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Background This study reviews the outcomes of our reoperative total arch repair technique using a trifurcated graft and selective antegrade cerebral perfusion. Methods Fifty patients underwent reoperative total arch repair from January 2005 to September 2020, with either a one-stage repair (n = 9) or two-stage repair (n = 41). The two-stage technique includes minimal dissection of the mediastinal structures, an arch-first technique using a trifurcated graft, and construction of a classical elephant trunk through a partial transverse incision distally in the old graft or in the aorta just distal to the old graft. Results The median age was 63 years. Chronic dissection was the most frequent indication (88%), and 98% had undergone a previous proximal aortic repair at a median interval of 3 years. The median cardiopulmonary bypass, myocardial ischemic, selective antegrade cerebral perfusion, and lower body circulatory arrest times were 226, 103, 97, and 98 minutes, respectively. The minimum nasopharyngeal and bladder temperature were 16.5°C and 20.0°C, respectively. Operative mortality was 2%, the incidence of stroke was 2%, and the incidence of spinal cord injury was 0%. Stage II repair was performed in 37 patients (open, 33 patients; endovascular, 4 patients), with 2 mortalities and no spinal cord injury. The median duration between stage I and II was 63 days. Survival and aortic event free rates at 3 years were 88.4% ± 4.9%, and 89.8% ± 5%, respectively. Conclusions We report a reoperative total arch repair technique that minimizes dissection of the cardiac structures, simplifies the distal anastomosis, and protects vital organs, such as the brain, heart, and spinal cord.

Massive pulmonary embolism (MPE) is associated with a 20-50% mortality rate with guideline directed therapy. MPE treatment with surgical embolectomy (SE) or venoarterial extracorporeal membrane oxygenation (VA-ECMO) have shown promising results. In the context of a surgical management strategy for MPE, a comparison of outcomes associated with VA-ECMO or SE was performed. A retrospective review of a single institution cardiac surgery database was performed, identifying MPE treated with SE or VA-ECMO between 2005-2020. Primary outcome was in-hospital survival. 59 MPE [27 (46.8%) VA-ECMO vs 32 (54.2%) SE] were identified. All presented with elevated cardiac biomarkers, tachycardia (mean heart rate 113 ± 20 beats/minute), hypotension (mean systolic blood pressure 85 ± 22 mm Hg) and vasopressors requirement, without significant differences between cohorts. Preoperative CPR was performed in 37.3% (22/59), without a significant difference between cohorts. More VA-ECMO presented with questionable neurologic status (GCS ≤ 4) [9/27 (33.3%) vs 2/32 (6.2%), P = 0.008] and more VA-ECMO failed thrombolysis [8/27 (29.6) vs 2/32 (6.3), P = 0.014]. All presented with severe RV dysfunction, by discharge all had normalization of echocardiographic RV function. Overall mortality was 10.2%, with a trend toward higher mortality among VA-ECMO [14.9% (4/27) vs 6.3% (2/32) P = 0.14]. CPR was independently associated with death (OR 10.8, P = 0.02) whereas treatment modality was not (OR 0.24). In an extremely unstable MPE population VA-ECMO and SE were safely performed with low mortality while achieving RV recovery. Adverse outcomes were more closely associated with preoperative CPR than with treatment modality.

The implications of poor maternal diet on offspring metabolic and neuroimmune development are well established. Increasing evidence now suggests that maternal obesity and poor diet can also increase the risk of postpartum mood disorders, but the mechanisms are unknown. Here we investigated the effects of a poor, high-fat-high-sugar diet (HFSD) on peripheral and central inflammation, neurogenesis and postpartum anxiety-like behaviours. We hypothesised that long-term consumption of a HFSD pre- and post-conception would increase the levels of circulating cytokines and induce microglial activation, particularly in the arcuate nucleus of the hypothalamus (ARC), as the primary brain region involved in the integration of satiety signalling; and this would lead to increased anxiety, stress responsivity and disrupted neurogenesis. We further hypothesised that these effects would be ameliorated by consumption of a healthier diet during pregnancy - specifically a diet high in omega-3 polyunsaturated fatty acids (PUFAs). As expected, the HFSD significantly increased pre-conception body weight, elevated circulating cytokines and activated microglia in the ARC, as well as in the basolateral amygdala. The HFSD also significantly increased the numbers of immature (doublecortin (DCX)-positive) neurons in the subgranular/granular region of the hippocampus, a neurogenic response that was, surprisingly, mimicked by consumption of a diet high in omega-3 PUFAs. Despite these effects of peri-pregnancy dietary imbalance, we detected no differences in anxiety-like behaviours or hypothalamic-pituitary-adrenal (HPA) axis reactivity between the groups. A shift to a healthier diet post-conception reversed the peripheral inflammation and alleviated the microglial activation. These novel data indicate the importance of a balanced peri-pregnancy diet and highlight the need for future research into key triggers that alter the neuroimmune balance in the maternal brain.

Accelerated models of care may be one solution to the problem of underutilization of mental health treatment in veterans. We report on a novel implementation of prolonged exposure (PE) therapy in a four-day, weekend-based intensive outpatient treatment program. Seventeen military veterans and service members (Mage = 45.23, SDage = 10.18; 76.47% male) completed the program. Symptoms of posttraumatic stress disorder (PTSD) and depression were targeted in five separate cohorts. Given that this was an uncontrolled pilot study, we assessed patient satisfaction and treatment completion. In a completers analysis, PTSD and depression symptoms decreased significantly from pre- to posttreatment (p's

BACKGROUND The learning slope is typically represented as the raw difference between the final score and the score of the first learning trial. A new method for calculating the learning slope, the learning ratio (LR), was recently developed; it is typically represented as the number of items that are learned after the first trial divided by the number of items that are yet to be learned. OBJECTIVE To evaluate the convergent and criterion validity of the LR in order to understand its sensitivity to Alzheimer disease (AD) pathology. METHOD Fifty-six patients from a memory clinic underwent standard neuropsychological assessment and quantitative brain imaging. LR scores were calculated from the Hopkins Verbal Learning Test-Revised and the Brief Visuospatial Memory Test-Revised and were compared with both standard memory measures and total hippocampal volumes, as well as between individuals with AD and those with mild cognitive impairment. RESULTS Lower LR scores were consistently associated with poorer performances on standard memory measures and smaller total hippocampal volumes, generally more so than traditional learning slope scores. The LR scores of the AD group were smaller than those of the group with mild cognitive impairment. Furthermore, the aggregation of LR scores into a single metric was partially supported. CONCLUSION The LR is sensitive to AD pathology along the AD continuum. This result supports previous claims that the LR score can reflect learning capacity better than traditional learning calculations can by considering the amount of information that is learned at trial 1.

OBJECTIVE While the comparative efficacy of prolonged exposure (PE) and cognitive processing therapy (CPT) has been examined in outpatient settings, there is a dearth of literature on the relative effectiveness of these interventions when adapted for an intensive treatment format. In an expanded secondary analysis of a previous study, we sought to examine the comparative effectiveness of PE and CPT delivered in the naturalistic setting of an intensive treatment format including maintenance of outcomes through a 6-month follow-up period. METHOD A sample of 296 veterans with posttraumatic stress disorder (PTSD) received either PE (n = 186) or CPT (n = 90), alongside other trauma-informed interventions, in a 2-week intensive clinical program. Treatment selection was determined collaboratively between patient and therapist. Our primary outcome was self-reported PTSD symptom severity (i.e., PTSD Checklist for DSM-5, PCL-5); secondarily, we examined self-reported depression (i.e., Patient Health Questionnaire) symptom severity outcomes. RESULTS A mixed-model regression controlling for age and gender revealed a significant effect of time from baseline to endpoint (p .05; model: Wald's χ² = 232.38, p < .001). Results were similar for depression outcomes. Attrition at posttreatment was not significantly different between groups: 7.2% for CPT and 6.5% PE (z score = 0.22). CONCLUSIONS Both PE and CPT are associated with comparable improvements when delivered as part of a 2-week intensive outpatient program. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Aims Sleep problems are common in people with a psychosis-spectrum diagnosis and are associated with worse psychotic symptoms and lower quality of life. Sleep problems are also frequent in individuals at a clinical high risk for psychosis (CHR-P) however, less is known about the prevalence and association with symptoms in this population. This study investigates the prevalence of sleep problems within CHR-P individuals and the associations with attenuated positive symptoms, transition to psychosis, time to transition to psychosis and functioning. Methods The clinical records interactive search (CRIS) tool was used to carry out a retrospective study of 795 CHR-P individuals. Sleep problems, subsequent psychotic diagnoses, attenuated positive symptoms and Health of The Nation Outcome Scale scores were extracted. Regression models were used to examine the association between sleep problems and clinical outcomes. Results 59.5% of CHR-P individuals experienced sleep problems. Perceptual abnormality severity (OR = 1.24, 95% CI = 1.05-1.48) and frequency (OR = 1.31, 95% CI = 1.08-1.58) as measured by the Comprehensive Assessment of At-Risk Mental State interview, predicted sleep problems. Sleep problems were not associated with transition to psychosis; however, they were significantly associated with a shorter time to transition in individuals who developed psychosis (HR = 1.4, 95% CI = 1.05-1.88) and higher follow-up Health of the Nation Outcome Scale scores (MD = 2.26, 95% CI = 0.55-3.96). Conclusions The high prevalence of sleep problems, along with the association with positive symptoms and worse functioning, highlights the need for effective sleep interventions in this population. Further research is needed to better understand the relationship between sleep problems and transition to psychosis.

OBJECTIVE To demonstrate discrepancies between operative times in the ACS NSQIP (American College of Surgeons National Surgical Quality Improvement Project) and self-reported operative time from the American Medical Association's Relative Value Scale Update Committee (RUC) and their effect on relative value units (RVU) determination. METHODS This is a cross-sectional review of registry data using the ACS NSQIP 2016 Participant User File and the Centers for Medicare & Medicaid Services physician procedure time file for 2018. We analyzed total RVUs for surgeries by operative time to calculate RVU per hour and stratified by specialty. Multivariate regression analysis adjusted for patient comorbidities, age, length of stay, and ACS NSQIP mortality and morbidity probabilities. The surgeon self-reported operative times from the Centers for Medicare & Medicaid Services physician were compared with operative times recorded in the ACS NSQIP, with excess time from RUC estimates termed "overreported time." RESULTS Analysis of 901,917 surgeries revealed a wide variation in median RVU per hour between specialties. Orthopedics (14.3), neurosurgery (12.9), and general surgery (12.1) had the highest RVU per hour, whereas gynecology (10.2), plastic surgery (9.5), and otolaryngology (9) had the lowest (P

Background The learning ratio (LR) is a novel learning slope score that has been developed to reduce the inherent competition between the first trial and subsequent trials in traditional learning slopes. In essence, the LR is the number of items learned after the first trial divided by the number of items yet to be learned. Criterion and convergent validation of this LR score is warranted to understand its sensitivity along the Alzheimer’s disease (AD) continuum. Method The LR metric was calculated for 123 participants from standard measures of memory, including the Hopkins Verbal Learning Test—Revised, Brief Visuospatial Memory Test—Revised, Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) list learning, and RBANS story memory. All participants were categorized as normal cognition, mild cognitive impairment (MCI), or AD. LR performances were compared between groups, among other standard memory measures, and with regards to how well they discriminated cognitively impaired from unimpaired samples—and within diagnostic subgroups. Results Lower LR scores were observed for the MCI and AD groups than the normal cognition group, with the AD group performing worse than the MCI group for several slope calculations. Lower LR scores were also consistently associated with poorer performances on traditional memory measures. LR scores further displayed excellent receiver operator characteristics when differentiating those with and without cognitive impairment—and MCI from normal cognition. Overall, LR scores consistently outperformed traditional learning slope calculations across all analyses. Conclusions This LR score is sensitive to memory dysfunction along the AD continuum, and results offer criterion and convergent validity for use of the LR metric to understand learning capacity.

Background:Vaginal cancer is a rare malignancy that poses a challenge to treat and cure, as surgical excision requires life-changing procedures because of the proximity and involvement of rectum, bladder and anus. We report in this case study the successful delivery of stereotactic ablative radiotherapy (SABR) for a patient with vaginal cancer after previous radiotherapy.Methods:A 71-year-old white female who presented with dyspareunia and irritative urinary symptoms proven by biopsy was our candidate patient. Subsequent PET/CT revealed a hypermetabolic 3 cm lesion at the 12–1 o’clock position in the distal vagina involving the clitoris. The patient was initially treated with volumetric-modulated arc therapy (VMAT) with simultaneous integrated boost technique to the involved nodes, and later upon recurrence treated with SABR using 30 Gy in six fractions.Findings:To our knowledge, this is the first report of a vaginal cylinder used to physically distance organs at risk from the treatment target and also as a localising device with image guidance for the delivery of SABR using an external beam.

PURPOSE: Physical activity is important for healthy cancer survivorship, yet many endometrial cancer survivors do not participate in recommended muscle-strengthening activity. The purpose of this study was to determine the feasibility of home-based muscle strengthening activity in endometrial cancer survivors. METHODS: Forty post-treatment endometrial cancer survivors were enrolled in a randomized trial, of twice-weekly home-based strength exercise versus wait-list control. The intervention included educational materials, exercise equipment (dumbbells, resistance bands), and support/feedback via video coaching sessions. Participants completed the exercises twice per week for 10 weeks, with a 5-week follow-up period. Feasibility was measured by program adherence, as well as safety of and satisfaction with the study. RESULTS: On average, participants were 60.9 years old (SD = 8.7), had a BMI of 39.9 kg/m(2) (SD = 15.2), and were 2.9 years (SD = 1.2) since diagnosis. The majority (83%) had stage I disease at diagnosis. Seventy-five percent adhered to the exercise prescription of twice/week, with 85% of participants missing fewer than 3 of the workouts. Forty percent of participants continued workouts during the 5-week follow-up. Participants were highly satisfied with intervention. No injuries or adverse everts occurred. CONCLUSION: This home-based program was feasible in endometrial cancer survivors. While adherence was measured, future research should focus on long-term maintenance of exercise and should explore progressions and modifications of exercises at a distance for various abilities. IMPLICATIONS FOR CANCER SURVIVORS: Muscle strengthening activities are recommended for all cancer survivors. This study shows that a home-based muscle strengthening exercise is feasible in endometrial cancer survivors.

In 2014, the Society of Gynecologic Oncology's Clinical Practice Committee published a clinical update reviewing the treatment of women with endometrial cancer. At that time, there had been significant advances in the diagnosis, work-up, surgical management, and available treatment options allowing for more optimal care of affected women. Despite these advances, the incidence of endometrial cancer as well as the deaths attributable to the disease have continued to rise; from 1987 to 2014 there has been a 75% increase in cases and almost 300% increase in endometrial cancer deaths. Fortunately, since then, there has been progress in the treatment of patients with endometrial cancer with increased utilization of molecular pathology, greater understanding of genetic predisposition, enhanced methods for lymph node assessment, a broader understanding of the efficacy of radiation and chemotherapy, and a more efficient approach to survivorship and surveillance. The purpose of this document is to present a comprehensive review of this progress.The authors reviewed the available evidence, contributed to the development of this manuscript, provided critical review of the guidelines, and finalized the manuscript recommendations. The review was also presented to and approved by the Society of Gynecologic Oncology (SGO) Clinical Practice Committee, SGO Publications Committee, and the SGO board members prior to submission for publication. The recommendations for this manuscript were developed by a panel of gynecologic oncologists who were members of the SGO Clinical Practice and Education Committees. Panelists reviewed and considered evidence from current uterine cancer literature. The terminology used in these guidelines was adopted from the ASCCP management guidelines [1] using a two-part rating system to grade the strength of recommendation and quality of evidence (Table 1). The rating for each recommendation is given in parentheses.

Background: The use of the vancomycin wrap to pretreat the hamstring graft in anterior cruciate ligament reconstruction (ACLR) has grown in popularity since it was first described in 2012 and has significantly reduced rates of postoperative infection. However, it remains unknown if this antibiotic treatment affects the molecular composition of the graft. Purpose: To establish whether treatment with vancomycin at 5 mg/mL, the most commonly used concentration, alters the molecular function of the hamstring graft in ACLR. Study Design: Controlled laboratory study. Methods: Surplus hamstring tendon collected after routine ACLR surgery was used for in vitro cell culture and ex vivo tissue experiments. Vancomycin was used at 5 mg/mL in RPMI or saline diluent to treat cells and tendon tissue, respectively, with diluent control conditions. Cell viability at 30, 60, and 120 minutes was assessed via colorimetric viability assay. Tendon cells treated with control and experimental conditions for 1 hour was evaluated using semiquantitative reverse transcription analysis, immunohistochemistry staining, and protein quantitation via enzyme-linked immunosorbent assay for changes in apoptotic, matrix, and inflammatory gene and protein expression. Results: Vancomycin treatment at 5 mg/mL significantly reduced tenocyte viability in vitro after 60 minutes of treatment ( P < .05); however, this was not sustained at 120 minutes. Vancomycin-treated tendon tissue showed no significant increase in apoptotic gene expression, or apoptotic protein levels in tissue or supernatant, ex vivo. Vancomycin was associated with a reduction in inflammatory proteins from treated tendon supernatants (IL-6; P < .05). Conclusion: Vancomycin did not significantly alter the molecular structure of the hamstring graft. Reductions in matrix protein and inflammatory cytokine release point to a potential beneficial effect of vancomycin in generating a homeostatic environment. Clinical Relevance: Vancomycin ACL wrap does not alter the molecular structure of the ACL hamstring graft and may improve graft integrity.

Aims Duchenne muscular dystrophy (DMD) is an X‐linked inherited disease due to dystrophin deficiency causing skeletal and cardiac muscle dysfunction. Affected patients lose ambulation by age 12 and usually die in the second to third decades of life from cardiac and respiratory failure. Symptomatic treatment includes the use of anti‐inflammatory corticosteroids, which are associated with side effects including weight gain, osteoporosis, and increased risk of cardiovascular disease. Novel treatment options include blockade of the renin–angiotensin–aldosterone system, because angiotensin as well as aldosterone contribute to persistent inflammation and fibrosis, and aldosterone blockade represents an efficacious anti‐fibrotic approach in cardiac failure. Recent preclinical findings enabled successful clinical testing of a combination of steroidal mineralocorticoid receptor antagonists (MRAs) and angiotensin converting enzyme inhibitors in DMD boys. The efficacy of MRAs alone on dystrophic skeletal muscle and heart has not been investigated. Here, we tested efficacy of the novel non‐steroidal MRA finerenone as a monotherapy in a preclinical DMD model. Methods and results The dystrophin‐deficient, utrophin haploinsufficient mouse model of DMD was treated with finerenone and compared with untreated dystrophic and wild‐type controls. Grip strength, electrocardiography, cardiac magnetic resonance imaging, muscle force measurements, histological quantification, and gene expression studies were performed. Finerenone treatment alone resulted in significant improvements in clinically relevant functional parameters in both skeletal muscle and heart. Normalized grip strength in rested dystrophic mice treated with finerenone (40.3 ± 1.0 mN/g) was significantly higher (P = 0.0182) compared with untreated dystrophic mice (35.2 ± 1.5 mN/g). Fatigued finerenone‐treated dystrophic mice showed an even greater relative improvement (P = 0.0003) in normalized grip strength (37.5 ± 1.1 mN/g) compared with untreated mice (29.7 ± 1.1 mN/g). Finerenone treatment also led to significantly lower (P = 0.0075) susceptibility to limb muscle damage characteristic of DMD measured during a contraction‐induced injury protocol. Normalized limb muscle force after five lengthening contractions resulted in retention of 71 ± 7% of baseline force in finerenone‐treated compared with only 51 ± 4% in untreated dystrophic mice. Finerenone treatment also prevented significant reductions in myocardial strain rate (P = 0.0409), the earliest sign of DMD cardiomyopathy. Moreover, treatment with finerenone led to very specific cardiac gene expression changes in clock genes that might modify cardiac pathophysiology in this DMD model. Conclusions Finerenone administered as a monotherapy is disease modifying for both skeletal muscle and heart in a preclinical DMD model. These findings support further evaluation of finerenone in DMD clinical trials.

The ability of skeletal muscle to regenerate declines significantly with aging. The expression of aryl hydrocarbon receptor nuclear translocator (ARNT), a critical component of the hypoxia signaling pathway, was less abundant in skeletal muscle of old (23‐25 months old) mice. This loss of ARNT was associated with decreased levels of Notch1 intracellular domain (N1ICD) and impaired regenerative response to injury in comparison to young (2‐3 months old) mice. Knockdown of ARNT in a primary muscle cell line impaired differentiation in vitro. Skeletal muscle‐specific ARNT deletion in young mice resulted in decreased levels of whole muscle N1ICD and limited muscle regeneration. Administration of a systemic hypoxia pathway activator (ML228), which simulates the actions of ARNT, rescued skeletal muscle regeneration in both old and ARNT‐deleted mice. These results suggest that the loss of ARNT in skeletal muscle is partially responsible for diminished myogenic potential in aging and activation of hypoxia signaling holds promise for rescuing regenerative activity in old muscle.

The use of non-nutritive sweeteners such as saccharin is widely prevalent. Although saccharin is considered safe for human consumption, it produces behavioral changes in experimental animals. We report that saccharin’s behavioral effects are much more pervasive than currently recognized. In a mouse model, saccharin exposure produced motor impulsivity not only in the saccharin-exposed males but also in their offspring. In addition, the offspring showed locomotor hyperactivity and working memory deficit not observed in fathers. Spermatazoal DNA was hypermethylated in the saccharin-exposed fathers, especially at dopamine receptor promoter regions, suggesting that epigenetic modification of germ cell DNA may mediate transgenerational transmission of behavioral phenotypes. Dopamine’s role in hyperactivity was further highlighted by the finding that the stimulant drug methylphenidate mitigated the hyperactivity. Nicotine is another substance that is widely used. Its use via smokeless tobacco products, some of which contain saccharin, is on the rise contributing to concerns about adverse outcomes of co-exposure to saccharin and nicotine. We found that co-exposure of male mice to saccharin and nicotine produced significant behavioral impairment in their offspring. Thus, our data point to potential adverse neurobehavioral consequences of exposure to saccharin alone or saccharin and nicotine for the exposed individuals and their descendants.

BACKGROUND The Montreal Cognitive Assessment (MoCA) is often used for cognitive screening across health care settings, especially in rehabilitation centers, where assessment and treatment of cognitive function is considered key for successful multidisciplinary treatment. Although the original MoCA validation study suggested a cut score of

Convergent validation of a verbal incidental learning (IL) task from the WAIS-IV using neuroimaging biomarkers is warranted to understand its sensitivity to Alzheimer's disease (AD) pathology. Fifty-five memory clinic patients aged 59 to 87 years received neuropsychological assessment, and measures of IL and quantitative brain imaging. Worse IL-Total Score and IL-Similarities performances were significantly associated with smaller hemispheric hippocampal volumes. IL measures were not significantly correlated with cerebral β-amyloid burden, though a trend was present and effect sizes were mild. These hippocampal volume results suggest that this IL task may be sensitive to AD pathology along the AD continuum.

Connections from intrinsic primary afferent neurons (IPANs), to ascending motor and interneurons have been described in guinea pig colon. These mono- and polysynaptic circuits may underlie polarized motor reflexes evoked by local gut stimulation. There is a need to translate findings in guinea pig to mouse, a species increasingly used in enteric neuroscience. Here, mouse distal colon was immunolabeled for CGRP, a marker of putative IPANs. This revealed a combination of large, intensely immunofluorescent axons in myenteric plexus and circular muscle, and thinner varicose axons with less immunofluorescence. The latter formed dense, basket-like varicosity clusters (CGRP+ baskets) that enveloped myenteric nerve cell bodies. Immunolabeling after 4-5 days in organ culture caused loss of large CGRP+ axons, but not varicose CGRP+ fibers and CGRP+ baskets. Baskets were characterized further by triple labeling with CGRP, nitric oxide synthase (NOS) and calretinin (CALR) antibodies. Approximately half (48%) of nerve cell bodies inside CGRP+ baskets lacked both NOS and CALR, while two overlapping populations containing NOS and/or CALR comprised the remainder. Quantitative analysis revealed CGRP+ varicosities were most abundant in baskets, followed by CALR+ varicosities, with a high degree of colocalization between the two markers. Few NOS+ varicosities occurred in baskets. Significantly higher proportions of CALR+ and CGRP+ varicosities colocalized in baskets than in circular muscle. In conclusion, CGRP+ baskets in mouse colon are formed by intrinsic enteric neurons with a neurochemical profile consistent with IPANs and have direct connections to both excitatory and inhibitory neurons.

Gemcitabine and docetaxel combination chemotherapy is the standard of care for patients with unresectable recurrent or metastatic leiomyosarcoma of the uterus. Although they are generally well-tolerated agents, they can also cause severe and life-threatening pulmonary toxicities. Here, we describe a case of grade 4 pneumonitis due to gemcitabine and docetaxel in a 74-year-old woman with recurrent, metastatic uterine leiomyosarcoma. Despite early recognition of chemotherapy-induced lung injury and early administration of corticosteroid, she developed noncardiogenic pulmonary edema, diffuse alveolar hemorrhage, and acute respiratory distress syndrome. She required multiple intubations and a tracheostomy. Physicians should not only be aware of gemcitabine and docetaxel’s potential to cause life-threatening pulmonary injuries but also recognize the variability in clinical presentations and treatment responses, the radiographic findings of these lung toxicities, and the need for early corticosteroid therapy in these cases.

Wrist-worn heart rate (HR) monitors are increasingly popular. A paucity of data exists on their accuracy in atrial fibrillation (AF) in ambulatory patients. We sought to assess the HR accuracy of two commercially available smart watches [SW] (Fitbit Charge HR [FB] and Apple Watch Series 3 [AW]) compared with Holter monitoring in an ambulant patient cohort.Thirty-two participants ≥18 years referred for 24-hour Holter monitoring were prospectively recruited. Each participant was randomly allocated to wear either a FB or AW along with their Holter monitor.Across all devices, 53,288 heart rate values were analysed from 32 participants. Twenty wore the AW (17 had persistent AF and 3 had sinus rhythm [SR]) while 12 participants wore the FB (9 in persistent AF and 3 in SR). Participants in SR demonstrated strong agreement compared to Holter monitoring (bias1 beat, limits of agreement [LoA] -11 to 11 beats). In AF, both devices underestimated HR measurements (bias -9 beats, LoA -41 to 23). The degree of underestimation was more pronounced when HR 100 bpm (bias of -28 beats for HR range 100-120 bpm, -48 for 120-140 bpm, and -69 for140 bpm) compared to a slower HR (bias of -6 for HR range 80-100 bpm,1 for 60-80 bpm, and -1 for60 bpm).In ambulatory patients, smartwatches underestimated HR in AF particularly at HR ranges100 bpm. Further improvements in device technology are needed before integrating them into the clinical management of rate control in AF.

The mechanisms underlying electrical rhythmicity in smooth muscle of the proximal colon are incompletely understood. Our aim was to identify patterns of electrical rhythmicity in smooth muscle of the proximal region of isolated whole mouse colon and characterize their mechanisms of origin. Two independent extracellular recording electrodes were used to record the patterns of electrical activity in smooth muscle of the proximal region of whole isolated mouse colon. Cross-correlation analysis was used to quantify spatial coordination of these electrical activities over increasing electrode separation distances. Four distinct neurogenic patterns of electrical rhythmicity were identified in smooth muscle of the proximal colon, three of which have not been identified and consisted of bursts of rhythmic action potentials at 1–2 Hz that were abolished by hexamethonium. These neurogenic patterns of electrical rhythmicity in smooth muscle were spatially and temporally synchronized over large separation distances (≥2 mm rosto-caudal axis). Myogenic slow waves could be recorded from the same preparations, but they showed poor spatial and temporal coordination over even short distances (≤1 mm rostro-caudal axis). It is not commonly thought that electrical rhythmicity in gastrointestinal smooth muscle is dependent upon the enteric nervous system. Here, we identified neurogenic patterns of electrical rhythmicity in smooth muscle of the proximal region of isolated mouse colon, which are dependent on synaptic transmission in the enteric nervous system. If the whole colon is studied in vitro, recordings can preserve novel neurogenic patterns of electrical rhythmicity in smooth muscle. NEW & NOTEWORTHY Previously, it has not often been thought that electrical rhythmicity in smooth muscle of the gastrointestinal tract is dependent upon the enteric nervous system. We identified patterns of electrical rhythmicity in smooth muscle of the mouse proximal colon that were abolished by hexamethonium and involved the temporal synchronization of smooth muscle membrane potential over large spatial fields. We reveal different patterns of electrical rhythmicity in colonic smooth muscle that are dependent on the ENS.

PURPOSE/OBJECTIVE Evaluate the reliability and validity of the Hopkins Rehabilitation Engagement Scale (HRERS) in a postacute rehabilitation sample. We hypothesized that HRERS items would comprise a single factor, and would demonstrate adequate internal consistency and temporal stability, and significant relationships with key constructs. Research Method and Design: Retrospective medical record review between 2016 and 2017 of older veterans (N = 107) admitted to a community living center postacute care (CLC-PAC) rehabilitation hospital unit to address targeted physical therapy rehabilitation goals. Inclusion criteria included availability of two HRERS administrations at Time 1 (admission) and Time 2 (approximately one-month follow-up or physical therapist/CLC-PAC discharge). RESULTS Across timepoints, HRERS items reflect a single factor of engagement, and the scale has good internal consistency at admission (Time 1, α = .759) and follow-up (Time 2, α = .877). The temporal stability of HRERS across ratings was r = .56 (p < .001). Increased pain rating (r = -.309, p < .01) and depressive symptoms (-.287, p < .01) at admission correlates with subsequent physical therapist (PT) engagement (HRERS Time 2). Low admission PT engagement correlates with less frequent PT attendance (r = -.242, p < .01) and greater number of consults placed during the CLC stay (r = -.222, p < .05). CONCLUSIONS/IMPLICATIONS HRERS is a reliable and valid measure of PT engagement in older CLC-PAC Veterans. Findings support the administration of the HRERS at more than one timepoint during rehabilitation to inform interventions targeting select behavioral health factors such as pain and depression. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Gastrointestinal conditions in which the transit of contents is altered may benefit from nutritional approaches to influencing health outcomes. Milk proteins modulate the transit of contents along different regions, suggesting that they have varying effects on neuromuscular function to alter gastrointestinal motility. We tested the hypothesis that bovine whey and casein milk protein hydrolysates could have direct modulatory effects on colonic motility patterns in isolated rat large intestine. Casein protein hydrolysate (CPH), whey protein concentrate (WPC), whey protein hydrolysate (WPH), and a milk protein hydrolysate (MPH; a hydrolyzed blend of 60% whey to 40% casein) were compared for their effects on spontaneous contractile waves. These contractions propagate along the length of the isolated intact large intestine (22 cm) between the proximal colon and rectum and were detected by measuring activity at 4 locations. Milk proteins were perfused through the tissue bath, and differences in contraction amplitude and frequency were quantified relative to pretreatment controls. Propagation frequency was decreased by CPH, increased by MPH, and unaffected by intact whey proteins. The reduced motility with CPH and increased motility with MPH indicate a direct action of these milk proteins on colon tissue and provide evidence for differential modulation by hydrolysate type. These findings mirror actions on lower gastrointestinal transit reported in vivo, with the exception of WPH, suggesting that other factors are required.

The practice of 'vancomycin wrapping' of harvested hamstring autografts during Anterior Cruciate Ligament Reconstruction (ACLR) surgery has gathered recent interest. This practice involves the wrapping of harvested grafts in a vancomycin-soaked swab during the preparatory phase. Different techniques are observed, and a small number of studies have shown that pre-soaking hamstring ACLR grafts in this manner dramatically reduces the post-surgical infection rate compared with standard intravenous antibiotic prophylaxis alone. However, the literature surrounding this practice is surprisingly limited and thus the basis and rationale of the 'vancomycin wrap' has established itself largely without question. The exact popularity of this practice is difficult to establish but there has been increasing disclosure of its efficacy in reducing post-operative infection in ACLR since 2012. We provide a synopsis of the current literature surrounding vancomycin and its use in 'wraps' in ACLR to help apprise the surgeon of the nature of infection in ACLR, the rationale for vancomycin, whilst considering evidence to support alternatives and discussing potential ramifications for future practice.

Chronic stress is a known suppressor of female reproductive function. However, attempts to isolate single causal links between stress and reproductive dysfunction have not yet been successful due to their multi-faceted aetiologies. The gut-derived hormone ghrelin regulates stress and reproductive function and may therefore be pivotal in the neuroendocrine integration of the hypothalamic–pituitary–adrenal (HPA) and –gonadal (HPG) axes. Here, we hypothesised that chronic stress disrupts ovarian follicle maturation and that this effect is mediated by a stress-induced increase in acyl ghrelin and activation of the growth hormone secretatogue receptor (GHSR). We gave C57BL/6J female mice 30 min daily chronic predator stress for 4 weeks, or no stress, and gave them daily GHSR antagonist (d-Lys3-GHRP-6) or saline. Exposure to chronic predator stress reduced circulating corticosterone, elevated acyl ghrelin levels and led to significantly depleted primordial follicle numbers. GHSR antagonism stress-dependently altered the expression of genes regulating ovarian responsiveness to gonadotropins and was able to attenuate the stress-induced depletion of primordial follicles. These findings suggest that chronic stress-induced elevations of acyl ghrelin may be detrimental for ovarian follicle maturation.

Neural mechanisms of lower urinary tract symptoms in obstruction-induced bladder overactivity remain unclear. We made the first single unit recordings from different types of spinal afferents to determine the effects of bladder outlet obstruction in guinea pigs. A model of gradual bladder outlet obstruction in male guinea pigs was used to produce overactive bladder. Conscious voiding was assessed in metabolic cages, and micturition was recorded in anesthetized guinea pigs in vivo. Single unit extracellular recordings were made ex vivo from spinal afferent nerves in flat sheet preparations of the bladder. Guinea pigs with partially obstructed bladders showed a significant increase in conscious voiding frequency compared with sham-operated guinea pigs. Also, nonvoiding contractions increased significantly in both frequency and amplitude. Although spontaneous firing of low-threshold bladder afferents was increased, their stretch-induced firing was reduced. The proportion of capsaicin-sensitive low-threshold afferents increased in obstructed bladders. Interestingly, spontaneous and stretch-induced firing were both significantly increased in high-threshold afferents after obstruction. In summary, sensory signaling increased in the obstructed bladder during the filling phase. This is largely mediated by low-threshold stretch-sensitive afferents that are activated by increased local nonvoiding contractions. Increased spontaneous firing by high-threshold afferents also contributes. Our findings revealed a complex effect of bladder outlet obstruction on different types of bladder afferents that needs consideration for potential therapeutic targeting of lower urinary tract symptoms in obstruction-induced bladder overactivity.

This review will address the current literature available regarding complications after intravesical Bacillus Calmette-Guerin (BCG) therapy for bladder cancer. Topics include intravesical BCG therapy–related complications, role of BCG therapy in immunosuppression, and future directions in the context of BCG-related complications. There are several new reviews and case reports discussing unique complications following intravesical BCG therapy that should raise awareness of possible short-term and long-term effects after using this common treatment modality in bladder cancer patients. Since intravesical BCG is a common treatment option for non-muscle invasive bladder cancer and can cause a variety of complications, it is important to recognize this aspect of the patient’s history when evaluating patients who present with symptoms similar to the ones discussed in this review. This will allow for prompt delivery of treatment as well as preventing unnecessary morbidity and mortality.

Microglia are highly sensitive to dietary influence, becoming activated acutely and long-term by high fat diet. However, their role in regulating satiety and feeding in healthy individuals remains unclear. Here we show that microglia are essential for the normal regulation of satiety and metabolism in rats. Short-term microglial depletion in a Cx3cr1-Dtr rat led to a dramatic weight loss that was largely accounted for by an acute reduction in food intake. This weight loss and anorexia were not likely due to a sickness response since the rats did not display peripheral or central inflammation, withdrawal, anxiety-like behavior, or nausea-associated pica. Hormonal and hypothalamic anatomical changes were largely compensatory to the suppressed food intake, which occurred in association with disruption of the gustatory circuitry at the paraventricular nucleus of the thalamus. Thus, microglia are important in supporting normal feeding behaviors and weight, and regulating preference for palatable food. Inhibiting this circuitry is able to over-ride strong compensatory drives to eat, providing a potential target for satiety control.

Returning home after surgery is a desirable patient-centered outcome associated with decreased costs compared to non-home discharge. Our objective was to develop a preoperative risk-scoring model predicting non-home discharge after surgery for gynecologic malignancy.Women who underwent surgery involving hysterectomy for gynecologic malignancy from 2013 to 2015 were identified from the Michigan Surgical Quality Collaborative database. Patients were divided by discharge destination, and a multivariable logistic regression model was developed to create a nomogram to assign case-specific risk scores. The model was validated using the National Surgical Quality Improvement Program (NSQIP) database.Non-home discharge occurred in 3.1% of 2134 women. The proportion of non-home discharges did not differ by cancer diagnosis (uterine 3.5%, ovarian 2.5%, and cervical 1.6%, p = 0.2). Skilled nursing facilities were the most common non-home destination (68.2%). Among patients with comorbidities (hypertension, diabetes, coronary artery disease, chronic obstructive pulmonary disease /dyspnea, arrhythmia, and history of deep vein thrombosis/pulmonary embolism), non-home discharge was more common in women with 1 (adjusted OR [aOR] 3.4; p = 0.03) or ≥2 of these comorbidities (aOR 5.1; p = 0.003) compared to none. Non-home discharge was more common after laparotomy (aOR 6.7; p 0.0001) than laparoscopy, and in those aged ≥70 years (aOR 3.4; p 0.0001) with American Society of Anesthesiologists class ≥ 3 (aOR 4.5; p = 0.0004) and dependent functional status (aOR 8.7; p 0.0001). The model C-statistic was 0.89. When the model was applied to 4248 eligible patients from the NSQIP dataset, the C-statistic was 0.84 (95% CI: 0.79-0.89).Non-home discharge after surgery for gynecologic malignancy was predicted with high accuracy in this retrospective analysis.

PURPOSE: Endometrial cancer is strongly linked to obesity and inactivity; however, increased physical activity has important benefits even in the absence of weight loss. Resistance (strength) training can deliver these benefits; yet few women participate in resistance exercise. The purpose of this study was to describe both physiological and functional changes following a home-based strength training intervention. METHODS: Forty post-treatment endometrial cancer survivors within 5 years of diagnosis were enrolled in a pilot randomized trial, comparing twice-weekly home-based strength exercise to wait list control. Participants conducted the exercises twice per week for 10 supervised weeks with 5 weeks of follow-up. Measures included DXA-measured lean mass, functional fitness assessments, blood biomarkers, and quality of life outcomes. RESULTS: On average, participants were 60.9 years old (SD = 8.7) with BMI of 39.9 kg/m(2) (SD = 15.2). At baseline, participants had 51.2% (SD = 6.0) body fat, which was not different between groups. Improvements were seen in the 30-s chair sit to stand (d = .99), the 30-s arm curl (d = .91), and the 8-ft up-and-go test (d = .63). No changes were measured for HbA1c or C-reactive protein. No changes were observed for flexibility (chair sit and reach, back scratch tests), 6-min walk test, maximum handgrip test, anxiety, depression, fatigue, or self-efficacy for exercise. CONCLUSIONS: Home-based muscle-strengthening exercise led to favorable and clinically relevant improvements in 3 of 7 physical function assessments. Physical function, body composition, blood biomarkers, and patient-reported outcomes were feasible to measure. These fitness improvements were observed over a relatively short time frame of 10 weeks.

Many returning military service members and veterans who were deployed following the September 11, 2001, terrorist attacks (9/11) suffer from posttraumatic stress disorder (PTSD) and insomnia. Although intensive treatment programs for PTSD have shown promise in the treatment of PTSD symptoms, recent research has demonstrated that sleep disturbance shows little improvement following intensive trauma-focused treatment. The aim of the present study was to evaluate changes in self-reported insomnia symptoms among veterans and service members following participation in a 2-week intensive program for PTSD. We further aimed to investigate if residual PTSD symptoms, specifically hyperarousal, were associated with residual insomnia symptoms. Participants (N = 326) completed self-report assessments of insomnia, PTSD symptoms, and depressive symptoms at pre- and posttreatment. At pretreatment, 73.9% of participants (n = 241) met the criteria for moderate or severe insomnia, whereas at posttreatment 67.7% of participants (n = 203) met the criteria. Results of paired t tests demonstrated statistically significant differences between pre- and posttreatment Insomnia Severity Index scores; however, the effect size was small, d = 0.34. Analyses revealed that posttreatment hyperarousal symptoms were associated with posttreatment insomnia. These findings suggest that although an intensive program for service members and veterans with PTSD may significantly reduce insomnia symptoms, clinically meaningful residual insomnia symptoms remain. Further research is warranted to elucidate the association between residual hyperarousal and insomnia symptoms following intensive trauma-focused treatment.

The dynamic changes in uterine contractility in response to distension are incompletely understood. Rhythmic, propagating contractions of nonpregnant uterine smooth muscle occur in the absence of nerve activity (i.e., myogenic), events that decline during pregnancy and reemerge at parturition. We therefore sought to determine how myogenic contractions of the nonpregnant uterus are affected by distension, which might provide mechanistic clues underlying distension-associated uterine conditions such as preterm birth. Uteri isolated from nulliparous adult female mice in proestrus were video imaged to generate spatiotemporal maps, and myoelectrical activity simultaneously recorded using extracellular suction electrodes. Motility patterns were examined under basal conditions and following ramped intraluminal distension with fluid to 5 and 10 cmH2O. Intraluminal distension caused pressure-dependent changes in the frequency, amplitude, propagation speed, and directionality of uterine contractions, which reversed upon pressure release. Altered burst durations of underlying smooth muscle myoelectric events were concurrently observed, although action potential spike intervals were unchanged. Voltage-gated sodium channel blockade [tetrodotoxin (TTX); 0.6 µM] attenuated both the amplitude of contractions and burst duration of action potentials, whereas all activity was abolished by L-type calcium channel blockade (nifedipine; 1 µM). These data suggest that myogenic motility patterns of the nonpregnant mouse uterus are sensitive to changes in intraluminal pressure and, at high pressures, may be modulated by voltage-gated sodium channel activity. Future studies may investigate whether similar distension-evoked changes occur in the pregnant uterus and the possible pathophysiological role of such activity in the development of preterm birth.

Background COVID-19 vaccine supply shortages are causing concerns about compromised immunity in some countries as the interval between the first and second dose becomes longer. Conversely, countries with no supply constraints are considering administering a third dose. We assessed the persistence of immunogenicity after a single dose of ChAdOx1 nCoV-19 (AZD1222), immunity after an extended interval (44–45 weeks) between the first and second dose, and response to a third dose as a booster given 28–38 weeks after the second dose. Methods In this substudy, volunteers aged 18–55 years who were enrolled in the phase 1/2 (COV001) controlled trial in the UK and had received either a single dose or two doses of 5 × 1010 viral particles were invited back for vaccination. Here we report the reactogenicity and immunogenicity of a delayed second dose (44–45 weeks after first dose) or a third dose of the vaccine (28–38 weeks after second dose). Data from volunteers aged 18–55 years who were enrolled in either the phase 1/2 (COV001) or phase 2/3 (COV002), single-blinded, randomised controlled trials of ChAdOx1 nCoV-19 and who had previously received a single dose or two doses of 5 × 1010 viral particles are used for comparison purposes. COV001 is registered with ClinicalTrials.gov, NCT04324606, and ISRCTN, 15281137, and COV002 is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137, and both are continuing but not recruiting. Findings Between March 11 and 21, 2021, 90 participants were enrolled in the third-dose boost substudy, of whom 80 (89%) were assessable for reactogenicity, 75 (83%) were assessable for evaluation of antibodies, and 15 (17%) were assessable for T-cells responses. The two-dose cohort comprised 321 participants who had reactogenicity data (with prime-boost interval of 8–12 weeks: 267 [83%] of 321; 15–25 weeks: 24 [7%]; or 44–45 weeks: 30 [9%]) and 261 who had immunogenicity data (interval of 8–12 weeks: 115 [44%] of 261; 15–25 weeks: 116 [44%]; and 44–45 weeks: 30 [11%]). 480 participants from the single-dose cohort were assessable for immunogenicity up to 44–45 weeks after vaccination. Antibody titres after a single dose measured approximately 320 days after vaccination remained higher than the titres measured at baseline (geometric mean titre of 66·00 ELISA units [EUs; 95% CI 47·83–91·08] vs 1·75 EUs [1·60–1·93]). 32 participants received a late second dose of vaccine 44–45 weeks after the first dose, of whom 30 were included in immunogenicity and reactogenicity analyses. Antibody titres were higher 28 days after vaccination in those with a longer interval between first and second dose than for those with a short interval (median total IgG titre: 923 EUs [IQR 525–1764] with an 8–12 week interval; 1860 EUs [917–4934] with a 15–25 week interval; and 3738 EUs [1824–6625] with a 44–45 week interval). Among participants who received a third dose of vaccine, antibody titres (measured in 73 [81%] participants for whom samples were available) were significantly higher 28 days after a third dose (median total IgG titre: 3746 EUs [IQR 2047–6420]) than 28 days after a second dose (median 1792 EUs [IQR 899–4634]; Wilcoxon signed rank test p=0·0043). T-cell responses were also boosted after a third dose (median response increased from 200 spot forming units [SFUs] per million peripheral blood mononuclear cells [PBMCs; IQR 127–389] immediately before the third dose to 399 SFUs per milion PBMCs [314–662] by day 28 after the third dose; Wilcoxon signed rank test p=0·012). Reactogenicity after a late second dose or a third dose was lower than reactogenicity after a first dose. Interpretation An extended interval before the second dose of ChAdOx1 nCoV-19 leads to increased antibody titres. A third dose of ChAdOx1 nCoV-19 induces antibodies to a level that correlates with high efficacy after second dose and boosts T-cell responses. Funding UK Research and Innovation, Engineering and Physical Sciences Research Council, National Institute for Health Research, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research Oxford Biomedical Research Centre, Chinese Academy of Medical Sciences Innovation Fund for Medical Science, Thames Valley and South Midlands NIHR Clinical Research Network, AstraZeneca, and Wellcome.

Current guidelines recommend restricting acetaminophen (APAP) use in patients with cirrhosis, but evidence to support that recommendation is lacking. Prior studies focused on pharmacokinetics (PK) of APAP in cirrhosis but did not rigorously examine clinical outcomes, sensitive biomarkers of liver damage, or serum APAP‐protein adducts, which are a specific marker of toxic bioactivation. Hence, the goal of this pilot study was to test the effects of regularly scheduled APAP dosing in a well‐defined compensated cirrhosis group compared to control subjects without cirrhosis, using the abovementioned outcomes. After a 2‐week washout, 12 subjects with and 12 subjects without cirrhosis received 650 mg APAP twice per day (1.3 g/day) for 4 days, followed by 650 mg on the morning of day 5. Patients were assessed in‐person at study initiation (day 1) and on days 3 and 5. APAP‐protein adducts and both conventional (alanine aminotransferase) and sensitive (glutamate dehydrogenase [GLDH], full‐length keratin 18 [K18], and total high‐mobility group box 1 protein) biomarkers of liver injury were measured in serum on the mornings of days 1, 3, and 5, with detailed PK analysis of APAP, metabolites, and APAP‐protein adducts throughout day 5. No subject experienced adverse clinical outcomes. GLDH and K18 were significantly different at baseline but did not change in either group during APAP administration. In contrast, clearance of APAP‐protein adducts was dramatically delayed in the cirrhosis group. Minor differences for other APAP metabolites were also detected. Conclusion: Short‐term administration of low‐dose APAP (650 mg twice per day, The safety of acetaminophen (APAP) use in cirrhosis is highly controversial. In this study, we compared novel, sensitive biomarkers of liver injury and pharmacokinetics between non‐cirrhotic and cirrhotic subjects with repeated APAP use over 5 days. There was no APAP‐induced liver damage in either group, but there was evidence of greater APAP‐protein binding and reduced APAP‐protein adduct clearance in the cirrhosis group that warrants caution and further study.

The authors would like to correct a typographical error in their recently published paper [...]

Our recent findings indicate that an acute depletion of monocytes has no sustained effects on ovarian follicle health. Here, we utilised a Cx3cr1-Dtr transgenic Wistar rat model to transiently deplete monocytes and investigated the impact of an acute immune challenge by lipopolysaccharide (LPS) on ovarian follicle health and ovulatory capacity relative to wt once the monocytes had repopulated. Monocyte depletion and repopulation exacerbated the effects of LPS in several domains. As such, monocyte perturbation decreased the numbers of secondary follicles in those challenged with LPS. Monocyte perturbation was also associated with reduced antral follicle numbers and circulating luteinising hormone (LH) levels, as well as potential changes in ovarian sensitivity to LH, exacerbated by LPS. These data suggest that monocyte depletion and repopulation induce a transient suppression of ovulatory capacity in response to a subsequent immune challenge, but this is likely to be restored once the pro-inflammatory environment is resolved.

Understanding the sensory mechanisms innervating the bladder is paramount to developing efficacious treatments for chronic bladder hypersensitivity conditions. The contribution of Mas-gene-related G protein-coupled receptors (Mrgpr) to bladder signalling is currently unknown. Here we show in mice with single-cell RT-PCR that sub-populations of dorsal root ganglion (DRG) neurons innervating the mouse bladder express MrgprA3 (14%) and MrgprC11 (38%), either individually or in combination, with high levels of co-expression with Trpv1 (81-89%). Calcium imaging studies demonstrated MrgprA3 and MrgprC11 agonists (chloroquine, BAM8-22 and neuropeptide FF) activated sub-populations of bladder-innervating DRG neurons, showing functional evidence of co-expression between MrgprA3, MrgprC11 and TRPV1. In ex vivo bladder-nerve preparations chloroquine, BAM8-22 and neuropeptide FF all evoked mechanical hypersensitivity in sub-populations (20-41%) of bladder afferents. These effects were absent in recordings from Mrgpr-clusterΔ−/− mice. In vitro whole-cell patch clamp recordings showed that application of an MrgprA3/C11 agonist cocktail induced neuronal hyper-excitability in 44% of bladder-innervating DRG neurons. Finally, in vivo instillation of an MrgprA3/C11 agonist cocktail into the bladder of wild-type mice induced a significant activation of dorsal horn neurons within the lumbosacral spinal cord, as quantified by pERK-immunoreactivity. This MrgprA3/C11 agonist-induced activation was particularly apparent within the superficial dorsal horn and the sacral parasympathetic nuclei of wild-type, but not Mrgpr-clusterΔ−/− mice. This study demonstrates, for the first time, functional expression of MrgprA3 and MrgprC11 in bladder afferents. Activation of these receptors is not required for normal bladder function but does trigger hypersensitivity to distension, a critically valuable factor for therapeutic target development.Significance statementDetermining how bladder afferents become sensitized is the first step in finding effective treatments for common urological disorders such as overactive bladder and interstitial cystitis/bladder pain syndrome. Here we show that two of the key receptors, MrgprA3 and MrgprC11, that mediate itch from the skin are also expressed on afferents innervating the bladder. Activation of these receptors results in sensitization of bladder afferents, resulting in sensory signals being sent into the spinal cord that prematurely indicate bladder fullness. Targeting bladder afferents expressing MrgprA3 or MrgprC11 and preventing their sensitisation may provide a novel approach for treating overactive bladder and interstitial cystitis/bladder pain syndrome.

The study aimed to quantify the excess risk of interaction between high free sugars (sugars) intake and lack of exposure to water fluoridation on child dental caries. Data from the Australian National Child Oral Health Study, a population-based survey of 24,664 children aged 5 to 14 y, were collected using parental questionnaires and oral epidemiological examinations by trained examiners. Information on socioeconomic status, dental health behaviors, and dental service use was used as covariates. The number of servings of sugars-containing foods and drinks consumed in a usual day was assessed as the main exposure, categorized into 5 groups. Residential history was used to calculate lifetime exposure to fluoridated water (LEFW), categorized as low (0) and experience (dmfs/DMFS) in the primary (ages 5–10 y) and permanent (ages 8–14 y) dentitions were the main dependent variables. The association of sugars intake and LEFW with each outcome was estimated in multivariable log-Poisson regression models with robust standard error estimation, adjusted for covariates. The relative excess risk due to interaction (RERI) between sugars intake and LEFW was estimated. Strong positive gradients in all outcomes were observed across sugars intake groups. Relative to the lowest intake group, the 3 highest intake groups had significantly higher adjusted prevalence ratios for having caries and higher adjusted mean ratios of caries experience in both dentitions, after controlling for all covariates. LEFW strongly and consistently attenuated the effects of all levels of sugars intake on the outcomes. RERI estimates indicated that a combination of lack of exposure to fluoridated water and high sugars intake resulted in greater excess risk of primary and permanent caries than if there was no interaction. Evidently, children with high sugars intakes and low exposure to water fluoridation are at disproportionately higher risk of dental caries.

Objective: While Spencer's verbal incidental learning (IL) task-from Vocabulary and Similarities subtests of the WAIS-has been validated relative to traditional memory measures and Alzheimer's disease (AD) pathology, the effectiveness of the particular scoring method used has not been assessed relative to alternative scoring weightings. The purpose of this study was to compare original and alternative scoring methods of this IL task by using an AD biomarker-benchmark to arrive at an optimal approach. Methods: Fifty-five memory-clinic patients aged 59-87 received neuropsychological assessment, measures of IL, and quantitative brain imaging. Partial correlation coefficients with total hippocampal volume-controlling for age, sex, and intracranial volume-were assessed across several IL scoring methods, and partial correlations with measures of memory were examined to evaluate convergent validity.Results: IL scoring methods maximizing the contribution of paired-associate-recall-performance were significantly correlated with both hippocampal volumes and traditional memory measures, whereas discrimination-emphasized scoring methods were not.Conclusions: IL scoring methods emphasizing memory paired-associate recall appeared to be preferable to those emphasizing memory discrimination. Administration of the IL- Similarities subtest alone, without IL- Vocabulary, may strike a balance between strength of relationships with both hippocampal volumes and standard memory measures, while also limiting administration time.

Background The aim of our study is to determine the incidence, timing, and risk factors for cerebral vasculopathy after cranial proton and photon radiation for pediatric brain tumors. Methods We performed a single-institution retrospective review of a cohort of children treated with proton radiation for brain tumors. MRA and/or MRI were reviewed for evidence of cerebral vascular stenosis and infarcts. Twenty-one similar studies (17 photon, 4 proton) were identified by systematic literature review. Results For 81 patients with median follow-up of 3 years, the rates of overall and severe vasculopathy were 9.9% and 6.2% respectively, occurring a median of 2 years post radiation. Dose to optic chiasm greater than 45 Gy and suprasellar location were significant risk factors. Results were consistent with 4 prior proton studies (752 patients) that reported incidence of 5% to 6.7%, 1.5 to 3 years post radiation. With significantly longer follow-up (3.7-19 years), 9 studies (1108 patients) with traditional photon radiation reported a higher rate (6.3%-20%) and longer time to vasculopathy (2-28 years). Significant risk factors were neurofibromatosis type 1 (NF-1; rate 7.6%-60%) and suprasellar tumors (9%-20%). In 10 studies with photon radiation (1708 patients), the stroke rate was 2% to 18.8% (2.3-24 years post radiation). Conclusions Childhood brain tumor survivors need screening for vasculopathy after cranial radiation, especially with higher dose to optic chiasm, NF-1, and suprasellar tumors. Prospective studies are needed to identify risk groups, and ideal modality and timing, for screening of this toxicity.

BACKGROUND: In the randomized phase 3 GALLIUM trial, first-line treatment with obinutuzumab (GA101; G) plus chemotherapy (G + chemo) resulted in superior progression-free survival (PFS) compared with rituximab plus chemotherapy (R + chemo) for patients with follicular lymphoma (FL). G + chemo was found to be cost-effective when compared with R + chemo (incremental cost-effectiveness ratio [ICER] of approximately $2,300 per quality-adjusted life-year [QALY] gained). Two rituximab biosimilars, rituximab-abbs (Ra) and rituximab-pvvr (Rp), have been approved by the FDA for use in this setting. However, the cost-effectiveness of G + chemo versus Ra + chemo and Rp + chemo has not yet been estimated. OBJECTIVE: To evaluate the cost-effectiveness of G + chemo versus Ra + chemo and Rp + chemo in the first-line treatment of FL. METHODS: We adapted an existing Markov model that compared G + chemo with R + chemo, using investigator-assessed PFS and postprogression survival data from the GALLIUM trial to model overall survival. All patients in the study received induction chemoimmunotherapy with either G + chemo or R + chemo, with responders then receiving obinutuzumab or rituximab maintenance therapy for 2 years or until disease progression. We assumed that the efficacy and safety of the rituximab biosimilars plus chemotherapy were the same as the R + chemo arm of the GALLIUM study. Drug utilization and treatment duration were also derived from GALLIUM. Health care costs were based on Medicare reimbursements, and drug costs were average sale prices for intravenous therapies or wholesale acquisition costs for oral therapies used after progression. Utility estimates were based on the GALLIUM trial data and published literature. Sensitivity analyses were conducted to assess the key drivers of the model and uncertainty in the results. Results: Treatment with G + chemo led to an increase of 0.93 QALYs relative to rituximab biosimilars plus chemotherapy (95% credible range [CR] = 0.36-1.46). The total cost of G + chemo was $191,317, whereas the total costs of Ra + chemo and Rp + chemo were $164,340 (Δ14.1%) and $169,755 (Δ11.3%), respectively, with G + chemo resulting in incremental costs of $26,978 (95% CR = $19,781-$33,119) and $21,562 (95% CR = $14,473-$28,389), respectively. The incremental total drug and administration costs were $32,678 (Δ25.4%) and $27,263 (Δ21.2%) for G + chemo versus Ra + chemo and G + chemo versus Rp + chemo, respectively. There were cost savings of $7,050 (Δ-12.4%) related to disease progression for G + chemo ($56,727) compared with Ra + chemo and Rp + chemo ($63,777). ICERs were $28,879 and $23,082 per QALY gained for G + chemo versus Ra + chemo and Rp + chemo, respectively. In probabilistic sensitivity analyses, G + chemo was cost-effective at the $50,000 and $100,000 per QALY thresholds versus both Ra + chemo (88% and 98% probabilities of cost-effectiveness, respectively) and Rp + chemo (93% and 98%, respectively). CONCLUSIONS: G + chemo is projected to be cost-effective versus rituximab biosimilars plus chemotherapy in the United States as first-line treatment for FL, driven by increased QALYs for G + chemo and cost savings from delayed disease progression. DISCLOSURES: This study was funded by Genentech, a member of the Roche Group. The study sponsor was involved in study design, data interpretation, and writing of the report. All authors approved the decision to submit the report for publication. Spencer and Guzauskas report fees from Genentech during the conduct of the study. Felizzi was employed by F. Hoffmann-La Roche at the time this study was conducted; Launonen is an employees of F. Hoffmann-La Roche. Felizzi and Launonen previously had share ownership in Novartis. Dawson and Masaquel are employees of Genentech, and they have stock options in F. Hoffmann-La Roche. Veenstra reports fees from Genentech, during the conduct of this study and outside of the submitted work. This work was presented, in part, at the AACR Virtual Meeting Advances in Malignant Lymphoma meeting (virtual; August 17-19, 2020) and the SOHO annual meeting (virtual; September 9-12, 2020).

Background This study seeks to assess the safety of direct axillary artery (AX) cannulation for acute type A dissection (ATAD) repair, including the impact of innominate artery dissection (IAD). Methods Of 281 consecutive patients who underwent ATAD repair from 2007 to 2020, preoperative computed tomography was available in 200 (IAD: N=101, non-IAD N=99). IAD with compromised true lumen was defined as dissection in which the false lumen was greater than 50% of the IA diameter (N=75/101). Results AX cannulation was attempted in 188 patients (94.0%), with a 1.6% vascular injury rate (3 patients; bypass to the distal AX: 2 patients, and local dissection: 1 patient). Most patients (89.5%) underwent hemiarch replacement using deep hypothermic circulatory arrest for the distal repair. Right AX cannulation was used in 80.2% of patients with IAD and in 88.9% without IAD (p=0.075). Patients with IAD had more cerebral (21.8%vs. 5.1%, p=0.001) and arm malperfsion (11.9% vs.4.0%, p=0.075). Operative mortality and stroke were comparable between Non-IAD and IAD groups (8.1% vs. 7.9%, p=1.00 and 4.0% vs. 5.3%, p=0.689). The right AX was successfully used in 77.3% of IAD patients having a compromised true lumen, with comparable hospital outcomes to non-compromised IAD patients. Upper extremity malperfusion, multi-organ malperfusion, low ejection fraction, and female gender were predictors for non-right AX cannulation. Conclusions Routine direct AX cannulation strategy is safe in ATAD repair. Right AX cannulation can be used in most patients with IAD, even with a compromised true lumen, with low mortality, stroke and vascular injury rates.

Chronic obstructive pulmonary disease (COPD) is a major incurable global health burden and currently the 3rd largest cause of death in the world, with approximately 3.23 million deaths per year. Globally, the financial burden of COPD is approximately €82 billion per year and causes substantial morbidity and mortality. Importantly, much of the disease burden and health care utilisation in COPD is associated with the management of its comorbidities and viral and bacterial-induced acute exacerbations (AECOPD). Recent clinical studies have shown that cognitive dysfunction is present in up to 60% of people with COPD, with impairments in executive function, memory, and attention, impacting on important outcomes such as quality of life, hospitalisation and survival. The high prevalence of cognitive dysfunction in COPD may also help explain the insufficient adherence to therapeutic plans and strategies, thus worsening disease progression in people with COPD. However, the mechanisms underlying the impaired neuropathology and cognition in COPD remain largely unknown. In this review, we propose that the observed pulmonary oxidative burden and inflammatory response of people with COPD 'spills over' into the systemic circulation, resulting in damage to the brain and leading to cognitive dysfunction. As such, drugs targeting the lungs and comorbidities concurrently represent an exciting and unique therapeutic opportunity to treat COPD and cognitive impairments, which may lead to the production of novel targets to prevent and reverse the debilitating and life-threatening effects of cognitive dysfunction in COPD.

Objectives: To advocate for National Cancer Institute (NCI) funding more effectively, we quantified funding to lethality (F:L) ratios, tracked changes in those ratios over time, and compared F:L to other measures of funding allocation, including funding to incidence (F:I), funding to mortality (F:M) and funding to years of life lost (F:YLL) across 19 cancer sites. Methods: We used the NCI research portfolio database to assess funding allocated to 19 different cancer sites from the years 2007-2017. We collected incidence rates (I), mortality rates (M), and years of life lost (YLL) from the Surveillance, Epidemiology and End Results (SEER) database over the same 11 years. We defined lethality (L) by the formula (M/I x (YLLx100)). We calculated median yearly funding ratios and ranked them by cancer site. The correlations between funding ratios were accessed using Pearson correlation test. For each ratio, we calculated rate of change over time by cancer site using linear regression with year as the independent variable. To compare rates of change of each ratio by cancer site, we performed multivariable linear regression incorporating year, cancer site and their interaction as covariates, after applying a log10 transformation on the ratio to achieve linearity. The reference groups for comparison were the gynecologic cancer sites uterus, ovary and cervix. All analyses were completed in R, version 4.0.2. Results: The three cancer sites with the highest F:L ratio were breast, prostate and melanoma despite these being the 12th, 17th and 16th in terms of lethality. Ovary, uterus and cervix ranked 12th, 15th and 13th in F:L ratios, but were 5th, 13th and 6th in terms of lethality. The top three F:I were brain, leukemia, cervix; F:M were melanoma, Hodgkin's lymphoma, brain; and F:YLL were breast, prostate, lung. All three gynecologic cancer sites experienced negative rate of change of F:L over the 11 years. Ovary, cervix and uterus also experienced negative rate of change for F:I, F:M, and F:YLL with the only exception being ovary with positive change in F:M. F:L rates of change were significantly different for ovary, cervix and uterus compared to breast, melanoma, and prostate. F:L ratio was strongly positively correlated to F/YLL with Pearson correlation coefficient of 0.86 (p Conclusions: F:L ratios correlate with other funding allocation measures, and highlight inadequate NCI funding to gynecologic cancers. Trends of the last 5 years (2013-2017) are consistent with trends of the last 11 years. This data should be used for advocacy to improve the disparities in funding to GYN cancers that affect laboratory science discoveries, clinical trial availability and survival outcomes. Download : Download high-res image (296KB) Download : Download full-size image

Variants of primary hyperparathyroidism (pHPT), described as normocalcemic (NC) and normohormonal (NH), can confuse the diagnosis of classic pHPT.A MEDLINE search was performed for variants of pHPT using the PubMed database (last queried October 2019).The search was restricted to articles published after 1960 that were specific to humans. Studies were included in our analysis if laboratory values and incidence of end-organ involvement were reported for NCpHPT and NHpHPT variants. The search returned 189 articles; 27 additional studies were identified and included for a total of 216. Non-English-language studies were excluded. Abstracts were screened, full-text articles were then assessed, and 82 articles were excluded. Data were pooled using a random-effects model in studies that compared NC or NH pHPT to classic pHPT. Comparative laboratory values are presented.This analysis compares NCpHPT and NHpHPT to classic pHPT. Nephrolithiasis was 21.7% (NCpHPT), 15.9% (classic pHPT), and 25.4% (NHpHPT). Decreased bone mineral density was 49.7% (NCpHPT), 39.7% (classic pHPT), and 40.3% (NHpHPT). Fractures in the NCpHPT group were not significantly different from the classic pHPT. Hypertension in the NCpHPT group was significantly less than classic pHPT (odds ratio, 0.59; 95% CI, 0.40-0.88).This information may serve to inform clinicians of the laboratory subtleties of these variants that are being seen with greater frequency in contemporary practice.

Recent work has suggested that disorganised speech might be a powerful predictor of later psychotic illness in clinical high risk subjects. To that end, several automated measures to quantify disorganisation of transcribed speech have been proposed. However, it remains unclear which measures are most predictive of psychosis-onset, how different measures relate to each other and what the best strategies are to elicit disorganised speech from participants. Here, we assessed the ability of twelve automated Natural Language Processing markers to differentiate transcribed speech excerpts from subjects at clinical high risk for psychosis (N=25), first episode psychosis patients (N=16) and healthy control subjects (N=13; N=54 in total). In-line with previous work, several of these measures showed significant differences between groups, including semantic coherence and speech graph connectivity. We also proposed two additional measures of repetition and whether speech was on topic, the latter of which exhibited significant group differences and outperformed the prior, related measure of tangentiality. Most measures examined were only weakly related to each other, suggesting they provide complementary information and that combining different measures could provide additional power to predict the onset of psychotic illness. Finally, we compared the ability of transcribed speech generated using different tasks to differentiate the groups. Speech generated from picture descriptions of the Thematic Apperception Test and a story re-telling task outperformed free speech, suggesting that choice of speech generation method may be an important consideration. Overall, quantitative speech markers represent a promising direction for future diagnostic applications for psychosis risk.

Identify factors influencing service delivery changes during COVID-19 and examine barriers and provider satisfaction with teleneuropsychology (teleNP). Licensed clinical neuropsychologists within the United States recruited via neuropsychology-specific listservs (July–August 2020) to complete an online survey. A total of 261 individuals completed the survey. Most (76%) reported delivering in-person testing in some capacity at the time of our survey. Relatively more private practitioners identified concerns with privacy/confidentiality (45.2% vs. 17.9%; χ2(2) = 6.99, p < 0.05), legal issues (47.6% vs. 17.9%; χ2(2) = 8.06, p < 0.05), and an undesirable precedent for legal/forensic cases (59.5% vs. 15.4%; χ2(2) = 17.54, p < 0.001) compared to hospital or other medical (non-VA) practitioners. Multiple resources informed teleNP protocols, such as organization guidelines (87.6%), literature review (75.9%), webinars (72.4%), and consultation (68%). Several factors influenced test selection, including availability of normative data (70.1%), test familiarity (66.4%), administration time (63.5%), and evidence base (60.6%). Reported barriers to continuing teleNP after COVID-19 included need for improved teleNP norms (85.9%), domain coverage (84.7%), improved patient access to technology (74.1%) and further validation studies (84.1%). TeleNP may not be feasible in all settings and/or referrals. Respondents employed multiple resources in aggregating teleNP protocols and considered several factors when selecting tests. Results highlight the complex and varied decision-making processes utilized by respondents to adapt to service delivery changes. Considering the many benefits of teleNP, future research addressing some of the potentially modifiable factors (e.g., technology access, attitudes regarding teleNP) and significant development needs for teleNP itself (i.e., improved teleNP norms, further validation studies, etc.) is warranted.

Background: The number of lung cancer resections performed annually in the United States has not been previously assessed. The objective of this study is to estimate the total number of lung cancer resections performed every year in the U.S. Methods: The number of lung cancer resections performed in the United States in 2016 and 2017 was estimated by using indirect multiplier methods based on the number of lung cancer resections in the National Cancer Data Base (NCDB) and the proportion of lung cancer cases captured by the NCDB using the United States Cancer Statistics Data Set as reference. Results: In 2016, 37,128 lung cancer resections were documented in the NCDB and the NCDB captured 65.2% of incident lung cancer cases in the U.S. In 2017, 36,882 lung cancer resections were documented in the NCDB and the NCDB captured 65.1% of incident lung cancer cases in the U.S. Based on these metrics, an estimated 57,000 lung cancer resections were performed in 2016 and an estimated 56,600 lung cancer resections were performed in 2017 in the U.S. Of these lung cancer resections, an estimated 10,300 (18.2%) wedge resections, 2,800 (4.9%) segmentectomies, 40,000 (70.6%) lobectomies, 80 (0.14%) bronchial sleeve resections, 1,400 (2.5%) extended lobectomies, 1,600 (2.8%) pneumonectomies, and 40 (0.07%) extended pneumonectomies were performed in 2017. Conclusion: Based on this national analysis, an approximately 56,000 to 57,000 lung cancer resections are performed in the U.S. annually. Lobectomies are the most common lung cancer operations performed in the U.S. Funding Information: None. Declaration of Interests: None. Ethics Approval Statement: Approval dated 2/2/21, Massachusetts General Hospital IRB, Institutional Review Board Number: 2020P004110.