Hereditary hemorrhagic telangiectasia (HHT) results in recurrent severe epistaxis, chronic gastrointestinal bleeding, and other morbid manifestations. Pomalidomide was recently demonstrated to be efficacious for bleeding in HHT in the landmark PATH-HHT trial. Given that the vascular remodeling that results in bleeding improvement may require several months, characteristics associated with treatment response would be invaluable to plan treatment. Using data from PATH-HHT (NCT03910244), we identified characteristics associated with change from baseline in Epistaxis Severity Score (ESS, a well-validated 10-point HHT bleeding scale and the trial’s primary endpoint) using multivariable-adjusted repeated measures models. Characteristics associated with a better response to pomalidomide at weeks 16-24 of the trial included a higher (more severe) baseline ESS (change from baseline, -0.76 [95% CI -0.99,-0.54] points per 1 point higher baseline score, P<0.001) and concomitant antifibrinolytic therapy (-0.73 [95% CI -1.48, 0.01] vs. no therapy, p=0.05). Characteristics associated with a less robust response were older age (0.29 [95% CI 0.05, 0.53] per 10 years older, P=0.02) and underlying ACVRL1 germline mutation (0.62 [95% CI -0.04,1.27] vs. ENG, SMAD4 or mutation not known, p=0.06]. Characteristics notably associated with placebo response (placebo effect) were patient-reported outcome measures, such that those experiencing more severe disease at baseline had less placebo effect. In conclusion, several baseline patient and disease characteristics were associated with pomalidomide response, findings that may help guide patient selection for the use of pomalidomide in HHT. Clinicaltrials.gov identifier: NCT03910244

Importance:The management of patent ductus arteriosus (PDA) in preterm infants is controversial. Objective:To determine whether expectant management compared with active treatment of a protocol-defined PDA in preterm infants decreases the incidence of death or bronchopulmonary dysplasia (BPD). Design, Setting, and Participants:A randomized clinical trial including infants born at 22 to 28 weeks' gestation and diagnosed with a protocol-defined PDA between the age of 48 hours and 21 days at screening. The trial was conducted from December 2018 to December 2024 at 33 hospitals within the National Institute of Child Health and Human Development Neonatal Research Network. The final date of follow-up was June 2025. Interventions:Infants with PDA were randomized to expectant management (n = 242) or active treatment (n = 240; acetaminophen, ibuprofen, or indomethacin) to close the PDA. Main Outcomes and Measures:The primary outcome was death or BPD at 36 weeks' postmenstrual age. The secondary outcomes included the components of the primary outcome and other morbidities of prematurity. Results:A total of 482 infants were randomized (median gestational age, 25 weeks [IQR, 24 to 27 weeks]; median birth weight, 760 g [IQR, 620 to 935 g]). The trial was stopped for futility and safety after the 50% interim analysis for the primary outcome due to higher survival in the expectant management group. The incidence of death or BPD was 80.9% (195/241) of infants in the expectant management group vs 79.6% (191/240) of infants in the active treatment group (adjusted risk difference, 1.2% [95% CI, -5.7% to 8.1%]; P = .73). The incidence of death before 36 weeks' postmenstrual age was 4.1% (10/241) of infants in the expectant management group vs 9.6% (23/240) of infants in the active treatment group (adjusted risk difference, -5.6% [95% CI, -10.1% to -1.2%]; P = .01). Infections resulting in death occurred in 0.8% (2/241) of infants in the expectant management group vs 3.8% (9/240) of infants in the active treatment group. Conclusions and Relevance:In extremely preterm infants with a protocol-defined PDA, death or BPD did not differ between the expectant management group and the active treatment group. Survival was substantially higher with expectant management. Trial Registration:ClinicalTrials.gov Identifier: NCT03456336.

ABSTRACT:Studies of behavioral interventions for opioid reduction, which have included individuals prescribed low-, moderate-, and high-dosage opioids for chronic noncancer pain, generally show small to no effect on opioid dosage. We compared the effectiveness of motivational interviewing plus cognitive behavioral therapy (MI + CBT) vs shared decision-making (SDM) on change in opioid dosage in a large pragmatic randomized trial. This study is a secondary analysis examining subgroup differences between participants prescribed high-dosage opioids (≥90 morphine milligram equivalents [MME])-who are at the highest risk for adverse events-and those prescribed lower dosages (<90 [MME]) at baseline. The primary outcome was change in average daily opioid dosage at 12 months postbaseline using prescribing data from electronic health records. Exploratory analysis evaluated potential baseline predictors of the primary outcome. Among participants prescribed high-dosage opioids at baseline, average daily opioid dosage at 12 months decreased similarly in both intervention groups: -33 MME (95% CI, -44 to -21) in the MI + CBT group and -25 MME (95% CI, -37 to -12) in the SDM group. In both groups, participants prescribed low-to-moderate dosages at baseline had essentially no dosage change. Baseline dosage was the strongest predictor of opioid reduction for both intervention groups. Both MI + CBT and SDM may be useful in decreasing opioid dosages among individuals prescribed high-dosage opioids for chronic noncancer pain. Researchers and clinicians should consider focusing dosage reduction efforts on individuals prescribed high-dosage opioids.

Background Hereditary hemorrhagic telangiectasia (HHT) is the second most common inherited bleeding disorder worldwide and results in substantial medical and psychosocial morbidity due to recurrent, often severe epistaxis, chronic gastrointestinal bleeding, hematologic support-dependent iron deficiency anemia, and serious bleeding and nonbleeding complications of visceral arteriovenous malformations. With disease-modifying therapeutics entering clinical trials, disease-specific health-related quality of life (HRQoL) instruments capable of longitudinal assessment of HHT-specific manifestations are essential. Objectives To externally validate and define the features relevant to clinical application of the HHT-specific Quality of Life scale. Methods The HHT-specific Quality of Life (HHT-QoL) scale was developed as an easily administered, 4-item instrument assessing physical, social, personal, and work impacts due to HHT longitudinally. Utilizing comprehensive, longitudinal data from pomalidomide for the treatment of HHT, the largest HHT randomized clinical trial to date, we evaluated internal consistency and external validity of the HHT-QoL and defined essential characteristics for clinical application. Results The HHT-QoL demonstrated good internal consistency and external validity, including directionally and clinically consistent correlations with the Epistaxis Severity Score, bleeding duration as assessed by epistaxis diary, and multiple well-validated generic HRQoL instruments measuring emotional distress, social roles and activities, and fatigue. Development of an HHT HRQoL severity classification utilizing HHT-QoL total scores was successful (0 as no limitation, 1-3 as mild, 4-7 as moderate, and 8-16 points as severe limitation), and the minimal clinically important difference was calculated to be 1.1 points (best rounded to 1 point as the scores are integers) utilizing anchor-based and distribution-based methods. Conclusion This study successfully externally validates the HHT-QoL. The HHT-QoL is a validated disease-specific HRQoL instrument with defined severity classification and minimal clinically important difference, making it ideal for use in clinical trials of bleeding in HHT.

Objective:To describe challenges and solutions for calculating longitudinal daily opioid dose in morphine milligram equivalents from electronic health record prescriptions for a clinical trial of voluntary opioid reduction in patients with chronic non-cancer pain. Materials and Methods:Researchers obtained opioid prescriptions for 525 participants from the National Patient-Centered Clinical Research Network datamart at three health systems. Daily opioid dose was calculated using dose conversions and summing across prescriptions after applying assumptions, reviewing suspect prescribing patterns, and removing spurious prescriptions. Results:Out of 16 071 extracted prescriptions, 1207 (8%) were unusable, and 14 864 (92%) were analyzed. Discussion:Numerous challenges were identified related to incomplete data, inaccurate refill dates, and overlapping or duplicate prescriptions. Conclusion:Using electronic prescription data to calculate daily doses of opioid consumption is challenging and requires significant cleaning prior to use in research. This paper recommends steps to review and clean electronic opioid prescription data.

OBJECTIVE:To compare the effectiveness of motivational interviewing plus cognitive behavioral therapy vs shared decision making on change in daily dosage of prescribed opioids for individuals with chronic non-cancer pain. DESIGN:Pragmatic randomized trial. SETTING:Three health systems in the southeastern United States. SUBJECTS:Adults (N = 525) prescribed opioid therapy for chronic non-cancer pain. METHODS:Participants were randomized to Arm 1 (a motivational interviewing visit plus eight group sessions of cognitive behavioral therapy) or Arm 2 (shared decision making medical visits). The primary outcome was change in average daily opioid dosage from baseline to 12 months using prescribing data from health records. Secondary outcomes were self-reported pain interference and physical function. RESULTS:Both arms experienced small decreases in dosage at 12 months from baseline: Arm 1 -12 milligram morphine equivalents (95% confidence interval: -19 to -4); Arm 2 - 6 milligram morphine equivalents (95% confidence interval: -14 to 2). The mean difference between arms for change in dosage, at -6 milligram morphine equivalents (95% confidence interval: -17 to 5), was neither statistically significant nor clinically meaningful. Those in Arm 1 with a mental health diagnosis had a larger reduction in dosage (-22 milligram morphine equivalents, 95% confidence interval: -33 to -11) than those in Arm 1 without a mental health diagnosis and those in Arm 2 with a mental health diagnosis (interaction P = .10). No change from baseline occurred in pain interference or physical function for either arm. CONCLUSIONS:Additional strategies are needed to support individuals prescribed opioid therapy for chronic pain with pain management and dosage reduction. Clinicaltrials.gov registration: NCT03454555. Participant enrollment began on June 26, 2019. https://classic.clinicaltrials.gov/ct2/show/NCT.03454555. Trial sponsor: RTI International.

The need for collaborative and transparent sharing of COVID-19 clinical trial and large-scale observational study data to accelerate scientific discovery and inform clinical practice is critical. Responsible data-sharing requires addressing challenges associated with data privacy and confidentiality, data linkage, data quality, variable harmonization, data formats, and comprehensive metadata documentation to produce a high-quality, contextually rich, findable, accessible, interoperable, and reusable (FAIR) dataset. This communication explores the experiences and lessons learned from sharing National Heart Lung and Blood Institute (NHLBI) COVID-19 clinical trial (including adaptive platform trials) and cohort study datasets through the NHLBI BioData Catalyst® (BDC) ecosystem, focusing on the challenges and successes of harmonizing these datasets for broader research use. Our findings highlight the importance of establishing standardized data formats, adopting common data elements and creating and maintaining robust data governance structures that address common challenges (i.e., data privacy and data-sharing limitations resulting from informed consent). These efforts resulted in a set of comprehensive and interoperable datasets from 5 clinical trials and 13 cohort studies that will enable downstream reuse in analyses and collaborations. The principles and strategies outlined, derived through experience with consortia data, can lay the groundwork for advancing collaborative and efficient data sharing.

Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) is the second most common inherited bleeding disorder worldwide, affecting approximately 1 in 5000 people. Development of disease-modifying and efficacious hemostatic agents to treat HHT has finally begun after decades without such medical therapies. However, the lack of consensus on standardized severity definitions, outcome criteria, and terminology remains a major obstacle to clinical investigation and therapeutic development in HHT. Additionally, with the ongoing repurposing of antiangiogenic agents and emerging development of novel HHT-specific therapies, comparative clinical trials are expected in the future. Therefore, to end the problematic heterogeneity hindering these efforts, the Global Research and Medical Advisory Board (GRMAB) of the Cure HHT Foundation, an international group of recognized HHT experts, convened a conference of expert HHT clinician-investigators from within GRMAB as well as invited external experts in HHT and bleeding disorders generally, patients with HHT, and patient advocates to define standard terminology and definitions for outcomes and severity classification for bleeding and anemia in HHT. These criteria and definitions should be adopted by regulators, investigators, and the pharmaceutical industry in the development and performance of interventional clinical trials and cohort studies to allow improved comparability between clinical trials, facilitate communication between clinicians and investigators, improve therapeutic guideline development, and provide a standardized framework for regulatory agencies. SEARCH STRATEGY AND SELECTION CRITERIA: Evidence for this report was systematically identified and evaluated utilizing two search strategies in Ovid MEDLINE, described in full detail in the Appendix, pp.4-13. The searches were conducted on January 7, 2025. The titles and abstracts of each record were reviewed, and the inclusion criteria were applied to all search results to identify full text articles to be retrieved for further review. All retrieved full texts were then reviewed to reach a final determination if a study met the inclusion criteria. Included references were then compiled into evidence tables, which were then utilized by the International Consensus Report Working Group throughout the development of report recommendations.

BACKGROUND: Many clinical trials use systematic methodology to monitor adverse events and determine grade (severity), expectedness, and relatedness to treatments as determined by clinicians. However, patient perspectives are often not included in this process. OBJECTIVE: This study aimed to compare clinician vs patient grading of adverse event severity in a urogynecologic surgical trial. Secondary objectives were to estimate the association of patient grading of adverse events with decision-making and quality of life outcomes and to determine if patient perspective changes over time. STUDY DESIGN: This was a planned supplementary study (Patient Perspectives in Adverse Event Reporting [PPAR]) to a randomized trial comparing 3 surgical approaches to vaginal apical prolapse. In the parent trial, adverse events experienced by patients were collected per a standardized protocol every 6 months during which clinicians graded adverse event severity (mild, moderate, severe/life-threatening). In this substudy, we obtained additional longitudinal patient perspectives for 19 predetermined "PPAR adverse events." Patients provided their own severity grading (mild, moderate, severe/very severe/life-threatening) at initial assessment and at 12 and 36 months postoperatively. Clinicians and patients were masked to each other's reporting. The primary outcome was the interrater agreement (kappa statistic) for adverse event severity between the initial clinician and patient assessment, combining patient grades of mild and moderate. The association between adverse event severity and the Decision Regret Scale, Satisfaction with Decision Scale, the 12-Item Short-Form Health Survey, and Patient Global Impression of Improvement scores was assessed using the Spearman correlation coefficient (rho) for continuous scales, the Mantel-Haenszel chi-square test for Patient Global Impression of Improvement, and t tests or chi-square tests comparing the assessments of patients who rated their adverse events or symptoms as severe with those who gave other ratings. To describe patient perspective changes over time, the intraobserver agreement was estimated for adverse event severity grade over time using weighted kappa coefficients. RESULTS: Of the 360 randomly assigned patients, 219 (61%) experienced a total of 527 PPAR adverse events (91% moderate and 9% severe/life-threatening by clinician grading). Mean patient age was 67 years; 87% were White and 12% Hispanic. Among the patients reporting any PPAR event, the most common were urinary tract infection (61%), de novo urgency urinary incontinence (35%), stress urinary incontinence (22%), and fecal incontinence (13%). Overall agreement between clinician and participant grading of severity was poor (kappa=0.24 [95% confidence interval, 0.14-0.34]). Of the 414 adverse events that clinicians graded as moderate, patients graded 120 (29%) as mild and 80 (19%) as severe. Of the 39 adverse events graded as severe by clinicians, patients graded 15 (38%) as mild or moderate. Initial patient grading of the most severe reported adverse event was mildly correlated with worse Decision Regret Scale (rho=0.2; P=.01), 12-Item Short-Form Health Survey (rho=-0.24; P<.01), and Patient Global Impression of Improvement (P<.01) scores. There was no association between adverse event severity and Satisfaction with Decision Scale score. Patients with an initial grading of "severe" had more regret, lower quality of life, and poorer global impressions of health than those whose worst severity grade was mild (P<.05). Agreement between the patients' initial severity ratings and their ratings at 12 months (kappa=0.48 [95% confidence interval, 0.39-0.58]) and 36 months (kappa=0.45 [95% confidence interval, 0.37-0.53]) was fair. CONCLUSION: Clinician and patient perceptions of adverse event severity are discordant. Worse severity from the patient perspective was associated with patient-centered outcomes. Including the patient perspective provides additional information for evaluating surgical procedures.

Importance:The optimal surgical repair of vaginal vault prolapse after hysterectomy remains undetermined. Objective:To compare the efficacy and safety of 3 surgical approaches for vaginal vault prolapse after hysterectomy. Design, Setting, and Participants:This was a multisite, 3-arm, superiority and noninferiority randomized clinical trial. Outcomes were assessed biannually up to 60 months, until the last participant reached 36 months of follow-up. Settings included 9 clinical sites in the US National Institute of Child Health and Human Development (NICHD) Pelvic Floor Disorders Network. Between February 2016 and April 2019, women with symptomatic vaginal vault prolapse after hysterectomy who desired surgical correction were randomized. Data were analyzed from November 2022 to January 2023. Interventions:Mesh-augmented (either abdominally [sacrocolpopexy] or through a vaginal incision [transvaginal mesh]) vs transvaginal native tissue repair. Main Outcomes and Measures:The primary outcome was time until composite treatment failure (including retreatment for prolapse, prolapse beyond the hymen, or prolapse symptoms) evaluated with survival models. Secondary outcomes included patient-reported symptom-specific results, objective measures, and adverse events. Results:Of 376 randomized participants (mean [SD] age, 66.1 [8.7] years), 360 (96%) had surgery, and 296 (82%) completed follow-up. Adjusted 36-month failure incidence was 28% (95% CI, 20%-37%) for sacrocolpopexy, 29% (95% CI, 21%-38%) for transvaginal mesh, and 43% (95% CI, 35%-53%) for native tissue repair. Sacrocolpopexy was found to be superior to native tissue repair (adjusted hazard ratio [aHR], 0.57; 99% CI, 0.33-0.98; P = .01). Transvaginal mesh was not statistically superior to native tissue after adjustment for multiple comparisons (aHR, 0.60; 99% CI, 0.34-1.03; P = .02) but was noninferior to sacrocolpopexy (aHR, 1.05; 97% CI, 0-1.65; P = .01). All 3 surgeries resulted in sustained benefits in subjective outcomes. Mesh exposure rates were low (4 of 120 [3%] for sacrocolpopexy and 6 of 115 [5%] for transvaginal mesh) as were the rates of dyspareunia. Conclusions and Relevance:Among participants undergoing apical repair for vaginal vault prolapse, sacrocolpopexy and transvaginal mesh resulted in similar composite failure rates at study completion; both had lower failure rates than native tissue repair, although only sacrocolpopexy met a statistically significant difference. Low rates of mesh complications and adverse events corroborated the overall safety of each approach. Trial Registration:ClinicalTrials.gov Identifier: NCT02676973.

AbstractIn response to the Covid-19 pandemic, the National Heart, Lung, and Blood Institute launched five multisite clinical trials testing candidate host tissue-directed medical interventions to hasten recovery, improve function, and reduce morbidity and mortality. Speed, flexibility, and collaboration were essential. This article from the Steering and Executive committees describes the Collaborating Network of Networks for Evaluating Covid-19 and Therapeutic Strategies (CONNECTS) research program that enrolled 6690 participants and evaluated 18 intervention strategies using 10 molecular agents across the care continuum (outpatient, inpatient, and post discharge), and reports lessons learned from this initiative. Successes include rapid trial execution through collaboration and adaptive platform designs. Challenges that impeded efficiency included time required to execute subcontracts, constraints on clinical research workforce, and limited research infrastructure in nonacademic settings.

Importance The optimal surgical repair of vaginal vault prolapse after hysterectomy remains undetermined. Objective To compare the efficacy and safety of 3 surgical approaches for vaginal vault prolapse after hysterectomy. Design, Setting, and Participants This was a multisite, 3-arm, superiority and noninferiority randomized clinical trial. Outcomes were assessed biannually up to 60 months, until the last participant reached 36 months of follow-up. Settings included 9 clinical sites in the US National Institute of Child Health and Human Development (NICHD) Pelvic Floor Disorders Network. Between February 2016 and April 2019, women with symptomatic vaginal vault prolapse after hysterectomy who desired surgical correction were randomized. Data were analyzed from November 2022 to January 2023. Interventions Mesh-augmented (either abdominally [sacrocolpopexy] or through a vaginal incision [transvaginal mesh]) vs transvaginal native tissue repair. Main Outcomes and Measures The primary outcome was time until composite treatment failure (including retreatment for prolapse, prolapse beyond the hymen, or prolapse symptoms) evaluated with survival models. Secondary outcomes included patient-reported symptom-specific results, objective measures, and adverse events. Results Of 376 randomized participants (mean [SD] age, 66.1 [8.7] years), 360 (96%) had surgery, and 296 (82%) completed follow-up. Adjusted 36-month failure incidence was 28% (95% CI, 20%-37%) for sacrocolpopexy, 29% (95% CI, 21%-38%) for transvaginal mesh, and 43% (95% CI, 35%-53%) for native tissue repair. Sacrocolpopexy was found to be superior to native tissue repair (adjusted hazard ratio [aHR], 0.57; 99% CI, 0.33-0.98; P = .01). Transvaginal mesh was not statistically superior to native tissue after adjustment for multiple comparisons (aHR, 0.60; 99% CI, 0.34-1.03; P = .02) but was noninferior to sacrocolpopexy (aHR, 1.05; 97% CI, 0-1.65; P = .01). All 3 surgeries resulted in sustained benefits in subjective outcomes. Mesh exposure rates were low (4 of 120 [3%] for sacrocolpopexy and 6 of 115 [5%] for transvaginal mesh) as were the rates of dyspareunia. Conclusions and Relevance Among participants undergoing apical repair for vaginal vault prolapse, sacrocolpopexy and transvaginal mesh resulted in similar composite failure rates at study completion; both had lower failure rates than native tissue repair, although only sacrocolpopexy met a statistically significant difference. Low rates of mesh complications and adverse events corroborated the overall safety of each approach. Trial Registration ClinicalTrials.gov Identifier: NCT02676973

Importance Mixed urinary incontinence (MUI) is common and can be challenging to manage. Objectives We present the protocol design and rationale of a trial comparing the efficacy of 2 procedures for the treatment of women with MUI refractory to oral treatment. The Midurethral sling versus Botulinum toxin A (MUSA) trial compares the efficacy of intradetrusor injection of 100 U of onabotulinimtoxinA (an office-based procedure directed at the urgency component) versus midurethral sling (MUS) placement (a surgical procedure directed at the stress component). Study Design The MUSA is a multicenter, randomized trial of women with MUI electing to undergo procedural treatment for MUI at 7 clinical centers in the NICHD Pelvic Floor Disorders Network. Participants are randomized to either onabotulinumtoxinA 100 U or MUS. OnabotulinimtoxinA recipients may receive an additional injection between 3 and 6 months. Participants may receive additional treatment (including crossover to the alternative study intervention) between 6 and 12 months. The primary outcome is change from baseline in Urogenital Distress Inventory (UDI) at 6 months. Secondary outcomes include change in UDI at 3 and 12 months, irritative and stress subscores of the UDI, urinary incontinence episodes, predictors of poor treatment response, quality of life and global impression outcomes, adverse events, use of additional treatments, and cost effectiveness. Results Recruitment and randomization of 150 participants is complete and participants are currently in the follow-up phase. Conclusions This trial will provide information to guide care for women with MUI refractory to oral treatment who seek surgical treatment with either onabotulinumtoxinA or MUS.

Background Hereditary hemorrhagic telangiectasia (HHT) is characterized by extensive telangiectasias and arteriovenous malformations. The primary clinical manifestation is epistaxis that results in iron-deficiency anemia and reduced health-related quality of life.Methods We conducted a randomized, placebo-controlled trial to evaluate the safety and efficacy of pomalidomide for the treatment of HHT. We randomly assigned patients, in a 2:1 ratio, to receive pomalidomide at a dose of 4 mg daily or matching placebo for 24 weeks. The primary outcome was the change from baseline through week 24 in the Epistaxis Severity Score (a validated bleeding score in HHT; range, 0 to 10, with higher scores indicating worse bleeding). A reduction of 0.71 points or more is considered clinically significant. A key secondary outcome was the HHT-specific quality-of-life score (range, 0 to 16, with higher scores indicating more limitations).Results The trial was closed to enrollment in June 2023 after a planned interim analysis met a prespecified threshold for efficacy. A total of 144 patients underwent randomization; 95 patients were assigned to receive pomalidomide and 49 to receive placebo. The baseline mean (+/- SD) Epistaxis Severity Score was 5.0 +/- 1.5, a finding consistent with moderate-to-severe epistaxis. At 24 weeks, the mean difference between the pomalidomide group and the placebo group in the change from baseline in the Epistaxis Severity Score was -0.94 points (95% confidence interval [CI], -1.57 to -0.31; P=0.004). The mean difference in the changes in the HHT-specific quality-of-life score between the groups was -1.4 points (95% CI, -2.6 to -0.3). Adverse events that were more common in the pomalidomide group than in the placebo group included neutropenia, constipation, and rash.Conclusions Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity. No unexpected safety signals were identified. (Funded by the National Heart, Lung, and Blood Institute; PATH-HHT Clinicaltrials.gov number, NCT03910244). Patients with HHT received pomalidomide or placebo for 24 weeks. Pomalidomide reduced epistaxis frequency and severity.

Objectives To identify ML tools in hospital settings and how they were implemented to inform decision-making for patient care through a scoping review. We investigated the following research questions: What ML interventions have been used to inform decision-making for patient care in hospital settings? What strategies have been used to implement these ML interventions?Design A scoping review was undertaken. MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews (CDSR) were searched from 2009 until June 2021. Two reviewers screened titles and abstracts, full-text articles, and charted data independently. Conflicts were resolved by another reviewer. Data were summarised descriptively using simple content analysis.Setting Hospital setting.Participant Any type of clinician caring for any type of patient.Intervention Machine learning tools used by clinicians to inform decision-making for patient care, such as AI-based computerised decision support systems or “‘model-based’” decision support systems.Primary and secondary outcome measures Patient and study characteristics, as well as intervention characteristics including the type of machine learning tool, implementation strategies, target population. Equity issues were examined with PROGRESS-PLUS criteria.Results After screening 17 386 citations and 3474 full-text articles, 20 unique studies and 1 companion report were included. The included articles totalled 82 656 patients and 915 clinicians. Seven studies reported gender and four studies reported PROGRESS-PLUS criteria (race, health insurance, rural/urban). Common implementation strategies for the tools were clinician reminders that integrated ML predictions (44.4%), facilitated relay of clinical information (17.8%) and staff education (15.6%). Common barriers to successful implementation of ML tools were time (11.1%) and reliability (11.1%), and common facilitators were time/efficiency (13.6%) and perceived usefulness (13.6%).Conclusions We found limited evidence related to the implementation of ML tools to assist clinicians with patient healthcare decisions in hospital settings. Future research should examine other approaches to integrating ML into hospital clinician decisions related to patient care, and report on PROGRESS-PLUS items.Funding Canadian Institutes of Health Research (CIHR) Foundation grant awarded to SES and the CIHR Strategy for Patient Oriented-Research Initiative (GSR-154442).Scoping review registration https://osf.io/e2mna.

Purpose: We determined the utility of intraoperative data in predicting sacral neuromodulation outcomes in urgency urinary incontinence. Materials and Methods: Intraoperative details of sacral neuromodulation stage 1 were recorded during the prospective, randomized, multicenter ROSETTA trial, including responsive electrodes, amplitudes, and response strengths (motor and sensory Likert scales). Stage 2 implant was performed for stage 1 success on 3-day diary with 24-month follow-up. An intraoperative amplitude response score for each electrode was calculated ranging from 0 (no response) to 99.5 (maximum response, 0.5 V). Predictors for stage 1 success and improvement at 24 months were identified by stepwise logistic regression confirmed with least absolute shrinkage and selection operator and stepwise linear regression. Results: Intraoperative data from 161 women showed 139 (86%) had stage 1 success, which was not associated with number of electrodes generating an intraoperative motor and/or sensory response, average amplitude at responsive electrodes, or minimum amplitude-producing responses. However, relative to other electrodes, a best amplitude response score for bellows at electrode 3 was associated with stage 1 failure, a lower reduction in daily urgency urinary incontinence episodes during stage 1, and most strongly predicted stage 1 outcome in logistic modeling. At 24 months, those who had electrode 3 intraoperative sensory response had lower mean reduction in daily urgency urinary incontinence episodes than those who had no response. Conclusions: Specific parameters routinely assessed intraoperatively during stage 1 sacral neuromodulation for urgency urinary incontinence show limited utility in predicting both acute and long-term outcomes. However, lead position as it relates to the trajectory of the sacral nerve root appears to be important.

BACKGROUND: Among women with symptomatic uterovaginal pro-lapse undergoing vaginal surgery in the Vaginal hysterectomy with Native Tissue Vault Suspension vs Sacrospinous Hysteropexy with Graft Sus-pension (Study for Uterine Prolapse Procedures Randomized Trial) trial, sacrospinous hysteropexy with graft (hysteropexy) resulted in a lower composite surgical failure rate than vaginal hysterectomy with uterosacral suspension over 5 years.OBJECTIVE: This study aimed to identify factors associated with the rate of surgical failure over 5 years among women undergoing sacro-spinous hysteropexy with graft vs vaginal hysterectomy with uterosacral suspension for uterovaginal prolapse.STUDY DESIGN: This planned secondary analysis of a comparative effectiveness trial of 2 transvaginal apical suspensions (NCT01802281) defined surgical failure as either retreatment of prolapse, recurrence of prolapse beyond the hymen, or bothersome prolapse symptoms. Baseline clinical and sociodemographic factors for eligible participants receiving the randomized surgery (N=173) were compared across categories of failure (<1 year, >1 year, and no failure) with rank-based tests. Factors with adequate prevalence and clinical relevance were assessed for minimally adjusted bivariate associations using piecewise exponential survival models adjusting for randomized apical repair and clinical site. The multivariable model included factors with bivariate P<.2, additional clinically important variables, apical repair, and clinical site. Backward selection determined final retained risk factors (P<.1) with statistical significance evaluated by Bonferroni correction (P<.005). Final factors were assessed for interaction with type of apical repair at P<.1. Associ-ation is presented by adjusted hazard ratios and further illustrated by categorization of risk factors.RESULTS: In the final multivariable model, body mass index (increase of 5 kg/m2: adjusted hazard ratio, 1.7; 95% confidence interval, 1.3-2.2; P<.001) and duration of prolapse symptoms (increase of 1 year: adjusted hazard ratio, 1.1; 95% confidence interval, 1.0-1.1; P<.005) were associated with composite surgical failure, where rates of failure were 2.9 and 1.8 times higher in women with obesity and women who are over-weight than women who have normal weight and women who are un-derweight (95% confidence intervals, 1.5-5.8 and 0.9-3.5) and 3.0 times higher in women experiencing >5 years prolapse symptoms than women experiencing <5 years prolapse symptoms (95% confidence in-terval, 1.8-5.0). Sacrospinous hysteropexy with graft had a lower rate of failure than hysterectomy with uterosacral suspension (adjusted hazard ratio, 0.6; 95% confidence interval, 0.4-1.0; P=.05). The interaction between symptom duration and apical repair (P=.07) indicated that failure was less likely after hysteropexy than hysterectomy for those with <5 years symptom duration (adjusted hazard ratio, 0.5; 95% confidence in-terval, 0.2-0.9), but not for those with >5 years symptom duration (adjusted hazard ratio, 1.0; 95% confidence interval 0.5-2.1).CONCLUSION: Obesity and duration of prolapse symptoms have been determined as risk factors associated with surgical failure over 5 years from transvaginal prolapse repair, regardless of approach. Providers and patients should consider these modifiable risk factors when discussing treatment plans for bothersome prolapse.

Importance:Insulin is recommended for pregnant persons with preexisting type 2 diabetes or diabetes diagnosed early in pregnancy. The addition of metformin to insulin may improve neonatal outcomes.Objective:To estimate the effect of metformin added to insulin for preexisting type 2 or diabetes diagnosed early in pregnancy on a composite adverse neonatal outcome.Design, Setting, and Participants:This randomized clinical trial in 17 US centers enrolled pregnant adults aged 18 to 45 years with preexisting type 2 diabetes or diabetes diagnosed prior to 23 weeks' gestation between April 2019 and November 2021. Each participant was treated with insulin and was assigned to add either metformin or placebo. Follow-up was completed in May 2022.Intervention:Metformin 1000 mg or placebo orally twice per day from enrollment (11 weeks -<23 weeks) through delivery.Main Outcome and Measures:The primary outcome was a composite of neonatal complications including perinatal death, preterm birth, large or small for gestational age, and hyperbilirubinemia requiring phototherapy. Prespecified secondary outcomes included maternal hypoglycemia and neonatal fat mass at birth, and prespecified subgroup analyses by maternal body mass index less than 30 vs 30 or greater and those with preexisting vs diabetes early in pregnancy.Results:Of the 831 participants randomized, 794 took at least 1 dose of the study agent and were included in the primary analysis (397 in the placebo group and 397 in the metformin group). Participants' mean (SD) age was 32.9 (5.6) years; 234 (29%) were Black, and 412 (52%) were Hispanic. The composite adverse neonatal outcome occurred in 280 (71%) of the metformin group and in 292 (74%) of the placebo group (adjusted odds ratio, 0.86 [95% CI 0.63-1.19]). The most commonly occurring events in the primary outcome in both groups were preterm birth, neonatal hypoglycemia, and delivery of a large-for-gestational-age infant. The study was halted at 75% accrual for futility in detecting a significant difference in the primary outcome. Prespecified secondary outcomes and subgroup analyses were similar between groups. Of individual components of the composite adverse neonatal outcome, metformin-exposed neonates had lower odds to be large for gestational age (adjusted odds ratio, 0.63 [95% CI, 0.46-0.86]) when compared with the placebo group.Conclusions and Relevance:Using metformin plus insulin to treat preexisting type 2 or gestational diabetes diagnosed early in pregnancy did not reduce a composite neonatal adverse outcome. The effect of reduction in odds of a large-for-gestational-age infant observed after adding metformin to insulin warrants further investigation.Trial Registration:ClinicalTrials.gov Identifier: NCT02932475.

Abstract Background Demand for rapid evidence-based syntheses to inform health policy and systems decision-making has increased worldwide, including in low- and middle-income countries (LMICs). To promote use of rapid syntheses in LMICs, the WHO’s Alliance for Health Policy and Systems Research (AHPSR) created the Embedding Rapid Reviews in Health Systems Decision-Making (ERA) Initiative. Following a call for proposals, four LMICs were selected (Georgia, India, Malaysia and Zimbabwe) and supported for 1 year to embed rapid response platforms within a public institution with a health policy or systems decision-making mandate. Methods While the selected platforms had experience in health policy and systems research and evidence syntheses, platforms were less confident conducting rapid evidence syntheses. A technical assistance centre (TAC) was created from the outset to develop and lead a capacity-strengthening program for rapid syntheses, tailored to the platforms based on their original proposals and needs as assessed in a baseline questionnaire. The program included training in rapid synthesis methods, as well as generating synthesis demand, engaging knowledge users and ensuring knowledge uptake. Modalities included live training webinars, in-country workshops and support through phone, email and an online platform. LMICs provided regular updates on policy-makers’ requests and the rapid products provided, as well as barriers, facilitators and impacts. Post-initiative, platforms were surveyed. Results Platforms provided rapid syntheses across a range of AHPSR themes, and successfully engaged national- and state-level policy-makers. Examples of substantial policy impact were observed, including for COVID-19. Although the post-initiative survey response rate was low, three quarters of those responding felt confident in their ability to conduct a rapid evidence synthesis. Lessons learned coalesced around three themes – the importance of context-specific expertise in conducting reviews, facilitating cross-platform learning, and planning for platform sustainability. Conclusions The ERA initiative successfully established rapid response platforms in four LMICs. The short timeframe limited the number of rapid products produced, but there were examples of substantial impact and growing demand. We emphasize that LMICs can and should be involved not only in identifying and articulating needs but as co-designers in their own capacity-strengthening programs. More time is required to assess whether these platforms will be sustained for the long-term.

Introduction Hereditary hemorrhagic telangiectasia (HHT), the second most common bleeding disorder worldwide, affects 1 in 5000 people and is characterized by extensive formation of telangiectasia and arteriovenous malformations (AVM) in mucosa, lung, brain, and liver. The primary clinical manifestation is recurrent, often severe epistaxis which commonly results in iron deficiency anemia, emergency room visits, hospitalizations, and reduced quality of life (QOL). Though non-randomized and/or underpowered studies have suggested that systemic bevacizumab or thalidomide may be effective in treating HHT, there have been no pivotal studies and therefore no FDA or EMA approved therapies. Methods PATH-HHT was an NHLBI-funded, randomized, placebo-controlled clinical trial conducted at 13 centers in the US to determine the safety and efficacy of pomalidomide for bleeding in HHT. Pomalidomide was supplied by Celgene and Bristol Myers Squibb. Patients were randomized in a 2:1 ratio to receive pomalidomide 4 mg daily or matching placebo for 6 months. Dose reductions were allowed for toxicity. The primary endpoint was the change in the Epistaxis Severity Score (ESS), a well-validated bleeding score in HHT, from baseline (randomization) to the end of the six-month treatment period, analyzed using a mixed model for repeated measures with adjustment for baseline value, center, treatment, visit, and treatment by visit interaction. Key secondary endpoints included 1) change in the average daily self-reported epistaxis duration from the four weeks preceding the baseline visit to weeks 20-24 of treatment, 2) amount of parenteral iron infused or blood transfused, and 3) change in QOL measurements, including an HHT-specific QOL score. Results PATH-HHT opened in November 2019 and was closed to enrollment by the NHLBI in June 2023 after a planned 75% interim analysis met a prespecified threshold for efficacy. A total of 144 patients were randomized and treated (95 pomalidomide, 49 placebo). Early study discontinuation was 25% in pomalidomide: 14% AE, 11% withdrawn, 1 unrelated death, compared with placebo (4% withdrawn). Across groups, 8% were terminated after 12 weeks for early study closure. Participants included 48% females, 11% non-white race; mean (± SD) age was 58.8±12.2 years. The mean ESS at baseline was 5.0±1.5 (4.9 pomalidomide, 5.2 placebo), consistent with moderate to severe epistaxis. At 24 weeks, the ESS in patients treated with pomalidomide decreased by a mean [95% CI] of -1.84 [-2.24, -1.44] and in the placebo group decreased by -0.89 [-1.39, -0.39] (mean difference -0.95 [-1.58, -0.32], p = 0.003) (Figure, Panel A). Difference between groups was apparent by 12 weeks (mean difference -0.52, 95% CI [-1.04, -0.01], p = 0.045). The HHT-specific QOL score, which ranges from 0 to 16 with higher scores indicating more limitations, also decreased more in the pomalidomide (mean -2.6, 95% CI [-3.3, -1.9]) vs the placebo group at 24 weeks (mean -1.2, 95% CI [-2.1, -0.3], p = 0.015) (Figure, Panel B). Adverse events that occurred more in the pomalidomide group included mild to moderate neutropenia (45% vs. 10%), constipation/diarrhea (60% vs. 37%), and rash (36% vs. 10%). Venous thrombosis occurred in 2% of patients in each group. Conclusion PATH-HHT is the largest and the first adequately powered, randomized trial of systemic therapy in HHT. The study demonstrated a significant and highly clinically relevant reduction in epistaxis in pomalidomide-treated patients as well as an improvement in the HHT-specific QOL score. Pomalidomide may offer a novel approach to management of HHT. Since plasma was collected from patients in this study before and at the end of treatment, additional studies may identify biomarkers predicting pomalidomide responses.