Increased peritoneal TGF-ß1 is associated with ascites-induced NK-cell dysfunction and reduced survival in high-grade epithelial ovarian cancer.

Natural killer (NK) cell therapy represents an attractive immunotherapy approach against recurrent epithelial ovarian cancer (EOC), as EOC is sensitive to NK cell-mediated cytotoxicity. However, NK cell antitumor activity is dampened by suppressive factors in EOC patient ascites. Here, we integrated functional assays, soluble factor analysis, high-dimensional flow cytometry cellular component data and clinical parameters of advanced EOC patients to study the mechanisms of ascites-induced inhibition of NK cells. Using a suppression assay, we found that ascites from EOC patients strongly inhibits peripheral blood-derived NK cells and CD34+ progenitor-derived NK cells, albeit the latter were more resistant. Interestingly, we found that higher ascites-induced NK cell inhibition correlated with reduced progression-free and overall survival in EOC patients. Furthermore, we identified transforming growth factor (TGF)-ß1 to correlate with ascites-induced NK cell dysfunction and reduced patient survival. In functional assays, we showed that proliferation and anti-tumor reactivity of CD34+ progenitor-derived NK cells are significantly affected by TGF-ß1 exposure. Moreover, inhibition of TGF-ß1 signaling with galunisertib partly restored NK cell functionality in some donors. For the cellular components, we showed that the secretome is associated with a different composition of CD45+ cells between ascites of EOC and benign reference samples with higher proportions of macrophages in the EOC patient samples. Furthermore, we revealed that higher TGF-ß1 levels are associated with the presence of M2-like macrophages, B cell populations and T-regulatory cells in EOC patient ascites. These findings reveal that targeting TGF-ß1 signaling could increase NK cell immune responses in high-grade EOC patients.

Smartphone Screen Time Characteristics in People With Suicidal Thoughts: Retrospective Observational Data Analysis Study.

Background: Smartphone-based monitoring in natural settings provides opportunities to monitor mental health behaviors, including suicidal thoughts and behaviors. To date, most suicidal thoughts and behaviors research using smartphones has primarily relied on collecting so-called "active" data, requiring participants to engage by completing surveys. Data collected passively from smartphone sensors and logs may offer an objectively measured representation of an individual's behavior, including smartphone screen time. Objective: This study aims to present methods for identifying screen-on bouts and deriving screen time characteristics from passively collected smartphone state logs and to estimate daily smartphone screen time in people with suicidal thinking, providing a more reliable alternative to traditional self-report. Methods: Participants (N=126; median age 22, IQR 16-33 years) installed the Beiwe app (Harvard University) on their smartphones, which passively collected phone state logs for up to 6 months after discharge from an inpatient psychiatric unit (adolescents) or emergency department visit (adults). We derived daily screen time measures from these logs, including screen-on time, screen-on bout duration, screen-off bout duration, and screen-on bout count. We estimated the mean of these measures across age subgroups (adults and adolescents), phone operating systems (Android and iOS), and monitoring stages after the discharge (first 4 weeks vs subsequent weeks). We evaluated the sensitivity of daily screen time measures to changes in the parameters of the screen-on bout identification method. Additionally, we estimated the impact of a daylight time change on minute-level screen time using function-on-scalar generalized linear mixed-effects regression. Results: The median monitoring period was 169 (IQR 42-169) days. For adolescents and adults, mean daily screen-on time was 254.6 (95% CI 231.4-277.7) and 271.0 (95% CI 252.2-289.8) minutes, mean daily screen-on bout duration was 4.233 (95% CI 3.565-4.902) and 4.998 (95% CI 4.455-5.541) minutes, mean daily screen-off bout duration was 25.90 (95% CI 20.09-31.71) and 26.90 (95% CI 22.18-31.66) minutes, and mean daily screen-on bout count (natural logarithm transformed) was 4.192 (95% CI 4.041-4.343) and 4.090 (95% CI 3.968-4.213), respectively; there were no significant differences between smartphone operating systems (all P values were >.05). The daily measures were not significantly different for the first 4 weeks compared to the fifth week onward (all P values were >.05), except average screen-on bout in adults (P value = .018). Our sensitivity analysis indicated that in the screen-on bout identification method, the cap on an individual screen-on bout duration has a substantial effect on the resulting daily screen time measures. We observed time windows with a statistically significant effect of daylight time change on screen-on time (based on 95% joint confidence intervals bands), plausibly attributable to sleep time adjustments related to clock changes. Conclusions: Passively collected phone logs offer an alternative to self-report measures for studying smartphone screen time characteristics in people with suicidal thinking. Our work demonstrates the feasibility of this approach, opening doors for further research on the associations between daily screen time, mental health, and other factors.

Vitamin D's Capacity to Increase Amphetamine-Induced Dopamine Release in Healthy Humans: A Clinical Translational [11C]-PHNO Positron Emission Tomography Study.

BACKGROUND: Dopaminergic tone and phasic release have transdiagnostic relevance. Preclinical research suggests that the active form of vitamin D, calcitriol, increases subcortical tyrosine hydroxylase, D2/3 receptors, and amphetamine-stimulated dopamine release in rodents. Comparable studies have not been conducted in humans. METHODS: Healthy, vitamin-D-sufficient adults (N=18; 32.8 ±6.6 years; 33% female) participated in a randomized, double-blind, placebo-controlled within-subjects study involving four total scans over two visits consisting of same-day pre-amphetamine and post-amphetamine (0.3 mg/kg) 11C-PHNO positron emission tomography (PET) scanning to examine D2/3 receptor availability (BPND) following active calcitriol (1.5 µg night before experimental day and 1.5 µg morning of experimental day) or placebo at least six days apart. Parametric images of 11C-PHNO PET BPND were computed using a simplified reference tissue model with the cerebellum as reference. Blood samples were acquired to measure serum calcitriol, amphetamine, and calcium levels. Regions of interest examined were the dorsal caudate, dorsal putamen, ventral striatum, globus pallidus, and substantia nigra. RESULTS: For pre-amphetamine scans, there was a medication-by-region-of-interest interaction (F4,153=2.59, p=0.039) and a main effect of medication (F1,153=4.88, p=0.029) on BPND, with higher BPND values on calcitriol in the ventral striatum (t=2.89, p=0.004) and dorsal putamen (t=2.15, p=0.033). There was a main effect of medication on post-amphetamine change in BPND (F4,153=5.93, p=0.016), with greater decreases on calcitriol in the ventral striatum (t=3.00, p=0.003), substantia nigra (t=2.49, p=0.014), and dorsal caudate (t=2.29, p=0.023). CONCLUSIONS: Results provide translational support for vitamin D to target dopaminergic tone, with implications for clinical disorders involving dysregulated dopamine function. CLINICAL TRIAL REGISTRATION: Vitamin D as a Therapeutic Adjunct in the Stimulant Treatment of ADHD; https://clinicaltrials.gov/study/NCT03103750; ClinicalTrials.gov ID: NCT03103750.

Evaluation of the clinical, biochemical, and molecular spectrum of Cobalamin C (CblC) defect in 33 patients from Pakistan.

BACKGROUND: Cobalamin C is the most common inborn error of intracellular cobalamin metabolism caused by biallelic pathogenic variants in the MMACHC gene, leading to impaired conversion of dietary vitamin B12 into its two metabolically active forms, methylcobalamin and adenosylcobalamin. Biochemical hallmarks are elevated plasma total homocysteine (HCYs) and low methionine accompanied by methylmalonic aciduria. This study aimed to evaluate the clinical, biochemical, and molecular analysis of Pakistani patients with CblC defect. METHODS: Medical charts, urine organic acid (UOA) chromatograms, plasma amino acid levels, plasma tHcy and MMACHC gene results of patients presenting at the Biochemical Genetics Clinic, AKUH from 2013-2021 were reviewed. Details were collected on a pre-structured questionnaire. SPSS 22 was used for data analysis. RESULTS: CblC was found in 33 cases (Male:Female 19:14). The median age of symptoms onset and diagnosis were 300 (IQR:135-1800) and 1380 (IQR: 240-2730) days. The most common clinical features were cognitive impairment (n = 29), seizures (n = 23), motor developmental delay (n = 20), hypotonia (n = 17), and sparse/hypopigmented scalp hair (n = 16). The MMACHC gene sequencing revealed homozygous pathogenic variant c.394C > T, (p.Arg132*) in 32 patients, whereas c.609G > A, (p.TRP203*) in one patient whose ancestors had settled in Pakistan from China decades ago. The median age of treatment initiation was 1530 (IQR: 240-2790). The median pre-treatment HCYs levels were 134 (IQR:87.2-155.5) compared to post-treatment levels of 33.3 (IQR: 27.3-44.95) umol/L. CONCLUSIONS: Thirty-three cases of CblC defect from a single center underscores a significant number of the disorder within Pakistan. Late diagnosis emphasizes the need for increased clinical awareness and adequate diagnostic facilities.

Use of silver collagen oxidized regenerated cellulose dressings in conjunction with negative pressure wound therapy: expert panel consensus recommendations.

BACKGROUND: A new indication for use of silver collagen oxidized regenerated cellulose (ORC) dressing in conjunction with negative pressure wound therapy (NPWT) and reticulated open cell foam (ROCF) dressings has recently become available. OBJECTIVE: An in-person meeting with 7 health care providers (HCPs) was held to identify clinical care settings and appropriate use of silver collagen ORC dressings in conjunction with NPWT and ROCF dressings. METHODS: Consensus statements were developed using a modified Delphi technique. An additional 25 HCPs completed an anonymous survey on the consensus statements. Consensus was defined as ≥80% agreement among survey respondents. RESULTS: Use of silver collagen ORC dressings with NPWT and ROCF dressings was recommended in inpatient and outpatient health care settings. Use in traumatic wounds, surgical wounds, diabetic ulcers, venous leg ulcers, and pressure injuries/ulcers was supported. Use was not recommended in the presence of exposed unprotected organs or exposed unprotected vessels, when the potential for inadequate wound hemostasis exists, acutely ischemic wounds, third-degree burns, or surgically closed incisions, or with patient hypersensitivity to product components. CONCLUSIONS: Limited evidence exists on use of NPWT in conjunction with silver collagen ORC dressings. A panel developed 12 consensus statements detailing the recommended and contraindicated uses of NPWT in conjunction with silver collagen ORC dressings.

Outcomes in peripheral right ventricular device support: Comparing the dual lumen, single canula and femoral vein cannulation strategies for right ventricular support.

INTRODUCTION: The Protek Duo (PtD) dual lumen, single cannula was developed as a percutaneous system for temporary mechanical support, inserted through the internal jugular vein (IJ) for both atrial inflow and pulmonary artery outflow. Outcomes of PtD compared to alternative Peripheral Right Ventricular Assist Device (pRVAD) methods are limited. METHODS: A retrospective analysis was conducted of pRVAD recipients from January 2017 - February 2022 (n = 111). These were classified into PtD (n = 52) patients and Non-Protek [(N-PtD) (n = 59)] recipients undergoing cannulation of the IJ and femoral vein. Results were further stratified by indication for pRVAD support: cardiogenic etiologies of heart failure and progressive ARDS. RESULTS: No survival benefit was detected between PtD and N-PtD groups at 1-week (OR: 1.32, 95% CI: 0.49-3.56, p = 0.58) or 6-month (OR: 9.83, 95% CI: 0.37-1.84, p = 0.64) follow-up. There were no statistically significant differences in whether patients' mobility progressed to out-of-bed activity (p = 0.26) or ambulation (p = 0.38). No differences were noted in time to out-of-bed (p = 0.26) or time to ambulation (p = 0.36). On subgroup analysis of patients by indication for pRVAD cannulation, these results persisted; no difference was noted in mid-term mortality (Cardiogenic: p = 0.39; ARDS: p = 0.91), progression to out-of-bed (p = 0.59; p = 1.00), or ambulation (p = 0.51; p-0.68). Among secondary outcomes, PtD patients had an increased dialysis requirement (p = 0.02). There were no differences in ability to wean from RVAD (p = 0.06), tracheostomy (p = 0.88), major bleeding events (p = 0.57), stroke (p = 0.58), or hospital length of stay (p = 0.39). CONCLUSIONS: Outcomes with PtD are comparable to those of traditional pRVAD cannulation strategies. Of note, no mobility benefit was observed to the use of PtD across several metrics.

Navigating electronic health record accuracy by examination of sex incongruent conditions.

OBJECTIVE: The increasing reliance on electronic health records (EHRs) for research and clinical care necessitates robust methods for assessing data quality and identifying inconsistencies. To address this need, we develop and apply the incongruence rate (IR) using sex-specific medical conditions. We also characterized participants with incongruent records to better understand the scope and nature of data discrepancies. MATERIALS AND METHODS: In this cross-sectional study, we used the All of Us Research Program's latest version 7 (v7) EHR data to identify prevalent sex-specific conditions and evaluated the occurrence of incongruent cases, quantified as IR. RESULTS: Among the 92 597 males and 152 551 females with condition occurrence data available from All of Us and sex-conformed gender, we identified 167 prevalent sex-specific conditions. Among the 37 537 biological males and 95 499 biological females with these sex-specific conditions, we detected an overall IR of 0.86%. Attempt to include non-cisgender participants result in inflated overall IR. Additionally, a significant proportion of participants with incongruent conditions also presented with conditions congruent to their biological sex, indicating a mix of accurate and erroneous records. These incongruences were not geographically or temporally isolated, suggesting systematic issues in EHR data integrity. DISCUSSION: Our findings call attention to the existence of systemic data incongruences in sex-specific conditions and the need for robust validation checks. Extending IR evaluation to non-cisgender participants or non-sex-based conditions remain a challenge. CONCLUSION: The sex condition-specific IR, when applied to adult populations, provides a valuable metric for data quality assessment in EHRs.

Cancer Metabolism: Aspirations for the Coming Decade.

Fueled by technological and conceptual advancements over the past two decades, research in cancer metabolism has begun to answer questions dating back to the time of Otto Warburg. But, as with most fields, new discoveries lead to new questions. This review outlines the emerging challenges that we predict will drive the next few decades of cancer metabolism research. These include developing a more realistic understanding of how metabolic activities are compartmentalized within cells, tissues, and organs; how metabolic preferences in tumors evolve during cancer progression from nascent, premalignant lesions to advanced, metastatic disease; and, most importantly, how we can best translate basic observations from preclinical models into novel therapies that benefit patients with cancer. With modern tools and an incredible amount of talent focusing on these problems, the upcoming decades should bring transformative discoveries.

Association of osteotomy, age, and component fixation with the outcomes of total hip arthroplasty in patients with hip dysplasia: a Dutch population-based registry study.

BACKGROUND AND PURPOSE:  Hip dysplasia can present challenges for total hip arthroplasty (THA) due to anatomic abnormalities. We aimed to assess the association of age, sex, osteotomies prior to THA, and fixation method on 5- and 10-year revision-free implant survival and patient-reported outcome measures (PROMs) of THAs in patients with hip dysplasia. METHODS: Using Dutch Arthroplasty Register data, we studied hip dysplasia patients receiving primary THAs in 2007-2021 (n = 7,465). THAs were categorized by age, pelvic osteotomy prior to THA (yes/no), and fixation (cemented, uncemented, hybrid, reverse hybrid). Kaplan-Meier and multivariable Cox models were used to determine 5- and 10-year revision-free implant survival and adjusted hazard ratios including 95% confidence intervals (CIs). Reasons for revision and PROMs were compared within the categories. RESULTS:  We found a 10-year revision-free implant survival of 94.9% (CI 94.3-95.5). Patients younger than 50 years had a 10-year implant survival of 93.3% (CI 91.9-94.7), Patients with prior pelvic osteotomy had a 10-year implant survival of 92.0% (CI 89.8-94.2). Fixation method and sex were not associated with implant survival. Patients with a prior pelvic osteotomy had more revisions due to cup loosening and reported lower PROM scores than patients without earlier osteotomy. CONCLUSION:  5- and 10-year revision-free implant survival rates of THA for hip dysplasia are 96.4% and 94.9%. Age and prior osteotomies were associated with decreased implant survival rates in patients with hip dysplasia, while fixation method was not. Prior osteotomies were also associated with reduced PROM scores.

Safety and efficacy of targeting the supplementary motor area with double-cone deep transcranial magnetic stimulation vs figure-eight coil in treatment of obsessive-compulsive disorder with comorbid major depressive disorder.

BACKGROUND AND OBJECTIVE: The Supplementary Motor Area (SMA), a relatively large brain structure predominantly located along the interhemispheric fissure, is an established target for repetitive Transcranial Magnetic Stimulation (rTMS) treatment of Obsessive-Compulsive Disorder (OCD). We investigated the feasibility, safety, and efficacy of targeting SMA using a double-cone "deep" TMS coil compared to conventional figure-eight coil for treatment of OCD with comorbid Major Depressive Disorder (MDD). METHODS: Sixty-two patients with treatment-resistant OCD and comorbid MDD participated in the study. All patients received high-frequency rTMS over the left dorsolateral prefrontal cortex (DLPFC) with a figure-eight coil (MagVenture B70), followed by 1 Hz rTMS over the bilateral SMA using either the B70 (N = 25) or double-cone deep coil (MagVenture DB80) (n = 23) for 36 treatment sessions. Weekly clinical assessments were conducted. RESULTS: Subjects overall had significant reductions in OCD and depressive symptom severity at the primary endpoint. Subjects stimulated at SMA with the double-cone deep coil had statistically significantly lesser reductions in overall OCD and depression symptom severity compared to the figure-eight group. The intensity of stimulation at SMA was significantly greater with the double-cone deep than figure-eight coil and e-field modeling showed that it affected broader regions beyond SMA (off-target stimulation). There was no significant difference in reported tolerability between groups. CONCLUSIONS: SMA stimulation using either a double-cone deep or conventional figure-of-eight coil was safe and was associated with a significant reduction in comorbid OCD and depression symptoms, but the higher intensities of stimulation with the double-cone deep coil used in this study were significantly less clinically beneficial than figure-eight coil stimulation.

Sequencing Quadruple Therapy for Heart Failure with Reduced Ejection Fraction: Does It Really Matter?

The conventional sequence of guideline-directed medical therapy (GDMT) initiation in heart failure with reduced ejection fraction (HFrEF) assumes that the effectiveness and tolerability of GDMT agents mirror their order of discovery, which is not true. In this review, the authors discuss flexible GDMT sequencing that should be permitted in special populations, such as patients with bradycardia, chronic kidney disease, or atrial fibrillation. Moreover, the initiation of certain GDMT medications may enable tolerance of other GDMT medications. Most importantly, the achievement of partial doses of all four pillars of GDMT is better than achievement of target dosing of only a couple.

Outcome One Year after Acetabular Rim Extension Using a Customized Titanium Implant for Treating Hip Dysplasia in Dogs.

The acetabular rim extension (ACE-X) implant is a custom-made three-dimensionally printed titanium device designed for the treatment of canine hip dysplasia. In this study, 34 dogs (61 hips) underwent ACE-X implantation, and assessments were conducted using computed tomography, force plate analysis, Ortolani's test, and the Helsinki chronic pain index (HCPI) questionnaires at five intervals: the pre-operative day, the surgery day, and the 1.5-month, 3-month, and 12-month follow-ups. Statistically significant increases in femoral head coverage with a negative Ortolani subluxation test were observed immediately after surgery and persisted throughout the study. Osteoarthritis (OA) scores remained stable, but osteophyte size significantly increased between the surgery day and the 12-month follow-up, especially in hips with a baseline OA score of 2 compared to those with a score of 1. The force plate data showed no significant changes during the study. The HCPI demonstrated a significant decrease in pain score from pre-operative value to six-week follow-up and gradually decreased over time. Major complications were identified in six hips (9.8%) of four dogs. In conclusion, the ACE-X implant effectively increased femoral head coverage, eliminated subluxation, and provided long-term pain relief with minimal complications, benefiting over 90% of the study population. The study supports the ACE-X implant as a valuable alternative treatment for canine hip dysplasia.

Niacin supplementation in a child with novel MTTN variant m.5670A>G causing early onset mitochondrial myopathy and NAD+ deficiency.

Myopathy is a common manifestation in mitochondrial disorders, but the pathomechanisms are still insufficiently studied in children. Here, we report a severe, progressive mitochondrial myopathy in a four-year-old child, who died at eight years. He developed progressive loss of muscle strength with nocturnal hypoventilation and dilated cardiomyopathy. Skeletal muscle showed ragged red fibers and severe combined respiratory chain deficiency. Mitochondrial DNA sequencing revealed a novel m.5670A>G mutation in mitochondrial tRNAAsn (MTTN) with 88 % heteroplasmy in muscle. The proband also had systemic NAD+ deficiency but rescuing this with the NAD+ precursor niacin did not stop disease progression. Targeted metabolomics revealed an overall shift of metabolism towards controls after niacin supplementation, with normalized tryptophan metabolites and lipid-metabolic markers, but most amino acids did not respond to niacin therapy. To conclude, we report a new MTTN mutation, secondary NAD+ deficiency in childhood-onset mitochondrial myopathy with metabolic but meager clinical response to niacin supplementation.

Exploring sleep difficulties, alcohol, illicit drugs, and suicidal ideation among adolescents with a history of depression.

Sleep difficulties and misuse of drugs/alcohol have been associated with suicidal ideation in young people. Using cross-sectional representative surveys of adolescents in the United States, we conducted adjusted logistic regression modeling to assess the relationships between sleep difficulties, substance use, and suicidal ideation among adolescents with a history of depression (n = 38,418) between 2015 and 2020. Sleep difficulties were associated with thinking about (aOR=1.6,95%CI:1.3-1.9), planning (aOR=1.8,95%CI:1.2-2.6), or attempting (aOR=1.7,95%CI:1.2-2.5) suicide. In those reporting alcohol abuse/dependence, sleep difficulties were associated with attempting suicide (aOR=3.1,95%CI:1.2-8.5). In those reporting illicit drug abuse/dependence, sleep difficulties were associated with thinking about (aOR=2.1,95%CI:1.1-4.1) and attempting (aOR=2.2,95%CI:1.2-4.1) suicide.

The role of sex and age in the differential efficacy of 10 Hz and intermittent theta-burst (iTBS) repetitive transcranial magnetic stimulation (rTMS) treatment of major depressive disorder (MDD).

BACKGROUND: Sex- and age-dependent outcome differences have been observed in treatment of Major Depressive Disorder (MDD), including 10 Hz repetitive Transcranial Magnetic Stimulation (rTMS). We examined whether there are sex- and age-dependent differences in outcome with intermittent Theta Burst Stimulation (iTBS), another rTMS protocol. METHODS: The relationship between biological sex, age, and treatment outcome was retrospectively examined among 414 patients with MDD treated with 10 Hz or iTBS rTMS. Linear mixed-effects modeling was used to examine the association between treatment and change in the 30-item Inventory of Depressive Symptomatology Self-Report (IDS-SR30) score from baseline to treatments 10 and 30, with biological sex (M/F), protocol (iTBS/10 Hz), age (≥/<50 years old), and time (treatment 1/10/30) included as fixed effects. The three-way sex-protocol-time and age-protocol-time interactions were used to determine any differential relationships between protocol and outcome dependent on sex and age. Post-hoc t-tests were conducted to examine differences in improvement. RESULTS: There was a significant three-way sex-protocol-time interaction at treatments 10 (p = 0.016) and 30 (p = 0.031). Males showed significantly greater improvement with iTBS than females at treatments 10 (p = 0.041) and 30 (p = 0.035), while females showed numerically greater improvement with 10 Hz treatment. While there was not a significant three-way age-protocol-time interaction, there was a significant interaction between age (≥50 years old) and time at treatments 10 (p = 0.007) and 30 (p = 0.042), and among age, sex, and time at treatment 30 (p = 0.028). LIMITATIONS: Retrospective naturalistic treatment protocol. CONCLUSIONS: iTBS appeared less efficacious in females than in males, and rTMS overall was more efficacious in patients over fifty, particularly females.

Improving HPV Vaccination Uptake Among Adolescents in Low Resource Settings: Sociocultural and Socioeconomic Barriers and Facilitators.

Background: Lower- and middle-income countries (LMICs) are disproportionately impacted by human papillomavirus (HPV) and would benefit from implementing the HPV vaccine. In the context of competing health priorities, utilizing scarce domestic infrastructure and human resources for HPV vaccination remains challenging for many LMICs. Given the high benefits of the HPV vaccine, the World Health Organization (WHO) is now encouraging for all countries, particularly LMICs, to introduce HPV vaccines into their routine immunization programs. Understanding the barriers and facilitators to HPV adolescent vaccine programs in LMICs may help strengthen how LMICs implement HPV vaccine programs, in turn, increasing HPV vaccine acceptance, uptake, and coverage. Objective: To identify and assess barriers and facilitators to implementing adolescent HPV vaccination programs in LMICs. Methods: This study comprised a review of literature assessing adolescent HPV vaccination in LMICs published after 2020 from a sociocultural perspective. Results: Overall, the findings showed that LMICs should prioritize increasing HPV vaccine availability and HPV vaccine knowledge, particularly focusing on cancer prevention, as knowledge reduces misinformation and increases vaccine acceptance. Evidence suggests that factors promoting HPV vaccine uptake include fostering low vaccine hesitancy, integrating HPV vaccination as a primary school routine vaccination, and vaccinating both genders. A one-dose HPV vaccine may enable many LMICs to increase vaccine acceptance, uptake, and coverage while controlling financial, infrastructure, and human resource costs. Conclusion: As HPV is one of the leading causes of death in many LMICs, implementing the HPV vaccine may be highly beneficial. Cohesive national HPV vaccine buy-in and understanding the success and challenges of prior LMIC HPV vaccine implementation is crucial to developing effective, efficient, and sustainable HPV vaccination programs.

Clinical, Genetic, and Histopathological Characteristics of CRX-associated Retinal Dystrophies.

PURPOSE: To describe phenotypic, genotypic, and histopathological features of inherited retinal dystrophies associated with the CRX gene (CRX-RDs). DESIGN: Retrospective multicenter cohort study including histopathology. SUBJECTS: Thirty-nine patients from 31 families with pathogenic variants in the CRX gene. METHODS: Clinical data of 152 visits were collected from medical records. The median follow-up time was 9.1 years (interquartile range (IQR), 3.3-15.3 years; range, 0.0-48.8 years). Histopathologic examination of the eye of a 17-year-old patient with advanced early-onset CRX-RD was performed. MAIN OUTCOME MEASURES: Visual acuity, retinal imaging, electroretinography, genotype-phenotype correlation, and histopathological examination were evaluated. RESULTS: The age at onset ranged from birth to the eighth decade of life. Median visual acuity was 1.00 logarithm of the minimum angle of resolution (logMAR) (IQR, 0.69-1.48 logMAR; range, 0.06-3.00 logMAR) at a mean age of 52.0 ± 19.9 years (range, 4.6-81.9 years). Sufficient imaging was available for 36 out of 39 patients (92.3%), and all showed degeneration of at least the macula. Of these 36 patients, 22 (61.1%) had only macular dystrophy. Another 10 patients (27.8%) had additional degeneration beyond the vascular arcades, and 4 patients (11.1%) panretinal degeneration. Two patients (5.1%) had Leber congenital amaurosis. In total, 21 different disease-associated heterozygous CRX variants were identified (10 frameshift, 7 missense, 2 deletion, 1 nonsense, 1 deletion-insertion variants). Missense variants in the CRX homeodomain and 2 variants deleting all functional domains, thus causing haploinsufficiency, generally tended to cause milder late-onset phenotypes. Histopathologic examination of the eye of a 17-year-old patient with advanced early-onset retinal dystrophy due to a heterozygous deletion of exons 3 and 4 of the CRX gene revealed loss of laminar integrity and widespread photoreceptor degeneration especially in the central retina, with extensive loss of photoreceptor nuclei and outer segments. CONCLUSIONS: This study illustrates the large clinical and genetic heterogenic spectrum of CRX-RDs, ranging from Leber congenital amaurosis to mild late-onset maculopathy resembling occult macular dystrophy. Haploinsufficiency and missense variants tended to be associated with milder phenotypes. Patients showed degeneration predominantly affecting the central retina on imaging. The histopathological findings also mirror these clinical findings and features similar to previously reported animal models of CRX-RDs. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Health Disparities among Patients with Cancer Who Received Molecular Testing for Biomarker-Directed Therapy.

Health disparities present a barrier to successful oncology treatment. The potential for precision oncology to reduce health disparities has not previously been analyzed. We performed a retrospective analysis of 12,627 patients from six major cancer centers whose tumors underwent molecular testing at Caris Life Sciences between 2010 and 2020. Kaplan-Meier and Cox regression were used to describe and analyze overall survival. The molecular and demographic features of the cohort were analyzed by χ2 and ANOVA tests. Black patients composed 25% of the cohort and White patients 63%. Among this molecularly-tested cohort, there were minimal outcome differences based on race, geographic location, or poverty level. When analyzing the interaction of age, race, and sex, racial-based disparities were noted primarily for young non-White women in the study cohort but were more pronounced for men and women of all ages in the broader patient population within the Surveillance, Epidemiology, and End Results database. Mutations in five genes-APC, EGFR, STK11, TP53, and KRAS-were found to affect overall survival among our cohort, and their prevalence varied by race in specific tumor types. Real-world outcomes data in mutation-defined cohorts also provided additional context to previously reported therapeutic response trends. Our study shows that patients who undergo molecular testing display reduced racial health disparities compared with the general population, whereas persistent racial disparities are influenced by age and sex. Genomic-driven racial disparities should be examined at a tumor lineage-specific level. Increased access to molecular testing for all eligible patients may play a role in improving health equity. Significance: This study is the largest of its kind to analyze health disparities and genomic features among a diverse multiinstitutional cohort of patients who underwent molecular testing. Continuing to increase awareness of and access to molecular testing approaches may help to reduce cancer health disparities and improve outcomes for all patients.

Mitochondrial complex I promotes kidney cancer metastasis.

Most kidney cancers are metabolically dysfunctional1-4, but how this dysfunction affects cancer progression in humans is unknown. We infused 13C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-13C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-13C]acetate and [U-13C]glutamine infusions in patients, coupled with measurements of respiration in isolated human kidney and tumour mitochondria, reveal lower electron transport chain activity in ccRCCs that contributes to decreased oxidative and enhanced reductive TCA cycle labelling. However, ccRCC metastases unexpectedly have enhanced TCA cycle labelling compared with that of primary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufficient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These findings in humans and mice indicate that metabolic properties and liabilities evolve during kidney cancer progression, and that mitochondrial function is limiting for metastasis but not growth at the original site.