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Objectives We assessed the effects of 3 new elementary school–based health centers (SBHCs) in disparate Georgia communities—predominantly non-Hispanic Black semi-urban, predominantly Hispanic urban, and predominantly non-Hispanic White rural—on asthma case management among children insured by Medicaid/Children’s Health Insurance Program (CHIP). Methods We used a quasi-experimental difference-in-differences analysis to measure changes in the treatment of children with asthma, Medicaid/CHIP, and access to an SBHC (treatment, n = 193) and children in the same county without such access (control, n = 163) in school years 2011-2013 and 2013-2018. Among children with access to an SBHC (n = 193), we tested for differences between users (34%) and nonusers of SBHCs. We used International Classification of Diseases diagnosis codes, Current Procedural Terminology codes, and National Drug Codes to measure well-child visits and influenza immunization; ≥3 asthma-related visits, asthma-relief medication, asthma-control medication, and ≥2 asthma-control medications; and emergency department visits during the child–school year. Results We found an increase of about 19 ( P = .01) to 33 ( P < .001) percentage points in the probability of having ≥3 asthma-related visits per child–school year and an increase of about 22 ( P = .003) to 24 ( P < .001) percentage points in the receipt of asthma-relief medication, among users of the predominantly non-Hispanic Black and Hispanic SBHCs. We found a 19 ( P = .01) to 29 ( P < .001) percentage-point increase in receipt of asthma-control medication and a 15 ( P = .03) to 30 ( P < .001) percentage-point increase in receipt of ≥2 asthma-control medications among users. Increases were largest in the predominantly non-Hispanic Black SBHC. Conclusion Implementation and use of elementary SBHCs can increase case management and recommended medications among racial/ethnic minority and publicly insured children with asthma.

The purpose of this article is to understand the complex pathologic spectrum of oculomotor nerve palsy. We review the detailed anatomy and function of the oculomotor nerve and demonstrate how the location of a lesion can drive the differential diagnosis. Lastly, we review atypical presentations of oculomotor nerve palsy to include oculomotor synkinesis and oculomotor nerve hyperactivity. Radiologists must be aware of the typical and atypical presentations of CN III palsy to accurately localize lesions as well as avoid premature exclusion of CN III pathology.

BACKGROUND: National recommendations allow for the omission of sentinel lymph node biopsy (SLNB) and post-lumpectomy radiotherapy in women ≥ 70 years-old with early-stage, hormone-receptor positive invasive breast cancer, but these therapies remain common. Previous work demonstrates an individual’s maximizing-minimizing (MM) trait—an inherent preference for more or less medical care—may influence the preference for low-value care. MATERIALS AND METHODS: We recruited an equal number of women ≥ 70 years who were maximizers, minimizers, or neutral based on a validated measure between September-November 2020. Participants were presented a hypothetical breast cancer diagnosis before randomization to one of three follow-up messages: maximizer-tailored, minimizer-tailored, or neutral. Tailored messaging aimed to redirect maximizers and minimizers towards declining SLNB and radiotherapy. The main outcome measure was predicted probability of choosing SLNB or radiotherapy. RESULTS: The final analytical sample (n=1600) was 515 maximizers (32%), 535 neutral (33%) and 550 (34%) minimizers. Higher maximizing tendency positively correlated with electing both SLNB and radiotherapy on logistic regression (p

Background This study evaluated E-selectin inhibition with GMI-1271 (Uproleselan [GMI]) alone and in combination with the standard of care low-molecular-weight heparin (LMWH) to improve vein recanalization, decrease vein wall inflammation and protect against adverse bleeding in a primate model. We sought to examine this novel treatment of venous thrombosis. Methods Using a well-documented primate animal model, iliac vein thrombosis was induced by balloon occlusion of the iliac vein for 6 hours. Starting on day 2 after thrombosis, animals began treatment in two phases. In phase one, nontreated controls received no treatment (n = 5) vs animals treated with the E-selectin inhibitor GMI, 25 mg/kg, subcutaneous (SC), once daily (n = 4) for 21 days (previously published data). In phase two, animals were treated with GMI plus a combination of LMWH 1.5 mg/kg or 40 mg (GMI + LMWHc) SC once daily (n = 8) for 19 days; and animals treated with LMWH 1.5 mg/kg or 40 mg (LMWHc) SC once daily (n = 6) for 19 days. Animals were evaluated by magnetic resonance venography for vein recanalization and inflammation by gadolinium extravasation, duplex ultrasound, coagulation tests (thromboelastography, bleeding time, prothrombin time, activated partial thromboplastin time, fibrinogen) and complete blood count at baseline, days 2, 7, 14, and 21 at euthanasia. Statistical analysis included using unpaired t test with Welch's correction for direct comparisons and one-way analysis of variance for comparison between the groups. Results Percent vein recanalization by magnetic resonance venography was highest in the GMI alone group followed by GMI + LMWHc, both significantly different from control. On ultrasound examination, animals treated with GMI alone had no decrease in open vein lumen by day 21, whereas decreases were observed in groups GMI + LMWHc (–26%), LMWHc (–27%), and controls (–80%). Vein wall inflammation decreased significantly in all treated groups. Intimal fibrosis and intimal thickness was best preserved in the GMI alone group. An analysis of total vein wall collagen revealed a trend in all treatment groups of decreasing vein wall collagen. No clinically significant bleeding events were noted in any group. The LMWH groups trended to have prolonged coagulation test values, whereas E-selectin inhibition with GMI did not cause clinically significant changes in coagulation measures. Conclusions Treatment with E-selectin inhibition results in improved vein recanalization, a decrease in vein wall inflammation and vein wall intimal thickness and fibrosis, with no changes in markers of coagulation. E-selectin inhibition with GMI alone is superior to E-selectin inhibition combined with LMWH, LMWH alone, and no treatment in this deep vein thrombosis model of iliac vein thrombosis.

Prostate cancer treatment planning is largely dependent upon examination of core-needle biopsies. The microscopic architecture of the prostate glands forms the basis for prognostic grading by pathologists. Interpretation of these convoluted three-dimensional (3D) glandular structures via visual inspection of a limited number of two-dimensional (2D) histology sections is often unreliable, which contributes to the under- and overtreatment of patients. To improve risk assessment and treatment decisions, we have developed a workflow for nondestructive 3D pathology and computational analysis of whole prostate biopsies labeled with a rapid and inexpensive fluorescent analogue of standard hematoxylin and eosin (H&E) staining. This analysis is based on interpretable glandular features and is facilitated by the development of image translation–assisted segmentation in 3D (ITAS3D). ITAS3D is a generalizable deep learning–based strategy that enables tissue microstructures to be volumetrically segmented in an annotation-free and objective (biomarker-based) manner without requiring immunolabeling. As a preliminary demonstration of the translational value of a computational 3D versus a computational 2D pathology approach, we imaged 300 ex vivo biopsies extracted from 50 archived radical prostatectomy specimens, of which, 118 biopsies contained cancer. The 3D glandular features in cancer biopsies were superior to corresponding 2D features for risk stratification of patients with low- to intermediate-risk prostate cancer based on their clinical biochemical recurrence outcomes. The results of this study support the use of computational 3D pathology for guiding the clinical management of prostate cancer. Significance: An end-to-end pipeline for deep learning–assisted computational 3D histology analysis of whole prostate biopsies shows that nondestructive 3D pathology has the potential to enable superior prognostic stratification of patients with prostate cancer.

Prostate cancer is a heterogeneous disease whose progression is linked to genome instability. However, the impact of this instability on the noncoding genome and its three-dimensional organization to aid progression is unclear. Using primary benign and tumor tissue, we find a high concordance in higher-order three-dimensional genome organization. This concordance argues for constraints to the topology of prostate tumor genomes. Nonetheless, we identified changes in focal chromatin interactions, typical of loops bridging noncoding cis-regulatory elements, and showed how structural variants can induce these changes to guide cis-regulatory element hijacking. Such events resulted in opposing differential expression of genes found at antipodes of rearrangements. Collectively, these results argue that changes to focal chromatin interactions, as opposed to higher-order genome organization, allow for aberrant gene regulation and are repeatedly mediated by structural variants in primary prostate cancer. Significance: This work showcases how the noncoding genome can be hijacked by focal insults to its three-dimensional organization that contribute to prostate cancer oncogenesis.

Following severe injury, biomineralization is disrupted and limited therapeutic options exist to correct these pathologic changes. This study utilized a clinically relevant murine model of polytrauma including a severe injury with concomitant musculoskeletal injuries to identify when bisphosphonate administration can prevent the paradoxical decrease of biomineralization in bone and increased biomineralization in soft tissues, yet not interfere with musculoskeletal repair. Systemic and intrinsic mechanisms in bone and soft tissues help promote biomineralization to the skeleton, while preventing it in soft tissues. However, severe injury can disrupt this homeostatic biomineralization tropism, leading to adverse patient outcomes due to a paradoxical decrease of biomineralization in bone and increased biomineralization in soft tissues. There remains a need for therapeutics that restore the natural tropism of biomineralization in severely injured patients. Bisphosphonates can elicit potent effects on biomineralization, though with variable impact on musculoskeletal repair. Thus, a critical clinical question remains as to the optimal time to initiate bisphosphonate therapy in patients following a polytrauma, in which bone and muscle are injured in combination with a severe injury, such as a burn. To test the hypothesis that the dichotomous effects of bisphosphonates are dependent upon the time of administration relative to the ongoing biomineralization in reparative bone and soft tissues, this study utilized murine models of isolated injury or polytrauma with a severe injury, in conjunction with sensitive, longitudinal measure of musculoskeletal repair. This study demonstrated that if administered at the time of injury, bisphosphonates prevented severe injury-induced bone loss and soft tissue calcification, but did not interfere with bone repair or remodeling. However, if administered between 7 and 21 days post-injury, bisphosphonates temporally and spatially localized to sites of active biomineralization, leading to impaired fracture callus remodeling and permanence of soft tissue calcification. There is a specific pharmacologic window following polytrauma that bisphosphonates can prevent the consequences of dysregulated biomineralization, yet not impair musculoskeletal regeneration.

BACKGROUND Pretransplant diabetes and new-onset diabetes after transplant (NODAT) are known risk factors for vascular events after kidney transplantation, but the incidence and magnitude of the risk of major adverse cardiovascular events (MACE) and cardiac deaths remain uncertain in recent era. METHODS A population cohort study of kidney transplant recipients identified using data from linked administrative healthcare databases from Ontario, Canada. The incidence rates of MACE (expressed as events with 95% confidence interval [95% CI] per 1000 person-years were reported according to diabetes status of pretransplant diabetes, NODAT, or no diabetes. Extended Cox regression model was used to examine the association between diabetes status, MACE, and cardiac death. RESULTS Of 5248 recipients, 1973 (38%) had pretransplant diabetes, and 799 (15%) developed NODAT with a median follow-up of 5.5 y. The incidence rates (95% CI) of MACE for recipients with pretransplant diabetes, NODAT, and no diabetes between 1 and 3 y posttransplant were 38.1 (32.1-45.3), 12.6 (6.3-25.2), and 11.8 (9.2-15.0) per 1000 person-years, respectively. Compared with recipients with pretransplant diabetes, recipients with NODAT experienced a lower risk of MACE (adjusted hazard ratio, 0.59; 95% CI, 0.47-0.74) but not cardiac death (adjusted hazard ratio, 0.97; 95% CI, 0.61-1.55). The rate of MACE and cardiac death was lowest in patients without diabetes. CONCLUSIONS Patients with pretransplant diabetes incur the greatest rate of MACE and cardiac deaths after transplantation. Having NODAT also bears high burden of vascular events compared with those without diabetes, but the magnitude of the increased rate remains lower than recipients with pretransplant diabetes.

Whole-genome sequencing of primary breast tumors enabled the identification of cancer driver genes and noncoding cancer driver plexuses from somatic mutations. However, differentiating driver from passenger events among noncoding genetic variants remains a challenge. Herein, we reveal cancer-driver cis-regulatory elements linked to transcription factors previously shown to be involved in development of luminal breast cancers by defining a tumor-enriched catalogue of approximately 100,000 unique cis-regulatory elements from 26 primary luminal estrogen receptor (ER)+ progesterone receptor (PR)+ breast tumors. Integrating this catalog with somatic mutations from 350 publicly available breast tumor whole genomes, we uncovered cancer driver cistromes, defined as the sum of binding sites for a transcription factor, for ten transcription factors in luminal breast cancer such as FOXA1 and ER, nine of which are essential for growth in breast cancer with four exclusive to the luminal subtype. Collectively, we present a strategy to find cancer driver cistromes relying on quantifying the enrichment of noncoding mutations over cis-regulatory elements concatenated into a functional unit. Implications: Mapping the accessible chromatin of luminal breast cancer led to discovery of an accumulation of mutations within cistromes of transcription factors essential to luminal breast cancer. This demonstrates coopting of regulatory networks to drive cancer and provides a framework to derive insight into the noncoding space of cancer.

Despite awareness regarding financial toxicity in breast cancer care, little is known about the financial strain associated with breast reconstruction. This study aims to describe financial toxicity and identify factors independently associated with financial toxicity for women pursuing post-mastectomy breast reconstruction. A 33-item electronic survey was distributed to members of the Love Research Army. Women over 18 years of age and at least 1 year after post-mastectomy breast reconstruction were invited to participate. The primary outcome of interest was self-reported financial toxicity due to breast reconstruction, while secondary outcomes of interest were patient-reported out-of-pocket expenses and impact of financial toxicity on surgical decision making. In total, 922 women were included (mean age 58.6 years, standard deviation 10.3 years); 216 women (23.8%) reported financial toxicity from reconstruction. These women had significantly greater out-of-pocket medical expenses. When compared with women who did not experience financial toxicity, those who did were more likely to have debt due to reconstruction (50.9% vs. 3.2%, p

Background Obesity is a barrier to kidney transplantation for patients with kidney failure. Consequently, bariatric surgery is often considered as a bridge to transplantation, even though its risks and benefits are poorly characterised in the dialysis population. Methods Systematic searches of observational studies indexed in Embase, MEDLINE and CENTRAL till April 2020 were performed to identify relevant studies. Risk of bias was assessed by the Newcastle Ottawa Scale and quality of evidence was summarised in accordance with GRADE methodology. Random effects meta-analyses were performed to obtain summary odds ratios for postoperative outcomes. Results Four cohort studies involving 4196 chronic dialysis and 732,204 non-dialysis patients undergoing bariatric surgery were included. Sleeve gastrectomy (61%), and Roux-en-Y gastric bypass (29%) were the most common procedures performed. Absolute rates of adverse events were low, but the odds of postoperative mortality (0.4–0.5% vs. 0.1%; odds ratio [OR] 4.7, 95%CI 2.2–9.9), and myocardial infarction (0.0–0.5% vs. 0.1%, OR 3.4, 95% CI 2.0–5.9) were higher in dialysis compared to non-dialysis patients. Patients on dialysis also had more than 2-fold increased odds of returning to theatre and having a readmission. Rates of kidney transplant wait-listing among dialysis patients was 59%, with 28% of all patients eventually receiving a kidney transplant. Conclusion Patients receiving chronic dialysis have substantially increased odds of postoperative mortality and myocardial infarction following bariatric surgery compared with patient who do not have kidney failure. It is uncertain whether bariatric surgery improves the likelihood of kidney transplantation, with mid- to long-term outcomes being poorly described.

Creutzfeld-Jakob Disease (CJD) is a rare disease but a common cause of rapidly progressive neurodegeneration. Although the "classic" presentation involves early dementia or behavioral changes, there are well-described atypical variants with less prominent cognitive symptoms at onset. One such variant is Corticobasal Syndrome (CBS), which may be seen with other underlying neurodegenerative processes, but when due to prion disease pathology involves much more rapid progression and certain characteristic imaging findings. This report presents a case presenting as CBS without cognitive or behavioral changes at onset, which rapidly progressed and was determined ultimately to be due to underlying CJD. This case illustrates the need for a high index of suspicion for CJD in order to drive appropriate diagnostic testing and careful review of imaging and EEG findings, which may be subtle in early disease.

Among racial subgroups, Black men have the highest prostate cancer–specific death rate, yet they also exhibit prolonged overall survival compared with White men when treated with standard therapies, including sipuleucel-T. Differential immune responses may play a role in these observations. We compared circulating immune markers from 54 men (18 Black and 36 White) with metastatic castrate-resistant prostate cancer who received sipuleucel-T and were enrolled on an immune monitoring registry. Markers included longitudinal serum cytokine concentrations, humoral responses, and cellular immunity from baseline until 52 weeks after sipuleucel-T administration. Black men had statistically significantly higher median concentrations of TH2-type (interleukin [IL]-4, IL-10, and IL-13) and inflammatory cytokines (IL-2, IL-12, and IL-6) compared with prostate-specific antigen-matched White men both at baseline and 52 weeks after sipuleucel-T (2-sided P

PURPOSE: We developed and tested a multi-level intervention, ConnectedCancerCare (CCC), which includes a tailored website and appointment reminder system for women with early-stage breast cancer and a provider summary letter sent to their medical oncologist and primary care provider to improve the delivery of team-based survivorship care. METHODS: We conducted a pilot randomized controlled trial to establish the feasibility and acceptability of CCC. Women diagnosed with stages 0-II breast cancer within one year of completing primary treatment were randomized to CCC (intervention), or a static online survivorship care plan (control). Participants completed baseline and 3 month follow-up surveys online. Post-trial interviews with 5 PCPs, 6 oncology providers, and 8 intervention patients were conducted. RESULTS: Of the 160 eligible women invited to participate, 66 completed the baseline survey and were randomized (41%), and 54 completed a follow-up survey (83%). Participants in the intervention arm found the CCC content to be acceptable, with 82% reporting it was easy to use, and 86% reporting they would recommend it to other patients. Women randomized to CCC (vs. control) more often reported scheduling a PCP follow-up visit (64% vs. 42%), communicating with their PCP about provider roles (67% vs. 18%), and higher mean team-based cancer care knowledge scores (3.7 vs. 3.4). CONCLUSIONS: Deploying CCC in medical oncology practices was feasible, and the intervention content was acceptable. CCC shows promise for improving patient knowledge and patient-provider communication about provider roles in team-based cancer care, and encouraging patients to engage with their PCP early in the survivorship period.

Background Few bariatric surgery programs exist at safety net hospitals which often serve patients of diverse racial and socioeconomic backgrounds. A bariatric surgery program was developed at a large urban safety net medical center serving a primarily Hispanic population. The purpose of this study was to evaluate safety, feasibility, and first-year outcomes to pave the way for other safety net bariatric programs. Methods The bariatric surgery program was started at a safety net hospital located in a neighborhood with over twice the national poverty rate. A retrospective review was performed for patient demographics, comorbidities, preoperative diet and exercise habits, perioperative outcomes, and 1-year outcomes including percent total weight lost (%TWL) and comorbidity reduction. Results A total of 153 patients underwent laparoscopic sleeve gastrectomy from May 2017 through December 2019. The average preoperative BMI was 47.9kg/m2, and 54% of patients had diabetes. The 1-year follow-up rate was 94%. There were no mortalities and low complication rates. The average 1-year %TWL was 22.8%. Hypertension and diabetes medications decreased in 52% and 55% of patients, respectively. The proportion of diabetic patients with postoperative HbA1c

Background There is an increase in elderly patients receiving kidney transplant internationally. This study describes elderly kidney transplant recipient outcomes in Australia and New Zealand. Methods The study included all adult first kidney transplant recipients in Australia and New Zealand from 2000 to 2015. Survival and graft outcomes were compared between elderly (≥70 years) and younger (18-69 years) recipients using Cox proportional hazards regression. Results Overall, 10651 kidney transplant recipients were included, of which 279 (2.6%) were elderly adults. The proportion of elderly recipients increased from 0.6 to 4.4% from 2000 to 2015. Compared with younger recipients, elderly recipients were more likely to receive kidneys from deceased donors, elderly donors, and expanded criteria donors. Elderly recipients experienced poorer patient survival with 1- and 5-year survival ranging from 96% to 97% and 79% to 81%, respectively, compared with 97% to 99% and 90% 95% in younger recipients, respectively. Elderly recipients experienced comparable rates of delayed graft function and, in living donor kidney recipients, lower rates of acute rejection. Conclusions Kidney transplantation in the elderly population is increasing. Although elderly recipients had inferior survival and graft outcomes, elderly recipients generally received poorer quality kidneys. The outcomes achieved in this cohort of elderly adults are encouraging, and improving elderly recipient outcomes should be an important focus for research.

Neurofibromatosis Type II (NF2) is an autosomal dominant cancer predisposition syndrome in which germline haploinsufficiency at the NF2 gene confers a greatly increased propensity for tumor development arising from tissues of neural crest derived origin. NF2 encodes the tumor suppressor, Merlin, and its biochemical function is incompletely understood. One well-established function of Merlin is as a negative regulator of group A serine/threonine p21-activated kinases (PAKs). In these studies we explore the role of PAK1 and its closely related paralog, PAK2, both pharmacologically and genetically, in Merlin-deficient Schwann cells and in a genetically engineered mouse model (GEMM) that develops spontaneous vestibular and spinal schwannomas. We demonstrate that PAK1 and PAK2 are both hyper activated in Merlin-deficient murine schwannomas. In preclinical trials, a pan Group A PAK inhibitor, FRAX-1036, transiently reduced PAK1 and PAK2 phosphorylation in vitro, but had insignificant efficacy in vivo. NVS-PAK1-1, a PAK1 selective inhibitor, had a greater but still minimal effect on our GEMM phenotype. However, genetic ablation of Pak1 but not Pak2 reduced tumor formation in our NF2 GEMM. Moreover, germline genetic deletion of Pak1 was well tolerated, while conditional deletion of Pak2 in Schwann cells resulted in significant morbidity and mortality. These data support the further development of PAK1-specific small molecule inhibitors and the therapeutic targeting of PAK1 in vestibular schwannomas and argue against PAK1 and PAK2 existing as functionally redundant protein isoforms in Schwann cells.

Purpose: There is strong epidemiologic evidence indicating that estrogens may not be the sole steroid drivers of breast cancer. We hypothesize that abundant adrenal androgenic steroid precursors, acting via the androgen receptor (AR), promote an endocrine-resistant breast cancer phenotype. Experimental Design: AR was evaluated in a primary breast cancer tissue microarray (n = 844). Androstenedione (4AD) levels were evaluated in serum samples (n = 42) from hormone receptor–positive, postmenopausal breast cancer. Levels of androgens, progesterone, and estradiol were quantified using LC/MS-MS in serum from age- and grade-matched recurrent and nonrecurrent patients (n = 6) before and after aromatase inhibitor (AI) therapy (>12 months). AR and estrogen receptor (ER) signaling pathway activities were analyzed in two independent AI-treated cohorts. Results: AR protein expression was associated with favorable progression-free survival in the total population (Wilcoxon, P < 0.001). Pretherapy serum samples from breast cancer patients showed decreasing levels of 4AD with age only in the nonrecurrent group (P < 0.05). LC/MS-MS analysis of an AI-sensitive and AI-resistant cohort demonstrated the ability to detect altered levels of steroids in serum of patients before and after AI therapy. Transcriptional analysis showed an increased ratio of AR:ER signaling pathway activities in patients failing AI therapy (t test P < 0.05); furthermore, 4AD mediated gene changes associated with acquired AI resistance. Conclusions: This study highlights the importance of examining the therapeutic consequences of the steroid microenvironment and demonstrable receptor activation using indicative gene expression signatures.

Background The "Foafoaga O le Ola (Beginning of Life)" study is a prospective birth cohort of n = 160 Samoan mother-infant dyads established in 2017-2018. A primary study aim is to explore how a missense variant at CREBRF rs373863828 impacts growth in early life, given its association with increased body size but lower risk of diabetes in adult Samoans. Here, we examine body size and composition by genotype among toddlers aged 18.7-24.5 months. Methods Height, weight, head circumference, mid-upper-arm circumference, and abdominal circumference, as well as subscapular, triceps, iliac crest and thigh skinfold thickness were measured among 107 toddlers with known rs373863828 genotype; 42 of these toddlers completed dual-energy X-ray absorptiometry (DXA) scans from which body composition (total body less head fat mass, lean mass, bone mass, % fat mass and % fat-free mass) was estimated. Results After controlling for sex and age, toddlers with at least one copy of the CREBRF minor allele (AA/AG) were 1.31 cm taller (SE = 0.64, p = 0.045) than toddlers with the GG genotype. Conclusion Whether greater linear growth in early childhood could contribute to the metabolically protective effects associated with the CREBRF variant in adulthood should be explored in future studies.

Aims/hypothesis We determined whether the time of day of exercise training (morning vs evening) would modulate the effects of consumption of a high-fat diet (HFD) on glycaemic control, whole-body health markers and serum metabolomics. Methods In this three-armed parallel-group randomised trial undertaken at a university in Melbourne, Australia, overweight/obese men consumed an HFD (65% of energy from fat) for 11 consecutive days. Participants were recruited via social media and community advertisements. Eligibility criteria for participation were male sex, age 30–45 years, BMI 27.0–35.0 kg/m2 and sedentary lifestyle. The main exclusion criteria were known CVD or type 2 diabetes, taking prescription medications, and shift-work. After 5 days, participants were allocated using a computer random generator to either exercise in the morning (06:30 hours), exercise in the evening (18:30 hours) or no exercise for the subsequent 5 days. Participants and researchers were not blinded to group assignment. Changes in serum metabolites, circulating lipids, cardiorespiratory fitness, BP, and glycaemic control (from continuous glucose monitoring) were compared between groups. Results Twenty-five participants were randomised (morning exercise n = 9; evening exercise n = 8; no exercise n = 8) and 24 participants completed the study and were included in analyses (n = 8 per group). Five days of HFD induced marked perturbations in serum metabolites related to lipid and amino acid metabolism. Exercise training had a smaller impact than the HFD on changes in circulating metabolites, and only exercise undertaken in the evening was able to partly reverse some of the HFD-induced changes in metabolomic profiles. Twenty-four-hour glucose concentrations were lower after 5 days of HFD compared with the participants’ habitual diet (5.3 ± 0.4 vs 5.6 ± 0.4 mmol/l, p = 0.001). There were no significant changes in 24 h glucose concentrations for either exercise group but lower nocturnal glucose levels were observed in participants who trained in the evening, compared with when they consumed the HFD alone (4.9 ± 0.4 vs 5.3 ± 0.3 mmol/l, p = 0.04). Compared with the no-exercise group, peak oxygen uptake improved after both morning (estimated effect 1.3 ml min−1 kg−1 [95% CI 0.5, 2.0], p = 0.003) and evening exercise (estimated effect 1.4 ml min−1 kg−1 [95% CI 0.6, 2.2], p = 0.001). Fasting blood glucose, insulin, cholesterol, triacylglycerol and LDL-cholesterol concentrations decreased only in participants allocated to evening exercise training. There were no unintended or adverse effects. Conclusions/interpretation A short-term HFD in overweight/obese men induced substantial alterations in lipid- and amino acid-related serum metabolites. Improvements in cardiorespiratory fitness were similar regardless of the time of day of exercise training. However, improvements in glycaemic control and partial reversal of HFD-induced changes in metabolic profiles were only observed when participants exercise trained in the evening. Trial registration anzctr.org.au registration no. ACTRN12617000304336. Funding This study was funded by the Novo Nordisk Foundation (NNF14OC0011493). Graphical abstract

Introduction:The arrival of coronavirus disrupted health care systems and forced delays in cancer treatment. We explored the experience of urologists who had to delay their patients’ cancer...

Purpose: To characterize the genetic architecture of left ventricular noncompaction (LVNC) and investigate the extent to which it may represent a distinct pathology or a secondary phenotype associated with other cardiac diseases. Methods: We performed rare variant association analysis with 840 LVNC cases and 125,748 gnomAD population controls, and compared results to similar analyses on dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Results: We observed substantial genetic overlap indicating that LVNC often represents a phenotypic variation of DCM or HCM. In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were uniquely associated with LVNC and may reflect a distinct LVNC etiology. In particular, MYH7 truncating variants (MYH7tv), generally considered nonpathogenic for cardiomyopathies, were 20-fold enriched in LVNC cases over controls. MYH7tv heterozygotes identified in the UK Biobank and healthy volunteer cohorts also displayed significantly greater noncompaction compared with matched controls. RYR2 exon deletions and HCN4 transmembrane variants were also enriched in LVNC, supporting prior reports of association with arrhythmogenic LVNC phenotypes. Conclusion: LVNC is characterized by substantial genetic overlap with DCM/HCM but is also associated with distinct noncompaction and arrhythmia etiologies. These results will enable enhanced application of LVNC genetic testing and help to distinguish pathological from physiological noncompaction.

SummaryWe describe variation across geographical regions of England in operations undertaken following presentation of hip fracture and in 30-day mortality. Some significant geographic variation in 30-day mortality was observed particularly for patients with trochanteric hip fractures and warrants further investigation of other aspects of post-hip fracture careIntroductionMortality after hip fracture has improved considerably in the UK over recent decades. Our aim here was to describe geographical variation in type of operation performed and 30-day mortality amongst patients in England with hip fracture.MethodsThe National Hip Fracture Database was used to carry out a prospective cohort study of nearly all over-60 year olds with hip fracture in England. These data were linked to Hospital Episode Statistics (HES), allowing us to explore regional variation in the operations performed for three fracture types (intracapsular, trochanteric and subtrochanteric), and use logistic regression models adjusted for demographic and clinical factors to describe associated 30-day mortality.ResultsNHFD recorded data for 64,211 patients who underwent surgery in England during 2017. Most had an intracapsular (59%) or trochanteric fracture (35%), and we found significant geographical variation across regions of England in use of total hip replacement (THR) (ranging from 10.1 to 17.4%) for intracapsular fracture and in intermedullary nailing (ranging from 14.9 to 27.0%) of trochanteric fracture. Some geographical variation in mortality amongst intracapsular fracture patients was found, with slightly higher mortality in the East of England (adjusted odds ratio [aOR]: 1.22, 95% CI: 1.02–1.46). Trochanteric fractures showed slightly more variation, with higher 30-day mortality (aOR: 1.40, 95%CI: 1.05–1.88) in the East of England and significantly lower mortality in the North East (aOR: 0.65, 95%CI: 0.46–0.93).ConclusionsWe have identified regional differences in operation type and 30-day mortality amongst hip fracture patients in England. The relationship between surgical approach and mortality has been explored, but the extent to which differential mortality reflects variation in approach to medical assessment, anaesthesia and other aspects of care warrants further investigation.v

Background/aimsThe primary aim of this study was to describe the causes of de novo uveitis in individuals 60 years and older. Secondary objectives were to determine the incidence of intraocular lymphoma and the clinical predictors of lymphoma.MethodsRetrospective chart review of all subjects presenting to the uveitis service at Auckland District Health Board (Auckland, New Zealand) between January 2006 and October 2020Results686 subjects (900 eyes) were aged ≥60 years at first presentation with uveitis, representing 23.4% of all subjects with uveitis during the study period. Non-infectious aetiology occurred in 631 (70.1%) eyes and infectious etiologies occurred in 269 (29.9%) eyes. The most frequent causes were idiopathic (36.3%), herpes zoster (14.8%), HLAB27 (8.7%) and sarcoidosis (4.8%). Twenty (2.2%) eyes of 13 (1.9%) subjects had a diagnosis of lymphoma. Lymphoma represented 11.2% of all intermediate uveitis. Subjects diagnosed with lymphoma did not develop posterior synechiae, epiretinal membrane, cystoid macular oedema or ocular hypertension.ConclusionsIntraocular lymphoma was uncommon in the overall cohort, but an important cause of intermediate uveitis. A diagnosis of lymphoma needs to be considered in any older subject with de novo intermediate uveitis. The lack of posterior synechiae, cystoid macular oedema, epiretinal membrane and ocular hypertension further increases the suspicion for lymphoma.

Background There are no antiviral therapies for parainfluenza virus (PIV) infections. DAS181, a sialidase fusion protein, has demonstrated activity in in vitro and in animal models of PIV. Methods Adult immunocompromised patients diagnosed with PIV lower respiratory tract infection (LRTI) who required oxygen supplementation were randomized 2:1 to nebulized DAS181 (4.5 mg/day) or matching placebo for up to 10 days. Randomization was stratified by need for mechanical ventilation (MV) or supplemental oxygen (SO). The primary endpoint was the proportion of patients reaching clinical stability survival (CSS) defined as returning to room air (RTRA), normalization of vital signs for at least 24 hours, and survival up to day 45 from enrollment. Results A total of 111 patients were randomized to DAS181 (n = 74) or placebo (n = 37). CSS was achieved by 45.0% DAS181-treated patients in the SO stratum compared with 31.0% for placebo (P = .15), whereas patients on MV had no benefit from DAS181. The proportion of patients achieving RTRA was numerically higher for SO stratum DAS181 patients (51.7%) compared with placebo (34.5%) at day 28 (P = .17). In a post hoc analysis of solid organ transplant, hematopoietic cell transplantation within 1 year, or chemotherapy within 1 year, more SO stratum patients achieved RTRA on DAS181 (51.8%) compared with placebo (15.8%) by day 28 (P = .012). Conclusions The primary endpoint was not met, but post hoc analysis of the RTRA component suggests DAS181 may have clinical activity in improving oxygenation in select severely immunocompromised patients with PIV LRTI who are not on mechanical ventilation. Clinical Trials Registration. NCT01644877., Immunocompromised adults with severe parainfluenza received nebulized DAS181 or placebo for up to 10 days. The primary endpoint was not met, but a subgroup of severely immunocompromised patients experienced a faster return to room air by day 28 (P = .012).

Introduction In pivotal trials of patients with autosomal dominant polycystic kidney disease at risk of rapid progression, tolvaptan slowed estimated glomerular filtration rate (eGFR) decline in early-to-moderate (TEMPO 3:4 [NCT00428948]) and moderate- to late-stage (REPRISE [NCT02160145]) chronic kidney disease (CKD). Discontinuation was less frequent in REPRISE (15.0%) than TEMPO 3:4 (23.0%), given that in REPRISE, only subjects who tolerated tolvaptan 60/30 mg daily initiated the double-blind phase. We evaluated whether the greater treatment effect in REPRISE was attributable to different completion rates. Methods We conducted post hoc analyses of TEMPO 3:4 and REPRISE completers, defined as subjects who took trial drug to the end of the treatment period in TEMPO 3:4 (3 years) or REPRISE (1 year). Efficacy (rate of change in eGFR for tolvaptan vs. placebo) was analyzed as in each trial. Subjects from TEMPO 3:4 and REPRISE were also matched by propensity score for age, gender, and baseline eGFR to explore potential additional determinants of treatment effect. Results The annualized tolvaptan treatment effect in TEMPO 3:4 completers (difference vs. placebo of 0.98 ml/min per 1.73 m2/y) and REPRISE completers (difference of 1.23) was similar to that of the respective total trial populations (TEMPO 3:4: 0.94; REPRISE: 1.27). The treatment effect of tolvaptan was also similar between matched subjects. Conclusion Greater treatment completion rate did not drive greater treatment effect in REPRISE. The more advanced CKD of REPRISE subjects may be more relevant. More rapid decline in kidney function in later-stage CKD enabled the effects of tolvaptan to be more easily discerned., Graphical abstract

Pediatric obsessive-compulsive disorder (OCD) often produces significant and chronic impairment for patients and their families. A subset of youths with OCD experience rapid-onset, severe OCD sympt...

Preoperative echocardiography is used routinely in neonates with esophageal atresia to identify patients in whom congenital cardiac disease will impact upon anesthetic and surgical decision-making. We aimed to determine the suitability of selective preoperative echocardiography. We performed a single-center retrospective review of neonates with esophageal atresia over 6 years (2010–2015) at our tertiary pediatric institution. Data included preoperative clinical examination, chest x-ray, and echocardiography. Endpoints were cardiovascular, respiratory, radiological, and echocardiography findings. Selective strategies were assessed using sensitivity, specificity, positive predictive value, and negative predictive value. We identified 115 neonates with esophageal atresia. All underwent preoperative echocardiography. Cardiac defects were identified in 49/115 (43%) (major 9/115, moderate 4/115). Sensitivity, specificity, positive predictive value, and negative predictive value of abnormal clinical and radiologic assessment for major and moderate cardiac defects were 92%, 25%, 13%, 96%; for clinical examination alone were 92%, 25%, 14%, 96%; for absence of murmur, cyanosis, and abnormal respiratory examination were 92%, 28%, 13%, 97%. Selective strategies reduce echocardiograms performed by 22%. Selective strategies allow for identification of neonates with esophageal atresia who may have deferral of echocardiogram unill after surgery. Selection may improve timeliness of care and resource utilization, without compromising patient safety.

Diagnostic laboratories gather phenotypic data through requisition forms, but there is no consensus as to which data are essential for variant interpretation. The ClinGen Cardiomyopathy Variant Curation Expert Panel defined a phenotypic data set for hypertrophic cardiomyopathy (HCM) variant interpretation, with the goal of standardizing requisition forms. Phenotypic data elements listed on requisition forms from nine leading cardiomyopathy testing laboratories were compiled to assess divergence in data collection. A pilot of 50 HCM cases was implemented to determine the feasibility of harmonizing data collection. Laboratory directors were surveyed to gauge potential for adoption of a minimal data set. Wide divergence was observed in the phenotypic data fields in requisition forms. The 50-case pilot showed that although demographics and assertion of a clinical diagnosis of HCM had 86% to 98% completion, specific phenotypic features, such as degree of left ventricular hypertrophy, ejection fraction, and suspected syndromic disease, were completed only 24% to 44% of the time. Nine data elements were deemed essential for variant classification by the expert panel. Participating laboratories unanimously expressed a willingness to adopt these data elements in their requisition forms. This study demonstrates the value of comparing and sharing best practices through an expert group, such as the ClinGen Program, to enhance variant interpretation, providing a foundation for leveraging cumulative case-level data in public databases and ultimately improving patient care.

Expanding our understanding of the effects of maternal medication exposure through research is a public health priority and will help inform both clinical and policy decision making, ultimately improving outcomes for pregnant women and their children. Our objective was to describe a linked-data research platform that facilitates studies of pregnancy medication exposures and policy changes on maternal and child health outcomes. Mothers receiving Medicaid benefits were probabilistically linked with newborns in the Tennessee Medicaid program (TennCare) through three distinct linkage processes. Medicaid claims data and state birth and fetal death certificate records (vital records) were used to identify and link potential mothers, deliveries, and newborn children. The linkage process started with the creation of a merged pool of potential mothers and eligible deliveries, which was linked to vital records and to children’s records. In the last step, linked records from the preceding steps were combined into the final Mother–child linked records. For each data linkage step, rubrics and scoring systems for exact and partial matches and mismatches among key linkage fields were applied and used to examine the strength of the probabilistic linkages. Summary linkage yields for year 2013 are reported for illustration purposes. Among the 84,253 potential deliveries, 1,761,557 eligible potential mothers, and 51,400 eligible children identified in Tennessee Medicaid records in 2013, a total of 60,265 of these records were uniquely linked to vital records, including 46,172 (77%) with linked mother–child–vital records. Among the 51,400 eligible children records identified in Tennessee Medicaid for that year, 97% (50,053) had at least one link to vital records or a mother–delivery record. In linked records, the median maternal age was 24 years, and the median gestational age was 39 weeks. About 33% of pregnant women underwent cesarean birth, and 1% of births were classified as complicated deliveries. Supplementing existing Medicaid claims data with birth certificate records complements administrative claims information and allows for detailed assessments of pregnancy exposures and policy changes on mother and child outcomes.

Background Intensity of resistance training history might be omitted or poorly ascertained in prescreening or data questionnaires involving musculoskeletal health. Failure to identify history of high-versus low-intensity training may overlook higher effect sizes with higher intensities and therefore diminish the precision of statistical analysis with resistance training as a covariate and bias the confirmation of baseline homogeneity for experimental group designation. The purpose was to determine the degree to which a single question assessing participant history of resistance training intensity predicted differences in musculoskeletal health. Methods In the first research aim, participants were separated into groups with a history (RT) and no history (NRT) of resistance training. The second research aim evaluated the history of resistance training intensity on muscular strength, lean mass, and bone mineral density (BMD), RT participants were reassigned into a low- (LIRT) or high-intensity resistance training group (HIRT). 83 males and 87 females (19.3 ± 0.6 yrs., 171.1 ± 9.9 cm, 67.1 ± 10.5 kg, 22.9 ± 2.8 BMI, 26.2 ± 7.2% body fat) completed handgrip dynamometry (HG) and dual-energy x-ray absorptiometry scans (DXA) for BMD and bone mineral-free lean mass (BFLM). Results A 3-group method (NRT, LIRT, HIRT) reduced type-I error compared with the 2-group method (NRT, RT) in characterizing the likely effects of one’s history of resistance training. For the second aim, HIRT had significantly (p 2) while LIRT revealed no significant skeletal differences to NRT. Conclusions Retrospective identification of high-intensity history of resistance training appears critical in characterizing musculoskeletal health and can be ascertained easily in as little as a single, standalone question. Both retrospective-questionnaire style investigations and pre-screening for potential participation in prospective research studies should include participant history of resistance training intensity.

BACKGROUND: Primary care provider’s (PCP) role in cancer care is expanding and may include supporting patients in their treatment decisions. However, the degree to which PCPs engage in this role for low-risk prostate cancer is unknown. OBJECTIVE: Characterize PCP perceptions regarding their role in low-risk prostate cancer treatment decision-making. DESIGN: Cross-sectional, national survey. MAIN MEASURES: For men with low-risk prostate cancer, PCP reports of (1) confidence in treatment decision-making (high vs. low); (2) intended participation in key aspects of active surveillance treatment decision-making (more vs. less). KEY RESULTS: A total of 347 from 741 eligible PCPs responded (adjusted response rate 56%). Half of respondent PCPs (50.3%) reported high confidence about engaging in low-risk prostate cancer treatment decision-making. The odds of PCPs reporting high confidence were greater among those in solo practice (vs working with > 1 PCP) (OR 2.18; 95% CI 1.14–4.17) and with higher volume of prostate cancer patients (> 15 vs. 6–10 in past year) (OR 2.16; 95% CI 1.02–4.61). PCP report of their intended participation in key aspects of active surveillance treatment decision-making varied: discussing worry (62.4%), reviewing benefits (48.5%) and risks (41.8%), and reviewing all treatment options (34.2%). PCPs who reported high confidence had increased odds of more participation in all aspects of active surveillance decision-making: reviewing all treatment options (OR 3.11; 95% CI 1.82–5.32), discussing worry (OR 2.12; 95% CI 1.28–3.51), and reviewing benefits (OR 3.13; 95% CI 1.89–5.16) and risks (OR 3.20; 95% CI 1.91–5.36). CONCLUSIONS: The majority of PCPs were confident about engaging with patients in low-risk prostate cancer treatment decision-making, though their intended participation varied widely across four key aspects of active surveillance care. With active surveillance being considered for other low-risk cancers (such as breast and thyroid), understanding factors influencing PCP involvement will be instrumental to supporting team-based cancer care.

In a large observational study in patients with COVID-19 and cancer, survival was not significantly influenced by receipt of COVID-19 treatments, except hydroxychloroquine plus any other treatment, which was associated with reduced survival., Among 2,186 U.S. adults with invasive cancer and laboratory-confirmed SARS-CoV-2 infection, we examined the association of COVID-19 treatments with 30-day all-cause mortality and factors associated with treatment. Logistic regression with multiple adjustments (e.g., comorbidities, cancer status, baseline COVID-19 severity) was performed. Hydroxychloroquine with any other drug was associated with increased mortality versus treatment with any COVID-19 treatment other than hydroxychloroquine or untreated controls; this association was not present with hydroxychloroquine alone. Remdesivir had numerically reduced mortality versus untreated controls that did not reach statistical significance. Baseline COVID-19 severity was strongly associated with receipt of any treatment. Black patients were approximately half as likely to receive remdesivir as white patients. Although observational studies can be limited by potential unmeasured confounding, our findings add to the emerging understanding of patterns of care for patients with cancer and COVID-19 and support evaluation of emerging treatments through inclusive prospective controlled trials. Significance: Evaluating the potential role of COVID-19 treatments in patients with cancer in a large observational study, there was no statistically significant 30-day all-cause mortality benefit with hydroxychloroquine or high-dose corticosteroids alone or in combination; remdesivir showed potential benefit. Treatment receipt reflects clinical decision-making and suggests disparities in medication access. This article is highlighted in the In This Issue feature, p. 1426

Background: Intervention strategies to prevent childhood obesity in the Pacific Islands encourage eating a variety of local and traditional foods, but context-specific data to support this approach are limited. The objective was to assess the association between 2-year adherence to modern and neotraditional dietary patterns and body mass index z-scores (BMIz) among Samoan children. Methods: A convenience sample of 214 Samoan biological mother-child dyads who participated in the Ola Tuputupua'e “Growing Up” cohort study in 2015 and 2017 was included. At each time point, modern and neotraditional dietary patterns were identified using food frequency data and factor analysis. Children were assigned to categories based on diet pattern adherence: consistently high, high to low, low to high, and consistently low. Associations between 2-year adherence to dietary patterns, BMIz (in 2017 and 2015–2017), and weight and height z-scores were examined using linear models adjusted for potential confounders. Results: Consistently high adherence to the modern pattern was associated with a 0.36 standard deviation (SD)-adjusted change in BMIz between 2015 and 2017 (95% confidence interval [CI]: 0.04–0.69, p = 0.03). While the estimates for the individual components of BMI were imprecise, on average, children with consistently high adherence to the modern pattern had a 0.13 SD greater change in weight z-score (95% CI: −0.10 to 0.37) and 0.15 SD lower change in height z-score (95% CI: −0.43 to 0.13). The change in BMIz between 2015 and 2017 did not significantly differ by adherence to the neotraditional pattern. Conclusion: A neotraditional dietary pattern, comprising local produce, should be encouraged as a possible childhood obesity prevention strategy in Samoa.

Background Hyperphosphatemia is associated with increased fibroblast growth factor 23 (FGF23), arterial calcification, and cardiovascular mortality. Effects of phosphate-lowering medication on vascular calcification and arterial stiffness in CKD remain uncertain.Methods To assess the effects of non-calcium-based phosphate binders on intermediate cardiovascular markers, we conducted a multicenter, double-blind trial, randomizing 278 participants with stage 3b or 4 CKD and serum phosphate >1.00 mmol/L (3.10 mg/dl) to 500 mg lanthanum carbonate or matched placebo thrice daily for 96 weeks. We analyzed the primary outcome, carotid-femoral pulse wave velocity, using a linear mixed effects model for repeated measures. Secondary outcomes included abdominal aortic calcification and serum and urine markers of mineral metabolism.Results A total of 138 participants received lanthanum and 140 received placebo (mean age 63.1 years; 69% male, 64% White). Mean eGFR was 26.6 ml/min per 1.73m(2); 45% of participants had diabetes and 32% had cardiovascular disease. Mean serum phosphate was 1.25 mmol/L (3.87 mg/dl), mean pulse wave velocity was 10.8 m/s, and 81.3% had abdominal aortic calcification at baseline. At 96 weeks, pulse wave velocity did not differ significantly between groups, nor did abdominal aortic calcification, serum phosphate, parathyroid hormone, FGF23, and 24-hour urinary phosphate. Serious adverse events occurred in 63 (46%) participants prescribed lanthanum and 66 (47%) prescribed placebo. Although recruitment to target was not achieved, additional analysis suggested this was unlikely to have significantly affected the principle findings.Conclusions In patients with stage 3b/4 CKD, treatment with lanthanum over 96 weeks did not affect arterial stiffness or aortic calcification compared with placebo. These findings do not support the role of intestinal phosphate binders to reduce cardiovascular risk in patients with CKD who have normophosphatemia.

BACKGROUND/OBJECTIVES: In Samoa, where 80% of the adult population is living with obesity, understanding the determinants of adiposity and growth during infancy may inform prevention efforts. We examined the association of a missense variant, rs373863828, in the CREBRF gene with body composition in Samoan infants. Adults with one or more copies of the rs373863828 minor allele (A) have higher odds of obesity, based on body-mass index (BMI), but paradoxically decreased odds of diabetes compared to those without the allele. Our study may offer novel insight into the natural history and pathogenesis of this unexpected relationship. SUBJECTS/METHODS: In a prospective study, we measured body composition in early infancy, and at 2- and 4-months of age using anthropometry and Dual-Energy X-Ray Absorptiometry (DXA). We genotyped subjects at the CREBRF rs373863828 locus and compared infants with (AA/AG) and without (GG) the variant. In longitudinal analyses, we calculated the absolute change in each outcome from the early infant to the 4-month assessment, adjusting for baseline and other covariates. RESULTS: In cross-sectional analyses, there was no significant difference in infant BMI or fat mass by genotype. After adjusting for covariates, infants with the variant had 4.0 ± 1.8g more bone mass (p=0.026) and 210.9 ±79.6g more lean mass (p=0.009) at 4-months and accumulated 176.9 ± 73.0g more lean mass between the early infant and 4-month assessment (p=0.017). CONCLUSIONS: The CREBRF rs373863828 minor allele (A) was not associated with increased BMI or adiposity in Samoan infants, but instead with increased lean and bone mass. Our findings suggest that lean (i.e. muscle) and bone mass accretion should be explored as pathways to explain the ‘protective’ effect of the CREBRF variant against diabetes.

The aim of this study was to determine the complications, incidence, and predictors of implant-based reconstruction failure (RF) among patients treated with mastectomy for breast cancer. We retrospectively reviewed 108 patients who underwent mastectomy, tissue expander, and implant-based breast reconstruction with or without radiation therapy (RT) at our institution (2000–2014). Descriptive statistics determined complication incidences, with major complications defined as any complications requiring surgical intervention or inpatient management. Chi square and Fisher’s exact tests determined differences in RF incidences, defined as implant loss. Logistic regression analyses identified predictors of RF. Median follow-up was 42.5 months. Sixty patients (55.6%) experienced major complications. Overall, 27 patients (25%) experienced RF. Incidences of RF were significantly increased in patients who had any major complication (43.3% vs. 2.1%; p 70% accuracy for stepwise prediction of RF.

Cardiovascular disease is the leading cause of death in patients with kidney failure or on chronic dialysis. Patients on chronic dialysis have a 10- to 50-fold increased risk of sudden cardiac death compared to patients with normal kidney function. Adverse changes in cardiac structure and function may not manifest with clinical symptoms in patients with kidney failure and, therefore, pose a challenge in identifying cardiac dysfunction early. Fortunately, there are multi-modality cardiac imaging techniques available, including echocardiography and cardiac magnetic resonance imaging, that can help our understanding of the pathophysiology of cardiac dysfunction in kidney failure. This review describes the benefits and limitations of these two commonly available cardiac imaging modalities to assess cardiac structure and function, thereby aiding nephrologists in choosing the most appropriate investigative tool based on individual clinical circumstances. For the purposes of this review, cardiac imaging for detection of coronary artery disease has been omitted.

The proliferation in the rate of diagnosis of obesity and type 2 diabetes mellitus continues unabated, with current recommendations for primary lifestyle changes (i.e. modification to dietary patterns) having a limited impact in reducing the incidence of these metabolic diseases. Part of the reason for the failure to alter nutritional practices is that current dietary recommendations may be unrealistic for the majority of adults. Indeed, round-the-clock access to energy-dense, nutrient-poor food makes long-term changes to dietary habits challenging. Hence, there is urgent need for innovations in the delivery of evidence-based diet interventions to rescue some of the deleterious effects on circadian biology induced by our modern-day lifestyle. With the growing appreciation that the duration over which food is consumed during a day has profound effects on numerous physiological and metabolic processes, we discuss dietary protocols that modify the timing of food intake to deliberately alter the feeding-fasting cycle. Such chrono-nutrition functions to optimise metabolism by timing nutrient intake to the acrophases of metabolic rhythms to improve whole-body insulin sensitivity and glycaemic control, and thereby positively impact metabolic health. Graphical abstract.

There is increasing appreciation of nephronophthisis (NPHP) as an autosomal recessive cause of kidney failure and earlier stages of chronic kidney disease among adults. We identified 2 families with presumed adult-diagnosed nonsyndromic NPHP and negative diagnostic genetic testing results from our Renal Genetics Clinic. Both had 2 affected siblings without extrarenal phenotypes. After informed consent, research whole-genome sequencing was undertaken. Biallelic NPHP4 variants were identified in trans and clinically confirmed in all 4 affected individuals, confirming a genetic diagnosis. Participant 1 of the first family (F1P1) had kidney failure diagnosed at 19 years of age. An affected younger sibling (F1P2) reached kidney failure at age 15 years after kidney biopsy suggested NPHP. Pathogenic variants detected in NPHP4 in this family were NM_015102.4:c.3766C>T (p.Gln1256*) and a 31-kb deletion affecting exons 12 to 16. In the second family, F2P3 reached kidney failure at age 27 years having undergone kidney biopsy suggesting NPHP. An affected younger sibling (F2P4) has chronic kidney disease stage 4 at age 39 years. The NPHP4 variants detected were NM_015102.4:c.1998_1999del (p.Tyr667Phefs*23) and c.3646G>T (p.Asp1216Tyr). The latter variant was initially missed in diagnostic sequencing due to inadequate NPHP4 coverage (94.3% exonic coverage). With these reports, we identify NPHP4 as an appreciable genetic cause for adult-diagnosed nonsyndromic NPHP that should be considered by adult nephrologists.

Background Reliable estimates of the absolute and relative risks of postoperative complications in kidney transplant recipients undergoing elective surgery are needed to inform clinical practice. This systematic review and meta-analysis aimed to estimate the odds of both fatal and non-fatal postoperative outcomes in kidney transplant recipients following elective surgery compared to non-transplanted patients. Methods Systematic searches were performed through Embase and MEDLINE databases to identify relevant studies from inception to January 2020. Risk of bias was assessed by the Newcastle Ottawa Scale and quality of evidence was summarised in accordance with GRADE methodology (grading of recommendations, assessment, development and evaluation). Random effects meta-analysis was performed to derive summary risk estimates of outcomes. Meta-regression and sensitivity analyses were performed to explore heterogeneity. Results Fourteen studies involving 14,427 kidney transplant patients were eligible for inclusion. Kidney transplant recipients had increased odds of postoperative mortality; cardiac surgery (OR 2.2, 95%CI 1.9–2.5), general surgery (OR 2.2, 95% CI 1.3–4.0) compared to non-transplanted patients. The magnitude of the mortality odds was increased in the presence of diabetes mellitus. Acute kidney injury was the most frequently reported non-fatal complication whereby kidney transplant recipients had increased odds compared to their non-transplanted counterparts. The odds for acute kidney injury was highest following orthopaedic surgery (OR 15.3, 95% CI 3.9–59.4). However, there was no difference in the odds of stroke and pneumonia. Conclusion Kidney transplant recipients are at increased odds for postoperative mortality and acute kidney injury following elective surgery. This review also highlights the urgent need for further studies to better inform perioperative risk assessment to assist in planning perioperative care.

About one-third of women of reproductive age are obese, predisposing both mother and baby to unfavourable pregnancy outcomes and initiating an intergenerational cycle of chronic metabolic disorders. Here we summarise recent research on the influence of maternal metabolic health on offspring susceptibility to future cardiometabolic diseases. Current primary lifestyle approaches (i.e., diet and exercise interventions) to halt the succession of inherited and epigenetic metabolic abnormalities have met with limited success due to late implementation, poor adherence, and/or generic guidelines. In our opinion, such interventions must commence prior to conception to improve both maternal and child health outcomes, with new approaches urgently needed to increase adherence to primary lifestyle changes among reproductive-age women.

BACKGROUND: Multiple studies have demonstrated the safety of omitting therapies in older women with breast cancer. Despite de-implementation guidelines, up to 65% of older women continue to receive one or more of these low-value services. Previous work has investigated the role of both provider and patient attitudes as barriers to de-implementation; however, the importance of the patient’s maximizing-minimizing preferences within this context remains unclear. METHODS: In this qualitative study, we conducted thirty (n = 30) semi-structured interviews with women ≥ 70 years old without a previous diagnosis of breast cancer to elicit perspectives on breast cancer treatment in relation to their medical maximizing-minimizing preferences, as determined by the single-item maximizer-minimizer elicitation question (MM1). We used an interpretive description approach in analysis to produce a thematic survey. RESULTS: Participants were relatively evenly distributed across the MM1 (minimizer n = 8, neutral n = 13, maximizer n = 9). Despite being told of recommendations allowing for the safe omission of SLNB and post-lumpectomy radiotherapy, maximizers consistently stated preferences for more medical intervention and aggressive therapies over minimizers and neutral individuals. CONCLUSION: Medical maximizing-minimizing preferences in older women correspond with preferences for breast cancer treatment options that guidelines identify as potentially unnecessary. Increased awareness of patient-level variability in maximizing-minimizing preferences may be valuable in developing optimal intervention strategies to reduce utilization of low-value care.

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) originated in China in late 2019 and has since spread rapidly to every continent in the world. This pandemic continues to cause widespread personal suffering, along with severe pressure on medical and health care providers. The symtoms of SARS‐CoV‐2 and the subsequent prognosis is worsened in individuals who have pre‐exisiting comorbidities prior to infection by the virus. Individuals with obesity/overweight, insulin resistance and diabetes typically have chronic low‐grade inflammation characterized by increased levels of several pro‐inflammatory cytokines and the inflammasome: this state predisposes to greater risk for infection along with more adverse outcomes. Here we consider whether a high level of cardiorespiratory fitness induced by prior exercise training may confer some innate immune‐protection against Covid‐19 by attenuating the “cytokine storm syndrome” often experienced by “at risk” individuals.

Background Elevated serum urate levels are associated with progression of chronic kidney disease. Whether urate-lowering treatment with allopurinol can attenuate the decline of the estimat...

The ACMG/AMP variant classification framework was intended for highly penetrant Mendelian conditions. While it is appreciated that clinically relevant variants exhibit a wide spectrum of penetrance, accurately assessing and expressing the pathogenicity of variants with lower penetrance can be challenging. The vinculin (VCL) gene illustrates these challenges. Model organism data provide evidence that loss of function of VCL may play a role in cardiomyopathy and aggregate case-control studies suggest low penetrance. VCL loss of function variants, however, are rarely identified in affected probands and therefore there is a paucity of family studies clarifying the clinical significance of individual variants. This study, which aggregated data from >18,000 individuals who underwent gene panel or exome testing for inherited cardiomyopathies, identified 32 probands with VCL loss-of-function variants and confirmed enrichment in probands with dilated cardiomyopathy (odds ratio [OR] = 9.01; confidence interval [CI] = 4.93–16.45). Our data revealed that the majority of these individuals (89.5%) had pediatric onset of disease. Family studies demonstrated that heterozygous loss of function of VCL alone is insufficient to cause cardiomyopathy but that these variants do contribute to disease risk. In conclusion, VCL loss-of-function variants should be reported in a diagnostic setting but need to be clearly distinguished as having lower penetrance.

Recognition of underlying genetic etiologies of disease is increasing at an exponential rate, likely due to greater access to and lower cost of genetic testing. Monogenic causes of disease, or conditions resulting from a mutation or mutations in a single gene, are now well recognized in every subspecialty, including pediatric pulmonary medicine; thus, it is important to consider genetic conditions when evaluating children with respiratory disease. In the pediatric pulmonary clinic, genetic testing should be considered when multiple family members present with similar or related clinical features and when individuals have unusual clinical presentations, such as early-onset disease or complex, syndromic features. This review provides a practical guide for genetic diagnosis in the pediatric pulmonary setting, including a review of genetic concepts, considerations for test selection and results in interpretation, as well as an overview of genetic differential diagnoses for common pediatric pulmonary phenotypes. Genetic conditions that commonly present to the pediatric pulmonary clinic are reviewed in a companion article by Yonker et al.

Summary Background Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness. Methods In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing. Findings Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57–76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53–2·21), male sex (1·63, 1·07–2·48), smoking status (former smoker vs never smoked: 1·60, 1·03–2·47), number of comorbidities (two vs none: 4·50, 1·33–15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11–7·18), active cancer (progressing vs remission: 5·20, 2·77–9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79–4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07–0·84) or the US-Midwest (0·50, 0·28–0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality. Interpretation Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments. Funding American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.

Background The vascular endothelium is a novel target for the detection, management, and prevention of doxorubicin (DOX)-induced cardiotoxicity. Objectives The study aimed to: 1) develop a methodology by computed tomography angiography (CTA) to evaluate stress-induced changes in epicardial coronary diameter; and 2) apply this to a chronic canine model of DOX-induced cardiotoxicity to assess vascular toxicity. Methods To develop and validate quantitative methods, sequential retrospectively gated coronary CTAs were performed in 16 canines. Coronary diameters were measured at prespecified distances during rest, adenosine (ADE) (280 μg/kg/min), rest 30 min post-ADE, and dobutamine (DOB) (5 μg/kg/min). A subgroup of 8 canines received weekly intravenous DOX (1 mg/kg) for 12 to 15 weeks, followed by rest-stress CTA at cumulative doses of ∼4-mg/kg (3 to 5 mg/kg), ∼8-mg/kg (7 to 9 mg/kg), and ∼12-mg/kg (12 to 15 mg/kg) of DOX. Echocardiograms were performed at these timepoints to assess left ventricular ejection fraction and global longitudinal strain. Results Under normal conditions, epicardial coronary arteries reproducibly dilated in response to ADE (left anterior descending coronary artery [LAD]: 12 ± 2%, left circumflex coronary artery [LCx]: 13 ± 2%, right coronary artery [RCA]: 14 ± 2%) and DOB (LAD: 17 ± 3%, LCx: 18 ± 2%, RCA: 15 ± 3%). With DOX, ADE vasodilator responses were impaired after ∼4-mg/kg (LAD: –3 ± 1%, LCx: 0 ± 2%, RCA: –5 ± 2%) and ∼8-mg/kg (LAD: –3 ± 1%, LCx: 0 ± 1%, RCA: –2 ± 2%). The DOB dilation response was preserved at ∼4-mg/kg of DOX (LAD: 18 ± 4%, LCx: 11 ± 3%, RCA: 11 ± 2%) but tended to decrease at ∼8-mg/kg of DOX (LAD: 4 ± 2%, LCx: 8 ± 3%, RCA: 3 ± 2%). A significant left ventricular ejection fraction reduction was observed only at 12 to 15 mg/kg DOX (baseline: 63 ± 2%, 12-mg/kg: 45 ± 3%). Global longitudinal strain was abnormal at ∼4-mg/kg of DOX (p = 0.011). Conclusions CTA can reliably assess epicardial coronary diameter in response to pharmacological stressors, providing a noninvasive functional index of coronary vasoreactivity. Impaired epicardial vasodilation occurs early in DOX-induced cardiotoxicity., Central Illustration

Background Social support, which is partly emotional support, is associated with adherence to colorectal cancer (CRC) treatment, quality of life, and survival. We hypothesized that the needs, sources, and availability of emotional support would vary by race and income among CRC patients and sought to quantify the emotional support and the perceived adequacy of support reported by patients. Methods We surveyed CRC patients from Detroit and Georgia Surveillance, Epidemiology and End Results registries about the quantity and quality of emotional support received from different sources. We tested differences using the chi-square test, t-tests, and logistic regression. Results There were 1909 patients who met inclusion criteria and 1301 (68%) completed surveys. Among respondents, 68% were white, 25% black, and 7% other. Black patients were more likely to be female and younger and reported lower annual income and education. Patients reported high support from several sources. Among those with a spouse/partner (58%), 95% reported high levels of support; however, older, black, female, or lower income patients were less likely to have spouses/partners ( P < .001). Patients also endorsed high support from family (88.6%), important others (82.9%), and clinicians (71.3%). Black patients were less likely than white patients to report support that was “just right” ( P < .001). Discussion Most patients reported high emotional support from at least 1 source. Black patients were most at risk for low support or unmet support needs. Spouse/partner support was important but only available to 58% of respondents. Patients at risk for unmet emotional support needs may benefit from additional support resources.