gender or seniority. Information from mHealth apps is considered reliable by PCPs. The main barrier to app use is unfamiliarity with relevant apps and preference for computer use., (© 2024. The Author(s).)

Background: The prevalence of Group A streptococcus (GAS) carriage among adults is studied less than in children. The variability of reported carriage rates is considerably large and differs among diverse geographic areas and populations., Objectives: To evaluate the prevalence of GAS carriage among adults in Israel., Methods: In this prospective study, conducted in a large healthcare maintenance organization in Israel, we obtained pharyngeal cultures from adults attending the clinic without upper respiratory tract complaints or fever. Patient data included sex, age, number of children, and religious sectors., Results: From May to December 2022, eight family physicians collected a total of 172 throat swabs (86% response rate). The median age was 37 years (range 18-65); 72.7% were females, 22.7% were ultra-Orthodox Jewish, and 69.2% had children. The prevalence of GAS carriage was 6.98%, 95% confidence interval (95%CI) 3.7%-11.9%. GAS carriers were younger (31.7 vs. 39.3 years, P = 0.046), and the majority were ultra-Orthodox Jews (58.3% vs. 20%, P = 0.006). All GAS carriers were from lower socioeconomic status. When assessing risk factors for GAS carriage using multivariate analysis, only being an ultra-Orthodox Jew was positively related to GAS carriage (adjusted odds ratio 5.6, 95%CI 1.67-18.8)., Conclusions: Being an ultra-Orthodox Jew was the single variable associated with a GAS carriage, which may be related to having many children at home and living in overcrowded areas. Primary care physicians in Israel should recognize this situation when examining patients with sore throats, mainly ultra-Orthodox Jews.

Background: The prevalence of obesity has been increasing worldwide and is associated with increased risk of morbidity and mortality. Weight management can reduce the risk of complications and improve the quality of life of patients with obesity. This study explored primary care physicians' (PCPs') attitudes and knowledge about weight management., Methods: An anonymous questionnaire was distributed to 400 PCPs between 2020 and 2021. The survey included questions on treatment approaches (pharmaceutical and surgical) and items regarding the respondents' demographic characteristics. We compared PCPs with low or high proactivity toward weight management. We explored attitudes and knowledge with the chi-square test for categorical variables or the Mann-Whitney test for continuous variables., Results: A total of 145 PCPs answered our survey (a response rate of 36.25%). More than half (53.8%) of the respondents showed low proactivity toward weight management in their practice. Proactive respondents were more likely to believe that pharmaceutical treatment effectively reduces weight and offered medical and surgical treatment options more frequently to their patients. Lack of knowledge was the most predominant reason for PCPs avoiding offering treatment to their patients, especially in less proactive PCPs (33.3% vs. 5.3%, p-value < 0.001). When comparing different pharmaceutical options, 46.6% of PCPs report they tend to prescribe liraglutide to their patients compared with only 11% who prescribe orlistat and 10.3% who prescribe phentermine (p-value < 0.001)., Conclusions: Many PCPs still do not actively provide obesity treatment despite improved awareness and therapeutic options. PCPs' proactivity and attitudes are vital to this effort., (© 2024. The Author(s).)

Atezolizumab (anti-PD-L1), combined with carboplatin and etoposide (CE), is now a standard of care for extensive-stage small-cell lung cancer (ES-SCLC). A clearer understanding of therapeutically relevant SCLC subsets could identify rational combination strategies and improve outcomes. We conduct transcriptomic analyses and non-negative matrix factorization on 271 pre-treatment patient tumor samples from IMpower133 and identify four subsets with general concordance to previously reported SCLC subtypes (SCLC-A, -N, -P, and -I). Deeper investigation into the immune heterogeneity uncovers two subsets with differing neuroendocrine (NE) versus non-neuroendocrine (non-NE) phenotypes, demonstrating immune cell infiltration hallmarks. The NE tumors with low tumor-associated macrophage (TAM) but high T-effector signals demonstrate longer overall survival with PD-L1 blockade and CE versus CE alone than non-NE tumors with high TAM and high T-effector signal. Our study offers a clinically relevant approach to discriminate SCLC patients likely benefitting most from immunotherapies and highlights the complex mechanisms underlying immunotherapy responses., Competing Interests: Declaration of interests B.Y.N., H.H., and D.S.S. are co-inventors on a provisional patent application filed by Genentech/Roche related to this manuscript. B.Y.N. is an employee and stockholder of Roche/Genentech. H.H. is an employee and stockholder of Roche/Genentech. R.B. is an employee and shareholder of Roche/Genentech. S.M. is an employee and shareholder of Roche. L.A. is an employee and shareholder of Roche. V.G. is an employee of Rancho Biosciences and a consultant to Roche/Genentech. M.C.L. is an employee of Roche/Genentech. A.M.E. is an employee of Roche/Genentech. M.K.S. is an employee and shareholder of Roche/Genentech. N.S.P. is an employee and shareholder of Roche/Genentech. K.A.S. is an employee of Roche/Genentech. R.J. is an employee and shareholder of Roche/Genentech. C.C. is an employee and shareholder of Roche/Genentech. P.S.C. is an employee and shareholder of Roche/Genentech. M.F. is an employee of Roche/Genentech. S.R. is an employee and shareholder of Roche/Genentech. L.M.M. is an employee and shareholder of Roche/Genentech. H.K. is an employee and shareholder of Roche/Genentech. J.D.M. receives royalties from the NIH and UTSW for distribution of human tumor cell lines and has the following grants: CA070907, CA213274, and CA213338. C.M.G. reports consulting/advisory fees from AstraZeneca, Bristol Myers Squibb, Catalyst Pharmaceuticals, Daiichi Sankyo, G1 Therapeutics, Insights Driven Research, Jazz Pharmaceuticals, and Monte Rosa Therapeutics, as well as speaking/travel fees from Aptitude Health, BeiGene, DAVA Oncology, MJH, and OncLive, and royalties from UpToDate, Inc. J.M.C. has been paid as a consultant for Sonata Therapeutics and also owns stock in Mirati Therapeutics. J.V.H. has advisory or consulting relationships with Genentech, Mirati Therapeutics, Eli Lilly & Co, Janssen Pharmaceuticals, Boehringer-Ingelheim Pharmaceuticals, Regeneron, Takeda Pharmaceuticals, BerGenBio, Jazz Pharmaceuticals, Curio Science, Novartis, AstraZeneca Pharmaceuticals, BioAtla, Sanofi, Spectrum Pharmaceuticals, GlaxoSmithKline, EMD Serono, Blueprint Medicine, and Chugai Pharmaceuticals. C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, AstraZeneca, D2G, Daiichi Sankyo, Epizyme, Genentech/Roche, Ipsen, Jazz, Kowa, Lilly, Merck, and Syros. He serves on the scientific advisory boards of Auron, Bridge Medicines, DISCO, Earli, and Harpoon Therapeutics. L.A.B. has consulted regarding oncology drug development Merck Sharp & Dohme Corp., Arrowhead Pharmaceuticals, Chugai Pharmaceutical Co., AstraZeneca Pharmaceuticals, Genetech Inc., BeiGene, AbbVie, Jazz Pharmaceuticals, Puma Biotechnology, Amgen, and Daiichi Sankyo. S.V.L. served as a paid consultant/advisor for oncology drug development with AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, Boehringer-Ingelheim, Bristol-Myers Squibb, Catalyst, AstraZeneca, D2G, Daiichi Sankyo, Eisai, Elevation Oncology Epizyme, Genentech/Roche, Gilead, Guardant Health, Janssen, Ipsen, Jazz Pharmaceuticals, Kowa, Lilly, Merck/MSD, Novartis, Regeneron, Sanofi, Takeda, Turning Point, and Syros. He serves on the scientific advisory boards of Bridge Medicines, Earli, and Harpoon Therapeutics and has received research funding (to institution). M.R. has received honoraria for lectures and consultancy from Amgen, AstraZeneca, BMS, BeiGene, Boehringer-Ingelheim, Daiichi Sankyo, GSK, Mirati, Merck, MSD, Lilly, Novartis, Pfizer, Regeneron, and Sanofi. He has received compensation for membership of DMSB by Daiichi Sankyo and Sanofi. D.S.S. is an employee and stockholder of Roche/Genentech., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The use of opioids has increased dramatically over the past several years in Israel. The aim of this study was to explore the trends of opioid consumption in Israel over a decade (2010-2020) stratified by socioeconomic status (SES), residence in the periphery, and ethnic background., Methods: This cross-sectional study included all adult Maccabi Healthcare Services (MHS) patients who filled at least one prescription for opioids during the past decade. In order to standardize dosages and compare different opioid medications, we used the Morphine Milligram Equivalent (MME) conversion factor. We performed The Mann-Kendall test with autocorrelation correction to assess each trend. We then checked the differences between the trends with the Mann-Whitney test (for periphery) and the Kruskal Wallis (for SES and ethnic background)., Results: Between the years 2010-2020, 261,270 MHS members met the study's inclusion criteria. The proportions of opioids consumption were 23.9/1000 patients in 2010 and 27.6/1000 patients in 2020, representing a 15% increase. The average daily consumption of opioids was 4.6 and 10.5 MME in 2010 and 2020, respectively, an increase of 227%. The daily MME during 2020 was higher for residents of the periphery compared to non-periphery residents (daily MME of 14.0 compared to 10.1, respectively). Average daily MME increased gradually during the study period for all levels of SES; the values were highest for the low SES group and the lowest for the high SES group (daily MME in 2020 for the lowest, middle, and high SES groups were 15.2 vs. 11.8 vs. 6.7 respectively)., Conclusions: This study highlights that the primary concern in the increase of opioid use is the increasing dosages. The increase in the number of patients using opioids is also significant but to a minor extent. These phenomena disproportionately impact vulnerable populations. Education programs should be offered to physicians regarding the possible harms of long-term use of opioids. These programs should emphasize the risk factors associated with the development of opioid use disorder (OUD) and the caution needed when increasing dosages or switching to higher-potency drugs. Pain clinics and centers for rehabilitation for patients with chronic pain or OUD should be available, not only in central areas but also in the periphery of the country. These clinics and centers should use a holistic approach and a multidisciplinary team that includes specialists in pain and addiction. They should be financially accessible for patients from low SES group and provide solutions in multiple languages., (© 2024. The Author(s).)

Background: The association between hearing impairment and attention-deficit/hyperactivity disorder (ADHD) is unclear. Therefore, we aimed to assess this association in Israel's national sample of over 1.1 million adolescents., Methods: We conducted a nationwide, population-based, cross-sectional study of all Israeli adolescents (n = 1,175,534, 58% males; mean age, 17 yrs) who were examined before mandatory military service during 2004 to 2020. Board-certified specialists confirmed diagnoses of hearing impairment and severe ADHD., Main Outcomes and Measures: We compared the prevalence of severe ADHD in adolescents with and without hearing impairment. Associations were analyzed using logistic regression models and sensitivity analyses accounting for hearing impairment type (sensorineural vs. conductive) and severity., Results: Of the 8,769 adolescents with hearing impairment, 57 were diagnosed with severe ADHD (prevalence = 0.65%). Of the 1,166,765 adolescents without hearing impairment, 3,936 were diagnosed with severe ADHD (prevalence = 0.29%). We found a significant association between hearing impairment and severe ADHD (odds ratio = 1.93 [95% confidence interval, 1.47-2.49]), which persisted in a multivariable model adjusted to age, sex, socioeconomic status, educational status, cognitive performance, and immigration status (odds ratio = 1.70 [95% confidence interval, 1.29-2.20]). The association also persisted when stratified by hearing impairment type (sensorineural vs. conductive) and severity., Conclusions: Adolescents with hearing impairment had 70% increased odds of severe ADHD. Study findings suggest that active screening of patients with hearing impairment for ADHD should be considered., Competing Interests: Conflict of interest disclosures: The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2024, Otology & Neurotology, Inc.)

Background: Physician burnout remains a prevalent issue globally, negatively affecting work satisfaction and patient care. However, exploration of the physical work environments of physicians, a potential influencing factor for burnout, remains scarce. The physical work environment is everything that surrounds the physician, including the doctor's office, the clinic, the clinic's building, the waiting, and staff rooms. The aims of this study were to describe aspects of the physical work environment of primary care physicians (PCPs) and to explore the association between the physical work environment and burnout., Methods: In this cross-sectional study, we emailed questionnaires to an online community of PCPs in Israel in October 2021. We asked physicians about their satisfaction with their physical work environment, evaluated elements of the work environment, and assessed burnout status (with the Shirom-Melamed Burnout Measure, SMBM). We used the Chi-square and Mann-Witney tests to compare categorical and continuous variables and used logistic regression for the final model., Results: Two hundred twenty-one PCPs answered the questionnaire (27.6% response rate). Over a third (35.7%) of respondents reported high burnout. PCPs who were satisfied with their general physical environment had lower burnout rates than those who were unsatisfied (28.1% vs. 47.8%, p-value < 0.001). We found positive correlations between general satisfaction with the physical work environment and the scores achieved for the doctor's office, the clinic, the clinic's building, and the waiting room. In the multivariate analysis, high satisfaction with the general physical work environment was associated with decreased odds for burnout (OR-0.50, 95% CI 0.25-0.99, p-value-0.048)., Conclusion: The doctor's office, the clinic, the clinic's building, and the waiting room affected general satisfaction from the physical work environment. High satisfaction with the physical work environment reduced burnout rates. Future studies are needed to determine whether PCPs and managers should invest in the physical work environment to decrease burnout and increase satisfaction., (© 2024. The Author(s).)

Purpose: SARS-CoV-2 vaccine safety is of major interest worldwide, and transparent information about potential side effects is essential to decrease vaccine hesitancy. The aim of this study was to assess SARS-CoV-2 BNT162b2 vaccine short-term side effects among children aged 5-11 years., Methods: An observational, cross sectional study of vaccine side-effects using electronic surveys sent to parents one week post administration of BNT162b2 vaccine to their child in a large health maintenance organization in Israel., Results: First dose and second dose surveys were filled for 5,842 and 6,126 children, respectively, with a response rate of 32.1% and 24.8%. Local side effects were reported by 68.7% and 69.1% of the first and second survey respondents, and general side effects were reported by 20.8% and 34.5% of them. The symptoms most frequently reported were fatigue, headache and myalgia. Duration of symptoms lasted three days or less among 86.5% and 81.5% of first and second dose survey respondents. Most respondents (92%) reported that their child did not need any medical consultation following vaccination., Conclusions: We found further support for the BNT162b2 SARS-CoV-2 vaccine short- term safety among children aged 5-11 years. With ongoing pandemic and future booster COVID-19 vaccines, these findings can encourage vaccine confidence for parents and providers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: Our study aimed to investigate the prevalence of female pelvic floor dysfunction (PFD) in Israeli women who experienced vaginal delivery and are in their reproductive years (premenopausal), as well as to understand their attitudes and health-seeking behavior and barriers towards treating this problem. Methods: In this cross-sectional study, we conducted a questionnaire-based Internet survey. The surveys were sent to Israeli women in their fertile years (18-50 years old). We asked the women about their PFD symptoms, attitudes, and help-seeking behaviors. We used two validated questionnaires, including the USIQ and the PFDI-20. The combined questionnaire was submitted in both Hebrew and Arabic. We assessed the prevalence of PFD symptoms in the study population. Symptomatic women were asked about their help-seeking behaviors and their beliefs, desires, and barriers regarding the clinical management of symptoms. Results: Between July and September 2020, 524 women completed the questionnaire (response rate 44%). In total, 95% reported at least one symptom (mostly urinary-related) at any grade of severeness in at least one category, and 66.8% suffered from at least one moderate to severe symptom in at least one category. Most women (93.7%) reported that they wanted to be asked and offered voluntary information about PFD from physicians and nurses; however, only 16.6% reported receiving such information. Barriers to seeking treatment were mainly related to low awareness. The study's main limitation was selection bias due to the questionnaire's design. Conclusions: These findings show the importance of raising awareness of the different therapeutic solutions to PFD symptoms and designing more available services for this common problem.

Background: ADHD is often described as a disorder of altered reward sensitivity, yet few studies have examined the extent to which: (i) treatments for ADHD impact reward-related mechanisms; and (ii) changes in the reward system are associated with clinical improvement. This study addresses these issues - examining the extent to which clinical improvement following lisdexamfetamine (LDX) treatment is associated with changes in brain reward system activation., Methods: Twenty adults (M = 11, 55%, F = 9, 45%), ages 19-52 (M = 33.9, SD = 10.0) with ADHD participated in a randomized cross-over study with lisdexamfetamine (LDX) and placebo (PB). Changes in brain activation were assessed during functional magnetic resonance (fMRI) scans: after receiving 3-5 weeks of treatment with LDX and 3-5 weeks of no drug/PB. fMRI contrasts were derived from the passive-avoidance (PA) learning task, which assessed reward-related learning using computational variables. We analyzed the following conditions: the Choice-Phase, modulated by the expected value (EV; i.e., object-choose and object-reject), and the Feedback-Phase, modulated by the prediction error (PE; i.e., reward and punish). Clinical symptom severity was assessed via interview with the ADHD-Rating Scale (ADHD-RS-IV). To address the primary objective, we performed group-level mass-univariate regression analyses between LDX and PB of percent change of the ADHD-RS total scores and the four contrast images under the Choice- and Feedback-conditions. Significance was set at a whole-brain voxel-wise threshold of p < 0.05 with family-wise error (FWE) correction and an extent (cluster) threshold of 50 contiguous voxels., Results: Improvement in ADHD symptoms with LDX was accompanied by significantly increased activation in a series of brain regions previously implicated in reinforcement processing in the choice and feedback conditions (e.g., left caudate and putamen, right orbitofrontal cortex, left middle frontal, superior frontal, and precentral gyri)., Conclusions: These findings, while preliminary, are the first to show that ADHD symptom improvement with stimulant treatment is associated with increased responsiveness of brain systems engaged in reward processing. Results support the hypothesis that LDX treatment may restore balance to dysfunction (e.g., hypoactivation) within the brain reward circuitry in adults with ADHD. Trial RegistrationClinicaltrials.gov Identifier: NCT01924429., Competing Interests: Declaration of competing interest The authors declare the following competing interests: Jeffrey Newcorn – in the last 3 years J.H.N. was a consultant/advisory board member for Adlon Therapeutics, Cingulate Therapeutics, Corium, Hippo T&C, Ironshore, Lumos, Lundbeck, Medice, Mind Tension, Myriad, NLS, OnDosis, Otsuka, Rhodes, Shire/Takeda, and Supernus; he received research support from Adlon, Otsuka, Shire, Supernus; honoraria for disease state lectures from Otsuka and Shire, and served as a consultant for the US National Football League; Iliyan Ivanov – no conflcits, Beth Krone – in the last 3 years was a consultant for Hippo T&C; Xioabo Li – no conflicts; Stephanie Duhoux – no conflict; Stuart White – no conflict; Kurt Schulz – no conflicts; AC Bedard-no conflicts; Juan Pedraza - Lenard Adler – in the last 3 years Dr Adler has received grant/research support from Shire/Takeda Pharmaceuticals, Otsuka; has served as a consultant to Bracket/Signant, Shire/Takeda Pharmaceuticals, Otsuka Pharmaceuticals, SUNY, the National Football League, and Major League Baseball; and has received royalty payments (as inventor) since 2004 from NYU for license of adult ADHD scales and training materials; James Blair – no conflicts., (Copyright © 2023. Published by Elsevier Ltd.)