Search

Background: Current guidelines recommend coronary artery calcium (CAC) scoring for stratification of atherosclerotic cardiovascular disease risk only in patients with borderline to intermediate risk score by the pooled cohort equation with low-density lipoprotein-cholesterol (LDL-C) of 70 to 190 mg/dL. It remains unknown if CAC or thoracic aorta calcification (TAC), detected on routine chest computed tomography, can provide further risk stratification in patients with LDL-C≥190 mg/dL. Methods: From a multisite medical center, we retrospectively identified all patients from March 2005 to June 2021 age ≥40 years, without established atherosclerotic cardiovascular disease and LDL-C≥190 mg/dL who had non-gated non-contrast chest computed tomography within 3 years of LDL-C measurement. Ordinal CAC and TAC scores were measured by visual inspection. Kaplan-Meier curves and multivariable Cox-regression models were built to ascertain the association of CAC and TAC scores with all-cause mortality. Results: We included 811 patients with median age 59 (53–68) years, 262 (32.3%) were male, and LDL-C median level was 203 (194–217) mg/dL. Patients were followed for 6.2 (3.29–9.81) years, and 109 (13.4%) died. Overall, 376 (46.4%) of patients had CAC=0 and 226 (27.9%) had TAC=0. All-cause mortality increased with any CAC and moderate to severe TAC. In a multivariate model, patients with CAC had a significantly higher mortality compared with those without CAC: mild hazard ratio (HR), 1.71 (1.03–2.83), moderate HR, 2.12 (1.14–3.94), and severe HR, 3.49 (1.94–6.27). Patients with moderate TAC (HR, 2.34 [1.19–4.59]) and those with severe TAC (HR, 3.02 [1.36–6.74]) had higher mortality than those without TAC. Conclusions: In patients without history of atherosclerotic cardiovascular disease and LDL-C≥190 mg/dL, the presence and severity of CAC and TAC are independently associated with all-cause mortality.

Objectives To evaluate the relationship between gingival phenotype and tooth location based on selected index teeth ("Ramfjord") and assess possible differences between women and men. Material and methods Thirty-six women and 20 men voluntarily participated in this investigation with an average age of 23 years (min: 19; max: 37). Gingival phenotypes (GP) were assessed by transparency of a periodontal probe through the buccal gingival margin. Results A comparable and similar GP on all index teeth was only found in seven out of the 56 subjects, that is, thin or thick only: Five participants (three male/two female) showed a uniform and constantly thick and two females a constantly thin GP. While the majority of molars (94.6%; p = 0.006) showed a thick GP, premolars (61.6%; p = 0.09) as well as incisors (70.5%; p = 0.046) were predominantly categorized as thin. In addition, significantly thicker GP was in general observed for maxillary teeth (p = 0.001) but without differences between genders (p = 0.722). Conclusion No constant GP can be expected within one dentition. The use of the "Ramfjord teeth" may serve as a quick overview and reliable method to screen GP distribution.

Satellite cells (SC) are of importance for muscular adaptation to various forms of exercise. A single bout of high-force eccentric exercise has been shown to induce SC activation and, for electrically stimulated exercise, SC differentiation. PURPOSE This study aimed to assess if one bout of concentric/eccentric exercise with damaging eccentric overload (CON/ECC+) provides a sufficient stimulus to induce SC activation, proliferation and differentiation. METHODS Biopsies from the vastus lateralis muscle of recreationally active males were obtained in the rested condition and again from the contralateral leg seven days after exhaustive concentric/eccentric (CON/ECC, n = 15) or CON/ECC+ (n = 15) leg extension exercise and in a non-exercising control group (CG, n = 10). Total SC number (Pax7+), activated (Pax7+/MyoD+), and differentiating (myogenin+) SCs, fiber type distribution, and myofibers expressing neonatal myosin heavy chain (MHCneo) were determined immunohistochemically. Creatine kinase (CK) and myoglobin were measured in venous blood. Isokinetic strength tests were repeatedly conducted. RESULTS Significant increases in CK and myoglobin (p = 0.001) indicated myofiber damage while maximal strength was not impaired. Only after CON/ECC+, SC content (p = 0.019) and SC related to type II fibers (p = 0.011) were significantly increased. A significant increase in the proportion of activated SCs occurred after CON/ECC+ only (p = 0.003), the increase being significantly (p < 0.05) different from the changes after CON/ECC and in CG. The number of differentiating SC and MHCneo remained unchanged. CONCLUSION Eccentric overload during leg extension exercise induced significant SC activation, increases in SC content and in SC number related to type II myofibers. However, there were no signs of increased SC differentiation or formation of new myofibers.

Objective Thoracic endovascular aortic repair (TEVAR) has become a mainstay of treatment for a variety of thoracic aortic pathologies. Expansion of the proximal aortic neck after endovascular repair of abdominal aortic aneurysms has been demonstrated; however, dilatation of the proximal aortic neck after TEVAR has not been well described. We sought to describe remodeling of the proximal neck following TEVAR. Methods This is a retrospective, single institution review of patients who underwent TEVAR for thoracic aortic aneurysm (TAA) and dissection with aneurysmal degeneration from 2010 to 2019. Postoperative computed tomography scans were reviewed and aortic diameter was measured in orthogonal planes using 3-dimensional centerline reconstruction software. The primary outcome was change in aortic diameter at the proximal aortic neck as compared to the initial postoperative computed tomography scan. Clinical and operative data were analyzed to identify factors associated with significant neck dilatation. Results Of 87 patients who underwent TEVAR during the study period, 30 met inclusion criteria. Median follow up was 20.5 months. Median age was 67 years, and 15 patients (50%) were female. The proximal aortic neck experienced an overall increase over time in aortic diameter. Five mm distal to the graft showed the greatest rate of expansion, with a median increase of 1.3, 2.9, and 6.2 mm at one year, two years, and three years, respectively. When comparing patients who had mean expansion at this location of >2.0 mm/year to patients who did not, a higher percentage had dissection pathology (81.8% vs. 31.6%, P = 0.008), had graft placement at aortic landing zone 2 (36.4% vs. 5.3%, P = 0.028), and were smokers (100% vs. 52.6%, P = 0.006). Higher percent oversizing was shown to be associated with significant aortic neck dilatation for true aneurysms only. Conclusions Aortic neck dilatation occurs over time for the majority of patients following TEVAR with the distal neck experiencing the highest rate of expansion. Dissection pathology, aortic landing zone 2, and smoking were found to be associated with a higher rate of neck dilatation.

Pigmented lesions from chronic UV photoaging are extremely common on the face and hands.To evaluate the safety and efficacy of a 532-nm picosecond laser for these types of pigmented lesions.This was a single-center, prospective, open-label clinical trial. Eligible subjects with pigmentation on the face and hands received 3 monthly treatments, with 1 month (1M) and 3 months (3M) follow-up. Change in investigator-graded overall facial and per lesion pigmentation and subject-graded satisfaction and pigmentation improvement was evaluated by a 5-point scale. Immediate skin response and adverse events (AEs) were evaluated post-treatment. The melanin index was measured using a mexameter. Randomized before and after photographs were graded by 3 blinded physicians for degree of pigmentation improvement.Twenty-five subjects (22F/3M) with Fitzpatrick skin types I-III were enrolled, with 23 subjects completing. Treatments used a 532 nm wavelength, 800 ps pulse duration, 4-6mm spot size, and 0.1 to 0.6J/cm2 fluence. Good-to-excellent clearance at 1M/3M was demonstrated in ≥95% of lesions (n = 116). Only mild treatment-related pain was reported, with transient post-treatment AEs (mean downtime of 2.1 ± 2.0 days) and no serious treatment-related AEs. Subject satisfaction (satisfied or very satisfied) was 95% at 1M and 91% at 3M.Treatment with a 532-nm picosecond laser is safe and highly effective for the treatment of the pigmented lesions of the face and dorsal hands.

Endovascular therapies are increasingly used in patients with complex multilevel disease and chronic limb-threatening ischemia (CLTI). Infrageniculate bypass with autologous vein conduit is considered the gold standard in these patients. However, many patients often lack optimal saphenous vein, leading to the use of nonautologous prosthetic conduit. We compared limb salvage and survival rates for patients with CLTI undergoing first time revascularization with either open nonautologous conduit or endovascular intervention.We retrospectively reviewed consecutive patients undergoing first time endovascular or open surgical revascularization at our institution between 2009 and 2016. Patients were divided into endovascular intervention or open bypass with nonautologous conduit (NAC) cohorts. Primary endpoints were amputation-free survival (AFS), freedom from reintervention, primary patency, and overall survival. Propensity scoring was used to construct matched cohorts. Outcomes were evaluated using Kaplan-Meier and Cox Proportional Hazards models.A total of 125 revascularizations were identified. There were 65 endovascular interventions and 60 NAC bypasses. In unmatched analysis, there was an elevated risk of perioperative MI (7% vs. 0%, P = 0.05) and amputation (10% vs. 2%, P = 0.04) for the NAC groups compared to the endovascular group. In matched analysis, endovascular patients had a lower incidence of 30-day amputation (1.5% vs. 10% P = 0.04) and length of stay (median days, 1 vs. 9, P0.01) compared to the open cohort. While not statistically significant, the endovascular group trended towards increased rates of two-year AFS (76% vs. 65%, P = 0.07) compared to the NAC group. There was no significant difference in overall survival when the endovascular cohort was compared to NAC (85% vs. 77%, P = 0.29) patients. In matched Cox analysis, nonautologous conduit use was associated with an increased risk of limb loss (HR 2.03, 95% CI 0.94-4.38, P = 0.07) compared to endovascular revascularization.An "endovascular first" approach offers favorable perioperative outcomes and comparable AFS compared to NAC and may be preferable when autologous conduit is unavailable.

PURPOSE Brentuximab vedotin, an effective anti-CD30 antibody-drug conjugate approved for use in adults with classical Hodgkin lymphoma (HL), was introduced in this frontline trial to reduce prescribed radiation in children and adolescents with classical HL. METHODS Open-label, single-arm, multicenter trial for patients (age ≤ 18 years) with stage IIB, IIIB, or IV classical HL was conducted. Brentuximab vedotin replaced each vincristine in the OEPA/COPDac (vincristine, etoposide, prednisone, and doxorubicin/cyclophosphamide, vincristine, prednisone, and dacarbazine) regimen according to GPOH-HD2002 treatment group 3 (TG3); two cycles of AEPA and four cycles of CAPDac. Residual node radiotherapy (25.5 Gy) was given at the end of all chemotherapy only to nodal sites that did not achieve a complete response (CR) at the early response assessment (ERA) after two cycles of therapy. Primary objectives were to evaluate the safety and efficacy (complete remission at ERA) of this combination and the 3-year event-free (EFS) and overall survival (OS). The trials are registered at ClinicalTrials.gov (identifier: NCT01920932 ). RESULTS Of the 77 patients enrolled in the study, 27 (35%) achieved complete remission at ERA and were spared radiation. Patients who were irradiated received radiation to individual residual nodal tissue. At a median follow-up of 3.4 years, the 3-year EFS was 97.4% (SE 2.3%) and the OS was 98.7% (SE 1.6%). One irradiated patient experienced disease progression at the end of therapy and now remains disease free more than 6 years following salvage therapy, and one unexpected death occurred. Only 4% of patients experienced grade 3 neuropathy. CONCLUSION The integration of brentuximab vedotin in the frontline treatment of pediatric high-risk HL is highly tolerable, facilitated significant reduction in radiation exposure, and yielded excellent outcomes.

Glioblastoma is considered one of the most aggressive malignancies in adult and pediatric patients. Despite decades of research no curative treatment is available and it thus remains associated with a very dismal prognosis. Although recent pre-clinical and clinical studies have demonstrated the feasibility of chimeric antigen receptors (CAR) T cell immunotherapeutic approach in glioblastoma, tumor heterogeneity and antigen loss remain among one of the most important challenges to be addressed. In this study, we identify p32/gC1qR/HABP/C1qBP to be specifically expressed on the surface of glioma cells, making it a suitable tumor associated antigen for redirected CAR T cell therapy. We generate p32 CAR T cells and find them to recognize and specifically eliminate p32 expressing glioma cells and tumor derived endothelial cells in vitro and to control tumor growth in orthotopic syngeneic and xenograft mouse models. Thus, p32 CAR T cells may serve as a therapeutic option for glioblastoma patients., Chimeric antigen receptor (CAR) T cell therapy has been proposed as a promising approach for treating glioblastoma. Here the authors show that p32 is expressed in murine and human glioma and that p32-directed CAR-T cells promote anti-tumor responses in preclinical models by targeting glioma cells and tumor derived endothelial cells.

Purpose To evaluate stability and performance of a new monofocal anterior capsulotomy–fixated intraocular lens (IOL) (FEMTIS; Teleon Surgical B.V., Spankeren, Netherlands) after femtosecond laser–assisted cataract surgery (FLACS). Design Prospective, multicenter, interventional, noncomparative case series. Methods FLACS with FEMTIS IOL was performed in 336 eyes of 183 cataract patients with fixation of the IOL to the anterior capsulotomy followed up for 12 months. Examination included uncorrected distance visual acuity (UDVA), best-corrected visual acuity (CDVA), subjective refraction, IOL centration, posterior capsule opacification (PCO), and investigators' satisfaction questionnaire. Results At 12 months, mean IOL rotation was 1.50 ± 1.76 degrees and decentration 0.14 ± 0.14 mm from baseline (day of surgery). Mean horizontal IOL tilt was 0.70 ± 0.60 degrees and vertical 1.15 ± 1.06 degrees relative to the baseline (crystalline lens). Mean distance between IOL and iris was 0.32 mm to 0.36 mm for all measured meridians. Mean UDVA was 0.12 ± 0.14 logMAR (range -0.20 to 0.54 logMAR), mean CDVA -0.01 ± 0.09 logMAR (range -0.30 to 0.20 logMAR). Mean spherical equivalent was 0.35 ± 0.53 diopter (D) and 98% of eyes (n = 235) were within ±1.0 D. Median PCO score was 1 with an Nd:YAG laser rate of 3.1% after 12 months. Most surgeons were very satisfied (median score: 1) with surgery and implanted IOL. Conclusions Implantation of FEMTIS IOL provided excellent visual and stable refractive outcomes. IOL decentration was very low compared to other published studies and showed an exceptional high in-the-bag stability over a 12-month period. This lens benefits from femtosecond laser capsulotomies. It can be positioned very predictably and offers an optimal platform for toric and multifocal IOL optics.

Background: Gastric cancer lacks specific symptoms, resulting in diagnosis at later stages and high mortality. Serum pepsinogen is a biomarker for atrophic gastritis, a gastric cancer precursor, and may be useful to detect persons at increased risk of gastric cancer. Methods: The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was conducted in the United States between 1993 and 2001. ELISA-based pepsinogen tests were conducted on prediagnostic serum samples of 105 PLCO participants who developed gastric cancer and 209 age, sex, and race-matched controls. Pepsinogen positive (PG+) was defined as pepsinogen I ≤ 70 μg/L and pepsinogen I/II ratio ≤3.0. Results of conditional logistic regression models, and sensitivity and specificity, of PG+ for gastric cancer are reported. Results: Gastric cancer cases were more likely to be PG+ (31.4% vs. 5.5%, P < 0.001) at baseline than controls. Compared to PG-, PG+ was associated with an 8.5-fold increased risk for gastric cancer [95% confidence interval (CI) = 3.8–19.4]. This risk remained significant after adjusting for Helicobacter pylori, family history of gastric cancer, education, smoking, and BMI (aOR, 10.6; 95% CI, 4.3–26.2). In subgroup analysis, PG+ individuals were 11-fold more like to develop non-cardia gastric cancer (OR, 11.1; 95% CI, 4.3–28.8); conversely, they were not significantly more likely to develop cardia gastric cancer (OR, 2.0; 95% CI = 0.3–14.2). PG+ status yielded low sensitivity but high specificity for both noncardia (44.3%; 93.6%) and cardia gastric cancer (5.7%; 97.2%). Conclusions: Prediagnostic serum pepsinogen levels from a large, prospective cohort study were associated with risk of gastric cancer, particularly noncardia gastric cancer. Impact: PG status may identify individuals at higher risk of noncardia gastric cancer for targeted screening or interventions. See related commentary by Zhou and Huang, p. 1257

Purpose Percutaneous muscle biopsy is the gold standard for tissue assessment in clinical practice and scientific studies. The aim of this study was to assess and quantify the ensuing tissue damage by in vivo magnetic resonance imaging (MRI). Methods In this prospective study, we enrolled 22 healthy participants who underwent MRI of the thigh musculature about 1 wk after a percutaneous muscle biopsy of the vastus lateralis muscle. A total of 17 participants also volunteered for a second MR examination 2 wk after biopsy. Volumes of susceptibility-weighted imaging (SWI) lesions and muscle edema were assessed by SWI and T2-weighted MRI, respectively, after manual segmentation by two independent readers. For quantitative in vivo hematoma volume assessment, we additionally determined signal changes induced by experimental hematoma in an ex vivo model. Results Mean overall volume of SWI lesions 1 wk after biopsy was 26.5 ± 21.7 μL, accompanied by a mean perifocal edema volume of 790.1 ± 591.4 μL. In participants who underwent two examinations, mean volume of SWI lesions slightly decreased from 29.8 ± 23.6 to 23.9 ± 16.8 μL within 1 wk (P = 0.13). Muscle edema volume decreased from 820.2 ± 632.4 to 359.6 ± 207.3 μL at the same time (P = 0.006). By calibration with the ex vivo findings, signal alterations on SWI corresponded to a blood volume of approximately 10-50 μL. Conclusions Intramuscular hematoma and accompanying muscle edema after percutaneous biopsy are small and decrease rapidly within the first 2 wk. These in vivo findings underline the limited invasiveness of the procedure.

Primary aldosteronism (PA) occurs in 10%-20% of patients with resistant hypertension. Guidelines recommend adrenal vein sampling (AVS) to identify patients for surgical management. We evaluate the use of AVS in managing PA to better understand the selection and outcomes of medical versus surgical treatment.A retrospective review was performed, and patients were divided into those who did (AVS) and did not have AVS (non-AVS). Demographics, aldosterone and renin levels, blood pressure, comorbidities, and antihypertensive medications were recorded. Reasons to defer AVS and medical versus surgical decision-making were examined and groups were compared.We included 113 patients; 39.8% (45/113) had AVS, whereas 60.2% (68/113) did not. Groups were similar in age, body mass index, and initial systolic blood pressure (SBP). In patients who underwent AVS, 31 of 45 (68.9%) had unilateral secretion and were referred for surgery, whereas 13 of 45 (28.9%) had bilateral secretion. Of the 31 referred for surgery, 26 underwent laparoscopic adrenalectomy, all cured; four refused surgery; and one counseled toward medical management by their physician. In 68 non-AVS patients, 6 (8.8%) underwent adrenalectomy without sampling and 2 with no clinical improvement. The remaining deferrals were because of normal or bilateral adrenal nodules on imaging (8/68, 11.8%); medical management due to poor surgical candidacy (12/68, 17.6%); patient refusal of intervention (13/68, 19.1%); or reasons not stated (28/68, 41.1%). At the follow-up, patients who underwent AVS had lower median SBP (135.4 mmHg versus 144.7 mmHg, P = 0.0241) and shorter follow-up (17.7 mo versus 54.0 mo, P 0.0001). Surgically managed patients had biochemical resolution of PA with normalization of potassium levels (3.6 to 4.7mEq/L, P 0.00001).AVS correctly selects patients for surgical management avoiding unnecessary surgery. However, despite guidelines, AVS is not always pursued as part of PA treatment, potentially excluding surgical candidates.

OBJECTIVES/HYPOTHESIS The American Academy of Otolaryngology-Head and Neck Surgery has published clinical practice guidelines (CPGs) to guide management of common otolaryngologic (ENT) conditions. While these CPGs have been disseminated within specialty journals, many patients' first presentation of certain ENT complaints is to primary and acute care settings, including the emergency department (ED). It is less clear whether practice in these settings is concordant with specialty CPGs. STUDY DESIGN Retrospective cohort study. METHODS A retrospective review of medical records was performed at an academic tertiary care center with ED diagnoses of 1) Bell's palsy/facial weakness (BP) or 2) acute otitis externa (AOE) from May 2014-June 2018. Individual chart abstraction was performed for all encounters with these diagnoses for the purpose of assessing providers' adherence to CPGs. RESULTS During the study period, 224 patients were diagnosed with BP and 465 patients were diagnosed with AOE. Of the patients diagnosed with BP, 94% (n = 211/224) were prescribed oral steroids, concordant with guidelines, while 36% of these patients received head computed tomography (CT) scans and 43% received laboratory tests, counter to the guidelines. For those with a diagnosis of AOE, 28.6% received topical antibiotics only as primary treatment (n = 133/465) in accordance with guidelines while systemic antibiotics were prescribed in 42.2% (n = 196/465) discordant with the guidelines and 29.2% received both topical and systemic antibiotics (n = 136/465). CONCLUSIONS CPGs developed by subspecialty societies provide evidence-based recommendations for the care of patients with particular conditions, but may not be disseminated broadly outside of the specialty. Further research is required to understand the reasons behind divergent management of such conditions. LEVEL OF EVIDENCE 3 Laryngoscope, 131:1266-1270, 2021.

Limited longitudinal studies have hindered the understanding of family adaptation after loss of a loved one in an intensive care unit (ICU). Based on the Double ABCX Model, this study examined changes in adaptation to bereavement for family members in the first year after the ICU death, with special attention to the effects of race/ethnicity. A repeated-measures design was used to conduct the investigation using 3 time points (1-3, 6, and 12 months) after the ICU death. Data were analyzed using linear mixed modeling. Family members (n = 30) consisted of 60% non-Hispanic Whites and 40% African Americans (AAs). During the first 1 to 3 months, moderate to severe symptoms of posttraumatic stress disorder, depression, anxiety, and stress were found (60%, 40%, 30%, and 26.7%, respectively). Initially, non-Hispanic Whites had higher depression scores than African Americans. The change in depression and posttraumatic stress disorder symptoms over 1 year differed by race/ethnicity. Many family members tended to be at risk of psychological sequelae in the early months after a patient's death in an ICU. Racial/ethnic differences in bereavement process need further exploration to understand the broader context within family members grieve and effectively offer support over the course of the first year.

The transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H2O2 or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma.

Identifying persons at high risk for gastric cancer is needed for targeted interventions for prevention and control in low-incidence regions. Combining ethnic/cultural factors with conventional gastric cancer risk factors may enhance identification of high-risk persons. Data from a prior case-control study (40 gastric cancer cases and 100 controls) were used. A "conventional model" using risk factors included in the Harvard Cancer Risk Index's gastric cancer module was compared with a "parsimonious model" created from the most predictive variables of the conventional model as well as ethnic/cultural and socioeconomic variables. Model probability cutoffs aimed to identify a cohort with at least 10 times the baseline risk using Bayes' Theorem applied to baseline U.S. gastric cancer incidence. The parsimonious model included age, U.S. generation, race, cultural food at ages 15-18 years, excessive salt, education, alcohol, and family history. This 11-item model enriched the baseline risk by 10-fold, at the 0.5 probability level cutoff, with an estimated sensitivity of 72% [95% confidence interval (CI), 64-80], specificity of 94% (95% CI, 90-97), and ability to identify a subcohort with gastric cancer prevalence of 128.5 per 100,000. The conventional model was only able to reach a risk level of 9.8 times baseline with a corresponding sensitivity of 31% (95% CI, 23-39) and specificity of 97% (95% CI, 94-99). Cultural and ethnic data may add important information to models for identifying U.S. individuals at high risk for gastric cancer, who then could be targeted for interventions to prevent and control gastric cancer. The findings of this pilot study remain to be validated in an external dataset.

Objectives While the use of protamine sulfate as a heparin reversal agent has been extensively reviewed in patients undergoing carotid endarterectomy and coronary artery bypass grafting, there is a lack of literature on protamine’s effects on lower extremity bypasses. The purpose of this study was to determine the risk of protamine sulfate dosing after tibial bypass on thrombotic or bleeding events, including early bypass failure. Methods We performed a retrospective review of our institutional database for patients undergoing primary distal peripheral bypass from January 2009 through December 2015 (contralateral bypass was considered to be a new primary bypass). Primary endpoints include composite thrombotic events (myocardial infarction, stroke, amputation at 30 days and patency less than 30 days) and composite bleeding events (bleeding or transfusion). Results A total of 152 tibial or peroneal bypasses in 136 patients with critical limb ischemia were identified. Of these, 78 (57.4%) patients received protamine sulfate intraoperatively and 58 (42.6%) did not. There were no differences in composite thrombotic or hemorrhagic outcomes. Protamine use had no effect on the rates of perioperative MI (9.0% versus 3.5%, p = 0.20), stroke (1.3% versus 1.7%, p = 0.83), or perioperative mortality (5.1% versus 3.5%, p = 0.64). There was no significant difference in composite post-operative bleeding events (20.7% versus 14.1%, p = 0.31) or composite thrombotic events (17.2% versus 18.0%, p = 0.91). Patients who received protamine undergoing bypass with non-autogenous conduit had significantly higher-recorded median operative blood loss (250 mL versus 150 mL, p = 0.0097) and median procedure lengths (265 min versus 201 min, p = 0.0229). No difference in 30-day amputation-free survival was noted (91.0% versus 91.4%, p = 0.94). Follow-up Kaplan–Meier estimation did not demonstrate a difference in 30-day patency (91.7% versus 88.5%, p = 0.52). Conclusions Heparin reversal with protamine sulfate after tibial or peroneal bypass grafting is not associated with higher cardiovascular morbidity, bypass thrombosis, amputation, or mortality. Additionally, there was no statistically significant difference in post-operative bleeding or thrombosis complications for patients who did not receive protamine, although the findings are suggestive of a potential difference in a more adequately powered study. Our results suggest that protamine sulfate is safe for intraoperative use without increased risk of thrombotic complications or early tibial bypass graft failure.

Purpose Cardiorespiratory fitness (CRF) seems to be prognostic prior to allogeneic stem cell transplantation (allo-HSCT). Influencing factors of CRF in allo-HSCT candidates have not been studied so far. Aim was to identify potentially influencing factors on CRF. Methods To assess CRF, a maximal cardiopulmonary exercise test (CPET) was performed on average 2.6 ± 7.2 days prior to admission. A regression analysis was conducted, with the following predictors: gender, age, body mass index (BMI), time between last therapy and allo-HSCT (t_Therapies), number of cardiotoxic therapies (n_Cardiotox), number of transplantations (n_Transplantations), comorbidity index (HCT-CI), hemoglobin level of the last 3 months (area under the curve), and physical activity. Results A total of 194 patients performed a CPET. VO2peak was significantly reduced compared with reference data. In total, VO2peak was 21.4 ml/min/kg (− 27.5%, p p 2peak was significantly (p Conclusions Our study demonstrates a decreased CRF indicating the potential need of prehabilitative exercise. We revealed some influencing factors on CRF. Those patients could benefit the most from exercise.

Background Coronary artery bypass graft (CABG) surgery represents the preferred revascularization strategy for most patients with diabetes and multivessel disease. We aimed to evaluate the role of optimized, perioperative cardiometabolic targets on long‐term survival in patients who underwent CABG. Methods and Results Single‐institution retrospective study was conducted in patients with diabetes who underwent CABG between January 2010 and June 2018. Demographic, surgical, and cardiometabolic determinants were identified during the perioperative period. Clinical characteristics and longitudinal survival outcomes data were obtained. A total of 1534 patients with CABG were considered for analysis and 1273 met inclusion criteria. The mean age of patients was 63.3 years (95% CI, 62.7–63.8 years), and most were men (65%) and Hispanic or Latino (47%). Comorbidities included hypertension (95%) and dyslipidemia (88%). In total, 490 patients (52%) had a low‐density lipoprotein cholesterol level >70 mg/dL. Furthermore, 390 patients (31%) had uncontrolled systolic blood pressure >130 mm Hg. Last, only 386 patients (29%) had a hemoglobin A 1c level between 6% and 7%. At 5 years, 121 patients (10%) died. Failure to achieve goal systolic blood pressure was associated with all‐cause (hazard ratio [HR], 1.573; 95% CI, 1.048–2.362 [ P =0.029]) and cardiovascular (HR, 2.023; 95% CI, 1.196–3.422 [ P =0.009]) mortality at 5 years post‐CABG. In contrast, prescription of a statin during the perioperative interval demonstrated a protective effect for all‐cause (HR, 0.484; 95% CI, 0.286–0.819 [ P =0.007]) and cardiovascular (HR, 0.459; 95% CI, 0.229–0.920 [ P =0.028]) mortality. There was no association between achievement of low‐density lipoprotein cholesterol, triglycerides, non–high‐density lipoprotein cholesterol, or hemoglobin A 1c level goals and mortality risk at 5 years. Conclusions Among patients with diabetes, blood pressure control and statin therapy were the most important perioperative cardiometabolic survival determinants 5 years after CABG.

Background Mass vaccination campaigns have significantly reduced the COVID-19 burden. However, vaccine hesitancy has posed significant global concerns. The purpose of this study was to determine the characteristics that influence perceptions of COVID-19 vaccine efficacy, acceptability, hesitancy and decision making to take vaccine among general adult populations in a variety of socioeconomic and cultural contexts. Methods Using a snowball sampling approach, we conducted an online cross-sectional study in 20 countries across four continents from February to May 2021. Results A total of 10,477 participants were included in the analyses with a mean age of 36±14.3 years. The findings revealed the prevalence of perceptions towards COVID-19 vaccine’s effectiveness (78.8%), acceptance (81.8%), hesitancy (47.2%), and drivers of vaccination decision-making (convenience [73.3%], health providers’ advice [81.8%], and costs [57.0%]). The county-wise distribution included effectiveness (67.8–95.9%; 67.8% in Egypt to 95.9% in Malaysia), acceptance (64.7–96.0%; 64.7% in Australia to 96.0% in Malaysia), hesitancy (31.5–86.0%; 31.5% in Egypt to 86.0% in Vietnam), convenience (49.7–95.7%; 49.7% in Austria to 95.7% in Malaysia), advice (66.1–97.3%; 66.1% in Austria to 97.3% in Malaysia), and costs (16.0–91.3%; 16.0% in Vietnam to 91.3% in Malaysia). In multivariable regression analysis, several socio-demographic characteristics were identified as associated factors of outcome variables including, i) vaccine effectiveness: younger age, male, urban residence, higher education, and higher income; ii) acceptance: younger age, male, urban residence, higher education, married, and higher income; and iii) hesitancy: male, higher education, employed, unmarried, and lower income. Likewise, the factors associated with vaccination decision-making including i) convenience: younger age, urban residence, higher education, married, and lower income; ii) advice: younger age, urban residence, higher education, unemployed/student, married, and medium income; and iii) costs: younger age, higher education, unemployed/student, and lower income. Conclusions Most participants believed that vaccination would effectively control and prevent COVID-19, and they would take vaccinations upon availability. Determinant factors found in this study are critical and should be considered as essential elements in developing COVID-19 vaccination campaigns to boost vaccination uptake in the populations., Author summary This large-scale multi-country study explores perceived COVID-19 vaccine effectiveness, acceptability, and hesitancy rates and their related factors among the general adult populations from 20 countries. We found that a considerable proportion of the participants has an intention to receive the COVID-19 vaccine. However, more than half still expressed their hesitancy to receive the vaccines. Countries where the majority of respondents responded that they would accept COVID-19 vaccination included Malaysia (96.0%), Bangladesh (93.6%), and Iraq (91.8%). The majority of the participants from Vietnam (86.0%) and Turkey (74.7%) expressed hesitance to receive COVID-19 vaccine. Perceived vaccine effectiveness ranged from 67.8% in Egypt to 95.9% in Malaysia. The participants believed that convenience, health providers’ advice, and costs of vaccines are important for people to decide whether to accept COVID-19 vaccines. Country of residence, age, sex, level of education, area of residence, marital status, and family economic status were significantly associated with tendency to undergo COVID-19 vaccination and the perception that COVID-19 vaccine decision-making is influenced by convenience. The findings of this study provide useful guidance for tailored interventions to enhance the acceptance of COVID-19 vaccine. Promotional program addressed on detected socioeconomic factors is warranted.

Summary Background Poor attendance at school, whether due to absenteeism or exclusion, leads to multiple social, educational, and lifelong socioeconomic disadvantages. We aimed to measure the association between a broad range of diagnosed neurodevelopmental and mental disorders and recorded self-harm by the age of 24 years and school attendance and exclusion. Methods In this nationwide, retrospective, electronic cohort study, we drew a cohort from the Welsh Demographic Service Dataset, which included individuals aged 7–16 years (16 years being the school leaving age in the UK) enrolled in state-funded schools in Wales in the academic years 2012/13–2015/16 (between Sept 1, 2012, and Aug 31, 2016). Using the Adolescent Mental Health Data Platform, we linked attendance and exclusion data to national demographic and primary and secondary health-care datasets. We identified all pupils with a recorded diagnosis of neurodevelopmental disorders (ADHD and autism spectrum disorder [ASD]), learning difficulties, conduct disorder, depression, anxiety, eating disorders, alcohol or drugs misuse, bipolar disorder, schizophrenia, other psychotic disorders, or recorded self-harm (our explanatory variables) before the age of 24 years. Outcomes were school absence and exclusion. Generalised estimating equations with exchangeable correlation structures using binomial distribution with the logit link function were used to calculate odds ratios (OR) for absenteeism and exclusion, adjusting for sex, age, and deprivation. Findings School attendance, school exclusion, and health-care data were available for 414 637 pupils (201 789 [48·7%] girls and 212 848 [51·3%] boys; mean age 10·5 years [SD 3·8] on Sept 1, 2012; ethnicity data were not available). Individuals with a record of a neurodevelopmental disorder, mental disorder, or self-harm were more likely to be absent or excluded in any school year than were those without a record. Unadjusted ORs for absences ranged from 2·1 (95% CI 2·0–2·2) for those with neurodevelopmental disorders to 6·6 (4·9–8·3) for those with bipolar disorder. Adjusted ORs (aORs) for absences ranged from 2·0 (1·9–2·1) for those with neurodevelopmental disorders to 5·5 (4·2–7·2) for those with bipolar disorder. Unadjusted ORs for exclusion ranged from 1·7 (1·3–2·2) for those with eating disorders to 22·7 (20·8–24·7) for those with a record of drugs misuse. aORs for exclusion ranged from 1·8 (1·5–2·0) for those with learning difficulties to 11·0 (10·0–12·1) for those with a record of drugs misuse. Interpretation Children and young people up to the age of 24 years with a record of a neurodevelopmental or mental disorder or self-harm before the age of 24 years were more likely to miss school than those without a record. Exclusion or persistent absence are potential indicators of current or future poor mental health that are routinely collected and could be used to target assessment and early intervention. Integrated school-based and health-care strategies to support young peoples' engagement with school life are required. Funding The Medical Research Council, MQ Mental Health Research, and the Economic and Social Research Council. Translation For the Welsh translation of the abstract see Supplementary Materials section.

PURPOSE Children’s Oncology Group (COG) AALL0331 tested whether intensified postinduction therapy that improves survival in children with high-risk B-cell acute lymphoblastic leukemia (ALL) would also improve outcomes for those with standard-risk (SR) ALL. PATIENTS AND METHODS AALL0331 enrolled 5,377 patients between 2005 and 2010. All patients received a 3-drug induction with dexamethasone, vincristine, and pegaspargase (PEG) and were then classified as SR low, SR average, or SR high. Patients with SR-average disease were randomly assigned to receive either standard 4-week consolidation (SC) or 8-week intensified augmented Berlin-Frankfurt-Münster (BFM) consolidation (IC). Those with SR-high disease were nonrandomly assigned to the full COG-augmented BFM regimen, including 2 interim maintenance and delayed intensification phases. RESULTS The 6-year event-free survival (EFS) rate for all patients enrolled in AALL0331 was 88.96% ± 0.46%, and overall survival (OS) was 95.54% ± 0.31%. For patients with SR-average disease, the 6-year continuous complete remission (CCR) and OS rates for SC versus IC were 87.8% ± 1.3% versus 89.1% ± 1.2% ( P = .52) and 95.8% ± 0.8% versus 95.2% ± 0.8% ( P = 1.0), respectively. Those with SR-average disease with end-induction minimal residual disease (MRD) of 0.01% to < 0.1% had an inferior outcome compared with those with lower MRD and no improvement with IC (6-year CCR: SC, 77.5% ± 4.8%; IC, 77.1% ± 4.8%; P = .71). At 6 years, the CCR and OS rates among 635 nonrandomly treated patients with SR-high disease were 85.55% ± 1.49% and 92.97% ± 1.08%, respectively. CONCLUSION The 6-year OS rate for > 5,000 children with SR ALL enrolled in AALL0331 exceeded 95%. The addition of IC to treatment for patients with SR-average disease did not improve CCR or OS, even in patients with higher MRD, in whom it might have been predicted to provide more value. The EFS and OS rates are excellent for this group of patients with SR ALL, with particularly good outcomes for those with SR-high disease.

A Boy with Jaundice A 16-year-old boy was admitted to the hospital in autumn because of malaise, abdominal cramping, and jaundice. Ultrasonography of the abdomen revealed splenomegaly. Atypical lym...

Although most cryolipolysis treatments are performed with vacuum applicators, some patients may have areas of fibrous, nonpinchable fat or find vacuum suction to be uncomfortable.This study evaluates a nonvacuum conformable-surface applicator for cryolipolysis of the periumbilical abdomen.Twenty subjects with periumbilical subcutaneous fat were treated with a nonvacuum cryolipolysis applicator in this prospective, single-center, open-label clinical trial. Each subject underwent a single treatment cycle with an optional second treatment 10 weeks later. Efficacy was evaluated by blinded review of digital photographs. Subject satisfaction was assessed at 10-week follow-up.Twenty subjects completed one treatment, of which 6 underwent the optional retreatment. Independent review demonstrated 77% correct identification of baseline photographs after one treatment, which improved to 100% after a second treatment. Patient questionnaires after one treatment revealed 50% satisfaction, with 60% willing to recommend the procedure and 60% reporting visible fat reduction. After second treatment, however, 100% were satisfied, 83% were willing to recommend, and 100% reported visible fat reduction.Cryolipolysis with a nonvacuum conformable-surface applicator is safe, effective, and well tolerated for noninvasive reduction of fibrous periumbilical abdominal fat. Efficacy and subject satisfaction is significantly greater with 2 treatments than with a single session.

OBJECTIVE To identify factors associated with referral and enrollment in early intervention (EI) for infants with neonatal abstinence syndrome (NAS). METHODS We conducted a retrospective cohort study of 256 infants born with NAS (2006-2013) at a tertiary care hospital in (Springfield), Massachusetts, linking maternal-infant birth hospitalization records with Department of Public Health EI records. We calculated the percent of infants retained at each step in the EI enrollment process over the first 3 years of life. We conducted separate multivariable logistic regression analyses to identify factors associated with EI referral and enrollment. RESULTS Among mothers, 82% received medication-assisted treatment at delivery, 36% endorsed illicit drug use during pregnancy, and 76% retained custody of their child at discharge. Among infants, 77% were referred to EI and 48% were enrolled in services. Of infants discharged to biological parents, 81% were referred to EI versus 66% of infants discharged to foster care (p ≤ 0.05); this difference persisted in multivariable analysis [adjusted odds ratio, 2.30; 95% confidence interval (CI), 1.09-4.86]. Infants in the highest tertile for length of stay had 2.70 times the odds of EI enrollment (95% CI, 1.37-5.31). CONCLUSION Fewer than half of the eligible infants with NAS were enrolled in EI services. Discharge to a biological parent and longer hospital stay had the strongest associations with EI referral and enrollment, respectively. Efforts to improve EI referral rates during the birth hospitalization, particularly among infants discharged into foster care, and close follow-up for infants with shorter hospital stays would enhance the developmental supports for this vulnerable population.

INTRODUCTION In 2016 the Cochlear CI532 received FDA approval and has since been the primary full-length electrode from this manufacturer implanted at our center. Our experience to date including surgical technique and early patient outcomes are reviewed here. METHODS Since 2016, this array was used as our standard full length Cochlear array, including children with normal anatomy, with 237 total implantations. Surgical experience and clinical outcomes including low frequency hearing preservation and speech perception on CNC words were analyzed in those with at least 6 months follow-up implanted through June 2017 (n = 94). RESULTS Speech perception scores are improving over clinical follow-up in accord with other electrode arrays. Hearing preservation is possible with a number of patients utilizing acoustic low frequency hearing in conjunction with electric stimulation from their CI. Tip fold overs were infrequent (4.6%) and always identified on intraoperative x-ray. No patients left the operating room with a tip fold over. CONCLUSIONS Speech perception outcomes with the CI532 slim periomodiolar array are similar to other full length arrays with the added potential for at least short term preservation of residual acoustic hearing. There is a learning curve to its use and intraoperative x-rays are valuable to ensure optimal placement.

Objective: To evaluate the reliability and validity of a standardized ultrasound examination protocol for measuring vastus lateralis muscle size. Design: Prospective cohort study. Subjects: Sixteen staff members of the university hospital of Heidelberg. Methods: Muscle thickness, cross-sectional area and subcutaneous adipose tissue thickness were measured at 3 standardized sites on the right and left vastus lateralis muscle. Ultrasound measurements were collected by 2 independent investigators on 2 different days and compared with magnetic resonance imaging measurements. Results: Intraclass correlation coefficients (ICC) for intra- and inter-rater reliability showed very good closeness of agreement for all parameters (ICC = 0.929–0.994, p

Background Niemann-Pick Disease, type C1 (NPC1) is a rare neurodegenerative genetic disorder characterized by impaired intracellular transport of cholesterol and other lipids. The Niemann-Pick Disease, type C1 Severity Scale (NPC-SS) was developed to quantify neurological progression of NPC; it is used to monitor the natural history of disease progression and assess response to treatment. Objective The objective of the study was to examine the inter-rater reliability of the NPC-SS in a Phase 2/3 clinical trial. Methods Study data were from a multicenter, prospective, randomized, double-blind, trial of adrabetadex in 56 subjects with NPC1. Clinical data recorded at each study site were distributed to two independent blinded central raters to generate a severity score. A composite four-item score was utilized as the primary clinical study endpoint, while a five-item focused score has been utilized in other NPC1 trials. Inter-rater reliability was assessed using two-way mixed models for instrument stability, Cohen's kappa, weighted kappa, and percent agreement for the four-item and five-item scores. Results The frequency distribution and mean (SD) of the NPC-SS domain assessments by the raters were almost identical. Evaluation at the patient visit level showed wide variability between visits, however, weighted kappa calculation provided a lower variability between visits. The average kappa coefficients ranged between 0.69 to 0.89, indicating good to very good agreement between raters. Conclusion These results support the NPC-SS, including derived 4- and 5-item composite scores, as reliable measures for use in a clinical trial setting.

Environmental stress like important soccer events can induce excitation, stress and anger. We aimed to investigate (i) whether the FIFA soccer world cup (WC) 2014 and (ii) whether the soccer games of the German national team had an impact on total numbers and in-hospital mortality of patients with myocardial infarction (MI) in Germany. We analyzed data of MI inpatients of the German nationwide inpatient sample (2013–2015). Patients admitted due to MI during FIFA WC 2014 (12th June–13th July2014) were compared to those during the same period 2013 and 2015 (12th June–13th July). Total number of MI patients was higher during WC 2014 than in the comparison-period 2013 (18,479 vs.18,089, P

International audience; Background: β-lactam antibiotics are associated with a variety of immune-mediated or hypersensitivity reactions, including immediate (type I) reactions mediated by antigen-specific IgE.Objective: We sought to identify genetic predisposing factors for immediate reactions to β-lactam antibiotics.Methods: Patients with a clinical history of immediate hypersensitivity reactions to either penicillins or cephalosporins, which were immunologically confirmed, were recruited from allergy clinics. A genome-wide association study was conducted on 662 patients (the discovery cohort) with a diagnosis of immediate hypersensitivity and the main finding was replicated in a cohort of 98 Spanish cases, recruited using the same diagnostic criteria as the discovery cohort.Results: Genome-wide association study identified rs71542416 within the Class II HLA region as the top hit (P = 2 × 10-14); this was in linkage disequilibrium with HLA-DRB1∗10:01 (odds ratio, 2.93; P = 5.4 × 10-7) and HLA-DQA1∗01:05 (odds ratio, 2.93, P = 5.4 × 10-7). Haplotype analysis identified that HLA-DRB1∗10:01 was a risk factor even without the HLA-DQA1∗01:05 allele. The association with HLA-DRB1∗10:01 was replicated in another cohort, with the meta-analysis of the discovery and replication cohorts showing that HLA-DRB1∗10:01 increased the risk of immediate hypersensitivity at a genome-wide level (odds ratio, 2.96; P = 4.1 × 10-9). No association with HLA-DRB1∗10:01 was identified in 268 patients with delayed hypersensitivity reactions to β-lactams.Conclusions: HLA-DRB1∗10:01 predisposed to immediate hypersensitivity reactions to penicillins. Further work to identify other predisposing HLA and non-HLA loci is required.

Children's Oncology Group (COG) AALL0331 tested whether pegaspargase intensification on a low-intensity chemotherapy backbone would improve the continuous complete remission (CCR) rate in a low-risk subset of children with standard-risk B-acute lymphoblastic leukemia (ALL). METHODS: AALL0331 enrolled 5,377 patients with National Cancer Institute standard-risk B-ALL (age 1-9 years, WBC < 50,000/μL) between 2005 and 2010. Following a common three-drug induction, a cohort of 1,857 eligible patients participated in the low-risk ALL random assignment. Low-risk criteria included no extramedullary disease, < 5% marrow blasts by day 15, end-induction marrow minimal residual disease < 0.1%, and favorable cytogenetics (ETV6-RUNX1 fusion or simultaneous trisomies of chromosomes 4, 10, and 17). Random assignment was to standard COG low-intensity therapy (including two pegaspargase doses, one each during induction and delayed intensification) with or without four additional pegaspargase doses at 3-week intervals during consolidation and interim maintenance. The study was powered to detect a 4% improvement in 6-year CCR rate from 92% to 96%. RESULTS: The 6-year CCR and overall survival (OS) rates for the entire low-risk cohort were 94.7% ± 0.6% and 98.7% ± 0.3%, respectively. The CCR rates were similar between arms (intensified pegaspargase 95.3% ± 0.8% v standard 94.0% ± 0.8%; P = .13) with no difference in OS (98.1% ± 0.5% v 99.2% ± 0.3%; P = .99). Compared to a subset of standard-risk study patients given identical therapy who had the same early response characteristics but did not have favorable or unfavorable cytogenetics, outcomes were significantly superior for low-risk patients (CCR hazard ratio 1.95; P = .0004; OS hazard ratio 5.42; P < .0001). CONCLUSION: Standard COG therapy without intensified pegaspargase, which can easily be given as an outpatient with limited toxicity, cures nearly all children with B-ALL identified as low-risk by clinical, early response, and favorable cytogenetic criteria.

Excessive alcohol use is a risk factor for most cardiac diseases. The prevalence of unhealthy alcohol use among hospitalized cardiac patients is uncertain as is the frequency with which it is addressed. We performed a single center, patient-level anonymous survey among hospitalized cardiac patients eligible for cardiac rehabilitation. Hazardous drinking was defined as an Alcohol Use Disorders Identification Test (AUDIT) score of 8 or greater. Binge drinking was defined as 5+ drinks for men or 4+ for women on ≥1 occasion within the past 30 days. Unhealthy drinking was defined as either hazardous or binge drinking. Of 300 patients approached, 290 (96.7%) completed the survey. Mean ( ± SD) age was 69 ± 11 years; 70% were male and 31% were cardiac surgical patients. The proportion (95% CI) of hazardous, binge, and unhealthy drinking was 12% (9 to 16), 16% (12 to 20), and 18% (14-23), respectively. Overall, 58% of subjects reported being screened for alcohol use, mostly by nurses (56%). Those with unhealthy drinking reported being counseled more frequently about their alcohol use compared to non-unhealthy drinkers (11% versus 3%, p = 0.03), but the large majority (89%) of unhealthy drinkers reported receiving no advice about their alcohol use while admitted. In conclusion, almost one-fifth of hospitalized cardiac patients reported unhealthy drinking, these patients were only screened about half of the time, and were rarely counseled about their alcohol use.

Objective: Recovery of the quadriceps femoris muscle after anterior ligament reconstruction is im-paired. The aim of this study was to investigate satellite cell content and function of the vastus lateralis muscle after anterior ligament reconstruction. Methods: Biopsies were obtained from the vastus lateralis muscle of 16 recreational athletes immediately before and again 12 weeks after anterior ligament reconstruction. Total satellite cell number (Pax7+), activated (Pax7+/MyoD+), differentiating (Pax7–/MyoD+), and apoptotic (Pax7+/TUNEL+) satellite cells, myofibers expressing myosin heavy chain (MHC) I and II, and neonatal MHC (MHCneo) were determined immunohistochemically. Results: After anterior ligament reconstruction, the number of apoptotic satellite cells was significantly (p = 0.019) increased, concomitant with a significant (p

Impaired muscle regeneration has repeatedly been described after anterior cruciate ligament reconstruction (ACL-R). The results of recent studies provided some evidence for negative alterations in knee extensor muscles after ACL-R causing persisting strength deficits in spite of the regain of muscle mass. Accordingly, we observed that 12 weeks of concentric/eccentric quadriceps strength training with eccentric overload (CON/ECC+) induced a significantly greater hypertrophy of the atrophied quadriceps muscle after ACL-R than conventional concentric/eccentric quadriceps strength training (CON/ECC). However, strength deficits persisted and there was an unexpected increase in the proportion of slow type I fibers instead of the expected shift towards a faster muscle phenotype after CON/ECC+. In order to shed further light on muscle recovery after ACL-R, the steady-state levels of 84 marker mRNAs were analyzed in biopsies obtained from the vastus lateralis muscle of 31 subjects before and after 12 weeks of CON/ECC+ (n = 18) or CON/ECC strength training (n = 13) during rehabilitation after ACL-R using a custom RT2 Profiler PCR array. Significant (p < 0.05) changes were detected in the expression of 26 mRNAs, several of them involved in muscle wasting/atrophy. A different pattern with regard to the strength training mode was observed for 16 mRNAs, indicating an enhanced hypertrophic stimulus, mechanical sensing or fast contractility after CON/ECC+. The effects of the type of autograft (quadriceps, QUAD, n = 19, or semitendinosus tendon, SEMI, n = 12) were reflected in the lower expression of 6 mRNAs involved in skeletal muscle hypertrophy or contractility in QUAD. In conclusion, the greater hypertrophic stimulus and mechanical stress induced by CON/ECC+ and a beginning shift towards a faster muscle phenotype after CON/ECC+ might be indicated by significant gene expression changes as well as still ongoing muscle wasting processes and a negative impact of QUAD autograft.

Aging is an established risk factor for vascular diseases, but vascular aging itself may contribute to the progressive deterioration of organ function. Here, we show in aged mice that vascular endothelial growth factor (VEGF) signaling insufficiency, which is caused by increased production of decoy receptors, may drive physiological aging across multiple organ systems. Increasing VEGF signaling prevented age-associated capillary loss, improved organ perfusion and function, and extended life span. Healthier aging was evidenced by favorable metabolism and body composition and amelioration of aging-associated pathologies including hepatic steatosis, sarcopenia, osteoporosis, "inflammaging" (age-related multiorgan chronic inflammation), and increased tumor burden. These results indicate that VEGF signaling insufficiency affects organ aging in mice and suggest that modulating this pathway may result in increased mammalian life span and improved overall health.

Objective To describe outcomes with cochlear implantation (CI) for rehabilitation of hearing loss in patients with sporadic vestibular schwannomas (VS) and other retrocochlear pathologies. Study design Retrospective review. Setting Tertiary-care center. Patients Twenty three cases in 19 patients (53% men, mean age 55.8 yr) with non-neurofibromatosis type 2 related retrocochlear pathology. Interventions Unilateral or bilateral CI. Main outcome measures Word recognition score, device usage. Results Etiology of deafness included sporadic VS (n = 9, 39%), radiation after head and neck or central nervous system (CNS) malignancy (n = 8, 35%), superficial siderosis (n = 3, 13%), neurosarcoidosis (n = 2, 9%), and pontine stroke (n = 1, 4%). Mean follow-up duration was 2.3 years (standard deviation [SD] 3.0; range, 0.2-9.4). Auditory perception was achieved in 20 out of 22 patients (91%) who have been activated. Mean WRS in patients with sporadic VS was 18% (SD 20; range, 0-44). Mean WRS in patients with non-VS retrocochlear pathology was 55% (SD 30; range, 0-94). Data logs showed 7.0 h/d of average use (SD 4.3; range, 0-13). Conclusions Appropriately selected patients with retrocochlear pathology may benefit from CI so long as the patient has a cochlear fluid signal and an intact cochlear nerve. Patients with sporadic VS patients and normal contralateral hearing exhibited guarded outcomes with CI, whereas most patients with non-VS retrocochlear pathologies demonstrated open-set speech understanding scores comparable to or slightly worse than conventional CI candidates. Since variable performance benefit is observed with CI in patients with retrocochlear pathology, counseling is imperative to align patient expectations with realistic outcomes.

Objective To describe our institutional experience with cochlear implantation (CI) for rehabilitation of hearing loss in Neurofibromatosis type 2 (NF2) patients. Study design Retrospective review between 1989 and 2019. Setting Tertiary-care center. Patients Twenty-four patients (67% female, mean age 45.6years) with NF2. Management of their ipsilateral vestibular schwannoma included microsurgery (n=12), stereotactic radiation (n=5), and observation (n=7). Interventions Cochlear implantation. Main outcome measures Ability to obtain open-set speech, daily device usage and long-term device benefit. Results All patients achieved some degree of sound awareness with CI. Nineteen patients (79%) achieved open-set speech understanding with a mean word-recognition score of 43% (range 0-88%). Patients with tumors 1.5 cm or less demonstrated the better speech understanding, without significant differences among treatment modalities. For tumors greater than 1.5 cm, patients who underwent microsurgery had a lower rate of open-set speech understanding compared to those treated with radiation or observation. Regular daily device use in 83% of patients was found. Long-term use (>10years) was observed in several patients, though some ultimately required reimplantation with an auditory brainstem implant due to progressive tumor growth. Mean follow-up duration was 4.1 years (range 0.4-15). Conclusions Cochlear implantation can be an effective treatment for hearing loss in NF2 patients provided the cochlear nerve is intact, regardless of prior management for the ipsilateral tumor. The degree of benefit varies and is influenced by tumor size. Management strategies that preserve the cochlear nerve maximize the interval during which a CI could be of benefit to NF2 patients.

INTRODUCTION: The brains of extant animals have evolved over hundreds of millions of years from simple circuits. Cell types diversified, connections elaborated, and new brain regions emerged. Models for brain region evolution range from duplication of existing regions to splitting of previously multifunctional regions and de novo assembly from existing cell types. These models, however, have not been demonstrated in vertebrate brains at cell-type resolution. RATIONALE: We investigated brain region evolution using the cerebellar nuclei as a model system. The cerebellum is a major hindbrain structure in jawed vertebrates, comprising the cerebellar cortex and cerebellar nuclei. It is thought to act as a feedforward model for motor control and cognitive processes. The cerebellar cortex receives and processes inputs and sends outputs to the cerebellar nuclei, which route the results of cerebellar computations to the rest of the brain. Whereas the cerebellar cortex is well conserved across vertebrates, the cerebellar nuclei vary in number, with none in jawless vertebrates, one pair in cartilaginous fishes and amphibians, two pairs in reptiles and birds, and three pairs in mammals. This pattern suggests that extant cerebellar nuclei evolved from a single ancestral nucleus. Cerebellar nuclei thus provide a good model to interrogate brain region evolution. RESULTS: We characterized the cerebellar nuclei in mice, chickens, and humans using whole-brain and spinal cord projection mapping in cleared samples, single-nucleus RNA sequencing (snRNAseq), and spatially resolved transcript amplicon readout mapping (STARmap) analysis. We first compared the projection patterns of the three cerebellar nuclei of mice. Our data reveal broad projections of all nuclei, which in common target regions are shifted relative to each other. To understand the transcriptomic differences that underlie these shifting projections, we produced a cell-type atlas of the mouse cerebellar nuclei using snRNAseq. We discovered three region-invariant inhibitory cell classes and 15 region-specific excitatory cell types. Excitatory cell types fall into two classes with distinct gene expression and electrophysiological properties. Members of each class are present in every nucleus and are putative sister cell types. STARmap analysis in mice revealed that the organizational unit of the cerebellar nuclei is cytoarchitectonically distinguishable subnuclei, each of which contains the three inhibitory and two excitatory classes. To test whether this archetypal subnucleus is also the evolutionary unit of the cerebellar nuclei, we performed snRNAseq and STARmap on the chicken cerebellar nuclei. We identified four subnuclei, three of which had direct orthologs in mice. Each chicken subnucleus contained the same cell-type set of three inhibitory and two excitatory classes already identified in mice, confirming our hypothesis. Cerebellar nuclei vary in size across vertebrates. In particular, the human lateral nucleus is markedly expanded. To understand this expansion, we performed snRNAseq in humans. We found that the medial and interposed nuclei maintained the archetypal cerebellar nuclei composition. However, the lateral nucleus expanded one excitatory cell class at the expense of the other. Conditional tracing in the mouse lateral nucleus revealed that the cell class expanded in humans preferentially accesses lateral frontal cortices via specific intermediate thalamic nuclei. CONCLUSION: We identified a conserved cell-type set that forms an archetypal cerebellar nucleus as the unit of cerebellar nuclei organization and evolution. We propose that this archetypal nucleus was repeatedly duplicated during evolution, accompanied primarily by transcriptomic divergence of excitatory neurons and shifts in their projection patterns. Our data support a model of duplication-and-divergence of entire cell-type sets for brain region evolution.

Objective To determine characteristics, outcomes, and clinical factors associated with death in patients with COVID-19 requiring extracorporeal membrane oxygenation (ECMO) support. Methods A multicenter, retrospective cohort study was conducted. The cohort consisted of adult patients (18 years of age and older) requiring ECMO in the period from March 1, 2020, to September 30, 2020. The primary outcome was in-hospital mortality after ECMO initiation assessed with a time to event analysis at 90 days. Multivariable Cox proportional regression was used to determine factors associated with in-hospital mortality. Results Overall, 292 patients from 17 centers comprised the study cohort. Patients were 49 (interquartile range, 39-57) years old and 81 (28%) were female. At the end of the follow-up period, 19 (6%) patients were still receiving ECMO, 25 (9%) were discontinued from ECMO but remained hospitalized, 135 (46%) were discharged or transferred alive, and 113 (39%) died during the hospitalization. The cumulative in-hospital mortality at 90 days was 42% (95% confidence interval [CI], 36%-47%). Factors associated with in-hospital mortality were age (adjusted hazard ratio [aHR], 1.31; 95% CI, 1.06-1.61 per 10 years), renal dysfunction measured according to serum creatinine level (aHR, 1.21; 95% CI, 1.01-1.45), and cardiopulmonary resuscitation before ECMO placement (aHR, 1.87; 95% CI, 1.01-3.46). Conclusions In patients with severe COVID-19 necessitating ECMO support, in-hospital mortality occurred in fewer than half of the cases. ECMO might serve as a viable modality for terminally ill patients with refractory COVID-19., Graphical abstract A multicenter, retrospective cohort study of 292 patients with COVID-19 given extracorporeal membrane oxygenation (ECMO) in 17 centers across the United States from March 1, 2020 to September 30, 2020. Clinical characteristics and outcomes were entered into a Research Electronic Data Capture (REDCap) database. The primary outcome of cumulative in-hospital mortality at 90 days was 42% (95% confidence interval [CI], 36%-47%).

OBJECTIVES: To describe the characteristics and outcomes associated with concomitant renal and respiratory failure in patients with critical coronavirus disease 2019. DESIGN, SETTING, AND PATIENTS: This is a case series of patients from a U.S. healthcare system in New York City. All adult patients (≥ 18 yr) admitted to the hospital with positive coronavirus disease 2019 testing between March 10, 2020, and March 31, 2020, who required mechanical ventilatory support were included. Patients who remained hospitalized were followed through May 1, 2020. INTERVENTIONS: Renal replacement therapy included at least one session of dialysis, continued venovenous hemofiltration, or peritoneal dialysis. MEASUREMENTS AND MAIN RESULTS: Baseline characteristics, laboratory markers, 30-day in-hospital outcomes, ventilator days, and survival to discharge were included. Multivariate predictors for mortality and need for renal replacement therapy were identified. A total of 330 patients were included in this analysis and were most commonly greater than or equal to 70 years (40%), male (61%), Black or African American (41%), and Hispanic or Latino (38%). Renal replacement therapy was required in 101 patients (29%), most commonly among Blacks or African Americans (50%). Elevated D-dimer, C-reactive protein, and procalcitonin were associated with renal replacement therapy, compared with the nondialysis cohort. Overall, 243 patients (74%) died and 56 (17%) were discharged from the hospital, of which 9 (3%) required renal replacement therapy. Male sex (odds ratio, 2.0; 1.1-3.5; p = 0.020), Black race (odds ratio, 1.8; 1.0-3.1; p = 0.453), and history of hypertension (odds ratio, 2.7; 1.3-5.4; p = 0.005) were predictors for requiring renal replacement therapy. Risk factors for in-hospital mortality included age greater than or equal to 60 years (odds ratio, 6.2; 3.0-13.0; p < 0.0001), male sex (odds ratio, 3.0; 1.4-6.4; p = 0.004), and body mass index greater than or equal to 30 kg/m (odds ratio, 2.1; 1.0-4.4; p = 0.039). Concomitant renal failure in critical coronavirus disease 2019 was not a significant predictor of death (odds ratio, 2.3; 0.98-5.5; p = 0.057). CONCLUSIONS: This case series concludes that respiratory failure conveys significant mortality risk in patients with coronavirus disease 2019 and that survival with concomitant renal failure is rare.

Robotic-assisted abdominal wall repair (RAWR) has seen an exponential adoption over the last 5 years. Skepticism surrounding the safety, efficacy, and cost continues to limit a more widespread adoption of the platform. We describe our initial experience of 312 patients undergoing RAWR at a large academic center. A retrospective review of all patients undergoing any RAWR from July 1, 2016 to March 18, 2020 was completed. Patient specific, operation specific, and 30-day outcomes specific data were collected. Univariate analysis and multivariate logistic regression were used to assess fa ctors associated with 30-day complications. There was a steady adoption of RAWR over the study period. A total of 312 patient were included, 138 (44%) were abdominal wall repairs and 174 (56%) were inguinal repairs. The mean age of the cohort was 54.2 years (SD 16), 69% were males, and the mean BMI was 29 kg/m2 (SD 4.8). There were two reported intraoperative events and nine operative conversions. 60 patients had at least one complication at 30-days. These include: 52 seromas, 4 hematomas, 2 surgical-site infections, 1 deep venous thrombus, and 1 recurrence at 30-days. BMI, type of hernia, and sex were not associated with complications at 30-days. The use of absorbable mesh, longer hospital stay, operative conversion, previous repair, and expert hernia surgeon were significant predictors of 30-day complications. Age, operative conversion, and previous repair were the only predictors of 30-day complications on multivariate regression. Our initial experience of 312 patients demonstrates the adoption and comparable short-term outcomes for a wide variety of robotic-assisted hernia repairs.

BACKGROUND: The most common dementia worldwide, Alzheimer’s disease is often diagnosed via biomarkers in cerebrospinal fluid, including reduced levels of Aβ1–42, and increases in total tau and phosphorylated tau-181. Here we describe results of a Phase 2a study of a promising new drug candidate that significantly reversed all measured biomarkers of Alzheimer’s disease, neurodegeneration and neuroinflammation. PTI-125 is an oral small molecule drug candidate that binds and reverses an altered conformation of the scaffolding protein filamin A found in Alzheimer’s disease brain. Altered filamin A links to the α7-nicotinic acetylcholine receptor to allow Aβ42’s toxic signaling through this receptor to hyperphosphorylate tau. Altered filamin A also links to toll-like receptor 4 to enable Aβ-induced persistent activation of this receptor and inflammatory cytokine release. Restoring the native shape of filamin A prevents or reverses filamin A’s linkages to the α7-nicotinic acetylcholine receptor and toll-like receptor 4, thereby blocking Aβ42’s activation of these receptors. The result is reduced tau hyperphosphorylation and neuroinflammation, with multiple functional improvements demonstrated in transgenic mice and postmortem Alzheimer’s disease brain. OBJECTIVES: Safety, pharmacokinetics, and cerebrospinal fluid and plasma biomarkers were assessed following treatment with PTI-125 for 28 days. Target engagement and mechanism of action were assessed in patient lymphocytes by measuring 1) the reversal of filamin A’s altered conformation, 2) linkages of filamin A with α7-nicotinic acetylcholine receptor or toll-like receptor 4, and 3) levels of Aβ42 bound to α7-nicotinic acetylcholine receptor or CD14, the co-receptor for toll-like receptor 4. DESIGN: This was a first-in-patient, open-label Phase 2a safety, pharmacokinetics and biomarker study. SETTING: Five clinical trial sites in the U.S. under an Investigational New Drug application. PARTICIPANTS: This study included 13 mild-to-moderate Alzheimer’s disease patients, age 50-85, Mini Mental State Exam ≥16 and ≤24 with a cerebrospinal fluid total tau/Aβ42 ratio ≥0.30. INTERVENTION: PTI-125 oral tablets (100 mg) were administered twice daily for 28 consecutive days. MEASUREMENTS: Safety was assessed by electrocardiograms, clinical laboratory analyses and adverse event monitoring. Plasma levels of PTI-125 were measured in blood samples taken over 12 h after the first and last doses; cerebrospinal fluid levels were measured after the last dose. Commercial enzyme linked immunosorbent assays assessed levels of biomarkers of Alzheimer’s disease in cerebrospinal fluid and plasma before and after treatment with PTI-125. The study measured biomarkers of pathology (pT181 tau, total tau and Aβ42), neurodegeneration (neurofilament light chain and neurogranin) and neuroinflammation (YKL-40, interleukin-6, interleukin-1β and tumor necrosis factor α). Plasma levels of phosphorylated and nitrated tau were assessed by immunoprecipitation of tau followed by immunoblotting of three different phospho-epitopes elevated in AD (pT181-tau, pS202-tau and pT231-tau) and nY29-tau. Changes in conformation of filamin A in lymphocytes were measured by isoelectric focusing point. Filamin A linkages to α7-nicotinic acetylcholine receptor and toll-like receptor 4 were assessed by immunoblot detection of α7-nicotinic acetylcholine receptor and toll-like receptor 4 in anti-filamin A immunoprecipitates from lymphocytes. Aβ42 complexed with α7-nicotinic acetylcholine receptor or CD14 in lymphocytes was also measured by co-immunoprecipitation. The trial did not measure cognition. RESULTS: Consistent with the drug’s mechanism of action and preclinical data, PTI-125 reduced cerebrospinal fluid biomarkers of Alzheimer’s disease pathology, neurodegeneration and neuroinflammation from baseline to Day 28. All patients showed a biomarker response to PTI-125. Total tau, neurogranin, and neurofilament light chain decreased by 20%, 32% and 22%, respectively. Phospho-tau (pT181) decreased 34%, evidence that PTI-125 suppresses tau hyperphosphorylation induced by Aβ42’s signaling through α7-nicotinic acetylcholine receptor. Cerebrospinal fluid biomarkers of neuroinflammation (YKL-40 and inflammatory cytokines) decreased by 5-14%. Biomarker effects were similar in plasma. Aβ42 increased slightly – a desirable result because low Aβ42 indicates Alzheimer’s disease. This increase is consistent with PTI-125’s 1,000-fold reduction of Aβ42’s femtomolar binding affinity to α7-nicotinic acetylcholine receptor. Biomarker reductions were at least p ≤ 0.001 by paired t test. Target engagement was shown in lymphocytes by a shift in filamin A’s conformation from aberrant to native: 93% was aberrant on Day 1 vs. 40% on Day 28. As a result, filamin A linkages with α7-nicotinic acetylcholine receptor and toll-like receptor 4, and Aβ42 complexes with α7-nicotinic acetylcholine receptor and CD14, were all significantly reduced by PTI-125. PTI-125 was safe and well-tolerated in all patients. Plasma half-life was 4.5 h and approximately 30% drug accumulation was observed on Day 28 vs. Day 1. CONCLUSIONS: PTI-125 significantly reduced biomarkers of Alzheimer’s disease pathology, neurodegeneration, and neuroinflammation in both cerebrospinal fluid and plasma. All patients responded to treatment. The magnitude and consistency of reductions in established, objective biomarkers imply that PTI-125 treatment counteracted disease processes and reduced the rate of neurodegeneration. Based on encouraging biomarker data and safety profile, approximately 60 patients with mild-to-moderate AD are currently being enrolled in a Phase 2b randomized, placebo-controlled confirmatory study to assess the safety, tolerability and efficacy of PTI-125.

Background: Childhood wheeze may be related to pesticide exposure, and diet and genetics (Paroxonase, PON1) may modify the effects of exposure. Methods: We analyzed data from the HOME Study, a prospective pregnancy and birth cohort, to examine the association of gestational urinary organophosphate (OP) and pyrethroid (3PBA) metabolite concentrations with child wheeze, forced expiratory volume in one second (FEV1) at ages 4 and 5 years, and wheeze trajectory patterns through age 8 years. Results: Among 367 singletons, the frequency of wheeze ranged from 10.6% to 24.1% at each measurement age. OP and 3PBA metabolite concentrations were not associated with wheeze at 8 years or from birth to 8 years, but there were three significant interactions: (1) maternal daily fruit and vegetable consumption (less than daily consumption and increasing 3PBA was associated with wheeze at age 8 years, OR = 1.40), (2) maternal PON1-108 allele (CT/TT genotypes and high DE was associated with wheeze at age 8 years, OR = 2.13, 2.74) and (3) PON1192 alleles (QR/RR genotypes with higher diethylphosphate (DE) and dialkyl phosphate (DAP) were associated with wheeze at age 8 years, OR = 3.84). Pesticide metabolites were not consistently related to FEV1 or wheeze trajectory. Conclusions: Gestational OP and 3PBA metabolites were associated with child respiratory outcomes in participants with maternal dietary and genetic susceptibility.

Background Ectrodactyly‐ectodermal dysplasia‐clefting syndrome 3 (EEC) is one of the six overlapping syndromes caused by mutations in the tumor protein p63 gene (TP63). EEC is suspected when patients have cleft hands or feet, polydactyly, and syndactyly, abnormal development of the ectodermally derived structures, and orofacial clefting. Genitourinary (GU) anomalies have been identified in patients with EEC, yet these are often under‐recognized and under‐reported. The available literature on sonographic prenatal findings is sparse, especially when considering GU anomalies. Methods We present the case of a male stillborn fetus, who was found antenatally to have multicystic dysplastic kidneys and anhydramnios. Following the termination of pregnancy, examination and autopsy further revealed unilateral polydactyly and bilateral syndactyly which had not been previously identified on antenatal ultrasound. Results Whole‐exome sequencing (WES) revealed a de novo heterozygous pathogenic variant in exon 5 of the TP63 gene: p.His247Arg: c.740A>G (NM_003722.4) which has been reported in the literature. The His247Arg variant has been published as a pathogenic variant in association with EEC, both with and without orofacial clefting. Conclusion Our prenatal case expands the phenotypic spectrum of TP63‐related disorders in general. In addition, it adds to the phenotype associated with the His247Arg pathogenic variant responsible for EEC. Further, we highlight the importance of WES as a postnatal tool to help clarify unexpected findings, and as a way to add to the spectrum of existing phenotypes of known single‐gene disorders., In this paper, we describe a prenatal presentation of multicystic dysplastic kidneys and anhydramnios in a male fetus with a postnatal autopsy finding of unilateral upper limb polydactyly and bilateral syndactyly. Whole exome sequencing (WES) revealed a de novo heterozygous pathogenic variant in the TP63 gene: p.His247Arg: c.740A>G (NM_003722.4), which has been reported with ectrodactyly‐ectodermal dysplasia‐clefting syndrome 3 (EEC), both with and without orofacial clefting.

Introduction: While cochlear implants (CI) prior to 12 months of age have become common, the prevalence and impact of issues that either arise or were not evident prior to implantation is unknown. ...

Background Limited data exist on factors predicting prolonged survival in left ventricular assist device (LVAD) recipients. We sought to identify patient characteristics and complications associated with prolonged survival. Methods We conducted retrospective review of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database, including primary continuous-flow LVAD recipients, between May 2012 and March 2013. Patients were identified as having survived with a device in place after 3 years or not, conditional on having initially survived 6 months. Patients who received a transplant, underwent explant due to recovery, or were lost to follow-up before 3 years were excluded. Multivariate logistic regression evaluated perioperative factors and adverse events within 6 months associated with long survival. Results Of 1,116 patients who survived past the initial 6 months, 725 (65%) survived beyond 3 years. On univariate analysis, long-term survivors were significantly younger, were less likely to be white, supported for destination therapy, have diabetes, solid-organ cancer, or take amiodarone. On multivariate analysis, factors associated with increased odds of death at 3 years included diabetes, amiodarone use, and developing stroke, gastrointestinal bleeding, hemolysis, or pump thrombosis within 6 months of implantation. Conclusions Preoperative diabetes and amiodarone use were associated with poor long-term survival in LVAD recipients. Development of early complications of stroke, gastrointestinal bleeding, hemolysis, or pump thrombosis was also associated with poor long-term survival. Early diagnosis and treatment of these complications may improve survival in LVAD recipients.

Background The role of tumor-associated macrophages (TAMs) in determining the outcome between the antitumor effects of the adaptive immune system and the tumor’s anti-immunity stratagems, is controversial. Macrophages modulate their activities and phenotypes by integration of signals in the tumor microenvironment. Depending on how macrophages are activated, they may adopt so-called M1-like, antitumor or M2-like, protumor profiles. In many solid tumors, a dominance of M2-like macrophages is associated with poor outcomes but in some tumor types, strong M1-like profiles are linked to better outcomes. We aimed to investigate the interrelationship of these TAM populations to establish how they modulate the efficacy of the adaptive immune system in early lung cancer. Methods Macrophages from matched lung (non-tumor-associated macrophages (NTAMs)) and tumor samples (TAMs) from resected lung cancers were assessed by bulk and single-cell transcriptomic analysis. Protein expression of genes characteristic of M1-like (chemokine (C-X-C motif) ligand 9) or M2-like (matrix metallopeptidase 12) functions was confirmed by confocal microscopy. Immunohistochemistry related the distribution of TAM transcriptomic signatures to density of CD8+ tissue-resident memory T cells (TRM) in tumors and survival data from an independent cohort of 393 patients with lung cancer. Results TAMs have significantly different transcriptomic profiles from NTAMs with >1000 differentially expressed genes. TAMs displayed a strong M2-like signature with no significant variation between patients. However, single-cell RNA-sequencing supported by immuno-stained cells revealed that additionally, in 25% of patients the M2-like TAMs also co-expressed a strong/hot M1-like signature (M1hot). Importantly, there was a strong association between the density of M1hot TAMs and TRM cells in tumors that was in turn linked to better survival. Our data suggest a mechanism by which M1hot TAMs may recruit TRM cells via CXCL9 expression and sustain them by making available more of the essential fatty acids on which TRM depend. Conclusions We showed that in early lung cancer, expression of M1-like and M2-like gene signatures are not mutually exclusive since the same TAMs can simultaneously display both gene-expression profiles. The presence of M1hot TAMs was associated with a strong TRM tumor-infiltrate and better outcomes. Thus, therapeutic approaches to re-program TAMs to an M1hot phenotype are likely to augment the adaptive antitumor responses.