The BTLA-HVEM axis restricts CAR T cell efficacy in cancer.

The efficacy of T cell-based immunotherapies is limited by immunosuppressive pressures in the tumor microenvironment. Here we show a predominant role for the interaction between BTLA on effector T cells and HVEM (TNFRSF14) on immunosuppressive tumor microenvironment cells, namely regulatory T cells. High BTLA expression in chimeric antigen receptor (CAR) T cells correlated with poor clinical response to treatment. Therefore, we deleted BTLA in CAR T cells and show improved tumor control and persistence in models of lymphoma and solid malignancies. Mechanistically, BTLA inhibits CAR T cells via recruitment of tyrosine phosphatases SHP-1 and SHP-2, upon trans engagement with HVEM. BTLA knockout thus promotes CAR signaling and subsequently enhances effector function. Overall, these data indicate that the BTLA-HVEM axis is a crucial immune checkpoint in CAR T cell immunotherapy and warrants the use of strategies to overcome this barrier.

Determining tissue distribution of the oral antileishmanial agent miltefosine: a physiologically-based pharmacokinetic modeling approach.

Miltefosine (MTS) is the only approved oral drug for treating leishmaniasis caused by intracellular Leishmania parasites that localize in macrophages of the liver, spleen, skin, bone marrow, and lymph nodes. MTS is extensively distributed in tissues and has prolonged elimination half-lives due to its high plasma protein binding, slow metabolic clearance, and minimal urinary excretion. Thus, understanding and predicting the tissue distribution of MTS help assess therapeutic and toxicologic outcomes of MTS, especially in special populations, e.g., pediatrics. In this study, a whole-body physiologically-based pharmacokinetic (PBPK) model of MTS was built on mice and extrapolated to rats and humans. MTS plasma and tissue concentration data obtained by intravenous and oral administration to mice were fitted simultaneously to estimate model parameters. The resulting high tissue-to-plasma partition coefficient values corroborate extensive distribution in all major organs except the bone marrow. Sensitivity analysis suggests that plasma exposure is most susceptible to changes in fraction unbound in plasma. The murine oral-PBPK model was further validated by assessing overlay of simulations with plasma and tissue profiles obtained from an independent study. Subsequently, the murine PBPK model was extrapolated to rats and humans based on species-specific physiological and drug-related parameters, as well as allometrically scaled parameters. Fold errors for pharmacokinetic parameters were within acceptable range in both extrapolated models, except for a slight underprediction in the human plasma exposure. These animal and human PBPK models are expected to provide reliable estimates of MTS tissue distribution and assist dose regimen optimization in special populations.

SOX11+ Large B-Cell Neoplasms: Cyclin D1-Negative Blastoid/Pleomorphic Mantle Cell Lymphoma or Large B-Cell Lymphoma?

Large or blastoid B-cell neoplasms that are SOX11+ are a diagnostic dilemma and raise a differential diagnosis of cyclin D1-negative blastoid/pleomorphic mantle cell lymphoma (MCL) versus diffuse large B-cell lymphoma (DLBCL) or blastoid high-grade B-cell lymphoma (HGBL) with aberrant SOX11 expression. Here we report a study cohort of 13 SOX11+ large/blastoid B-cell neoplasms. Fluorescence in situ hybridization analysis was negative for CCND1 rearrangement in all 13 cases; 1 of 8 (12.5%) cases tested showed CCND2 rearrangement and 2 (25%) cases had extracopies of CCND2. Gene expression profiling showed that the study group had a gene expression signature similar to cyclin D1+ blastoid/pleomorphic MCL but different from DLBCL. Principal component analysis revealed that the cohort cases overlapped with cyclin D1+ blastoid/pleomorphic MCL but had minimal overlap with DLBCL. All patients in the cohort had clinicopathologic features similar to those reported for patients with cyclin D1+ MCL. We also performed a survey of SOX11 expression in a group of 85 cases of DLBCL and 24 cases of blastoid HGBL. SOX11 expression showed a 100% specificity and positive predictive value for the diagnosis of MCL. Overall, the results support the conclusion that large or blastoid B-cell neoplasms that are positive for SOX11 are best classified as cyclin D1-negative blastoid/pleomorphic MCL, and not as DLBCL or blastoid HGBL. We also conclude that SOX11 is a specific marker for the diagnosis of MCL, including cyclin D1-negative blastoid/pleomorphic MCL cases and should be performed routinely on blastoid/large B-cell neoplasms to help identify potential cases of cyclin D1-negative blastoid/pleomorphic MCL.

Retrospective chart review of GI bleeding in people with von Willebrand disease.

INTRODUCTION: Gastrointestinal (GI) bleeding events (BEs) in von Willebrand disease (VWD) are difficult to diagnose and often recurrent. Limited data from clinical trials has led to lack of consensus on treatment options. AIM: Describe current treatments and outcomes for GI BEs in people with VWD. METHODS: This retrospective, observational, multicentre chart review study was conducted from January 2018 through December 2019 and included patients with inherited VWD with ≥1 GI BE in the preceding 5 years. Baseline characteristics, number and aetiology of BEs, associated GI-specific morbidities/lesions, treatment and outcomes were analysed descriptively. RESULTS: Sixty bleeds were reported in 20 patients with type 1 (20%), type 2 (50%) and type 3 (30%) VWD. During the 5-year study period, 31 (52%) BEs had one identified or suspected cause; multiple causes were reported in 11 (18%). Most GI BEs (72%) were treated with a combination of von Willebrand factor (VWF), antifibrinolytics and/or other haemostatic or non-haemostatic treatments. Time to resolution did not differ by VWF treatment use; however, BEs treated with non-VWF treatments tended to resolve later. In patients with GI-specific morbidities/lesions, 84% resolved with first-line treatment; time to resolution tended to be longer than in patients without such morbidities/lesions. Thirteen BEs occurred in patients receiving prophylaxis and 47 in patients receiving on-demand treatment; 18 BEs resulted in a switch to prophylaxis after bleed resolution. CONCLUSIONS: This study confirms the unmet need for the management of recurrent GI BEs in people with VWD and the need for prospective data, especially on prophylaxis.

Treatment Location Variation for Chronic Limb-Threatening Ischemia in Patients With Kidney Failure.

INTRODUCTION: End-stage kidney disease (ESKD) is an established risk factor for chronic limb-threatening ischemia (CLTI). Procedural location for ESKD patients has not been well described. This study aims to examine variation in index procedural location in ESKD versus non-ESKD patients undergoing peripheral vascular intervention for CLTI and identify preoperative risk factors for tibial interventions. METHODS: Chronic limb-threatening ischemia (CLTI) patients were identified in the Vascular Quality Initiative (VQI) peripheral vascular intervention dataset. Patient demographics and comorbidities were compared between patients with and without ESKD and those undergoing index tibial versus nontibial interventions. A multivariable logistic regression evaluating risk factors for tibial intervention was conducted. RESULTS: A total of 23,480 procedures were performed on CLTI patients with 13.6% (n = 3154) with ESKD. End-stage kidney disease (ESKD) patients were younger (66.56 ± 11.68 versus 71.66 ± 12.09 y old, P = 0.019), more often Black (40.6 versus 18.6%, P < 0.001), male (61.2 versus 56.5%, P < 0.001), and diabetic (81.8 versus 60.0%, P < 0.001) than non-ESKD patients. Patients undergoing index tibial interventions had higher rates of ESKD (19.4 versus 10.6%, P < 0.001) and diabetes (73.4 versus 57.5%, P < 0.001) and lower rates of smoking (49.9 versus 73.0%, P < 0.001) than patients with nontibial interventions. ESKD (odds ratio (OR) 1.67, 95% confidence interval (CI) 1.52-1.86, P < 0.001), Black race (OR 1.19, 95% CI 1.09-1.30, P < 0.001), and diabetes (OR 1.82, 95% CI 1.71-2.00, P < 0.001) were risk factors for tibial intervention. CONCLUSIONS: Patients with ESKD and CLTI have higher rates of diabetes and tibial disease and lower rates of smoking than non-ESKD patients. Tibial disease was associated with ESKD, diabetes, and Black race.

Addition of pyloroplasty may improve glycemic control and refractory early satiety in gastroparesis at rates similar to gastric neurostimulation alone: a retrospective analysis.

OBJECTIVES: Gastroparesis that is refractory to standard dietary and medical management may benefit from surgical treatment with gastric electrical neurostimulation, which has shown promise in reducing symptoms of the disease. Pyloroplasty may serve an adjunctive role to a gastric stimulator, but the precise benefit remains unclear. The present study compares reported rates of symptom improvement following gastric neurostimulator implantation with and without pyloroplasty. MATERIALS AND METHODS: A single center retrospective analysis of consecutive patients who received operative management for symptom refractory gastroparesis from 1 January 2020 to 31 December 2021 was performed. Subjects were assigned to cohorts based on treatment with gastric electrical stimulation alone (GES-only) or combined with pyloroplasty (GES + PP). A survey-based assessment was administered post-operatively that evaluated cardinal symptoms of gastroparesis (nausea, vomiting, early satiety) before and after treatment. RESULTS: In total, 42 patients (15 GES-only, 27 GES + PP) were included in the study. Both groups reported a high degree of improvement in global symptom control following surgery (93% vs 81%) with no differences between treatment cohorts (p = 0.09). Early satiety demonstrated better improvement in patients who received gastric stimulation alone (p = 0.012). Subgroup analysis of diabetic gastroparesis patients showed a 2.2% decrease in hemoglobin A1c levels in the GES + PP group (p-0.034). CONCLUSIONS: Symptom reduction in refractory gastroparesis appears to improve after placement of a gastric neurostimulator with or without the addition of a pyloroplasty procedure.

Safety of Extended Pirtobrutinib Exposure in Relapsed and/or Refractory B-Cell Malignancies.

INTRODUCTION: Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment. METHODS: Here we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs). RESULTS: Of 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy. CONCLUSIONS: Pirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals.

Long-Term Outcomes of Vein Adjuncts in Distal Infrainguinal Bypass.

INTRODUCTION: Autologous vein is recommended for infrainguinal bypass due to improved freedom from occlusion compared to prosthetic graft. In patients without adequate vein, vein adjunct at the distal anastomosis has been suggested to improve patency in small studies. This study aimed to determine if performance of a distal vein adjunct was associated with improved freedom from occlusion in below knee popliteal and tibial bypasses compared to prosthetic bypass alone. METHODS: A retrospective review of the Vascular Quality Initiative Infrainguinal Bypass database was conducted. Patients undergoing prosthetic-only and prosthetic with vein adjunct were compared. Inclusion criteria included age >18 years, and bypass to below knee popliteal or tibial vessels. Exclusion criteria included autologous vein conduits and prior interventions. Groups were further divided into below knee popliteal and tibial subgroups. RESULTS: A cohort of 3,939 patients underwent bypass to the below knee popliteal artery, with 287 (7.3%) receiving vein adjunct. More patients were male (68.8 vs 57.8%, p<.001) and had higher rates of CHF (21.1 vs 16.0%, p=.040) within the below knee popliteal group. Two-year bypass occlusion was decreased in patients receiving vein adjuncts (11.6 vs 17.1%, p=.004). A cohort of 2,378 patients underwent tibial bypass, with 473 (19.9%) receiving vein adjunct. Within the tibial group, patients were similar in age, BMI, race, comorbidities, and indications. Bypass occlusion (24.8 vs. 17.6%, p=.005) and amputation (20.5 vs. 15.9%, p=.048) rates at two years were worse for patients who did not receive a distal vein adjuncts to tibial arteries. CONCLUSION: Distal vein adjuncts are associated with improved freedom from occlusion, amputation, MALEs, and overall survival when compared to bypasses performed with prosthetic graft alone for tibial bypasses within the VQI. Vein adjunct was not associated with improved freedom from occlusion in below knee popliteal bypasses. Consideration should be given to utilization of a distal vein adjunct to improve prosthetic bypass longevity and limb salvage for patients requiring tibial bypasses.

Directionally-Resolved Phononic Properties of Monolayer 2D Molybdenum Ditelluride (MoTe2) under Uniaxial Elastic Strain.

Understanding the phonon characteristics of two-dimensional (2D) molybdenum ditelluride (MoTe2) under strain is critical to manipulating its multiphysical properties. Although there have been numerous computational efforts to elucidate the strain-coupled phonon properties of monolayer MoTe2, empirical validation is still lacking. In this work, monolayer 1H-MoTe2 under uniaxial strain is studied via in situ micro-Raman spectroscopy. Directionally dependent monotonic softening of the doubly degenerate in-plane E2g1 phonon mode is observed with increasing uniaxial strain, where the E2g1 peak red-shifts -1.66 ± 0.04 cm-1/% along the armchair direction and -0.80 ± 0.07 cm-1/% along the zigzag direction. The corresponding Grüneisen parameters are calculated to be 1.09 and 0.52 along the armchair and zigzag directions, respectively. This work provides the first empirical quantification and validation of the orientation-dependent strain-coupled phonon response in monolayer 1H-MoTe2 and serves as a benchmark for other prototypical 2D transition-metal tellurides.

Thermal stability and secondary aggregation of self-limiting, geometrically frustrated assemblies: Chain assembly of incommensurate polybricks.

In geometrically frustrated assemblies, equilibrium self-limitation manifests in the form of a minimum in the free energy per subunit at a finite, multisubunit size which results from the competition between the elastic costs of frustration within an assembly and the surface energy at its boundaries. Physical realizations-from ill-fitting particle assemblies to self-twisting protein superstructures-are capable of multiple mechanisms of escaping the cumulative costs of frustration, resulting in unlimited equilibrium assembly, including elastic modes of "shape flattening" and the formation of weak, defective bonds that screen intra-assembly stresses. Here we study a model of one-dimensional chain assembly of incommensurate "polybricks" and determine its equilibrium assembly as a function of temperature, concentration, degree of shape frustration, elasticity, and interparticle binding, notably focusing on how weakly cohesive, defective bonds give rise to strongly temperature-dependent assembly. Complex assembly behavior derives from the competition between multiple distinct local minima in the free-energy landscape, including self-limiting chains, weakly bound aggregates of self-limiting chains, and strongly bound, elastically defrustrated assemblies. We show that this scenario, in general, gives rise to anomalous multiple aggregation behavior, in which disperse subunits (stable at low concentration and high temperature) first exhibit a primary aggregation transition to self-limiting chains (at intermediate concentration and temperature) which are ultimately unstable to condensation into unlimited assembly of finite-chains through weak binding beyond a secondary aggregation transition (at low temperature and high concentration). We show that window of stable self-limitation is determined both by the elastic costs of frustration in the assembly as well as energetic and entropic features of intersubunit binding.

Advances and Challenges in Minimally Invasive Spine Surgery.

Minimally invasive spine surgery continues to grow and develop. Over the past 50 years, there has been immense growth within this subspecialty of neurosurgery. A deep understanding of the historical context and future directions of this subspecialty is imperative to developing safe adoption and targeted innovation. This review aims to describe the advancements, and challenges that we face today in minimally invasive spine surgery.

CASi: A framework for cross-timepoint analysis of single-cell RNA sequencing data.

Single-cell RNA sequencing (scRNA-seq) technology has been widely used to study the differences in gene expression at the single cell level, providing insights into the research of cell development, differentiation, and functional heterogeneity. Various pipelines and workflows of scRNA-seq analysis have been developed but few considered multi-timepoint data specifically. In this study, we develop CASi, a comprehensive framework for analyzing multiple timepoints' scRNA-seq data, which provides users with: (1) cross-timepoint cell annotation, (2) detection of potentially novel cell types emerged over time, (3) visualization of cell population evolution, and (4) identification of temporal differentially expressed genes (tDEGs). Through comprehensive simulation studies and applications to a real multi-timepoint single cell dataset, we demonstrate the robust and favorable performance of the proposal versus existing methods serving similar purposes.

Effects of liposomal bupivacaine on opioid use and healthcare resource utilization after outpatient spine surgery: a real-world assessment.

BACKGROUND CONTEXT: Perioperative pain management affects cost and outcomes in elective spine surgery. PURPOSE: This study investigated the association between liposomal bupivacaine (LB) and outpatient spine surgery outcomes, including perioperative, postoperative, and postdischarge opioid use and healthcare resource utilization. STUDY DESIGN: This was a retrospective comparative study. PATIENT SAMPLE: Eligibility criteria included adults with ≥6 months of continuous data before and after outpatient spine procedures including discectomy, laminectomy, or lumbar fusion. Patients receiving LB were matched 1:3 to patients receiving non-LB analgesia by propensity scores. OUTCOME MEASURES: Outcomes included (1) opioid use in morphine milligram equivalents (MMEs) during the perioperative and postdischarge periods and (2) postdischarge readmission and emergency department (ED) visits up to 3 months after surgery. Generalized linear mixed-effects modeling with appropriate distributions was used for analysis. METHODS: Deidentified data from the IQVIA linkage claims databases (2016-2019) were used for the analysis. This study was funded by Pacira BioSciences, Inc. RESULTS: In total, 381 patients received LB and 1143 patients received non-LB analgesia. Baseline characteristics were well balanced after propensity score matching. The LB cohort used fewer MMEs versus the non-LB cohort before discharge (80 vs 132 MMEs [mean difference, -52 MMEs; p=.0041]). Following discharge, there was a nonsignificant reduction in opioid use in the LB cohort versus the non-LB cohort within 90 days (429 vs 480 MMEs [mean difference, -50 MMEs; p=.289]) and from >90 days to 180 days (349 vs 381 MMEs [mean difference, -31 MMEs; p=.507]). The LB cohort had significantly lower rates of ED visits at 2 months after discharge versus the non-LB cohort (3.9% vs 7.6% [odds ratio, 0.50; p=.015]). Postdischarge readmission rates did not differ between cohorts. CONCLUSIONS: Use of LB for outpatient spine surgery was associated with reduced opioid use at the hospital and nonsignificant reduction in opioid use at all postoperative timepoints examined through 90 days after surgery versus non-LB analgesia. ED visit rates were significantly lower at 60 days after discharge. These findings support reduced cost and improved quality metrics in patients treated with LB versus non-LB analgesia for outpatient spine surgery.

Examining a punishment-related brain circuit with miniature fluorescence microscopes and deep learning.

In humans experiencing substance use disorder (SUD), abstinence from drug use is often motivated by a desire to avoid some undesirable consequence of further use: health effects, legal ramifications, etc. This process can be experimentally modeled in rodents by training and subsequently punishing an operant response in a context-induced reinstatement procedure. Understanding the biobehavioral mechanisms underlying punishment learning is critical to understanding both abstinence and relapse in individuals with SUD. To date, most investigations into the neural mechanisms of context-induced reinstatement following punishment have utilized discrete loss-of-function manipulations that do not capture ongoing changes in neural circuitry related to punishment-induced behavior change. Here, we describe a two-pronged approach to analyzing the biobehavioral mechanisms of punishment learning using miniature fluorescence microscopes and deep learning algorithms. We review recent advancements in both techniques and consider a target neural circuit.

Neuro-ophthalmic evaluation and management of pituitary disease.

Neuro-ophthalmic evaluation is a crucial component of the diagnostic and prognostic assessment of pituitary disease and compressive chiasmopathy, and can inform the timing of vision-restoring tumour resection surgery. The most common disease affecting the pituitary with neuro-ophthalmic implications are pituitary adenomas. Neuro-ophthalmic manifestations include decreased vision, abnormal colour vision and impaired visual field or diplopia. The recognition of these syndromes is critical to achieve early diagnosis and treatment and to improve prognosis. The pattern of vision loss in chiasmal compression is determined by the anatomical relationship between the pituitary lesion and optic chiasm, and potential visual field defects include bitemporal deficits, junctional scotomas, monocular cecocentral defects, and incongruous homonymous hemianopias. Rarer neuro-ophthalmic manifestations of pituitary disease include ophthalmoplegia, nystagmus, and obstructive hydrocephalus. There is growing evidence that demonstrates the strong diagnostic utility of optical coherence tomography (OCT) parameters in detecting the presence of compressive chiasmopathy, as well as the prognostic ability to predict the rate and degree of visual recovery following decompression surgery. Long-term neuro-ophthalmic monitoring is critical for detecting delayed vision loss following resection surgery, which may represent tumour recurrence or secondary complications.

Discriminative performance of ocular surface staining and lid wiper epitheliopathy in dry eye disease: An investigator-masked, prospective registry-based, diagnostic accuracy study.

PURPOSE: To evaluate the diagnostic performance of corneal and conjunctival staining, and lid wiper epitheliopathy (LWE) in detecting dry eye disease, as defined by the global consensus Tear Film and Ocular Surface Society Dry Eye Workshop II (TFOS DEWS II) criteria. METHODS: A total of 2066 community residents (1285 females; mean ± SD age, 40 ± 19 years) were recruited in an investigator-masked, prospective registry-based, diagnostic accuracy study. Dry eye symptomology and ocular surface parameters were assessed in a single clinical session. The Sjögren's International Collaborative Clinical Alliance (SICCA) corneal and conjunctival staining scoring and Korb lid wiper epitheliopathy (LWE) grading were evaluated by an independent masked assessor. RESULTS: Overall, 807 (39 %) participants fulfilled the TFOS DEWS II criteria for dry eye disease, of which 178 (9 %) participants were classified as moderate-to-severe disease. The discriminative abilities of superior and inferior LWE (C-statistics, 0.724 and 0.712, respectively) were greater than corneal and conjunctival staining (C-statistics, 0.573 and 0.627, respectively). The Youden-optimal diagnostic cut-offs for the SICCA corneal and conjunctival staining scores were both ≥1, and the optimal thresholds for the Korb superior and inferior LWE grades were both ≥1. LWE was more commonly detected in both mild-to-moderate and moderate-to-severe dry eye disease, and demonstrated more consistent correlation with other ocular surface parameters across a broader range of disease severity. CONCLUSIONS: LWE demonstrates superior diagnostic performance relative to corneal and conjunctival staining. These findings would support the routine incorporation of LWE evaluation as part of the diagnostic workup of dry eye disease.

Racial, Ethnic, and Gender Diversity in United States Ophthalmology Clinical Trials.

Purpose: To investigate the representation of various gender, racial, and ethnic groups in ophthalmology clinical trials conducted in the United States (US) between 1997 and 2022. Design: Retrospective cross-sectional study. Participants: We included all participants in completed phase II/III, III, and IV ophthalmology clinical trials reported on the ClincialTrials.gov database. Methods: The proportional enrollment of each racial/ethnic and gender group in the clinical trials was calculated and compared with the US population. We also investigated the impact of various clinical trial features on the rate of reporting demographic information and enrollment of minorities. Main Outcome Measures: Proportional enrollment of each gender and race/ethnicity group compared with the US Census. Results: Of the total clinical trials included in the study, less than half (43.6%) provided information on the racial or ethnic backgrounds of their participants. The majority of the enrollees in trials were female (median: 57.5%, interquartile range [IQR]: 47.2%-65.8%). Among the trials that reported race and/or ethnicity data, White populations were overrepresented (median: 76.6%, IQR: 69.0%-84.0%, P = 0.001), and minorities, including Asian, Hispanic, and "other" groups, were underrepresented compared with the 2010 US Census (P < 0.001). Enrollment of Black individuals was found to be comparable to the US population estimates (median: 12.4%, IQR: 6.2%-20.8%, P = 0.44). The trial phase, the number of study participants, the primary clinical condition, and the year the trial started all affected demographic reporting and minority enrollments. Conclusions: Our findings highlight the need for increased efforts to promote diversity and inclusivity in ophthalmology clinical trials. Ensuring equitable inclusion of different gender, racial, and ethnic groups in the trials is essential for minimizing disparities and producing unbiased scientific findings generalizable to the entire population. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Parenting by individuals with fetal alcohol spectrum disorders and neurobehavioral outcomes in their offspring.

BACKGROUND: The neurobehavioral health impairments associated with prenatal alcohol exposure are now known to persist through adulthood. However, little is known about how these impairments affect individuals' parenting abilities and the neurobehavioral health of their offspring. This study compares parents with fetal alcohol spectrum disorder (FASD) with socioeconomically matched, nonexposed parents on measures of parenting and family support and assesses the neurobehavioral health of the children in both groups. METHODS: Forty-nine parent-child dyads were recruited from a longitudinal cohort of low socioeconomic status. Measures included the Parenting Styles and Dimensions Questionnaire, Family Support Scale, an in-depth psychosocial history, the Pediatric Symptom Checklist (PSC; parent and child reports), the Achenbach Child Behavior Checklist (CBCL), a screening psychiatric evaluation of the child, the NIH Toolbox Cognition Battery for Children, The Vineland Adaptive Behavior Scales-Third Edition caregiver rating form, and the Traumatic Events Screening Inventory (parent and child reports). RESULTS: Cognitive functioning was impaired for both offspring of parents with FASD ( x ¯ = 81.1, SD = 13.0) and control parents ( x ¯ = 79.9, SD = 16.1), but despite similar impairments, children of parents with FASD were less likely to have an Individualized Education Plan than controls. Adaptive functioning was adequate for both groups ( x ¯ = 92.1, SD = 15.4 in exposed vs. x ¯ = 94.3, SD = 12.3 in controls) and CBCL and PSC scores in both groups were within normal limits. Parents in both groups showed a predominantly authoritative parenting style. Despite a similar frequency of adverse childhood experiences in both groups, parents with FASD were less likely to recognize their child's adverse experiences. CONCLUSION: Parents with FASD display notable strengths including a predominantly authoritative parenting style. However, parents with FASD underrecognize child trauma and underutilize developmental services compared to socioeconomically matched controls, despite similar neurocognitive impairments. Impairments in adaptive functioning in parents with FASD may translate into difficulties with child-parent communication and limit both insight into neurobehavioral problems and advocacy skills. There is a need to identify and support parents with FASD to optimize their parenting abilities in the context of their individual strengths and difficulties.

Streptococcus canis Native Aortic Valve Endocarditis Linked to Cat Exposure: A Case Report and Review.

Streptococcus canis is an uncommon human pathogen, but documented infections have been mostly associated with exposure to dogs. There are only five documented cases of endocarditis secondary to streptococcus canis, with all cases except one documenting exposure to a canine. We present a 74-year-old male with a history of Type 2 diabetes mellitus, CKD 3, moderate aortic stenosis and remote exposure to agent orange, who was found to have Streptococcus canis native valve endocarditis without exposure to a dog. To the best of our knowledge this case is the first case of endocarditis linked to feline exposure.