Potent antibody-dependent cellular cytotoxicity of a V2-specific antibody is not sufficient for protection of macaques against SIV challenge.

Fc-mediated antibody effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), can contribute to the containment HIV-1 replication but whether such activities are sufficient for protection is unclear. We previously identified an antibody to the variable 2 (V2) apex of the HIV-1 Env trimer (PGT145) that potently directs the lysis of SIV-infected cells by NK cells but poorly neutralizes SIV infectivity. To determine if ADCC is sufficient for protection, separate groups of six rhesus macaques were treated with PGT145 or a control antibody (DEN3) by intravenous infusion followed five days later by intrarectal challenge with SIVmac239. Despite high concentrations of PGT145 and potent ADCC activity in plasma on the day of challenge, all animals became infected and viral loads did not differ between the PGT145- and DEN3-treated animals. To determine if PGT145 can protect against a neutralization-sensitive virus, two additional groups of six macaques were treated with PGT145 and DEN3 and challenged with an SIVmac239 variant with a single amino acid change in Env (K180S) that increases PGT145 binding and renders the virus susceptible to neutralization by this antibody. Although there was no difference in virus acquisition, peak and chronic phase viral loads were significantly lower and time to peak viremia was significantly delayed in the PGT145-treated animals compared to the DEN3-treated control animals. Env changes were also selected in the PGT145-treated animals that confer resistance to both neutralization and ADCC. These results show that ADCC is not sufficient for protection by this V2-specific antibody. However, protection may be achieved by increasing the affinity of antibody binding to Env above the threshold required for neutralization.

Prospects of CSF shunt independence among chronically shunted patients.

BACKGROUND AND OBJECTIVES: CSF shunt placement for hydrocephalus and other etiologies has arguably been the most life-saving intervention in pediatric neurosurgery in the past 6 decades. Yet, chronic shunting remains a source of morbidity for patients of all ages. Neuroendoscopic surgery has made shunt independence possible for newly diagnosed hydrocephalic patients. In this study, we examine the prospects of shunt independence with or without endoscopic third ventriculostomy (ETV) in chronically shunted patients. METHODS: After IRB approval, a retrospective analysis was completed on patients whose shunt was ligated or removed to achieve shunt independence, with or without ETV. Clinical and imaging data were collected. RESULTS: Eighty-eight patients with CSF shunts had their shunt either ligated or removed, 57 of whom had a concomitant ETV. Original reasons for shunting included: congenital hydrocephalus 20 (23%), post-hemorrhagic hydrocephalus (PHH) of prematurity 14 (16%), aqueductal stenosis 10 (11%), intracranial cyst 8 (9%), tumor 8 (9%), infantile subdural hematomas 8 (9%), myelomeningocele 7 (8%), post-traumatic hydrocephalus 7 (8%) and post-infectious hydrocephalus 6 (7%). The decision to perform a simultaneous ETV was made based on etiology. Forty-nine (56%) patients became shunt independent. The success rate was 46% in the ETV group and 73% in the no ETV group. Using multivariate analysis and Cox Proportional Hazards models, age > 4 months at shunt placement (p = 0.032), no shunt revisions (p = 0.01), select etiologies (p = 0.043), and ETVSS > 70 (in the ETV group) (p = 0.017), were protective factors for shunt independence. CONCLUSION: Considering the long-term complications of shunting, achieving shunt independence may provide hope for improved quality of life. While this study is underpowered, it provides pilot data identifying factors that predict shunt independence in chronically shunted patients, namely age, absence of prior shunt revision, etiology, and in the ETV group, the ETVSS.

Predictors of Swallowing-Related Quality of Life in United States Veterans with Dysphagia.

While both dysphagia and poor health-related quality of life frequently occur in United States (US) Veterans, swallowing-related quality of life in this population has not been systematically examined. This retrospective clinical observation study aimed to determine the independent predictors of swallowing-related quality of life for a sample of US Veterans. We examined the following variables in a multivariate analysis to determine the predictors of Swallowing Quality of Life Questionnaire scores: demographic information, Modified Barium Swallow Impairment Profile (MBSImP) scores, Penetration-Aspiration Scale scores, anterior lingual pressures, and Functional Oral Intake Scale scores. MBSImP oral phase score was the only variable that reached statistical significance (p ≤ 0.01), demonstrating that a more severe physiologic impairment in the oral phase of swallowing was independently predictive of worse swallowing-related quality of life. These findings highlight the need for clinicians to consider how impairments in swallowing physiology may impact the quality of life more broadly for patients with dysphagia.

Esophageal disease and loss to follow-up are common among patients who experience non-endoscopic resolution of food impaction.

Many patients who experience esophageal food impaction (EFI) will have non-endoscopic resolution (NER) of their EFI, but this population is poorly defined. The purpose of this study is to describe the outcomes of patients with NER of EFI. A retrospective chart review from 2007 to 2017 was performed at a single tertiary care center. There were 593 patients who presented to the emergency department with EFI, defined as recent soft food ingestion and inability to tolerate oral secretions. Adequate follow-up was defined as a gastroenterology clinic visit or EGD within 6 months of EFI. Out of these, 149 patients (25.1%) had NER of their EFI. Patients with NER were less likely to have adequate follow-up than those with ER (45.0% vs. 59.5%, P = 0.003). Of those without established esophageal disease and NER, 92.5% had significant esophageal pathology on endoscopy, including stricture (34.0%), features of eosinophilic esophagitis (30.2%), and esophagitis (22.6%). Recurrent EFI occurred at a similar rate between patients with NER and ER (9.4% vs. 14.6%, P = 0.14). Patients with established esophageal disease (odds ratio [OR]: 1.51, P = 0.04) and recommendation to follow-up at time of EFI (OR: 6.06, P < 0.001) were most likely to follow up after EFI. Approximately, a quarter of patients with EFI will experience NER of their EFI. Virtually, all patients (92.5%) were found to have esophageal disease warranting longitudinal care. Importantly, follow-up rates are significantly lower in those with NER than their counterparts requiring EGD. Our study highlights the need to develop standardized protocols that improve follow-up for patients after NER of EFI.

Clinical Manifestations and Outcomes in Immunocompetent and Immunocompromised Patients With Blastomycosis.

BACKGROUND: Blastomyces is a dimorphic fungus that infects persons with or without underlying immunocompromise. To date, no study has compared the clinical features and outcomes of blastomycosis between immunocompromised and immunocompetent persons. METHODS: A retrospective study of adult patients with proven blastomycosis from 2004-2016 was conducted at the University of Wisconsin. Epidemiology, clinical features, and outcomes were analyzed among solid-organ transplantation (SOT) recipients, persons with non-SOT immunocompromise (non-SOT IC), and persons with no immunocompromise (NIC). RESULTS: A total of 106 cases met the inclusion criteria including 74 NIC, 19 SOT, and 13 non-SOT IC (malignancy, HIV/AIDS, idiopathic CD4+ lymphopenia). The majority of patients (61.3%) had at least 1 epidemiologic risk factor for acquisition of Blastomyces. Pneumonia was the most common manifestation in all groups; however, immunocompromised patients had higher rates of acute pulmonary disease (P = .03), more severe infection (P = .007), respiratory failure (P = .010), and increased mortality (P = .02). Receipt of SOT primarily accounted for increased severity, respiratory failure, and mortality in immunosuppressed patients. SOT recipients had an 18-fold higher annual incidence of blastomycosis than the general population. The rate of disseminated blastomycosis was similar among NIC, SOT, and non-SOT IC. Relapse rates were low (5.3-7.7%). CONCLUSIONS: Immunosuppression had implications regarding the acuity, severity, and respiratory failure. The rate of dissemination was similar across the immunologic spectrum, which is in sharp contrast to other endemic fungi. This suggests that pathogen-related factors have a greater influence on dissemination for blastomycosis than immune defense.

Empiric proton pump inhibitor therapy after esophageal food impaction may mask eosinophilic esophagitis diagnosis at follow-up.

Esophageal food impaction (EFI) is often the first presentation for patients with eosinophilic esophagitis (EoE); however, there is significant heterogeneity in the management of EFI. We aimed to study the impact of EFI management, particularly post-EFI medication prescriptions on EoE diagnosis, follow-up, and recurrence in patients with endoscopic features of EoE. In our retrospective study, adults presenting between 2007 and 2017 with EFI requiring endoscopic dis-impaction with endoscopic features of EoE (furrows, rings, and/or exudates) were included. We examined the impact of demographics and EFI management on EoE diagnosis, follow-up (esophagogastroduodenoscopy [EGD] or clinic visit within 6 months), and recurrence. We identified 164 cases of EFI due to suspected EoE. Biopsy was performed in 68 patients (41.5%), and 144 patients (87.8%) were placed on proton pump inhibitor (PPI) and/or swallow corticosteroids after EFI, including 88.5% of those not biopsied. PPI use at time of biopsy was negatively associated with EoE diagnosis (odds ratio: 0.39, confidence interval: 0.17-0.85). Sixty-one (37.4%) patients were lost to follow-up at 6 months. Recurrent EFI at 1 year occurred in 3.7% of patients. Medications, most commonly PPI, are frequently prescribed after EFI when the endoscopic features of EoE are present, which may mask the diagnosis of EoE on follow-up EGD. We estimated that for every five patients biopsied on PPI, one case of EoE is masked. As recurrent EFI within 1 year is uncommon, empiric therapy should be avoided until diagnostic biopsies are obtained. Further efforts to reduce loss to follow-up after EFI are also needed.

Thin myelin sheaths as the hallmark of remyelination persist over time and preserve axon function.

The presence of thin myelin sheaths in the adult CNS is recognized as a marker of remyelination, although the reason there is not a recovery from demyelination to normal myelin sheath thickness remains unknown. Remyelination is the default pathway after myelin loss in all mammalian species, in both naturally occurring and experimental disease. However, there remains uncertainty about whether these thin sheaths thicken with time and whether they remain viable for extended periods. We provide two lines of evidence here that thin myelin sheaths may persist indefinitely in long-lived animal models. In the first, we have followed thin myelin sheaths in a model of delayed myelination during a period of 13 years that we propose results in the same myelin sheath deficiencies as seen in remyelination; that is, thin myelin sheaths and short internodes. We show that the myelin sheaths remain thin and stable on many axons throughout this period with no detrimental effects on axons. In a second model system, in which there is widespread demyelination of the spinal cord and optic nerves, we also show that thinly remyelinated axons with short internodes persist for over the course of 2 y. These studies confirm the persistence and longevity of thin myelin sheaths and the importance of remyelination to the long-term health and function of the CNS.

Islet proteomics reveals genetic variation in dopamine production resulting in altered insulin secretion.

The mouse is a critical model in diabetes research, but most research in mice has been limited to a small number of mouse strains and limited genetic variation. Using the eight founder strains and both sexes of the Collaborative Cross (C57BL/6J (B6), A/J, 129S1/SvImJ (129), NOD/ShiLtJ (NOD), NZO/HILtJ (NZO), PWK/PhJ (PWK), WSB/EiJ (WSB), and CAST/EiJ (CAST)), we investigated the genetic dependence of diabetes-related metabolic phenotypes and insulin secretion. We found that strain background is associated with an extraordinary range in body weight, plasma glucose, insulin, triglycerides, and insulin secretion. Our whole-islet proteomic analysis of the eight mouse strains demonstrates that genetic background exerts a strong influence on the islet proteome that can be linked to the differences in diabetes-related metabolic phenotypes and insulin secretion. We computed protein modules consisting of highly correlated proteins that enrich for biological pathways and provide a searchable database of the islet protein expression profiles. To validate the data resource, we identified tyrosine hydroxylase (Th), a key enzyme in catecholamine synthesis, as a protein that is highly expressed in ß-cells of PWK and CAST islets. We show that CAST islets synthesize elevated levels of dopamine, which suppresses insulin secretion. Prior studies, using only the B6 strain, concluded that adult mouse islets do not synthesize l-3,4-dihydroxyphenylalanine (l-DOPA), the product of Th and precursor of dopamine. Thus, the choice of the CAST strain, guided by our islet proteomic survey, was crucial for these discoveries. In summary, we provide a valuable data resource to the research community, and show that proteomic analysis identified a strain-specific pathway by which dopamine synthesized in ß-cells inhibits insulin secretion.

Mindfulness, Experiential Avoidance, and Recovery From Hematopoietic Stem Cell Transplantation.

BACKGROUND: Mood disturbance, pain, and fatigue are prevalent and distressing concerns for patients with hematologic cancer recovering from hematopoietic stem cell transplantation (HSCT). The way in which individuals approach difficult thoughts and emotions may affect symptoms and functioning. Specifically, mindfulness has been associated with more optimal psychological and physical functioning, whereas experiential avoidance has been associated with poorer outcomes. PURPOSE: The primary objective was to determine whether mindfulness and experiential avoidance measured prior to HSCT were associated with recovery of psychological and physical functioning following HSCT. We also evaluated dimensions of mindfulness to determine which were most robustly associated with outcomes. METHODS: Participants completed measures of mindfulness and experiential avoidance prior to HSCT. Depression and anxiety symptoms and pain and fatigue interference with daily activities were assessed prior to HSCT and 1, 3, and 6 months post-HSCT. RESULTS: Participants who reported better ability to describe their internal experiences and who were better able to act with awareness experienced less depression, anxiety, and fatigue interference following HSCT. Participants who were nonjudgmental and nonreactive toward thoughts and emotions experienced less depression and anxiety following HSCT, but these traits were not associated with pain or fatigue interference. Being a good observer of internal experiences was not associated with outcomes, nor was experiential avoidance. CONCLUSIONS: Results suggest that most facets of mindfulness may optimize psychological functioning following HSCT, and the ability to describe one's internal experience and to focus on the present moment may have a beneficial influence on physical functioning.

Musculoskeletal Injuries Are Commonly Reported Among Gastroenterology Trainees: Results of a National Survey.

BACKGROUND: Endoscopy-related musculoskeletal injuries are increasingly recognized among gastroenterologists. While injury rates and risk factors have been studied among practicing gastroenterologists, little is known about rates among trainees during fellowship. AIMS: This study analyzes the prevalence of endoscopy-related overuse injuries and risk factors for injuries among a national sample of gastroenterology (GI) fellows. We also surveyed GI fellowship program directors and fellows about perceptions of overuse injuries during GI training. METHODS: We distributed a 29-item electronic survey to GI fellows at accredited programs in the USA in April 2016. Survey items included demographic information, questions pertaining to injuries, and level of agreement on the importance of ergonomics training in GI fellowship. Additionally, we distributed a 7-item electronic survey to fellowship program directors evaluating perception of overuse injuries and prevention during fellowship training. Fisher's exact test determined factors associated with sustaining an injury. RESULTS: An estimated 1509 fellows received the survey. Eleven percent (n = 165) of gastroenterology fellows completed the survey. Twenty percent reported having a musculoskeletal injury. Female gender was the only factor associated with a higher rate of reported injury (p < 0.01). The most common injuries reported were thumb and other hand-related pain (n = 28 [64%]). CONCLUSIONS: Musculoskeletal injuries may affect up to 20% of GI fellows. Female fellows more frequently report injuries and may be at particularly high risk which has not been found in previously reported surveys of practicing gastroenterologists. Standardized curricula on ergonomic considerations and injury prevention are needed to enhance GI fellowship training and reduce injury rates.

The Transcription Factor Nfatc2 Regulates ß-Cell Proliferation and Genes Associated with Type 2 Diabetes in Mouse and Human Islets.

Human genome-wide association studies (GWAS) have shown that genetic variation at >130 gene loci is associated with type 2 diabetes (T2D). We asked if the expression of the candidate T2D-associated genes within these loci is regulated by a common locus in pancreatic islets. Using an obese F2 mouse intercross segregating for T2D, we show that the expression of ~40% of the T2D-associated genes is linked to a broad region on mouse chromosome (Chr) 2. As all but 9 of these genes are not physically located on Chr 2, linkage to Chr 2 suggests a genomic factor(s) located on Chr 2 regulates their expression in trans. The transcription factor Nfatc2 is physically located on Chr 2 and its expression demonstrates cis linkage; i.e., its expression maps to itself. When conditioned on the expression of Nfatc2, linkage for the T2D-associated genes was greatly diminished, supporting Nfatc2 as a driver of their expression. Plasma insulin also showed linkage to the same broad region on Chr 2. Overexpression of a constitutively active (ca) form of Nfatc2 induced ß-cell proliferation in mouse and human islets, and transcriptionally regulated more than half of the T2D-associated genes. Overexpression of either ca-Nfatc2 or ca-Nfatc1 in mouse islets enhanced insulin secretion, whereas only ca-Nfatc2 was able to promote ß-cell proliferation, suggesting distinct molecular pathways mediating insulin secretion vs. ß-cell proliferation are regulated by NFAT. Our results suggest that many of the T2D-associated genes are downstream transcriptional targets of NFAT, and may act coordinately in a pathway through which NFAT regulates ß-cell proliferation in both mouse and human islets.

Longitudinal growth of receptive language in children with cerebral palsy between 18 months and 54 months of age.

AIM: We examined receptive language developmental trajectories between 18 months and 54 months for three clinical speech-language profile groups of children with cerebral palsy (those with speech motor involvement, without speech motor involvement, and with anarthria) and quantified differences from age-level expectations. We identified latent classes of comprehension development, related these classes to clinical profile groups, and examined how well early receptive language predicted outcomes. METHOD: We used a prospective longitudinal design. Eighty-five children with cerebral palsy (43 females, 42 males) were followed longitudinally from 18 to 54 months of age. Children were seen two to eight times (322 data points). Children were classified into clinical profile groups. Language comprehension age-equivalent scores were the primary measures of interest. RESULTS: Children with anarthria had significant language delays, limited developmental change over time, and comprised their own latent class. Children with speech motor impairment had slight receptive language delays over time. Children with no speech motor impairment had age-appropriate receptive language over time. Early language comprehension scores were highly predictive of later latent profile group membership. INTERPRETATION: Early language comprehension abilities are highly predictive of language comprehension growth trajectory and suggest that children with early language delay, particularly those who are non-speaking, should receive language intervention to support development. WHAT THIS PAPER ADDS: There are two growth trajectories for language comprehension among children with cerebral palsy. Children with speech motor impairment had a constant 6-month receptive language delay. Children without speech motor impairment had age-appropriate receptive language. Non-speaking children had significant receptive language delay. Early language comprehension change was highly predictive of later trajectory group.

Clinical outcomes after magnetic resonance angiography (MRA) versus computed tomographic angiography (CTA) for pulmonary embolism evaluation.

PURPOSE: To compare patient outcomes following magnetic resonance angiography (MRA) versus computed tomographic angiography (CTA) ordered for suspected pulmonary embolism (PE). METHODS: In this IRB-approved, single-center, retrospective, case-control study, we reviewed the medical records of all patients evaluated for PE with MRA during a 5-year period along with age- and sex-matched controls evaluated with CTA. Only the first instance of PE evaluation during the study period was included. After application of our exclusion criteria to both study arms, the analysis included 1173 subjects. The primary endpoint was major adverse PE-related event (MAPE), which we defined as major bleeding, venous thromboembolism, or death during the 6 months following the index imaging test (MRA or CTA), obtained through medical record review. Logistic regression, chi-square test for independence, and Fisher's exact test were used with a p < 0.05 threshold. RESULTS: The overall 6-month MAPE rate following MRA (5.4%) was lower than following CTA (13.6%, p < 0.01). Amongst outpatients, the MAPE rate was lower for MRA (3.7%) than for CTA (8.0%, p = 0.01). Accounting for age, sex, referral source, BMI, and Wells' score, patients were less likely to suffer MAPE than those who underwent CTA, with an odds ratio of 0.44 [0.24, 0.80]. Technical success rate did not differ significantly between MRA (92.6%) and CTA (90.5%) groups (p = 0.41). CONCLUSION: Within the inherent limitations of a retrospective case-controlled analysis, we observed that the rate of MAPE was lower (more favorable) for patients following pulmonary MRA for the primary evaluation of suspected PE than following CTA.

Fungal Morphology, Iron Homeostasis, and Lipid Metabolism Regulated by a GATA Transcription Factor in Blastomyces dermatitidis.

In response to temperature, Blastomyces dermatitidis converts between yeast and mold forms. Knowledge of the mechanism(s) underlying this response to temperature remains limited. In B. dermatitidis, we identified a GATA transcription factor, SREB, important for the transition to mold. Null mutants (SREBΔ) fail to fully complete the conversion to mold and cannot properly regulate siderophore biosynthesis. To capture the transcriptional response regulated by SREB early in the phase transition (0-48 hours), gene expression microarrays were used to compare SREB∆ to an isogenic wild type isolate. Analysis of the time course microarray data demonstrated SREB functioned as a transcriptional regulator at 37°C and 22°C. Bioinformatic and biochemical analyses indicated SREB was involved in diverse biological processes including iron homeostasis, biosynthesis of triacylglycerol and ergosterol, and lipid droplet formation. Integration of microarray data, bioinformatics, and chromatin immunoprecipitation identified a subset of genes directly bound and regulated by SREB in vivo in yeast (37°C) and during the phase transition to mold (22°C). This included genes involved with siderophore biosynthesis and uptake, iron homeostasis, and genes unrelated to iron assimilation. Functional analysis suggested that lipid droplets were actively metabolized during the phase transition and lipid metabolism may contribute to filamentous growth at 22°C. Chromatin immunoprecipitation, RNA interference, and overexpression analyses suggested that SREB was in a negative regulatory circuit with the bZIP transcription factor encoded by HAPX. Both SREB and HAPX affected morphogenesis at 22°C; however, large changes in transcript abundance by gene deletion for SREB or strong overexpression for HAPX were required to alter the phase transition.

Right ventricular outflow tract diameter change with exercise: a prospective exercise echocardiography and invasive CPET study.

While cardiac output reserve with exercise predicts outcomes in cardiac and pulmonary vascular disease, precise quantification of exercise cardiac output requires invasive cardiopulmonary testing (iCPET). To improve the accuracy of cardiac output reserve estimation with transthoracic echocardiography (TTE), this prospective study aims to define changes in right ventricular outflow tract diameter (RVOTd) with exercise and its relationship with invasively measured haemodynamics. Twenty subjects underwent simultaneous TTE and iCPET, with data collected at rest, leg-raise, 25 W, 50 W (n = 16), 75 W (n = 14), and 100 W (n = 6). This was followed by a second exercise study with real-time RV pressure-volume loops at similar stages (except leg-raise). The overall cohort included heart failure with preserved ejection fraction (n = 12), pulmonary arterial hypertension (n = 5), and non-cardiac dyspnoea (n = 3). RVOTd was reverse engineered from the TTE-derived RVOT velocity time integral (VTI) and iCPET-derived stroke volume, using the formula: Fick stroke volume = RVOT VTI × RVOT area (wherein RVOT area = π × [RVOTd/2]2). RVOTd increased by nearly 3-4% at every 25 W increment. Using linear regression models, where each subject is treated as a categorical variable and adjusting for subject intercept, RVOTd was correlated with haemodynamic variables (cardiac output, heart rate, pulmonary artery and RV pressures). Of all the predictor haemodynamic variables, cardiac output had the highest r2 model fit (adjusted r2 = 0.68), with a unit increase in cardiac output associated with a 0.0678 increase in RVOTd (P < 0.001). Our findings indicate that RVOTd increases by 3-4% with every 25 W increment, predominantly correlated with cardiac output augmentation. These results can improve the accuracy of cardiac output reserve estimation by adjusting for RVOTd with graded exercise during non-invasive CPET and echocardiogram. However, future studies are needed to define these relationships for left ventricular outflow tract diameter.

Multi-modal MRI of hippocampal morphometry and connectivity after pediatric severe TBI.

This investigation explores memory performance using the California Verbal Learning Test in relation to morphometric and connectivity measures of the memory network in severe traumatic brain injury. Twenty-two adolescents with severe traumatic brain injury were recruited for multimodal MRI scanning 1-2 years post-injury at 13 participating sites. Analyses included hippocampal volume derived from anatomical T1-weighted imaging, fornix white matter microstructure from diffusion tensor imaging, and hippocampal resting-state functional magnetic resonance imaging connectivity as well as diffusion-based structural connectivity. A typically developing control cohort of forty-nine age-matched children also underwent scanning and neurocognitive assessment. Results showed hippocampus volume was decreased in traumatic brain injury with respect to controls. Further, hippocampal volume loss was associated with worse performance on memory and learning in traumatic brain injury subjects. Similarly, hippocampal fornix fractional anisotropy was reduced in traumatic brain injury with respect to controls, while decreased fractional anisotropy in the hippocampal fornix also was associated with worse performance on memory and learning in traumatic brain injury subjects. Additionally, reduced structural connectivity of left hippocampus to thalamus and calcarine sulcus was associated with memory and learning in traumatic brain injury subjects. Functional connectivity in the left hippocampal network was also associated with memory and learning in traumatic brain injury subjects. These regional findings from a multi-modal neuroimaging approach should not only be useful for gaining valuable insight into traumatic brain injury induced memory and learning disfunction, but may also be informative for monitoring injury progression, recovery, and for developing rehabilitation as well as therapy strategies.

Genetic Analysis of Obesity-Induced Diabetic Nephropathy in BTBR Mice.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the U.S. and has a significant impact on human suffering. Leptin-deficient BTBR (BTBRob/ob) mice develop hallmark features of obesity-induced DN, whereas leptin-deficient C57BL/6J (B6ob/ob) mice do not. To identify genetic loci that underlie this strain difference, we constructed an F2 intercross between BTBRob/ob and B6ob/ob mice. We isolated kidneys from 460 F2 mice and histologically scored them for percent mesangial matrix and glomerular volume (∼50 glomeruli per mouse), yielding ∼45,000 distinct measures in total. The same histological measurements were made in kidneys from B6 and BTBR mice, either lean or obese (Lepob/ob), at 4 and 10 weeks of age, allowing us to assess the contribution of strain, age, and obesity to glomerular pathology. All F2 mice were genotyped for ∼5,000 single nucleotide polymorphisms (SNPs), ∼2,000 of which were polymorphic between B6 and BTBR, enabling us to identify a quantitative trait locus (QTL) on chromosome 7, with a peak at ∼30 Mbp, for percent mesangial matrix, glomerular volume, and mesangial volume. The podocyte-specific gene nephrin (Nphs1) is physically located at the QTL and contains high-impact SNPs in BTBR, including several missense variants within the extracellular immunoglobulin-like domains.

Adeno-associated viral delivery of Env-specific antibodies prevents SIV rebound after discontinuing antiretroviral therapy.

An alternative to lifelong antiretroviral therapy (ART) is needed to achieve durable control of HIV-1. Here we show that adeno-associated virus (AAV)-delivery of two rhesus macaque antibodies to the SIV envelope glycoprotein (Env) with potent neutralization and antibody-dependent cellular cytotoxicity can prevent viral rebound in macaques infected with barcoded SIVmac239M after discontinuing suppressive ART. Following AAV administration, sustained antibody expression with minimal anti-drug antibody responses was achieved in all but one animal. After ART withdrawal, SIV replication rebounded within two weeks in all of the control animals but remained below the threshold of detection in plasma (<15 copies/mL) for more than a year in four of the eight animals that received AAV vectors encoding Env-specific antibodies. Viral sequences from animals with delayed rebound exhibited restricted barcode diversity and antibody escape. Thus, sustained expression of antibodies with potent antiviral activity can afford durable, ART-free containment of pathogenic SIV infection.

Outcomes Following Standardized Implantable Cardioverter-defibrillator Reprogramming.

Multiple randomized controlled trials have demonstrated that programming implantable cardioverter-defibrillators (ICDs) with longer detection intervals and higher detection rates results in significant reductions in the delivery of inappropriate therapy without increasing the number of adverse events. Despite these findings, however, implementation of this evidence-based programming, particularly in previously implanted ICDs, remains inconsistent throughout the United States, with significant provider-dependent variability. We developed an institutionally standardized ICD reprogramming protocol for primary prevention ICDs utilizing high detection rates and long detection intervals, then prospectively evaluated outcomes in patients programmed with this protocol compared to a historical cohort. A total of 193 patients with primary prevention ICDs underwent standardized reprogramming and were monitored over a 1-year period. A historical cohort of 254 patients with ICD with non-standardized programming implanted prior to initiation of the standardized protocol were used as a comparison group. The primary outcomes were rates of appropriate or inappropriate ICD therapy. Secondary outcomes were rates of syncope, emergency department (ED) or urgent care (UC) visits, hospitalization, and death. All patients seen in the device clinic who qualified for device standardization were reprogrammed according to the previously developed evidence-based, institutionally standardized protocol. Patients who underwent standardized reprogramming had a lower prevalence of inappropriate therapy compared to the historical cohort (0% vs. 2.4%, P = .04); the prevalence of appropriate therapy was also lower in the reprogrammed group (4.1% vs. 7.1%) but not to a statistically significant degree (P = .19). There was a lower prevalence of syncope in the reprogrammed group (0% vs. 2.8%, P = .02). No significant difference in the prevalence of ED or UC utilization (37.8% vs. 33.9%, P = .39) or mortality (4.1% vs. 3.5%, P = .74) was found. Prospective standardized reprogramming of new and previously implanted primary prevention ICDs with high-rate detection and longer detection intervals may be an effective method to obtain high adherence to evidence-based reprogramming and reduce rates of inappropriate device therapies without a significant impact on appropriate therapies or mortality.

Postoperative Respiratory Compromise following Cesarean Birth: The Impact of Obesity and Systemic Opioids.

Objective The aim of this study was to measure the effect of obesity and systemic opioids on respiratory events within the first 24 hours following cesarean. Methods Opioid-naive women undergoing cesarean between January 2016 and December 2017 were included in this retrospective cohort study. The primary outcome was the proportion of women experiencing at least one composite respiratory outcome (oxygen saturation less than 95% lasting 30+ seconds or need for respiratory support) within 24 hours of cesarean. The impact of obesity and total systemic opioid dose in 24 hours (measured in morphine milligram equivalents [MMEs]) on the composite respiratory compromise outcome were evaluated. Results Of 2,230 cesarean births, 790 women had at least one composite respiratory event. Predictors of the composite respiratory outcome included body mass index (BMI) as a continuous variable (odds ratio = 1.063 for every one unit increase in BMI [95% confidence interval (CI): 1.021-1.108], p = 0.003), and MME (odds ratio = 1.005 [95% CI: 1.002-1.008], p = 0.003), adjusting for magnesium sulfate use. The interaction between obesity and opioid dose demonstrated an odds ratio of 1.000 (95% CI: 0.999-1.000, p = 0.030). Conclusion The proportion of women experiencing respiratory events following cesarean birth increases with the degree of obesity and opioid dose. Key Points Respiratory events increase with obesity.Respiratory events increase with systemic opioid use.Odds ratio of respiratory events is 1.063/unit BMI increase.