Mechanical influence of facet tropism in patients with chronic discogenic pain disorder.

Aims: The presence of facet tropism has been correlated with an elevated susceptibility to lumbar disc pathology. Our objective was to evaluate the impact of facet tropism on chronic lumbosacral discogenic pain through the analysis of clinical data and finite element modelling (FEM). Methods: Retrospective analysis was conducted on clinical data, with a specific focus on the spinal units displaying facet tropism, utilizing FEM analysis for motion simulation. We studied 318 intervertebral levels in 156 patients who had undergone provocation discography. Significant predictors of clinical findings were identified by univariate and multivariate analyses. Loading conditions were applied in FEM simulations to mimic biomechanical effects on intervertebral discs, focusing on maximal displacement and intradiscal pressures, gauged through alterations in disc morphology and physical stress. Results: A total of 144 discs were categorized as 'positive' and 174 discs as 'negative' by the results of provocation discography. The presence of defined facet tropism (OR 3.451, 95% CI 1.944 to 6.126) and higher Adams classification (OR 2.172, 95% CI 1.523 to 3.097) were important predictive parameters for discography-'positive' discs. FEM simulations showcased uneven stress distribution and significant disc displacement in tropism-affected discs, where loading exacerbated stress on facets with greater angles. During varied positions, notably increased stress and displacement were observed in discs with tropism compared to those with normal facet structure. Conclusion: Our findings indicate that facet tropism can contribute to disc herniation and changes in intradiscal pressure, potentially exacerbating disc degeneration due to altered force distribution and increased mechanical stress.

Circulating tumor DNA predicts venous thromboembolism in patients with cancers.

INTRODUCTION: Despite rapid advances in liquid biopsy for circulating tumor DNA (ctDNA), its prognostic value for venous thromboembolism (VTE) in patients with cancer is underexplored, particularly in underserved and minoritized populations. METHODS: We analyzed data from 1,038 cancer patients who underwent ctDNA measurement for oncologic care at a large safety-net hospital system in the US. We investigated the association between ctDNA and VTE after adjusting for cancer type, stage, treatment, and time from initial diagnosis using Fine-Gray models. We further assessed the discrimination of the genetic, clinical-only, and combined models using the area under the time-dependent receiver operating characteristic curve (AUC). RESULTS: The presence of pathogenic ctDNA was independently associated with VTE after adjusting for clinical variables. Independent of tumor type, the number of pathogenic ctDNA mutations was predictive of future VTE risk (adjusted subdistribution hazard ratio 2.75, 1.94, and 1.38 for ≥3, 2, and 1 pathogenic mutation, respectively, compared to none; p<0.0001). The association was primarily driven by mutations in KRAS, PTEN, CDKN2A, NF1, and EGFR genes. Compared to the clinical-only model (AUC 0.71, 95% CI 0.64-0.76), the combined clinical and ctDNA model had a numerically higher time-dependent AUC (AUC 0.74, 95% CI 0.67-0.80). CONCLUSIONS: CtDNA testing may serve as an adjunctive tool to clinical risk assessment models in cancer patients to improve personalized VTE risk assessment and management.

Identifying priority challenges of older adults with COPD: A multiphase intervention refinement study.

BACKGROUND: Identifying priority challenges of older adults with chronic obstructive pulmonary disease (COPD) is critical to designing interventions aimed at improving their well-being and independence. OBJECTIVE: To prioritize challenges of older adults with COPD and those who care for them to guide refinement of a telephonic nurse coach intervention for patients with COPD and their family caregivers (EPIC: Empowering People to Independence in COPD). DESIGN: Multiphase study guided by Baltes Theory of Successful Aging and the 5Ms Framework: Phase 1: Nominal group technique (NGT), a structured process of prioritizing responses to a question through group consensus. Phase 2: Rapid qualitative analysis. Phase 3: Intervention mapping and refinement. SETTING: Ambulatory, virtual. PARTICIPANTS: Older adults with COPD, family caregivers, clinic staff (nurses, respiratory therapists), clinicians (physicians, nurse practitioners), and health system leaders. RESULTS: NGT sessions were conducted by constituency group with 37 participants (n = 7 patients, n = 6 family caregivers, n = 8 clinic staff, n = 9 clinicians, n = 7 health system leaders) (Phase 1). Participants generated 92 statements across five themes (Phase 2): (1) "Barriers to care", (2) "Family caregiver needs", (3) "Functional status and mobility issues", (4) "Illness understanding", and (5) "COPD care complexities". Supplemental oxygen challenges emerged as a critical problem, and prioritized challenges differed by group. Patients and clinic staff prioritized "Functional status and mobility issues", family caregivers prioritized "Family caregiver needs", and clinicians and health system leaders prioritized "COPD care complexities". Intervention mapping (Phase 3) guided EPIC refinement focused on meeting patient priorities of independence and mobility but accounting for all priorities. CONCLUSIONS: Diverse constituency groups identified priority challenges for older adults with COPD. Functional status and mobility issues, particularly related to supplemental oxygen, emerged as patient prioritized challenges. IMPLICATIONS: Patient-centered interventions for older adults with COPD must account for their prioritized functional and supplemental oxygen needs and explore diverse constituent perspectives to facilitate intervention enrichment.

Association Between the Timing of Atrial Fibrillation Detection and Functional Outcome Following Mechanical Thrombectomy.

BACKGROUND: Atrial fibrillation detected after stroke (AFDAS) refers to the identification of newly diagnosed atrial fibrillation (AF) following an ischemic stroke in patients without known AF (KAF). The objective of this study was to compare the functional outcomes of patients diagnosed with AFDAS and those with KAF who underwent mechanical thrombectomy. METHODS AND RESULTS: We conducted a retrospective analysis of patients who underwent mechanical thrombectomy and with either new AF diagnosed during hospitalization or KAF. We compared the baseline characteristics, clinical, and procedure-related variables between those with AFDAS and KAF. The primary outcome was the achievement of functional independence, defined as a modified Rankin Scale score of 0 to 2, at 3 months after stroke. Of the 252 patients, 101 (40.1%) were classified into the AFDAS group. The KAF group exhibited a higher rate of stroke history compared with the AFDAS group (32.5% versus 13.9%; P=0.001). Tandem occlusion was more common in the KAF group (13.2% versus 5.9%), while M2 occlusion was more common in the AFDAS group (11.3% versus 20.8%). The proportion of patients who achieved functional independence was higher in the AFDAS group (37.7% versus 52.5%; P=0.029). Multivariable analysis showed that AFDAS was associated with a favorable functional outcome (odds ratio, 2.67 [95% CI, 1.39-5.14]; P=0.003). CONCLUSIONS: AFDAS demonstrated a positive association with functional independence in patients with stroke who underwent mechanical thrombectomy and were finally diagnosed to have AF during hospitalization. The observed disparities in occlusion site, intractable thrombus, and history of previous stroke may have contributed to these findings.

Project EPIC (Empowering People to Independence in COPD): Study protocol for a hybrid effectiveness-implementation pilot randomized controlled trial of telephonic, geriatrics-palliative care nurse-coaching in older adults with COPD and their family caregivers.

BACKGROUND: EPIC (Empowering People to Independence in COPD) is a geriatric-palliative care telephonic, nurse coach intervention informed by Baltes' Theory of Successful Aging and adapted from the ENABLE (Educate, Nurture, Advise, Before Life Ends) intervention. EPIC, focused on improving independence, mobility, well-being, and COPD symptoms, has undergone formative and summative evaluation for adults with COPD. METHODS: The primary study aim is to assess the refined EPIC intervention's feasibility and acceptability via a pilot hybrid effectiveness-implementation randomized control trial in community-dwelling older adults with moderate to severe COPD and their family caregivers. The secondary aim is to explore the impact of EPIC on patient and caregiver outcomes. Older adults with COPD and their family caregivers (target N = 60 dyads) will be randomized to EPIC (intervention) or usual COPD care (control). EPIC includes six patient and four family caregiver weekly, telephone-based nurse coach sessions using a manualized curriculum (Charting Your Course), plus three monthly follow-up calls. Feasibility will be measured as completion of EPIC intervention and trial components (e.g., recruitment, retention, data collection). Acceptability will be evaluated using satisfaction surveys and post-study feedback interviews. A blinded data collector will assess exploratory outcomes (e.g., Life-Space mobility, quality of life, caregiver burden, emotional symptoms, loneliness, cognitive impairment, functional status, healthcare utilization) at baseline, 12, and 24 weeks. DISCUSSION: This intervention fills a gap in addressing the geriatrics and palliative care needs and equity for adults with COPD and their family caregivers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05040386.

Developing a genetic testing panel for evaluation of morbidities in kidney transplant recipients.

Cardiovascular disease, infection, malignancy, and thromboembolism are major causes of morbidity and mortality in kidney transplant recipients (KTR). Prospectively identifying monogenic conditions associated with post-transplant complications may enable personalized management. Therefore, we developed a transplant morbidity panel (355 genes) associated with major post-transplant complications including cardiometabolic disorders, immunodeficiency, malignancy, and thrombophilia. This gene panel was then evaluated using exome sequencing data from 1590 KTR. Additionally, genes associated with monogenic kidney and genitourinary disorders along with American College of Medical Genetics (ACMG) secondary findings v3.2 were annotated. Altogether, diagnostic variants in 37 genes associated with Mendelian kidney and genitourinary disorders were detected in 9.9% (158/1590) of KTR; 25.9% (41/158) had not been clinically diagnosed. Moreover, the transplant morbidity gene panel detected diagnostic variants for 56 monogenic disorders in 9.1% KTRs (144/1590). Cardiovascular disease, malignancy, immunodeficiency, and thrombophilia variants were detected in 5.1% (81), 2.1% (34), 1.8% (29) and 0.2% (3) among 1590 KTRs, respectively. Concordant phenotypes were present in half of these cases. Reviewing implications for transplant care, these genetic findings would have allowed physicians to set specific risk factor targets in 6.3% (9/144), arrange intensive surveillance in 97.2% (140/144), utilize preventive measures in 13.2% (19/144), guide disease-specific therapy in 63.9% (92/144), initiate specialty referral in 90.3% (130/144) and alter immunosuppression in 56.9% (82/144). Thus, beyond diagnostic testing for kidney disorders, sequence annotation identified monogenic disorders associated with common post-transplant complications in 9.1% of KTR, with important clinical implications. Incorporating genetic diagnostics for transplant morbidities would enable personalized management in pre- and post-transplant care.

Extracorporeal shockwave therapy of the perineum for male patients with chronic pelvic pain syndrome: a pilot study.

Background: Chronic pelvic pain syndrome (CPPS) is a complex condition that is often difficult to treat and may sometimes require a multidisciplinary team. Among the wide array of treatment options is extracorporeal shockwave therapy (ESWT). However, its role in CPPS remains controversial. The purpose of our study is to assess the efficacy and safety of ESWT of the perineum in male patients with CPPS. Methods: Fourteen patients aged between 21 and 85 years were recruited in this single-center, single-arm prospective trial from October 2018 to October 2020. ESWT was delivered to the perineum weekly for up to 8 weeks. Assessment was done via International Index for Erectile Function, International Prostate Symptom Score, King's Health Questionnaire, National Institutes of Health - Chronic Prostatitis Symptom Index, Visual Analogue Scale, Analgesic Questionnaire, and UPOINT (urinary symptoms [U], psychosocial dysfunction [P], organ-specific symptoms [O], infection-related symptoms [I], neurological/systemic conditions [N], tenderness of skeletal muscles [T]) phenotype system. The parameters are assessed before the start and end of treatment as well as at regular time points on follow-up appointments up to 20 weeks. Results: Thirteen patients completed the study. There was improvement in the Visual Analogue Scale pain score, Tenderness domain on UPOINT, King's Health Questionnaire, and National Institutes of Health - Chronic Prostatitis Symptom Index scores. In terms of erectile function, improvement in the erectile function domain of International Index for Erectile Function was observed. There was also significant improvement in lower urinary tract symptoms assessed on International Prostate Symptom Score. There were no adverse events reported post treatment and during the follow-up period. Conclusions: ESWT improved pain and quality of life of male patients with CPPS. It can be a safe and effective treatment modality in the armamentarium of CPPS.

Symptomatology and Quality of Life of Older People With HIV and Comorbid Chronic Obstructive Pulmonary Diseases From an HIV Clinic in Birmingham, Alabama.

ABSTRACT: Psychological symptomatology and quality of life (QoL) have been studied in older people with HIV (PWH) and those with chronic obstructive pulmonary disease (COPD), respectively, but there is a dearth of studies in older PWH with COPD. Our study compared depressive symptoms, anxiety, and QoL between older PWH with and without COPD using data from an HIV clinic in Birmingham, Alabama, from January 2018 to February 2020. Data on depressive symptoms (Patient Health Questionnaire-9), anxiety (Patient Health Questionnaire-5 Anxiety), and QoL (EuroQoL-5 Dimension) were analyzed. Among 690 PWH aged 50 years or older, 102 individuals (14.8%) had COPD. Significant differences were found between the two groups in depressive symptoms and components of QoL (e.g., mobility, self-care, usual activities, and pain/discomfort), but not in anxiety and general health. Experiencing COPD may worsen depressive symptomatology and QoL in older PWH, highlighting the need for tailored health care and research for this population.

Natural history of cancer-associated splanchnic vein thrombosis.

BACKGROUND: There is uncertainty in the management of cancer-associated isolated splanchnic vein thrombosis (SpVT). OBJECTIVES: To describe the natural history of SpVT by cancer type and thrombus composition and to review anticoagulation (AC) practices and associated rates of usual-site venous thromboembolism (VTE), major and clinically relevant nonmajor bleeding (MB/CRNMB), recanalization/progression, and mortality. METHODS: We performed a retrospective cohort study in patients with SpVT at 2 cancer care centers in Houston, Texas. We estimated the incidence of usual-site VTE and MB/CRNMB at 6 months using competing risk methods and examined venous patency in a subset of patients with repeat imaging. We assessed associations with mortality using Cox regression. RESULTS: Among 15 342 patients with an incident cancer diagnosis from 2011 to 2020, we identified 298 with isolated SpVT. Patients with hepatocellular carcinoma (HCC) and SpVT (n = 146) had the highest disease prevalence (20%), lowest rate of AC treatment (2%), and similar rate of usual-site VTE (4.2%) vs those without SpVT (5.2%) at 6 months, though tumor thrombus vs bland was associated with worse overall survival. In patients with non-HCC bland SpVT (n = 114), AC (n = 37) was more common in those with non-upper gastrointestinal cancers and fewer comorbidities. AC was associated with more recanalization (44% vs 15%, P = .041) but no differences in usual-site VTE, MB/CRNMB, or mortality at 6 months. CONCLUSION: Cancer-associated isolated SpVT is a common but heterogeneous thrombotic disease that is treated differently from usual-site VTE. Tumor thrombus is a negative prognostic factor. Initiation of AC in bland thrombi requires judicious consideration of thrombotic and bleeding risk.

Genetic versus self-reported African ancestry of the recipient and neighborhood predictors of kidney transplantation outcomes in 2 multiethnic urban cohorts.

African American (AA) kidney recipients have a higher risk of allograft rejection and failure compared to non-AAs, but to what extent these outcomes are due to genetic versus environmental effects is currently unknown. Herein, we tested the effects of recipient self-reported race versus genetic proportion of African ancestry (pAFR), and neighborhood socioeconomic status (SES) on kidney allograft outcomes in multiethnic kidney transplant recipients from Columbia University (N = 1083) and the University of Pennsylvania (N = 738). All participants were genotyped with SNP arrays to estimate genetic admixture proportions. US census tract variables were used to analyze the effect of neighborhood factors. In both cohorts, self-reported recipient AA race and pAFR were individually associated with increased risk of rejection and failure after adjustment for known clinical risk factors and neighborhood SES factors. Joint analysis confirmed that self-reported recipient AA race and pAFR were both associated with a higher risk of allograft rejection (AA: HR 1.61 (1.31-1.96), P = 4.05E-06; pAFR: HR 1.90 (1.46-2.48), P = 2.40E-06) and allograft failure (AA: HR 1.52 (1.18-1.97), P = .001; pAFR: HR 1.70 (1.22-2.35), P = .002). Further research is needed to disentangle the role of genetics versus environmental, social, and structural factors contributing to poor transplantation outcomes in kidney recipients of African ancestry.

The yield of tuberculosis contact investigation on relapsed TB patients and analysis of associated risk factors: Singapore's experience.

The yield of contact investigation on relapsed tuberculosis (TB) cases can guide strategies and resource allocation in the TB control programme. We conducted a retrospective cohort study to review the yield of contact investigation in relapsed TB cases and identify factors associated with TB infection (TBI) among close contacts of relapsed TB cases notified between 2018 and 2022 in Singapore. TB infection positivity was higher among contacts of relapsed cases which were culture-positive for Mycobacterium tuberculosis complex compared to those who were only polymerase chain reaction (PCR)-positive (14.8% vs. 12.3%). On multivariate analysis, after adjusting for age and gender of the index, gender, and existing comorbidities of contacts, factors independently associated with TBI were culture and smear positivity of the index (AOR 1.41, 95%CI 1.02-1.94), higher odds with every 10 years of increase in age compared to contacts below aged 30, contacts who were not Singapore residents (AOR 2.09, 95%CI 1.46-2.97), and household contacts (AOR 2.19, 95%CI 1.44-3.34). Although the yield of screening was higher for those who were culture-positive compared to only PCR-positive relapsed cases, contact tracing for only PCR-positive cases may still be important in a country with moderate TB incidence, should resources allow.

Socioeconomic differences between medically and surgically treated prolactinomas: a retrospective review of 598 patients.

OBJECTIVE: Socioeconomic status (SES) is known to affect presentations and outcomes in pituitary neuroendocrine tumor resections, but there is a paucity of literature examining its impact specifically on patients with prolactinomas, who may be treated medically or surgically. The authors sought to determine whether SES was associated with differences in treatment choice or outcomes for prolactinoma patients. METHODS: The authors retrospectively reviewed patient records at a high-volume academic pituitary center for prolactinoma diagnoses. Patients were split into medically and surgically treated cohorts. Race, ethnicity, insurance status, primary care physician (PCP) status, and zip code-based income data were collected and examined as socioeconomic covariates. Outcomes of interest included pretreatment likelihood of surgical cure, medical versus surgical treatment allocation, and posttreatment remission rates. RESULTS: The authors analyzed 568 prolactinoma patients (351 medically treated and 217 surgically treated). Patients receiving surgery were more likely to have Medicaid or private insurance (p < 0.001) and have lower incomes (p < 0.001) than medically treated patients. Lower-income surgical patients were more likely to require surgical intervention for an indication such as tumor decompression than higher-income patients (p = 0.023). Surgical patients with a PCP had a higher estimated likelihood of surgical cure (p = 0.008), while no SES-based differences in surgical remission likelihood existed in the medical cohort. After surgery, surgical patients who achieved remission had significantly higher income than those who did not (p < 0.001). Other SES factors were not associated with surgical remission, and among medically treated patients, remission rates were not affected by any SES factor. Income was inversely related to prolactinoma size in both cohorts (surgical, p < 0.001; medical, p = 0.005) but was associated more prominently in surgical patients (surgical, -0.65 mm per $10,000; medical, -0.37 mm per $10,000). CONCLUSIONS: While surgical prolactinoma patients were prone to income and PCP-related disparities, no SES disparities were found among medically treated patients. Income had a more pronounced association with tumor size in the surgical cohort and likely contributed to the increased need for surgical intervention seen in low-income surgical patients. Addressing socioeconomic healthcare disparities is needed among surgical prolactinoma patients to increase rates of early presentation and improve the outcomes of low-SES populations.

Does Olfactory Training Improve Brain Function and Cognition? A Systematic Review.

Olfactory training (OT), or smell training,consists of repeated exposure to odorants over time with the intended neuroplastic effect of improving or remediating olfactory functioning. Declines in olfaction parallel declines in cognition in various pathological conditions and aging. Research suggests a dynamic neural connection exists between olfaction and cognition. Thus, if OT can improve olfaction, could OT also improve cognition and support brain function? To answer this question, we conducted a systematic review of the literature to determine whether there is evidence that OT translates to improved cognition or altered brain morphology and connectivity that supports cognition. Across three databases (MEDLINE, Scopus, & Embase), 18 articles were identified in this systematic review. Overall, the reviewed studies provided emerging evidence that OT is associated with improved global cognition, and in particular, verbal fluency and verbal learning/memory. OT is also associated with increases in the volume/size of olfactory-related brain regions, including the olfactory bulb and hippocampus, and altered functional connectivity. Interestingly, these positive effects were not limited to patients with smell loss (i.e., hyposmia & anosmia) but normosmic (i.e., normal ability to smell) participants benefitted as well. Implications for practice and research are provided.

Sequential appetite suppression by oral and visceral feedback to the brainstem.

The termination of a meal is controlled by dedicated neural circuits in the caudal brainstem. A key challenge is to understand how these circuits transform the sensory signals generated during feeding into dynamic control of behaviour. The caudal nucleus of the solitary tract (cNTS) is the first site in the brain where many meal-related signals are sensed and integrated1-4, but how the cNTS processes ingestive feedback during behaviour is unknown. Here we describe how prolactin-releasing hormone (PRLH) and GCG neurons, two principal cNTS cell types that promote non-aversive satiety, are regulated during ingestion. PRLH neurons showed sustained activation by visceral feedback when nutrients were infused into the stomach, but these sustained responses were substantially reduced during oral consumption. Instead, PRLH neurons shifted to a phasic activity pattern that was time-locked to ingestion and linked to the taste of food. Optogenetic manipulations revealed that PRLH neurons control the duration of seconds-timescale feeding bursts, revealing a mechanism by which orosensory signals feed back to restrain the pace of ingestion. By contrast, GCG neurons were activated by mechanical feedback from the gut, tracked the amount of food consumed and promoted satiety that lasted for tens of minutes. These findings reveal that sequential negative feedback signals from the mouth and gut engage distinct circuits in the caudal brainstem, which in turn control elements of feeding behaviour operating on short and long timescales.

Effects of defoliant exposure and medication use on the development of Parkinson's disease in veterans.

BACKGROUND: Vietnam-era veterans were exposed to Agent Orange (AO), which is associated with a high prevalence of Parkinson's disease (PD). However, little is known about the development of PD-like symptoms caused by drug-induced parkinsonism (DIP) in such populations. This study aimed to investigate PD incidence and PD risk following exposure to AO or DIP-risk drugs in veterans. METHODS: A retrospective cohort study was conducted using 12 years (2009-2020) of electronic medical records of the Veterans Health Service Medical Center, the largest Veterans Affairs hospital in South Korea (n = 37,246; 100% male; age, 65.57 ± 8.12 years). Exposure to AO or DIP-risk drugs, including antipsychotic, prokinetic, anti-epileptic, dopamine-depleting and anti-anginal agents, was assessed in veterans with PD, operationally defined as having a PD diagnosis and one or more prescriptions for PD treatment. The PD risk was calculated using multiple logistic regression analysis adjusted for age and comorbidities. RESULTS: The rates of DIP-risk drug use and AO exposure were 37.92% and 62.62%, respectively. The PD incidence from 2010 to 2020 was 3.08%; 1.30% with neither exposure, 1.63% with AO exposure, 4.38% with DIP-risk drug use, and 6.33% with both. Combined exposure to AO and DIP-risk drugs increased the PD risk (adjusted odds ratio = 1.68, 95% confidence interval, 1.36-2.08, P < 0.001). CONCLUSIONS: The PD incidence was 1.31 times higher with AO exposure alone and 1.68 times higher with AO exposure and DIP-risk drug use. The results suggest the necessity for careful monitoring and DIP-risk drug prescription in patients with AO exposure.

Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy.

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.

Metabolic Barriers to Glioblastoma Immunotherapy.

Glioblastoma (GBM) is the most common primary brain tumor with a poor prognosis with the current standard of care treatment. To address the need for novel therapeutic options in GBM, immunotherapies which target cancer cells through stimulating an anti-tumoral immune response have been investigated in GBM. However, immunotherapies in GBM have not met with anywhere near the level of success they have encountered in other cancers. The immunosuppressive tumor microenvironment in GBM is thought to contribute significantly to resistance to immunotherapy. Metabolic alterations employed by cancer cells to promote their own growth and proliferation have been shown to impact the distribution and function of immune cells in the tumor microenvironment. More recently, the diminished function of anti-tumoral effector immune cells and promotion of immunosuppressive populations resulting from metabolic alterations have been investigated as contributory to therapeutic resistance. The GBM tumor cell metabolism of four nutrients (glucose, glutamine, tryptophan, and lipids) has recently been described as contributory to an immunosuppressive tumor microenvironment and immunotherapy resistance. Understanding metabolic mechanisms of resistance to immunotherapy in GBM can provide insight into future directions targeting the anti-tumor immune response in combination with tumor metabolism.

Rare Single Nucleotide and Copy Number Variants and the Etiology of Congenital Obstructive Uropathy: Implications for Genetic Diagnosis.

SIGNIFICANCE STATEMENT: Congenital obstructive uropathy (COU) is a prevalent human developmental defect with highly heterogeneous clinical presentations and outcomes. Genetics may refine diagnosis, prognosis, and treatment, but the genomic architecture of COU is largely unknown. Comprehensive genomic screening study of 733 cases with three distinct COU subphenotypes revealed disease etiology in 10.0% of them. We detected no significant differences in the overall diagnostic yield among COU subphenotypes, with characteristic variable expressivity of several mutant genes. Our findings therefore may legitimize a genetic first diagnostic approach for COU, especially when burdening clinical and imaging characterization is not complete or available. BACKGROUND: Congenital obstructive uropathy (COU) is a common cause of developmental defects of the urinary tract, with heterogeneous clinical presentation and outcome. Genetic analysis has the potential to elucidate the underlying diagnosis and help risk stratification. METHODS: We performed a comprehensive genomic screen of 733 independent COU cases, which consisted of individuals with ureteropelvic junction obstruction ( n =321), ureterovesical junction obstruction/congenital megaureter ( n =178), and COU not otherwise specified (COU-NOS; n =234). RESULTS: We identified pathogenic single nucleotide variants (SNVs) in 53 (7.2%) cases and genomic disorders (GDs) in 23 (3.1%) cases. We detected no significant differences in the overall diagnostic yield between COU sub-phenotypes, and pathogenic SNVs in several genes were associated to any of the three categories. Hence, although COU may appear phenotypically heterogeneous, COU phenotypes are likely to share common molecular bases. On the other hand, mutations in TNXB were more often identified in COU-NOS cases, demonstrating the diagnostic challenge in discriminating COU from hydronephrosis secondary to vesicoureteral reflux, particularly when diagnostic imaging is incomplete. Pathogenic SNVs in only six genes were found in more than one individual, supporting high genetic heterogeneity. Finally, convergence between data on SNVs and GDs suggest MYH11 as a dosage-sensitive gene possibly correlating with severity of COU. CONCLUSIONS: We established a genomic diagnosis in 10.0% of COU individuals. The findings underscore the urgent need to identify novel genetic susceptibility factors to COU to better define the natural history of the remaining 90% of cases without a molecular diagnosis.

Tools for Screening and Measuring Anxiety Among Women Living with HIV of Reproductive Age: A Scoping Review.

Emerging evidence suggests that women living with HIV (WLWH) may experience higher rates of anxiety than men living with HIV and women living without HIV. To date, relatively little knowledge exists on valid anxiety screening and diagnostic tools and how they are used among WLWH, specifically WLWH of reproductive age. Thus, the purpose of this scoping review was to describe what is known in the published literature about anxiety among WLWH and the tools used to measure and screen for anxiety in clinical and research contexts. The Arksey and O'Malley methodological framework was used to guide a scoping review of published articles in PsycINFO, Scopus, Sociological Abstracts, and PubMed databases. Twenty-one measures of anxiety were used across the 52 articles identified in the search. Most measures used were self-report. Inconsistencies in standardized screening tools and cutoff scores were observed across studies. Further, measures to assess anxiety varied among studies focused on WLWH. Based on the results from this review, there is a need for consistent, valid measures of anxiety to advance research and clinical practice to support the well-being of WLWH.

Clinical and Genetic Characteristics of CKD Patients with High-Risk APOL1 Genotypes.

SIGNIFICANCE STATEMENT: APOL1 high-risk genotypes confer a significant risk of kidney disease, but variability in patient outcomes suggests the presence of modifiers of the APOL1 effect. We show that a diverse population of CKD patients with high-risk APOL1 genotypes have an increased lifetime risk of kidney failure and higher eGFR decline rates, with a graded risk among specific high-risk genotypes. CKD patients with high-risk APOL1 genotypes have a lower diagnostic yield for monogenic kidney disease. Exome sequencing revealed enrichment of rare missense variants within the inflammasome pathway modifying the effect of APOL1 risk genotypes, which may explain some clinical heterogeneity. BACKGROUND: APOL1 genotype has significant effects on kidney disease development and progression that vary among specific causes of kidney disease, suggesting the presence of effect modifiers. METHODS: We assessed the risk of kidney failure and the eGFR decline rate in patients with CKD carrying high-risk ( N =239) and genetically matched low-risk ( N =1187) APOL1 genotypes. Exome sequencing revealed monogenic kidney diseases. Exome-wide association studies and gene-based and gene set-based collapsing analyses evaluated genetic modifiers of the effect of APOL1 genotype on CKD. RESULTS: Compared with genetic ancestry-matched patients with CKD with low-risk APOL1 genotypes, those with high-risk APOL1 genotypes had a higher risk of kidney failure (Hazard Ratio [HR]=1.58), a higher decline in eGFR (6.55 versus 3.63 ml/min/1.73 m 2 /yr), and were younger at time of kidney failure (45.1 versus 53.6 years), with the G1/G1 genotype demonstrating the highest risk. The rate for monogenic kidney disorders was lower among patients with CKD with high-risk APOL1 genotypes (2.5%) compared with those with low-risk genotypes (6.7%). Gene set analysis identified an enrichment of rare missense variants in the inflammasome pathway in individuals with high-risk APOL1 genotypes and CKD (odds ratio=1.90). CONCLUSIONS: In this genetically matched cohort, high-risk APOL1 genotypes were associated with an increased risk of kidney failure and eGFR decline rate, with a graded risk between specific high-risk genotypes and a lower rate of monogenic kidney disease. Rare missense variants in the inflammasome pathway may act as genetic modifiers of APOL1 effect on kidney disease.