Mitochondrial small RNA alterations associated with increased lysosome activity in an Alzheimer's Disease Mouse Model uncovered by PANDORA-seq.

Emerging small noncoding RNAs (sncRNAs), including tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs), are critical in various biological processes, such as neurological diseases. Traditional sncRNA-sequencing (seq) protocols often miss these sncRNAs due to their modifications, such as internal and terminal modifications, that can interfere with sequencing. We recently developed panoramic RNA display by overcoming RNA modification aborted sequencing (PANDORA-seq), a method enabling comprehensive detection of modified sncRNAs by overcoming the RNA modifications. Using PANDORA-seq, we revealed a novel sncRNA profile enriched by tsRNAs/rsRNAs in the mouse prefrontal cortex and found a significant downregulation of mitochondrial tsRNAs and rsRNAs in an Alzheimer's disease (AD) mouse model compared to wild-type controls, while this pattern is not present in the genomic tsRNAs and rsRNAs. Moreover, our integrated analysis of gene expression and sncRNA profiles reveals that those downregulated mitochondrial sncRNAs negatively correlate with enhanced lysosomal activity, suggesting a crucial interplay between mitochondrial RNA dynamics and lysosomal function in AD. Given the versatile tsRNA/tsRNA molecular actions in cellular regulation, our data provide insights for future mechanistic study of AD with potential therapeutic strategies.

Mental health and its consequences in people living with HIV: A network approach.

OBJECTIVES: Psychiatric symptoms occur frequently in people living with human immunodeficiency virus (PLWH), which may affect quality of life, sexual risk behavior, and adherence to antiretroviral therapy (ART). Data from large cohorts are limited, and symptoms are often analyzed in isolation. Therefore, we applied a network analysis to assess the interrelatedness of mental health indicators in a large cohort of PLWH. METHODS: We included 1615 PLWH on ART. Participants reported on the severity of depression, anxiety, impulsivity, substance use, quality of life, sexual risk behavior, and ART adherence. An Ising network model was constructed to analyze interrelations between mental health indicators and connections with clinical consequences. RESULTS: Our network analysis revealed that symptoms of depression, anxiety, and indicators of impulsivity were interrelated. Substance use was prevalent and strongly connected with sexual risk behavior. Quality of life was most strongly connected with symptoms of depression. Unexpectedly, ART adherence did not display connections with any of the mental health indicators. CONCLUSION: In PLWH, the interrelatedness between symptoms of depression and anxiety and indicators of impulsivity is high. Mainly, depressive symptoms seem to impact quality of life, which warrants attention for depression in PLWH. We did not observe evidence for the common assumption that patients suffering from psychiatric symptoms are less adherent to HIV treatment.

Ovarian Aging and Fertility.

This JAMA Insights discusses ovarian aging and provides strategies to address infertility due to ovarian aging.

Third eyelid cartilage eversion in an adult mare.

PURPOSE: To describe the first report of third eyelid cartilage eversion in an adult American Quarter Horse mare. CASE PRESENTATION: A 22-year-old American Quarter Horse mare presented to the University of Missouri Veterinary Health Center Equine Hospital for a 2-week history of a third eyelid cartilage abnormality of the left eye with no known recent trauma. Complete ophthalmic examination revealed third eyelid cartilage eversion of the left nictitans. The abnormal scrolled cartilage was surgically excised using a handheld cautery unit and submitted for histopathologic evaluation. RESULTS: Histopathologic findings displayed normal third eyelid cartilage, without evidence of neoplasia or inflammation. Mucosal hyperplasia and increased vascularity of the submucosa were observed. The horse healed well after electrocautery excision and normal third eyelid conformation was restored. CONCLUSION: To the authors' knowledge, this is the first report of an acquired, presumed spontaneous, third eyelid cartilage eversion in a horse.

Rate of motor progression in Parkinson's disease: a systematic review and meta-analysis.

Background: The search for neuroprotective treatments for Parkinson's disease (PD) still relies largely on motor disability scales. A limitation of these tools is the strong influence of symptomatic dopaminergic treatment effects. Drawing on a wealth of published information, we conducted a systematic review and meta-analysis of motor progression in PD and its relationships with dopaminergic therapy. Methods: We searched Medline, Embase, and Central to identify 84 publications with adequate serial motor scores to calculate progression, expressed as an increase in the percentage of maximum disability. Results: A random-effects model showed motor progression at 2.0% p.a. (95% CI 1.7-2.4%). There were no significant differences by baseline age, sample size, or observation period. However, untreated patients, in 8 publications, progressed at 4.5% p.a. compared to 1.6% p.a. in 76 studies containing individuals on dopaminergic drugs (p = 0.0004, q = 0.003). This was supported by research on phenoconversion in prodromal PD, where motor progression exceeded 5% p.a. in the 2 years before diagnosis. Starting levodopa improved pre-treatment disability by 40.3 ± 15.2%. Practically defined off state measurements increase faster than on scores by a modest degree (p = 0.05). Conclusion: This survey suggests that accurate long-term measurements of motor progression to assess disease-modifying therapies can be conducted despite the sequential commencement of dopaminergic drugs and sample attrition over time. While study designs involving prodromal or untreated PD avoid confounding effects of symptomatic treatment, different assumptions about motor progression may be needed. A defined off state with the levodopa test dose method maximizes information about the medication cycle once dopaminergic therapy has begun.

Plasma proteomic signatures of liver steatosis and fibrosis in people living with HIV: a cross-sectional study.

BACKGROUND: Insights into the mechanisms driving metabolic dysfunction-associated steatotic liver disease (MASLD) in people living with HIV (PLHIV) remain limited. Plasma proteomics holds promise for biomarker discovery and the elucidation of biological mechanisms. METHODS: We performed cross-sectional analyses on data from 1036 virally suppressed PLHIV using antiretroviral treatment (ART) from the Dutch multi-centre 2000HIV cohort. Participants underwent transient elastography to assess liver steatosis (controlled attenuation parameter (CAP) ≥263 dB/m) and -fibrosis (liver stiffness measurement (LSM) ≥7.0 kPa). Plasma protein concentrations (n = 2367) (Olink® Explore Panel) were compared between PLHIV with vs. without liver steatosis and PLHIV with vs. without fibrosis. Enriched pathways (using GO, KEGG and Reactome libraries) and correlations with clinical characteristics were assessed, and analyses were stratified by BMI category. In addition, concentrations of 242 proteins were compared between individuals ("controls") with and without liver steatosis (ratio of methylene:methylene and water >5.6% on magnetic resonance spectroscopy) from a separate cohort (300-OB), all having a BMI >26 kg/m2. FINDINGS: Steatosis and fibrosis were associated with 67/2367 (2.2%) and 17/2367 (0.7%) differentially expressed proteins (DEP), respectively, enriched in mostly metabolic pathways. Immunoglobulin superfamily member 9 (IGSF9) was amongst the top DEP associated with both steatosis and fibrosis. Stratifying by BMI revealed 8/2367 DEP associated with steatosis in lean- and 12/2367 DEP in overweight/obese individuals, with two shared DEP (IGSF9 and GHR). Conversely, protein signatures of overweight/obese PLHIV (32/242 DEP) and overweight/obese HIV-uninfected individuals (32/242 DEP) exhibited substantial overlap with 16 shared DEP. Notably, DEP correlated with HIV characteristics in lean individuals but not in overweight/obese PLHIV. INTERPRETATION: Lean and overweight/obese PLHIV exhibit distinct proteomic signatures associated with liver steatosis, with the former being more strongly correlated with HIV-specific factors and ART. In addition, we identified a protein, IGSF9, strongly related to liver fibrosis and steatosis across BMI categories. FUNDING: The 2000HIV study is funded by ViiV Healthcare.

In Defense of IVF: Time To Get Involved in State-Level Advocacy!

We share experiences in advocating to defend in vitro fertilization (IVF) in Virginia, Missouri, and Mississippi, provide historical context on the "Personhood" anti-IVF movement, and discuss why "embryo donation" is a more accurate term than "embryo adoption." Some individuals and communities have a deeply-held belief that a fertilized oocyte is a very early human life, and we will likely never change their minds. In the fertility community, most providers consider embryos to be an important part of the continuum between gametes (sperm and eggs) to live birth. Embryos are neither life, nor property, but rather a special class of "potential life" deserving of particular respect. The premise of the "Personhood" movement is that each fertilized oocyte is already an individual living being, subject to child-custody and similar legal protections. Both in nature and in the laboratory, however, only a minority of fertilized eggs result in live birth. Not all IVF embryos are of adequate quality for transfer, and most transferred embryos result in negative pregnancy tests or miscarriages, and rarely, ectopic pregnancies. "Personhood" bills would also criminalize the life-saving, appropriate standard-of-care management of ectopic pregnancies, the most common cause of first-trimester maternal mortality. Efforts to apply a religious and moral lens to regulate and interfere with the practice of IVF based on a mistaken perception that all fertilized eggs are early human beings, would make standard-of-care IVF practice impossible. By equating all fertilized eggs with live-born children, the broadly-worded measures in "Personhood" bills would consign fertility patients to less effective treatments. As a practical matter, "Personhood" bills simply cannot co-exist with legislation to protect the practice of IVF, without inordinate risks to physicians, their practices, and their patients. In response to recent events, the authors encourage all readers to consider participating in state-level advocacy. Sharing IVF experiences and clinical expertise with state legislators (and other officials) can help protect patients, their providers, and the families that they strive to create. Efforts to inappropriately-regulate and restrict in vitro fertilization will decrease access to care, to essential family-building treatments and services.

Navigating the diagnostic gray zone: a challenging case of pancreatic high-grade neuroendocrine neoplasm.

BACKGROUND: Grade 3 neuroendocrine tumor (G3 PanNET) and poorly differentiated neuroendocrine carcinoma (PanNEC) of the pancreas are considered distinct entities from a biological and prognostic perspective but may have overlapping features complicating a definitive diagnosis. CASE PRESENTATION: A 52-year-old female presented with a pancreatic body mass and liver lesions. Initial biopsies showed variable lower- and higher-grade morphologies and modestly elevated Ki67 proliferation index up to 30%, leading to a diagnosis of G3 PanNET. The patient underwent everolimus treatment followed by surgical resection, revealing a complex tumor with features of both G3 PanNET and PanNEC, including admixed well- and poorly differentiated morphologies, modestly elevated hotspot Ki67 of 28%, retained ATRX/DAXX expression, and loss of RB expression. The final diagnosis rendered was "high-grade neuroendocrine neoplasm" with discussion of both entities in the differential. Post-operatively, the patient remains alive with stable metastases. CONCLUSIONS: This case highlights the diagnostic complexities of distinguishing G3 PanNET and PanNEC even with the support of ancillary immunohistochemical and molecular studies. In addition, such cases raise the possibility that G3 PanNET and PanNEC may lie on a spectrum of disease with potential biological overlap.

Analyzing Alignment Error in Tibial Tuberosity-Trochlear Groove Distance in Clinical Scans Using 2D and 3D Methods.

BACKGROUND: Tibial tuberosity-trochlear groove distance (TT-TG) is often used as a primary metric for surgical decision-making in the treatment of patellofemoral instability (PFI), particularly when considering tibial tubercle transfer. Although TT-TG has high interrater reliability, it is prone to measurement differences caused by the alignment of the patient's leg in a scanner gantry, potentially influencing surgical decision-making. Quantification of this error within the clinical literature remains limited. PURPOSE: To quantify and specify the error in TT-TG caused by leg-scanner alignment by using detailed topographical landmarks and 3-dimensional (3D) analysis of computed tomography scans of patients with PFI. STUDY DESIGN: Controlled laboratory study. METHODS: Three-dimensional models of knees with PFI were created from computed tomography scans and used to identify TT-TG landmarks. TT-TG was measured using the established 2-dimensional (2D) and 3D methods. A model to estimate the differences between these 2 methods was created, and the orientation of the patients' legs in relation to scanner longitudinal axis was measured to validate this model via linear regression. Interrater reliability was calculated via intraclass correlation coefficients (ICC). RESULTS: A total of 44 knees of patients with PFI were analyzed. Differences between the 2D and 3D methods ranged from -4.0 to 14.7 mm (mean ± SD, 2.7 ± 4.1 mm) with a root mean square difference of 4.8 mm. The TT-TG distance of the 2D method (19.8 ± 7.2 mm) was significantly (P = .045) longer than that of the 3D method (17.1 ± 4.9 mm). The variance of the 2D method was significantly larger than that of the 3D method. In total, 13 (29.5%) of the knees had a difference of >5 mm between 2D and 3D TT-TG. The estimation model had an adjusted r2 value of 1.00 and a resulting root mean square difference of 0.21 mm. 3D TT-TGs interrater reliability was good to excellent (ICC, 0.94 [95 CI%, 0.81-0.98]). CONCLUSION: 3D TT-TG can be used to correct scanner-leg alignment errors, some of which are substantial when using only 2D TT-TG measurements. CLINICAL RELEVANCE: The findings in this study suggest a need for caution and awareness of the potential effects of differences in alignment of the axes of the leg and scanner when using purely 2D TT-TG as a basis for surgical planning.

The risk of non-AIDS defining events is lower in ART-naive HIV controllers than in normal progressors on suppressive ART.

BACKGROUND: We aimed to compare the non-AIDS events (nADE) risk between normal progressors using ART (NP-ART) and people with HIV (PWH) that naturally control HIV infection (HIV controllers), as well as the outcomes after ART in HIV controllers on nADE. METHODS: The primary endpoint was major nADE defined as the composite of cardiovascular disease, non-AIDS malignancy or all-cause mortality, whichever came first.. The role of ART in HIV controllers was assessed as a time-varying covariate. RESULTS: We included 1007 ART-naive HIV controllers (of which 60 elite controllers), 1510 Early-ART (<6 months after negative HIV test) and 15437 NP-ART (reference group), contributing 3813, 11,060 and 160,050 years of follow-up, respectively. HIV controllers had lower risk of the primary endpoint (HR 0.55, 95%CI 0.38-0.81, P = 0.0023), all-cause mortality (Adjusted Hazard ratio [aHR]: 0.45, 95% confidence interval [CI] 0.25-0.79, P = 0.0054), cardiovascular disease (aHR 0.47, 95%CI 0.22-0.99, P = 0.046) , but not non-AIDS malignancy (aHR 0.74, 95%CI 0.41-1.35, P = 0.33) than NP-ART. Among HIV controllers, each log10 lower baseline viral load further decreased the risk of nADE (aHR 0.54, 95% CI 0.29-0.99, P = 0.045). ART in HIV controllers did not reduce the risk of any nADE (aHR 1.22, 95% CI 0.66-2.29, P = 0.53). CONCLUSIONS: We found a lower risk of nADE in HIV controllers than NP-ART, especially in those with low plasma viral loads. Initiation of ART did not alter the nADE risk in HIV controllers. Our findings help clinicians to decide on prescribing ART in HIV controllers.

Using the SCAR-Q to Evaluate Morbidity of Scars in Craniosynostosis Repair.

OBJECTIVE: While previous literature has investigated the psychosocial impact and aesthetic satisfaction associated with post-operative scarring for certain pediatric craniofacial conditions, the impact of the scar burden resulting from craniosynostosis surgery has not been adequately studied. PARTICIPANTS: SCAR-Q was shared with patients ages 8 and older. Thirty-two complete patient responses were recorded. INTERVENTIONS: SCAR-Q is a PROM that consists of three independent scales - appearance, symptoms, and psychosocial impact - associated with a scar. MAIN OUTCOME MEASURES: Mann-Whitney U, linear regression, and Pearson correlation tests were used to evaluate associations between the scales, in addition to patient characteristics such as sex and suture involvement. RESULTS: Mean ages at time of surgery and survey completion were 9.65 ± 10.10 months and 12.10 ± 3.92 years, respectively. Mean scale scores were 81.5 ± 17.9 for appearance, 86.8 ± 12.4 for symptoms, and 79.3 ± 25.7 for psychosocial impact. Higher patient dissatisfaction with scar appearance correlated with more scar-related symptoms (r = 0.389; p = 0.028) and a greater psychosocial impact (r = 0.725; p < 0.001). SCAR-Q scales did not significantly correlate with age at surgery, age at survey completion, type of synostosis, or type of surgery; however, female patients reported lower mean appearance (65.4 vs. 86.0; p = 0.012) and psychosocial impact (57.3 vs. 85.5; p = 0.010) scores when compared to their male counterparts. CONCLUSIONS: It is vital that surgeons discuss patients' aesthetic satisfaction following craniosynostosis surgery in order to appropriately address and limit deleterious, long-term physical and psychosocial outcomes.

A Nationwide Analysis of Complications, Reoperations and Cost of Wide-Awake Flexor Tendon Repairs.

INTRODUCTION: Some papers suggest that wide-awake flexor tendon repair (FTR) may reduce rates of postoperative tendon gapping and rupture due to improved intraoperative testing of the repair. The current study is a nationwide cohort study comparing FTRs performed wide-awake and with traditional anesthesia. METHODS: Patients undergoing zone II FTR between 2010-2022 were identified in PearlDiver. Exclusion criteria were other tendon repairs, concomitant treatment for vascular injury, fracture, dislocation or amputation, inpatient or office surgery, age <18 years and <1 year of follow-up. Patients were stratified by anesthesia technique: traditional anesthesia (general anesthesia, monitored anesthesia care, regional blocks) or wide-awake. Patients were matched based on age, sex, Elixhauser Comorbidity Index (ECI) score, geographical region, insurance coverage, number of tendon repairs and presence of concomitant nerve repair. 30-day wound complications, emergency department visits and readmissions and 1-year reoperations were identified. Total reimbursement for surgery was determined. RESULTS: Each matched cohort included 2,563 patients. Wide-awake patients had fewer 30-day emergency department visits (2.7% vs 4.8%). There were no differences in 30-day wound complications or readmissions. There was no difference in 1-year reoperations for rupture or for stiffness. Multivariable linear regression identified wide-awake surgery to be a significantly associated with lower total reimbursement. CONCLUSIONS: Performing digital FTR using wide-awake techniques can reduce costs, but the hypothesis that wide-awake repairs may reduce rates of tendon rupture was not supported by the current study.

Soil amendments reduce PFAS bioaccumulation in Eisenia fetida following exposure to AFFF-impacted soil.

The efficacy of RemBind® 300 to immobilize per- and polyfluoroalkyl substances (PFAS) in aqueous film forming foam (AFFF)-impacted soil (∑28 PFAS 1280-8130 ng g-1; n = 8) was assessed using leachability (ASLP) and bioaccumulation (Eisenia fetida) endpoints as the measure of efficacy. In unamended soil, ∑28 PFAS leachability ranged from 26.0 to 235 µg l-1, however, following the addition of 5% w/w RemBind® 300, ∑28 PFAS leachability was reduced by > 99%. Following exposure of E. fetida to unamended soil, ∑28 PFAS bioaccumulation ranged from 18,660-241,910 ng g-1 DW with PFOS accumulating to the greatest extent (15,150-212,120 ng g-1 DW). Biota soil accumulation factors (BSAF) were significantly (p < 0.05) higher for perfluoroalkyl sulfonic acids (PFSA; 13.2-50.9) compared to perfluoroalkyl carboxylic acids (PFCA; 1.2-12.7) while for individual PFSA, mean BSAF increased for C4 to C6 compounds (PFBS: 42.6; PFPeS: 52.7; PFHxS: 62.4). In contrast, when E. fetida were exposed to soil amended with 5% w/w RemBind® 300, significantly lower PFAS bioaccumulation occurred (∑28 PFAS: 339-3397 ng g-1 DW) with PFOS accumulation 23-246 fold lower compared to unamended soil. These results highlight the potential of soil amendments for reducing PFAS mobility and bioavailability, offering an immobilization-based risk management approach for AFFF-impacted soil.

Importance of early consideration of scaling and sustainability for aging-related care models: Case study of Hospital at Home.

For aging-related research, there is a pressing need to attend to the dissemination and implementation of evidence-based interventions. Some aging-related interventions with established effectiveness may be poorly disseminated and implemented due to behavioral, organizational, payment, or other constraints. To provide insight into the beginning to end process of translation and implementation, we present a case history of the three-decade progression of Hospital at Home (HaH) now nearing national dissemination. We summarize research at various phases with particular attention to implementation considerations. Reviewing over three decades of HaH-related research dating from initial discovery to translation and implementation, we found that the content and importance of different constructs (e.g., inner practice vs. outer environmental setting) and the choice of implementation strategies differed depending on implementation context (testing of effectiveness, scaling, or sustainability). Early effectiveness studies mostly examined implementation issues related to the intervention, the practice setting, and the individuals involved. However, explicit and early consideration of scale and sustainment was not the primary focus. For example, HaH program intake is primarily through hospital emergency departments (ED). Initial efforts would have benefited from incorporating strategies (e.g., incorporating ED leadership into program leadership) to address night and weekend admissions. Many regulatory barriers did not surface during initial considerations. Considering implementation issues late may contribute to delay in bringing discoveries to population impact. The experience with HaH suggests that scale and sustainability bear earlier consideration because barriers and facilitators to implementation are likely to be different in content and importance at different phases of implementation.

Liver Steatosis is Prevalent in Lean People With HIV and Associated With Exposure to Antiretroviral Treatment-A Cross-sectional Study.

Background: Steatotic liver disease is suggested to have a higher prevalence and severity in people with HIV (PHIV), including in those with a normal body mass index (BMI). In this study, we used data from the 2000HIV cohort to (1) assess the prevalence of liver steatosis and fibrosis in lean versus overweight/obese PHIV and (2) assess associations in these subgroups between steatosis and fibrosis with traditional risk factors and HIV-specific characteristics. Methods: The 2000HIV study cohort comprises 1895 virally suppressed PHIV that were included between 2019 and 2021 in 4 HIV treatment centers in the Netherlands. The majority (58.5%) underwent vibration-controlled transient elastography for the assessment of liver steatosis and fibrosis. The prevalence of steatosis (controlled attenuation parameter ≥263 dB/m) and fibrosis (liver stiffness measurement ≥7.0 kPa) was estimated. Multiple factors including HIV characteristics and antiretroviral drugs were tested in a logistic regression model for association with steatosis and fibrosis. Analyses were performed separately for lean (Asian descent: BMI < 23 kg/m2, other descent: BMI < 25 kg/m2) and overweight/obese (other BMI) participants. Results: Of 1050 PHIV including 505 lean and 545 overweight/obese PHIV, liver steatosis was observed in 37.7% of the overall study population, 19.7% of lean, and 54% of overweight/obese PHIV, whereas fibrosis was observed in 9.0% of the overall study population, 5.9% of lean, and 12.0% of overweight/obese PHIV.All associations with fibrosis and most associations with steatosis concerned metabolic factors such as type 2 diabetes mellitus (overall population: adjusted odds ratio [aOR] for steatosis: 2.3 [1.21-4.4], P = .011; aOR for fibrosis: 3.7 [1.82-7.53], P < .001). Furthermore, in lean PLHIV, liver steatosis was associated with CD4 and CD8 counts at enrollment, dual therapy, and history of treatment with raltegravir (aOR: 3.6 [1.53-8.47], P = .003), stavudine (aOR: 3.73 [1.69-8.2], P = .001), and indinavir (aOR: 3.86 [1.59-9.37], P = .003). These associations were not observed in overweight/obese PHIV. Conclusions: Liver steatosis was highly prevalent, affecting approximately one-fifth of lean PHIV and half of overweight/obese PHIV. Fibrosis was observed in a minority. Both steatosis and fibrosis were associated with traditional metabolic risk factors. In addition, (prior) exposure to specific antiretroviral drugs was associated liver steatosis in lean, but not in overweight/obese PHIV. Implementing increased screening protocols could enhance the identification of steatotic liver disease in lean PHIV.

Increased Risk of 90-Day Complications in Patients With Fibromyalgia Undergoing Total Shoulder Arthroplasty.

INTRODUCTION: Anatomic and reverse total shoulder arthroplasties (TSAs) are effective treatment options for end-stage glenohumeral osteoarthritis. Those undergoing TSA may also have fibromyalgia, a musculoskeletal condition. However, the association of fibromyalgia with shorter and longer term outcomes after TSA has not been well characterized. METHODS: Patients undergoing TSA for osteoarthritis indications were identified in the PearlDiver M165 database from January 2016 to October 2022. Exclusion criteria included age younger than 18 years, shoulder infection, neoplasm, or trauma within 90 days before surgery, and inactivity in the database within 90 days of surgery. Patients with fibromyalgia were matched in a 1:4 ratio to patients without based on age, sex, and Elixhauser Comorbidity Index. Ninety-day adverse events were compared using univariable and multivariable analyses. Five-year revision-free survival was compared using the log-rank test. RESULTS: Of 163,565 TSA patients, fibromyalgia was identified for 9,035 (5.52%). After matching, cohorts of 30,770 non-fibromyalgia patients and 7,738 patients with fibromyalgia were identified. Multivariable analyses demonstrated patients with fibromyalgia were at independently increased odds ratios (ORs) for the following 90-day complications (decreasing OR order): urinary tract infection (OR = 4.49), wound dehiscence (OR = 3.63), pneumonia (OR = 3.46), emergency department visit (OR = 3.45), sepsis (OR = 3.15), surgical site infection (OR = 2.82), cardiac events (OR = 2.72), acute kidney injury (OR = 2.65), deep vein thrombosis (OR = 2.48), hematoma (OR = 2.03), and pulmonary embolism (OR = 2.01) (P < 0.05 for each). These individual complications contributed to the increased odds of aggregated minor adverse events (OR = 3.68), all adverse events (OR = 3.48), and severe adverse events (OR = 2.68) (P < 0.05 for each). No statistically significant difference was observed in 5-year revision-free survival between groups. DISCUSSION: This study found TSA patients with fibromyalgia to be at increased risk of adverse events within 90 days of surgery. Proper surgical planning and patient counseling are crucial to this population. Nonetheless, it was reassuring that those with fibromyalgia had similar 5-year revision-free survival compared with those without.

HIV immunological non-responders are characterized by extensive immunosenescence and impaired lymphocyte cytokine production capacity.

Introduction: Immunological non-responders (INR) are people living with HIV (PLHIV) who fail to fully restore CD4+ T-cell counts despite complete viral suppression with antiretroviral therapy (ART). INR are at higher risk for non-HIV related morbidity and mortality. Previous research suggest persistent qualitative defects. Methods: The 2000HIV study (clinical trials NTC03994835) enrolled 1895 PLHIV, divided in a discovery and validation cohort. PLHIV with CD4 T-cell count <350 cells/mm3 after ≥2 years of suppressive ART were defined as INR and were compared to immunological responders (IR) with CD4 T-cell count >500 cells/mm3. Logistic and rank based regression were used to analyze clinical data, extensive innate and adaptive immunophenotyping, and ex vivo monocyte and lymphocyte cytokine production after stimulation with various stimuli. Results: The discovery cohort consisted of 62 INR and 1224 IR, the validation cohort of 26 INR and 243 IR. INR were older, had more advanced HIV disease before starting ART and had more frequently a history of non-AIDS related malignancy. INR had lower absolute CD4+ T-cell numbers in all subsets. Activated (HLA-DR+, CD38+) and exhausted (PD1+) subpopulations were proportionally increased in CD4 T-cells. Monocyte and granulocyte immunophenotypes were comparable. INR lymphocytes produced less IL-22, IFN-γ, IL-10 and IL-17 to stimuli. In contrast, monocyte cytokine production did not differ. The proportions of CD4+CD38+HLA-DR+ and CD4+PD1+ subpopulations showed an inversed correlation to lymphocyte cytokine production. Conclusions: INR compared to IR have hyperactivated and exhausted CD4+ T-cells in combination with lymphocyte functional impairment, while innate immune responses were comparable. Our data provide a rationale to consider the use of anti-PD1 therapy in INR.

Sports participation after craniosynostosis repair: the critical role of post-operative guidance in parental decision-making.

PURPOSE: Despite previous research supporting patient safety in sports after craniosynostosis surgery, parental anxiety remains high. This study sought to evaluate the role of healthcare providers in guiding patients and families through the decision-making process. METHODS: Parents of children with repaired craniosynostosis were asked to assess sports involvement and parental decision-making in children ages 6 and older. Questions were framed primarily on 5-point Likert scales. Sport categorizations were made in accordance with the American Academy of Pediatrics. Chi-squared, linear regression, and Pearson correlation tests were used to analyze associations between the questions. RESULTS: Forty-three complete parental responses were recorded. Mean ages at surgery and time of sports entry were 7.93 ± 4.73 months and 4.76 ± 2.14 years, respectively. Eighty-two percent of patients participated in a contact sport. Discussions with the primary surgeon were more impactful on parental decisions about sports participation than those with other healthcare providers (4.04 ± 1.20 vs. 2.69 ± 1.32). Furthermore, children whose parents consulted with the primary surgeon began participating in sports at a younger age (4.0 ± 1.0 vs. 5.8 ± 2.7 years, p = 0.034). The mean comfort level with contact sports (2.8 ± 1.4) was lower than that with limited-contact (3.8 ± 1.1, p = 0.0001) or non-contact (4.4 ± 1.3, p < 0.0001) sports. CONCLUSION: This study underscores the critical role that healthcare professionals, primarily surgeons, have in guiding families through the decision-making process regarding their children's participation in contact sports.

Cardiometabolic Differences in People Living with HIV Receiving Integrase Strand Transfer Inhibitors Compared to Non-nucleoside Reverse Transcriptase Inhibitors: Implications for Current ART Strategies.

In people living with HIV (PLHIV), integrase strand transfer inhibitors (INSTIs) are part of the first-line combination antiretroviral therapy (cART), while non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens are alternatives. Distinct cART regimens may variably influence the risk for non-AIDS comorbidities. We aimed to compare the metabolome and lipidome of INSTI and NNRTI-based regimens. The 2000HIV study includes asymptomatic PLHIV (n = 1646) on long-term cART, separated into a discovery cohort with 730 INSTI and 617 NNRTI users, and a validation cohort encompassing 209 INSTI and 90 NNRTI users. Baseline plasma samples from INSTI and NNRTI users were compared using mass spectrometry-based untargeted metabolomic (n = 500) analysis. Perturbed metabolic pathways were identified using MetaboAnalyst software. Subsequently, nuclear magnetic resonance spectroscopy was used for targeted lipoprotein and lipid (n = 141) analysis. Metabolome homogeneity was observed between the different types of INSTI and NNRTI. In contrast, higher and lower levels of 59 and 45 metabolites, respectively, were found in the INSTI group compared to NNRTI users, of which 77.9% (81/104) had consistent directionality in the validation cohort. Annotated metabolites belonged mainly to 'lipid and lipid-like molecules', 'organic acids and derivatives' and 'organoheterocyclic compounds'. In pathway analysis, perturbed 'vitamin B1 (thiamin) metabolism', 'de novo fatty acid biosynthesis', 'bile acid biosynthesis' and 'pentose phosphate pathway' were detected, among others. Lipoprotein and lipid levels in NNRTIs were heterogeneous and could not be compared as a group. INSTIs compared to individual NNRTI types showed that HDL cholesterol was lower in INSTIs compared to nevirapine but higher in INSTIs compared to doravirine. In addition, LDL size was lower in INSTIs and nevirapine compared to doravirine. NNRTIs show more heterogeneous cardiometabolic effects than INSTIs, which hampers the comparison between these two classes of drugs. Targeted lipoproteomic and lipid NMR spectroscopy showed that INSTI use was associated with a more unfavorable lipid profile compared to nevirapine, which was shifted to a more favorable profile for INSTI when substituting nevirapine for doravirine, with evidently higher fold changes. The cardiovascular disease risk profile seems more favorable in INSTIs compared to NNRTIs in untargeted metabolomic analysis using mass-spectrometry.