Citations

Menopausal hormone therapy (HT) was widely used in the past, but with the publication of seminal primary and secondary prevention trials that reported an excess cardiovascular risk with combined estrogen-progestin, HT use declined significantly. However, over the past 20 years, much has been learned about the relationship between the timing of HT use with respect to age and time since menopause, HT route of administration, and cardiovascular disease risk. Four leading medical societies recommend HT for the treatment of menopausal women with bothersome menopausal symptoms. In this context, this review, led by the American College of Cardiology Cardiolovascular Disease in Women Committee, along with leading gynecologists, women’s health internists, and endocrinologists, aims to provide guidance on HT use, including the selection of patients and HT formulation with a focus on caring for symptomatic women with cardiovascular disease risk.

AbstractBackground and ObjectivesThe impact upon wound healing of targeted molecular therapies, when incorporated into neoadjuvant therapy of soft tissue sarcoma, is largely unknown. Here, we describe wound complications following addition of pazopanib, a tyrosine kinase inhibitor (TKI), to neoadjuvant radiotherapy (RT) +/− chemotherapy for soft tissue sarcoma.MethodsWound complications were evaluated on dose‐finding and randomized arms of ARST1321, a phase II/III study incorporating neoadjuvant RT, +/− pazopanib, +/− ifosfamide/doxorubicin (ID) for sarcoma therapy.ResultsOf 85 evaluable patients, 35 (41%) experienced postoperative wound complications. Most (57%) were grade III. Randomization to pazopanib + RT + ID carried a 50% wound complication rate (17/34, with 47% grade III), compared to 22% (5/23) with ID + RT alone. In nonchemotherapy study arms, pazopanib + RT resulted in a 59% wound complication rate versus 25% for those receiving RT alone. Grade III wound complications occurred among 26% (15/58) of all patients receiving pazopanib. Wound complications occurred a median of 35 days postoperatively. Some occurred following diagnostic biopsies and at remote surgical sites.ConclusionThe addition of pazopanib to neoadjuvant chemotherapy and RT resulted in a higher wound complication rate following therapy of soft tissue sarcoma. The rate of grade III complications remained comparable to that reported in contemporary literature.

Abstract There are few causes of treatable neurodevelopmental diseases described to date. Branched-chain ketoacid dehydrogenase kinase (BCKDK) deficiency causes branched-chain amino acid (BCAA) depletion and is linked to a neurodevelopmental disorder characterized by autism, intellectual disability and microcephaly. We report the largest cohort of patients studied, broadening the phenotypic and genotypic spectrum. Moreover, this is the first study to present newborn screening findings and mid-term clinical outcome. In this cross-sectional study, patients with a diagnosis of BCKDK deficiency were recruited via investigators’ practices through a MetabERN initiative. Clinical, biochemical and genetic data were collected. Dried blood spot (DBS) newborn screening (NBS) amino acid profiles were retrieved from collaborating centres and compared to a healthy newborn reference population. Twenty-one patients with BCKDK mutations were included from 13 families. Patients were diagnosed between 8 months and 16 years (mean: 5.8 years, 43% female). At diagnosis, BCAA levels (leucine, valine and isoleucine) were below reference values in plasma and in CSF. All patients had global neurodevelopmental delay; 18/21 had gross motor function (GMF) impairment with GMF III or worse in 5/18, 16/16 intellectual disability, 17/17 language impairment, 12/17 autism spectrum disorder, 9/21 epilepsy, 12/15 clumsiness, 3/21 had sensorineural hearing loss and 4/20 feeding difficulties. No microcephaly was observed at birth, but 17/20 developed microcephaly during follow-up. Regression was reported in six patients. Movement disorder was observed in 3/21 patients: hyperkinetic movements (1), truncal ataxia (1) and dystonia (2). After treatment with a high-protein diet (≥ 2 g/kg/day) and BCAA supplementation (100–250 mg/kg/day), plasma BCAA increased significantly (P < 0.001), motor functions and head circumference stabilized/improved in 13/13 and in 11/15 patients, respectively. Among cases with follow-up data, none of the three patients starting treatment before 2 years of age developed autism at follow-up. The patient with the earliest age of treatment initiation (8 months) showed normal development at 3 years of age. NBS in DBS identified BCAA levels significantly lower than those of the normal population. This work highlights the potential benefits of dietetic treatment, in particular early introduction of BCAA. Therefore, it is of utmost importance to increase awareness about this treatable disease and consider it as a candidate for early detection by NBS programmes.

Objectives: To evaluate the association between preoperative international normalized ratio (INR) and postoperative mortality and other outcomes after hemiarthroplasty for geriatric femoral neck fractures. Design: Retrospective cohort study. Setting: A single Level-I trauma center. Patients/Participants: Patients ≥55 years of age with OTA/AO 31B proximal femur fractures [1556 patients (1616 hips)] Intervention: Hip hemiarthroplasty. Main Outcome Measurements: Ninety-day mortality, postoperative transfusion within 72 hours, and 90-day postoperative outcomes. Results: Adjusting for confounders, the association of preoperative INR and 90-day mortality was not statistically significant [hazard ratio (HR): 1.3; 95% confidence interval (CI): 0.97, 1.8; P = 0.08]. Dementia (HR: 1.9; 95% CI: 1.4–2.6; P < 0.001), Charlson Comorbidity Index (HR: 1.1; 95% CI: 1.1–1.2; P < 0.001), and age by decade (HR: 1.4; 95% CI: 1.1–1.8; P = 0.002) were associated with 90-day mortality. Increasing INR was significantly associated with blood transfusion [odds ratio (OR) 1.4; 95% CI 1.03–1.6; P = 0.031]. Preoperative hemoglobin <10 g/dL (OR 13.7; 95% CI 8.4–23.3; P < 0.001) was also associated with a postoperative transfusion, whereas intraoperative tranexamic acid use (OR 0.3; 95% CI 0.2–0.5; P < 0.001) was inversely associated with postoperative transfusion rate. INR was associated with superficial wound infection (HR: 2.0; 95% CI: 1.1–3.7; P = 0.02) and noninfected wound complications (HR: 1.6; 95% CI: 1.1–2.4; P = 0.007). Risk of superficial infection increased when INR was >1.8. Conclusion: When controlling for confounders, preoperative INR was not significantly associated with 90-day mortality. Underlying medical conditions contribute to postoperative mortality more than an elevated INR. However, INR is associated with superficial wound complications. This risk becomes statistically significant as INR rises above 1.8. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Background: The Green-Anderson (GA) leg-length data remain the gold standard for the age-based assessment of leg lengths in children despite their methodologic weaknesses. We aimed to summarize current growth trends among a cross-sectional cohort of modern U.S. children using quantile regression methods and to compare the median femoral and tibial lengths of the modern U.S. children with those of the GA cohort. Methods: A retrospective review of scanograms and upright slot-scanning radiographs obtained in otherwise healthy children between 2008 and 2020 was completed. A search of a radiology registry revealed 3,508 unique patients between the ages of 2 and 18 years for whom a standard-of-care scanogram or slot-scanning radiograph had been made. All patients with systemic illness, genetic conditions, or generalized diseases that may affect height were excluded. Measurements from a single leg at a single time point per subject were included, and the latest available time point was used for children who had multiple scanograms made. Quantile regression analysis was used to fit the lengths of the tibia and femur and overall leg length separately for male patients and female patients. Results: Seven hundred patients (328 female and 372 male) met the inclusion criteria. On average, the reported 50th percentile tibial lengths from the GA study at each time point were shorter than the lengths in this study by 2.2 cm (range, 1.4 to 3.3 cm) for boys and 2 cm (range, 1.1 to 3.1 cm) for girls. The reported 50th percentile femoral lengths from the GA study at each time point were shorter than the lengths in this study by 1.8 cm (range, 1.1 to 2.5 cm) for boys and 1.7 cm (range, 0.8 to 2.3 cm) shorter for girls. Conclusions: This study developed new growth charts for femoral and tibial lengths in a modern U.S. population of children. The new femoral and tibial lengths at nearly all time points are 1 to 3 cm longer than traditional GA data. The use of GA data for epiphysiodesis could result in underestimation of expected childhood growth. Level of Evidence: Prognostic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Background: Quantitative susceptibility mapping (QSM) is a measure of iron content, and ≥6% increase in QSM has been correlated with new hemorrhage in previously stable cavernous angiomas. Longitudinal changes in QSM are not known in cavernous angiomas with symptomatic hemorrhage (CASH) with high rates of rebleeding and are the targets of novel pharmacotherapies. In a prospective multisite Trial Readiness project (clinicaltrials.gov NCT03652181), QSM is longitudinally assessed. Methods: Trial eligible subjects with CASH in the prior year and not undergoing lesion resection or radiation, were enrolled. Mean QSM of CASH lesion was acquired at baseline and at 1 and 2 year planned follow-ups. Relative change in mean lesional QSM during each follow-up year was assessed, and any symptomatic hemorrhage (SH), asymptomatic changes (AC; defined as subclinical bleed or growth) in the lesion during the same epoch. Results: Paired QSM assessments were completed to date in 99 CASH lesions (67 year 1, and 32 year 2) and are reported herein. Four SH and 6 ACs occurred during 1 st follow-up year, and 3 SH during 2 nd year. QSM increased in 54 lesion-years, decreased in 44, and remained stable in 1. The % lesional QSM change in year 1 was significantly higher than that observed in year 2 (mean +9.33, SD 37.52 vs. +5.20; SD= 24.86; p=0.05; Spearman correlation ρ -0.36). CAs with clinical SH or AC had a significantly higher % QSM change than lesions without (mean +28.03, SD 17.77 vs. +4.97, SD= 34.75; p=0.0014). All 13 lesions with SH/AC demonstrated a QSM increase ≥6% while 31 of 86 (36%) lesions with no clinical events had a ≥6% QSM increase. Conclusion: QSM change of ≥6% is present in every CASH lesion manifesting a new SH or AC (100% specificity), and is more common than clinical events (3.4X higher sensitivity). The biomarker can hence be used as a more sensitive categorical outcome than SH or AC in clinical trials of novel therapies aimed at bleeding in CASH lesions. Effect of an intervention on % QSM change may also be proposed as a time-averaged difference between 2 arms using a repeated measures analysis implemented as an unadjusted linear mixed model. These results are the basis of application for certification by the U.S F.D.A. of QSM as a monitoring biomarker of drug effect in CASH.

Abstract Objective The aim of this study was to compare the association between migraine and sleep quality in premenopausal versus perimenopausal women. Methods A cross-sectional analysis from the Data Registry on the Experiences of Aging, Menopause and Sexuality was conducted using questionnaire data from premenopausal and perimenopausal women seen at women's health clinics at 3 geographic locations from 2015 to 2021. Sleep quality and duration were assessed with the Pittsburgh Sleep Quality Index. Associations between poor sleep quality (Pittsburgh Sleep Quality Index >5) and self-reported migraine history (Y/N) were evaluated using a multivariable logistic regression model, adjusting for body mass index, anxiety, depression, and vasomotor symptoms. Results Of 2,067 women (mean age 43.2 years) included in the analysis, 594 (28.7%) reported a migraine history. Women were mostly white (92.2%), partnered (75.1%), and educated (86% with at least some college); 46.5% (n = 962) were premenopausal, 53.5% (n = 1,105) were perimenopausal, and 71.2% met the criteria for poor sleep. In univariate analysis, migraine history predicted poor sleep in both premenopausal and perimenopausal women (P = 0.005 and P = 0.004, respectively). However, in multivariable analysis, migraine history remained associated with poor sleep in premenopausal women (P = 0.044), but not in perimenopausal women (P = 0.46). Conclusions A migraine history was associated with poor sleep in premenopausal women. The relationship in perimenopausal women seemed to be influenced by confounding factors that are more prevalent during the menopause transition and are known to affect the frequency of migraine and sleep disturbances, such as anxiety, depression, and vasomotor symptoms. These conditions may need to be the focus of management in migraineurs with sleep disturbances during the menopause transition.

Abstract Background Respiratory distress is a leading cause of preterm infant mortality in sub-Saharan Africa. Bubble continuous positive airway pressure (CPAP) is emerging as a potentially safe, cost-effective way of delivering noninvasive respiratory support in low-income and middle-income countries. However, without healthcare providers who are knowledgeable and skilled in the use of this technology, suboptimal neonatal care and related health disparities are likely to persist. Objective We hypothesized that an Internet-based, blended curriculum on bubble CPAP for bedside providers in low-resource mother-baby units (MBUs) could be developed and implemented and lead to improvements in clinical knowledge, reasoning, and learner confidence in bubble CPAP. Methods Clinical educators from Israel, Ghana, and the United States used the analysis, design, development, implementation, and evaluation (ADDIE) design framework to create an online curriculum for two MBUs in Kumasi, in the Ashanti Region of Ghana. Participants completed pre and post curriculum knowledge tests and completed surveys on their perspectives. Results Fifty-four interdisciplinary health professionals from the MBUs participated in the curriculum. Median knowledge test scores improved from 64% (interquartile range [IQR] = 50–72%) to 81% (IQR = 71–89%) after participation in the curriculum (P &lt; 0.001). Learners reported high levels of confidence with bubble CPAP after participating in the curriculum and evaluated the curricular components highly. Conclusion An online curriculum was successfully implemented and led to changes in healthcare worker knowledge in bubble CPAP. This may be an effective way to deliver education to healthcare professionals in resource-constrained countries and warrants further study.

Abstract Background Laboratory medicine has reached the era where promises of artificial intelligence and machine learning (AI/ML) seem palpable. Currently, the primary responsibility for risk-benefit assessment in clinical practice resides with the medical director. Unfortunately, there is no tool or concept that enables diagnostic quality assessment for the various potential AI/ML applications. Specifically, we noted that an operational definition of laboratory diagnostic quality – for the specific purpose of assessing AI/ML improvements – is currently missing. Methods A session at the 3rd Strategic Conference of the European Federation of Laboratory Medicine in 2022 on “ AI in the Laboratory of the Future” prompted an expert roundtable discussion. Here we present a conceptual diagnostic quality framework for the specific purpose of assessing AI/ML implementations. Results The presented framework is termed diagnostic quality model (DQM) and distinguishes AI/ML improvements at the test, procedure, laboratory, or healthcare ecosystem level. The operational definition illustrates the nested relationship among these levels. The model can help to define relevant objectives for implementation and how levels come together to form coherent diagnostics. The affected levels are referred to as scope and we provide a rubric to quantify AI/ML improvements while complying with existing, mandated regulatory standards. We present 4 relevant clinical scenarios including multi-modal diagnostics and compare the model to existing quality management systems. Conclusions A diagnostic quality model is essential to navigate the complexities of clinical AI/ML implementations. The presented diagnostic quality framework can help to specify and communicate the key implications of AI/ML solutions in laboratory diagnostics.

AbstractBackgroundDecisions to transplant organs from severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) nucleic acid test‐positive (NAT+) donors must balance risk of donor‐derived transmission events (DDTE) with the scarcity of available organs.MethodsOrgan Procurement and Transplantation Network (OPTN) data were used to compare organ utilization and recipient outcomes between SARS‐CoV‐2 NAT+ and NAT– donors. NAT+ was defined by either a positive upper or lower respiratory tract (LRT) sample within 21 days of procurement. Potential DDTE were adjudicated by OPTN Disease Transmission Advisory Committee.ResultsFrom May 27, 2021 (date of OTPN policy for required LRT testing of lung donors) to January 31, 2022, organs were recovered from 617 NAT+ donors from all OPTN regions and 53 of 57 (93%) organ procurement organizations. NAT+ donors were younger and had higher organ quality scores for kidney and liver. Organ utilization was lower for NAT+ donors compared to NAT– donors. A total of 1241 organs (776 kidneys, 316 livers, 106 hearts, 22 lungs, and 21 other) were transplanted from 514 NAT+ donors compared to 21 946 organs from 8853 NAT– donors. Medical urgency was lower for recipients of NAT+ liver and heart transplants. The median waitlist time was longer for liver recipients of NAT+ donors. The match run sequence number for final acceptor was higher for NAT+ donors for all organ types. Outcomes for hospital length of stay, 30‐day mortality, and 30‐day graft loss were similar for all organ types. No SARS‐CoV‐2 DDTE occurred in this interval.ConclusionsTransplantation of SARS‐CoV‐2 NAT+ donor organs appears safe for short‐term outcomes of death and graft loss and ameliorates the organ shortage. Further study is required to assure comparable longer term outcomes. image