Prevalence and Risk Factors for Early, Undesired Weaning Attributed to Lactation Dysfunction

Background: Breastfeeding durations in the United States fall short of public health objectives. We sought to quantify the prevalence and identify risk factors for early, undesired weaning that mothers attribute to physiologic difficulties with breastfeeding

The Effect of Water Disinfection By-products on Pregnancy Outcomes in Two Southeastern US Communities

To determine if exposure to DBPs during gestation increases the risk of adverse birth outcomes, specifically term small for gestational age (SGA) birth, preterm birth (PTB), and very PTB (<32 weeks gestation)

A Global Collaboration to Develop and Pilot Test a Mobile Application to Improve Cancer Pain Management in Nepal

INTRODUCTION: Quality palliative care, which prioritizes comfort and symptom control, can reduce global suffering from non-communicable diseases, such as cancer. To address this need, the Nepalese Association of Palliative Care (NAPCare) created pain management guidelines (PMG) to support healthcare providers in assessing and treating serious pain. The NAPCare PMG are grounded in World Health Organization best practices but adapted for the cultural and resource context of Nepal. Wider adoption of the NAPCare PMG has been limited due to distribution of the guidelines as paper booklets. METHODS: Building on a long-standing partnership between clinicians and researchers in the US and Nepal, the NAPCare PMG mobile application (“app”) was collaboratively designed. Healthcare providers in Nepal were recruited to pilot test the app using patient case studies. Then, participants completed a Qualtrics survey to evaluate the app which included the System Usability Scale (SUS) and selected items from the Mobile App Rating Scale (MARS). Descriptive and summary statistics were calculated and compared across institutions and roles. Regression analyses to explore relationships (α = 0.05) between selected demographic variables and SUS and MARS scores were also conducted. RESULTS: Ninety eight healthcare providers (n = 98) pilot tested the NAPCare PMG app. Overall, across institutions and roles, the app received an SUS score of 76.0 (a score > 68 is considered above average) and a MARS score of 4.10 (on a scale of 1 = poor, 5 = excellent). 89.8% (n = 88) “agreed” or “strongly agreed” that the app will help them better manage cancer pain. Age, years of experience, and training in palliative care were significant in predicting SUS scores (p-values, 0.0124, 0.0371, and 0.0189, respectively); institution was significant in predicting MARS scores (p = 0.0030). CONCLUSION: The NAPCare PMG mobile app was well-received, and participants rated it highly on both the SUS and MARS. Regression analyses suggest end-user variables important to consider in designing and evaluating mobile apps in lower resourced settings. Our app design and pilot testing process illustrate the benefits of cross global collaborations to build research capacity and generate knowledge within the local context

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

High dose-rate tandem and ovoid brachytherapy in cervical cancer: dosimetric predictors of adverse events

Abstract Background Brachytherapy (BT) is a vital component of the curative treatment of locally advanced cervical cancer. The American Brachytherapy Society has published guidelines for high dose rate (HDR) BT with recommended dose limits. However, recent reports suggest lower doses may be needed to avoid toxicity. The purpose of this study is to investigate incidence and predictive factors influencing gastrointestinal (GI) and genitourinary (GU) toxicity following HDR intracavitary brachytherapy for locally advanced cervical cancer. Methods We retrospectively evaluated a cohort of patients with locally advanced cervical cancer who received CT-based HDR BT. Cumulative doses were calculated using the linear-quadratic model. Statistical analyses were used to investigate clinical and dosimetric predictors of GI and GU toxicity following HDR brachytherapy according to CTCAE v4.0 grading criteria. Results Fifty-six women with FIGO IB1 – IVA cervical cancer were included. The overall rate of any GU adverse event (Grade 1+) was 23.3% (n = 13) and severe adverse events (Grade 3+) was 7.1% (n = 4). Of those, the bladder equivalent dose in 2- Gray (Gy) fractions (EQD2) D2cc was ≥80 for three of the four patients. The overall rate of any GI adverse event was 26.8% (n = 15) and the rate of severe adverse events was 14.3% (n = 8). Of those, six of the eight patients had a rectal EQD2 D2cc ≥ 65 Gy and seven patients had a sigmoid D2cc ≥ 65 Gy. Amongst clinically meaningful factors for development of adverse events (i.e. diabetes, smoking status, ovoid size, and treatment duration), there were no statistically significant prognostic factors identified. Conclusions Severe adverse events are observed even with adherence to current ABS guidelines. In the era of recent multi-institutional study results, our data also supports more stringent dosimetric goals. We suggest cumulative D2cc dose limits of: less than 80 Gy for the bladder and less than 65 Gy for the rectum and sigmoid

Prevalence and Risk Factors for Early, Undesired Weaning Attributed to Lactation Dysfunction

Background: Breastfeeding durations in the United States fall short of public health objectives. We sought to quantify the prevalence and identify risk factors for early, undesired weaning that mothers attribute to physiologic difficulties with breastfeeding. Methods: We analyzed data from the Infant Feeding Practices Study (IFPS) II, a longitudinal study of US women. We defined disrupted lactation as early, undesired weaning attributed to at least two of the following three problems: breast pain, low milk supply, and difficulty with infant latch. We used logistic regression to estimate the association maternal body mass index (BMI), postpartum depressive symptoms, and disrupted lactation. Results: Of 4,902 women enrolled in the IFPS II, we analyzed 2,335 women who reported prenatal intention and breastfeeding initiation. The prevalence of disrupted lactation was 12 per 100 women (95% confidence interval [CI] 11, 13) during the first year of life. Women in this group weaned earlier (median 1.2 months, interquartile range [IQR] 0.5–2.8) than women without disrupted lactation (median 7.0 months, IQR 2.8–2.0, p<0.01). In multivariable-adjusted (MV-adj.) models, we found increased odds of disrupted lactation among overweight (odds ratio [OR] 1.6, 95% CI 1.1–2.3) or obese (OR 1.7, 95% CI 1.2–2.6) women, compared with women with a normal pregravid BMI. Maternal depressive symptoms at 2 months, defined as Edinburgh Postnatal Depression Scale ≥13, were also associated with disrupted lactation (MV-adj. OR 1.7, 95% CI 1.1–2.7). Conclusion: In a longitudinal sample of US women, disrupted lactation affected one in eight mothers who initiated breastfeeding. These findings underscore the need for both improved early breastfeeding support and targeted research to define the underlying pathophysiology and to determine management strategies that will enable more mothers to achieve their breastfeeding goals