Citations

Abstract Health and biomedical science-related academic societies have played significant roles in the development and evolution of science and medicine, as well as the evolution of disciplines, including the diversification of medicine into specialties and subspecialties. They have also had formative roles in the development of clinical practice, professionalism, and training standards. The communities they establish promote knowledge creation and dissemination, provide career and professional development opportunities, articulate professional matters, offer networking opportunities, provide recognition, support members, and perform public engagement and advocacy work. They also play increasingly important roles in educating the public and disseminating objective, evidence-based medical and scientific information. Academic societies face challenges related to membership (recruiting new members and engaging and retaining current members), technology, hosting meetings and conferences, generational shifts (e.g., in demographics and attitudes toward working conditions, career paths, work-life integration), costs and logistics related to operations, and morale within institutions and professions. The Council of Faculty and Academic Societies of the Association of American Medical Colleges plays a unique role in supporting academic medical and related societies by providing an interprofessional forum for their interaction and dialogue, and is a vehicle for asserting their collective voice. To the extent that past is prologue, future advances in health care and science will depend, in part, on the resilience of academic societies and on the health professional workforces that they nourish.

PURPOSE Preclinical studies suggest the combination of the poly(adenosine diphosphate[ADP]-ribose) polymerase (PARP) inhibitor olaparib and the ataxia telangiectasia–mutated and Rad3-related (ATR) inhibitor ceralasertib has synergistic antitumor activity in homologous recombination proficient (HRP) and homologous recombination repair gene mutation (HRRm) patients. This study aims to determine the efficacy of olaparib plus ceralasertib in metastatic castration-resistant prostate cancer (mCRPC) with and without HRRm. PATIENTS AND METHODS Thirty-five HRP and 12 HRRm PARP inhibitor–naïve patients with mCRPC progressing on ≥1 line of therapy or previous androgen receptor pathway inhibitor were enrolled. Patients received olaparib (300 mg twice daily) and ceralasertib (160 mg once daily, days 1-7) in 28-day cycles. HRRm was defined as biallelic inactivation of BRCA2 or BRCA1 , monoallelic inactivation of ATM , or germline inactivation of any of these genes. The primary end point was disease response rate (dRR; confirmed prostate-specific antigen decline ≥50% and/or complete/partial radiographic response by RECIST v1.1) in HRP patients. Secondary end points included dRR in HRRm patients, progression-free survival (PFS), and safety/toxicity. Two-stage designs were used. RESULTS Four of 35 (11%; 95% CI, 3.2 to 26.7) HRP and four of 12 HRRm patients responded. Median PFS was 8.2 months (95% CI, 5.3 to not reached) for HRP patients. Thirty-six percent of patients had ≥grade 3 toxicity, most commonly from anemia. Limitations include small, single-arm, nonrandomized trial design. CONCLUSION Combining ceralasertib with olaparib had limited activity in patients with HRP mCRPC. HRRm response rate was not greater than previous single-agent PARP inhibitor clinical trials.

OBJECTIVES: This study aimed to establish a set of guiding principles for data sharing and harmonization in critical care, focusing on the use of real-world data (RWD) and real-world evidence (RWE) to improve patient outcomes and research efficacy. The principles were developed through a systematic literature review and a modified Delphi process, with the goal of enhancing data accessibility, standardization, and interoperability across critical care settings. DATA SOURCES: Data sources included a comprehensive search of peer-reviewed literature, specifically studies related to the use of RWD and RWE in healthcare, guidelines, best practices, and recommendations on data sharing and harmonization. A total of 8150 articles were initially identified through databases such as MEDLINE and Web of Science, with 257 studies meeting inclusion criteria. STUDY SELECTION: Inclusion criteria focused on publications discussing health-related informatics, recommendations for RWD/RWE usage, data sharing, and harmonization principles. Exclusion criteria ruled out non-human studies, case studies, conference abstracts, and articles published before 2013, as well as those not available in English. DATA EXTRACTION: From the 257 selected studies, 322 statements were extracted. After removing irrelevant definitions and off-topic content, 232 statements underwent content validation and thematic analysis. These statements were then consolidated into 24 candidate guiding principles after rigorous review and consensus-building among the expert panel. DATA SYNTHESIS: A three-phase modified Delphi process was employed, involving a conceptualization group, a review group, and a Delphi group. In phase 1, experts identified key themes and search terms for the systematic review. Phase 2 involved validating and refining the prospective guiding principles, while phase 3 employed a Delphi panel to rate principles on acceptability, importance, and feasibility. This process resulted in 24 guiding principles, with high consensus achieved in rounds 2 and 3 on their relevance and applicability. CONCLUSIONS: The systematic review and Delphi process resulted in 24 guiding principles to improve data sharing and harmonization in critical care. These principles address challenges across the data lifecycle, including generation, storage, access, and usage of RWD and RWE. This framework is designed to promote more effective and equitable data practices, with relevance for the development of artificial intelligence-based decision support tools and clinical research. The principles are intended to guide the responsible use of data science in critical care, with emphasis on ethics and equity, while acknowledging the variability of resources across settings.

Abstract Background Calcitonin gene‐related peptide (CGRP) inhibitors were introduced in the United States (US) in 2018. To understand the changing patterns of preventive treatment following the introduction of these new agents, we must first characterize the patterns which preceded their introduction. Objective To characterize the burden, unmet need, and treatment patterns in patients with migraine initiating preventive migraine medications before the introduction of CGRP inhibitors in the US. Methods Between March 2016 and October 2017, we enrolled episodic (EM) and chronic migraine (CM) patients initiating or changing preventive treatment at primary care or neurology clinic visits in the US, in a real‐world observational study using a prospective cohort design. At baseline and monthly thereafter for 6 months, we collected data from study sites and patients on migraine frequency, treatment modifications, migraine impact on functioning, and work productivity for a descriptive analysis of migraine patient experience and treatment patterns. Results From the sample of 234 completers, 118 had EM (50.4%) and 116 had CM (49.6%). Mean age at enrollment was 41 years (SD = 12) and mean age at first migraine diagnosis was 22 years (SD = 11). Most participants were females ( n = 204/234; 87.2%) and white ( n = 178/234; 76.1%). The majority ( n = 164/234; 70.1%) had not used preventive migraine treatment in the 5 years prior to enrollment (treatment naïve). At baseline, mean monthly migraine days were 9.6 days (SD = 5.0) for the preventive treatment naïve group and 12.4 days (SD = 7.0) for treatment experienced patients. The majority had severe Migraine Disability Assessment (Grade IV, total score ≥21), including 67.1% ( n = 110/164) of the preventive treatment naïve and 77.1% ( n = 54/70) of the preventive treatment experienced patients. Headache Impact Test total scores indicating severe impairment (score >59) occurred in 88.4% ( n = 145/164) of the treatment naïve and 88.6% ( n = 62/70) of treatment experienced patients. Mean work productivity loss as measured by the Work Productivity and Activity Impairment questionnaire in the subsample of employed patients was 53.3% loss. The most used acute medications at baseline were nonsteroidal anti‐inflammatory agents ( n = 124/234; 53.0%), acetaminophen‐based products ( n = 112/234; 47.9%), and triptans ( n = 105/234; 44.9%). The most commonly initiated preventive treatments were topiramate ( n = 100/234; 42.7%), tricyclic antidepressants ( n = 39/234; 16.7%), beta‐blockers ( n = 26/234; 11.1%), and onabotulinumtoxinA ( n = 24/234; 10.3%). Over the 6‐month follow‐up period, almost half of patients ( n = 116/234, 49.6%) modified their preventive treatment and discontinued treatment ( n = 88/312 total modifications; 28.2%) or modified their pattern of use by increasing, decreasing, or skipping doses ( n = 224/312 total modifications; 71.8%), often without seeking medical advice. Avoiding side effects was the main reason reported among patients who discontinued ( n = 52/88; 59.1%), decreased frequency or dose ( n = 37/89; 41.6%), and skipped doses ( n = 29/86; 33.7%). Perceived lack of efficacy was another frequent reason reported among those who discontinued ( n = 20/88; 22.7%), decreased frequency or dose ( n = 15/89; 16.9%), and skipped doses ( n = 18/86; 20.9%). Despite initiation of preventive treatment and improvements observed in number of headache and migraine days, migraine patients continued to experience substantial disability, headache impact, and reduced productivity throughout the 6‐month follow‐up period. Conclusions Prior to 2018, the burden of migraine was high for patients initiating preventive treatments. Despite having more than 9 days of migraine per month on average, the majority (70.1%) of patients initiating prevention had been treatment naïve, indicating underuse of preventive treatments. The preventive treatments used in this study were poorly tolerated and were reported by patients to lack efficacy, resulting in suboptimal adherence. The high discontinuation rates suggest that the preventive medications being offered during the period of the study did not meet the treatment needs of patients. In addition, the decisions by about half of patients to alter their prescribed treatment plan without consulting their provider can pose substantial health risks. These findings pertain to the broad set of preventive treatments initiated in this study and do not support inferences about individual preventive treatments, due to limitations in sample size. These findings suggest the need for more effective and better tolerated preventive treatment options.

Objective To understand treatment preferences of people with migraine and the relative importance of improvements in efficacy and avoiding adverse events (AEs), such as cognition problems or weight gain. Background Current preventive migraine medicines are associated with poor adherence and tolerability. There is an unmet need for effective migraine‐specific preventive treatments with fewer AEs. Methods In a web‐based discrete‐choice experiment survey, respondents who self‐reported having ≥6 migraine days/month were offered choices between pairs of hypothetical preventive migraine medicines. Six attributes, each with 3 levels, defined the medicines: reduction in headache days per month (10%, 25%, or 50%), frequency of limitations with physical activities (none, 1‐category improvement, or 2‐category improvement), cognition problems (no problems, thinking problems, or memory problems), weight gain (none, 5% body weight gain, or 10% body weight gain), how the medicine is taken (daily oral pill, once‐monthly injection, or twice‐monthly injection), and monthly out‐of‐pocket cost ($5, $60, or $175). The attributes and levels were informed by clinician input, the clinical literature, and 2 focus groups. An experimental design was used to create the pairs of hypothetical medicines for the discrete‐choice experiment questions. Random‐parameters logit was used to estimate the relative importance of the medicine attributes, and the results were used to predict the percentage of respondents who would select one medicine profile over another and to calculate willingness to pay for changes in attribute levels. Results The sample included 300 respondents; 72% indicated that migraines make physical activities difficult all or most of the time, and 81% had taken a prescription medicine to prevent migraine in the last 6 months. Respondents reported having, on average, approximately 16 headache days per month. Among noncost attributes, respondents valued a change from a 10% reduction in migraine days to a 50% reduction more highly than avoiding the worst levels of AEs, but were willing to trade off efficacy for less‐severe AEs. Avoiding memory problems was more important than avoiding thinking problems. Avoiding a 10% weight gain was more important than avoiding thinking and memory problems. Respondents preferred a once‐monthly injection or daily pill to twice‐monthly injection. Respondents, on average, were willing to pay $84 (95% confidence interval [CI], $64‐$103) per month to avoid a 10% weight gain, $59 (95% CI, $42‐$76) per month to avoid memory problems, $35 (95% CI, $20‐$51) per month to avoid a 5% weight gain, and $32 (95% CI, $18‐$46) per month to avoid thinking problems. Conclusions A preventive migraine medicine with improved efficacy and AE profile and a favorable mode of administration would be valuable to migraine sufferers. Patients may be willing to trade off efficacy for better AE profiles. Clinicians should work with patients to select treatments that meet each patient’s needs.

Abstract Clinical trials have established the benefit of androgen deprivation therapy (ADT) combined with radiotherapy in prostate cancer. ADT sensitizes prostate cancer to radiotherapy-induced death at least in part through inhibition of DNA repair machinery, but for unknown reasons, adjuvant ADT provides further survival benefits. Here, we show that androgen receptor (AR) expression and activity are durably upregulated following radiotherapy in multiple human prostate cancer models in vitro and in vivo. Moreover, the degree of AR upregulation correlates with survival in vitro and time to tumor progression in animal models. We also provide evidence of AR pathway upregulation, measured by a rise in serum levels of AR-regulated hK2 protein, in nearly 20% of patients after radiotherapy. Furthermore, these men were three-fold more likely to experience subsequent biochemical failure. Collectively, these data demonstrate that radiotherapy can upregulate AR signaling after therapy to an extent that negatively affects disease progression and/or survival. Cancer Res; 75(22); 4688–96. ©2015 AACR.

We present here a novel case of an atypical Omenn syndrome (OS) phenotype due to mutations in theADAgene encoding adenosine deaminase. This case is noteworthy for a significant increase in circulating CD56brightCD16- cytokine-producing NK cells after treatment with steroids for skin rash.