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Abstract Background Physiatry is a specialty with high rates of burnout. Although organizational strategies to combat burnout are key, it is also important to understand strategies that individual physiatrists can use to address burnout. Objective To identify changes that resulted in improvement of occupational well‐being of physiatrists over a 6‐ to 9‐month period. Design We employed two quantitative surveys spaced 6 to 9 months apart to identify physiatrists who experienced meaningful improvement in occupational burnout and/or professional fulfillment between the two survey timepoints. These physiatrists were subsequently recruited to participate in a qualitative study using semi‐structured interviews to identify changes that respondents felt contributed to improvements in burnout and professional fulfillment. Setting Online surveys and interviews. Participants Physiatrists in the American Academy of Physical Medicine and Rehabilitation (AAPM&R) Membership Masterfile. Main Outcome Measure Burnout and professional fulfillment were assessed using the Stanford Professional Fulfillment Index. Results One hundred twelve physiatrists responded to the baseline and follow‐up surveys. Of these, 35 were eligible for interviews based on improvements in the Stanford Professional Fulfillment Index, and 23 (64%) agreed to participate. Themes from the qualitative interviews highlighted the importance of personal lifestyle choices, approaches to improve professional satisfaction, and strategies to foster work‐life harmony. Personal lifestyle strategies included investing in wellness and mental health. Efforts to improve professional satisfaction included decreasing work intensity, prioritizing meaningful aspects of work, and building relationships with colleagues. Fostering work‐life harmony also included making trade‐offs in both domains, setting boundaries at work, setting expectations at home, and overcoming personal challenges. Conclusion Our findings illustrate that, in addition to organizational strategies demonstrated to be effective, there are actions that individual physiatrists can take to recover from burnout and foster professional fulfillment.

Neutrophil accumulation is a key feature of ARDS, but their contribution to the pathogenesis is still uncertain. We investigated the effect of reducing neutrophils in a clinically relevant mouse model of pneumococcal pneumonia treated with antibiotics. When appropriate antibiotics were administered, neutrophil reduction with Ly6G antibody markedly attenuated lung injury and improved oxygenation. In the early phase of bacterial pneumonia, neutrophils contribute to the severity of lung injury, although they also participate in host defense.

ImportanceProviding assisted ventilation during delayed umbilical cord clamping may improve outcomes for extremely preterm infants.ObjectiveTo determine whether assisted ventilation in extremely preterm infants (23 0/7 to 28 6/7 weeks’ gestational age [GA]) followed by cord clamping reduces intraventricular hemorrhage (IVH) or early death.Design, Setting, and ParticipantsThis phase 3, 1:1, parallel-stratified randomized clinical trial conducted at 12 perinatal centers across the US and Canada from September 2, 2016, through February 21, 2023, assessed IVH and early death outcomes of extremely preterm infants randomized to receive 120 seconds of assisted ventilation followed by cord clamping vs delayed cord clamping for 30 to 60 seconds with ventilatory assistance afterward. Two analysis cohorts, not breathing well and breathing well, were specified a priori based on assessment of breathing 30 seconds after birth.InterventionAfter birth, all infants received stimulation and suctioning if needed. From 30 to 120 seconds, infants randomized to the intervention received continuous positive airway pressure if breathing well or positive-pressure ventilation if not, with cord clamping at 120 seconds. Control infants received 30 to 60 seconds of delayed cord clamping followed by standard resuscitation.Main Outcomes and MeasuresThe primary outcome was any grade IVH on head ultrasonography or death before day 7. Interpretation by site radiologists was confirmed by independent radiologists, all masked to study group. To estimate the association between study group and outcome, data were analyzed using the stratified Cochran-Mantel-Haenszel test for relative risk (RR), with associations summarized by point estimates and 95% CIs.ResultsOf 1110 women who consented to participate, 548 were randomized and delivered infants at GA less than 29 weeks. A total of 570 eligible infants were enrolled (median [IQR] GA, 26.6 [24.9-27.7] weeks; 297 male [52.1%]). Intraventricular hemorrhage or death occurred in 34.9% (97 of 278) of infants in the intervention group and 32.5% (95 of 292) in the control group (adjusted RR, 1.02; 95% CI, 0.81-1.27). In the prespecified not-breathing-well cohort (47.5% [271 of 570]; median [IQR] GA, 26.0 [24.7-27.4] weeks; 152 male [56.1%]), IVH or death occurred in 38.7% (58 of 150) of infants in the intervention group and 43.0% (52 of 121) in the control group (RR, 0.91; 95% CI, 0.68-1.21). There was no evidence of differences in death, severe brain injury, or major morbidities between the intervention and control groups in either breathing cohort.Conclusions and RelevanceThis study did not show that providing assisted ventilation before cord clamping in extremely preterm infants reduces IVH or early death. Additional study around the feasibility, safety, and efficacy of assisted ventilation before cord clamping may provide additional insight.Trial RegistrationClinicalTrials.gov Identifier: NCT02742454

Thoracic aortic aneurysm (TAA) is a prominent condition that can progress to both aortic dissection and rupture, and has a higher prevalence in patients with bicuspid aortic valves. While smooth muscle cell proliferation and matrix remodeling are hallmarks of TAA, mechanisms regulating these phenomena are poorly understood. Thus, we tested the hypothesis that mTOR signaling, a positive regulator of cell proliferation and matrix remodeling enzyme elaboration, is increased in human TAA samples from patients with tricuspid and bicuspid aortic valves. Tissue was acquired at the time of operation, and mTOR activation was measured in aortic tissue from patients with TAA and tricuspid aortic valves (n = 29), TAA and bicuspid aortic valves (n = 29) and normal, non-aneurysmal aortic tissue from organ donors (n = 13). qRT-PCR expression of mTOR (1.29±0.1), Raptor (1.31±0.09, an mTORC1-specific subunit), and Rictor (1.44±0.1, an mTORC2-specific subunit) was significantly increased in tricuspid TAA samples compared to normal aorta (1 ±0.1; p < 0.05 for all). Similar changes were observed in patients with bicuspid TAA, as expression of mTOR (1.33±0.04), Raptor (1.27±0.06) and Rictor (1.65±0.09) were increased compared to normal (p < 0.05 for all). Importantly, protein levels of p-S6K and p-4E-BP1, both of which are well-defined targets of mTORC1 signaling, were increased by approximately two-fold in bicuspid and tricuspid TAA samples compared to normal aorta. Collectively, to our knowledge, this is the first report suggesting increased activity of both mTORC1 and mTORC2 signaling in human thoracic aortic aneurysm. We propose that inhibition of mTOR signaling may be a useful and efficacious intervention to inhibit cellular proliferation and matrix metalloproteinase activation in TAA, ultimately slowing aneurysmal dilatation and progression to aortic dissection and rupture.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases (NOS), and is degraded primarily by dimethylarginine dimethylaminohydrolase-1 (DDAH1). While ADMA is elevated in patients with fibrocalcific aortic valve stenosis (FCAVD), is it unknown whether tissue levels of DDAH1 are altered in FCAVD, and whether systemic elevations in ADMA levels accelerate initiation and/or progression of FCAVD. In the present study, we measured expression of DDAH1 in normal and stenotic human aortic valves, and tested the hypothesis that increases in ADMA worsen hypertension and endothelial dysfunction and accelerate the initiation and progression of FCAVD in hypercholesterolemic mice. In tissue from humans with FCAVD, expression of DDAH1 was significantly increased compared to normal valve tissue (normal = 1.0 ± 0.1, FCAVD = 1.3 ± 0.1, ⋔⋔Ct method; p < 0.05). To experimentally alter DDAH1 levels, we used low density lipoprotein receptor-deficient, apolipoprotein B100-only (LA) mice that were either wild-type (D +/+ ) or heterozygous (D +/- ) for DDAH1. Blood pressure (tail cuff), aortic endothelial function (isolated organ bath), and aortic valve function (echocardiography), were measured at 3 and 6 month time points in these mice. Compared to LA-D +/+ mice, systolic arterial pressure was significantly increased in LA-D +/- mice at both 3 month (121±4 mmHg and 144±4 mmHg) and 6 months (138±6 mmHg and 148±4 mmHg). Aortic endothelial function progressively declined with prolonged hypercholesterolemia, but maximum relaxation to acetylcholine did not differ between LA-D +/+ and LA-D +/- mice at 3 or 6 months. While aortic valve function was similar between LA-D +/+ and LA-D +/- mice at 3 months (peak transvalvular velocity: 1.98±0.07 m/sec versus 1.94±0.06 m/s, respectively), aortic valve function was significantly worse in LA-D +/- (2.41±0.11 m/sec) compared to LA-D +/+ mice (2.20±0.09 m/sec) at 6 months (p < 0.05). In conclusion, our data support a working model in which increases in valvular DDAH1 levels protect against progression of FCAVD. Importantly, loss of DDAH1 in mice does not alter aortic valve function during early stages of FCAVD, but accelerates progression of FCAVD independently of changes in endothelial function.

Abstract Purpose: AB160 is a 160-nm nano-immunoconjugate consisting of nab-paclitaxel (ABX) nanoparticles noncovalently coated with bevacizumab (BEV) for targeted delivery into tissues expressing high levels of VEGF. Preclinical data showed that AB160 resulted in greater tumor targeting and tumor inhibition compared with sequential treatment with ABX then BEV. Given individual drug activity, we investigated the safety and toxicity of AB160 in patients with gynecologic cancers. Patients and Methods: A 3+3 phase I trial was conducted with three potential dose levels in patients with previously treated endometrial, cervical, and platinum-resistant ovarian cancer to ascertain the recommended phase II dose (RP2D). AB160 was administered intravenously on days 1, 8, and 15 of a 28-day cycle (ABX 75–175 mg/m2, BEV 30–70 mg/m2). Pharmacokinetic analyses were performed. Results: No dose-limiting toxicities (DLT) were seen among the three dose levels tested. Grade 3/4 toxicities included neutropenia, thromboembolic events, and leukopenia. DL2 (ABX 150 mg/m2, BEV 60 mg/m2) was chosen as the RP2D. Seven of the 19 patients with measurable disease (36.8%) had confirmed partial responses (95% confidence interval, 16.3%–61.6%). Pharmacokinetic analyses demonstrated that AB160 allowed 50% higher paclitaxel dosing and that paclitaxel clearance mirrored that of therapeutic antibodies. Conclusions: The safety profile and clinical activity of AB160 supports further clinical testing in patients with gynecologic cancers; the RP2D is DL2 (ABX 150 mg/m2, BEV 60 mg/m2).