Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial.

People with lower extremity peripheral artery disease (PAD) have increased oxidative stress, impaired mitochondrial activity, and poor walking performance. NAD+ reduces oxidative stress and is an essential cofactor for mitochondrial respiration. Oral nicotinamide riboside (NR) increases bioavailability of NAD+ in humans. Among 90 people with PAD, this randomized double-blind clinical trial assessed whether 6-months of NR, with and without resveratrol, improves 6-min walk distance, compared to placebo, at 6-month follow-up. At 6-month follow-up, compared to placebo, NR significantly improved 6-min walk (+7.0 vs. -10.6 meters, between group difference: +17.6 (90% CI: + 1.8,+∞). Among participants who took at least 75% of study pills, compared to placebo, NR improved 6-min walk by 31.0 meters and NR + resveratrol improved 6-min walk by 26.9 meters. In this work, NR meaningfully improved 6-min walk, and resveratrol did not add benefit to NR alone in PAD. A larger clinical trial to confirm these findings is needed.

How will early onset scoliosis surgery affect my child's future as a young adult? A follow-up study using patient-reported outcome measures.

PURPOSE: Using patient-reported outcome measures (PROMs), this study was undertaken to determine how well patients with early onset scoliosis (EOS) fare in adulthood. METHODS: Among eight healthcare centers, 272 patients (≥ 18 years) surgically managed for EOS (≥ 5 years) completed the Scoliosis Research Society (SRS)-22r, Functional Assessment of Chronic Illness Therapy-10 (FACIT-Dyspnea-10), and Short Form (SF)-12. Functional and demographic data were collected. RESULTS: The response rate was 40% (108/272). EOS etiologies were congenital (45%), neuromuscular (20%), idiopathic (20%) syndromic (11%), and unknown (4%). All patients scored within normal limits on the FACIT-Dyspnea-10 pulmonary (no breathing aids, 78%; no oxygen, 92%). SF-12 physical health scores and most SRS-22r domains were significantly decreased (p < 0.05 and p < 0.001, respectively) compared with normative values. SF-12 and SRS-22r mental health scores (MHS) were lower than normative values (p < 0.05 and p < 0.02, respectively). Physical health PROMs varied between etiologies. Treatment varied by etiology. Patients with congenital EOS were half as likely to undergo definitive fusion. There was no difference between EOS etiologies in SF-12 MHS, with t scores being slightly lower than normative peers. CONCLUSION: Good long-term physical and social function and patient-reported quality of life were noted in surgically managed patients. Patients with idiopathic EOS physically outperformed those with other etiologies in objective and PROM categories but had similar MHS PROMs. Compared to normative values, EOS patients demonstrated decreased long-term physical capacity, slightly lower MHS, and preserved cardiopulmonary function. LEVEL OF EVIDENCE: Level IV Case Series.

Lower Income and Nonheterosexual Orientation Are Associated With Poor Access to Care in Patients With Knee Osteoarthritis.

Background: Social determinants of health are implicated in the experience of knee osteoarthritis, a key component of which is access to care and healthcare utilization. The objective of this study was to describe difficulties in access to care and healthcare utilization in the United States knee osteoarthritis population. Methods: The publicly available All of Us Database was utilized to conduct a retrospective cohort study. Patients with a diagnosis of knee osteoarthritis were included and matched to a control group who did not have knee osteoarthritis. The association of knee osteoarthritis and patient-specific demographic features with self-reported domains of access to care was analyzed. Results: Among 15,718 patients with knee osteoarthritis, 27.6% reported delayed care (n = 4343), 25.6% reported inability to afford care (n = 4015), 12.8% reported skipped medications (n = 2011), and 1.6% reported not seeing a healthcare provider in over 1 year (n = 247). Patients with knee osteoarthritis were more likely to be unable to afford care (odds ratio 1.21, P < .001) or skip medications (odds ratio 1.12, P = .004) in comparison to matched patients without knee osteoarthritis. Among the knee osteoarthritis cohort, low income and nonheterosexual orientation were both associated with increased rates of delayed care and an inability to afford care. Conclusions: Patients with knee osteoarthritis report significant challenges with delayed care, affordability of care, and medication adherence. Among patients with knee osteoarthritis, patients who are younger age, female sex, low-income, low-education, nonheterosexual orientation, or have poor physical and mental health are at increased risk of having decreased access to treatment.

Regional Variation from 2013 to 2021 in Primary Total Shoulder Arthroplasty Utilization, Reimbursement, and Patient Populations.

BACKGROUND: Total shoulder arthroplasty (TSA), encompassing both anatomical and reverse total shoulder arthroplasty, has increased in popularity worldwide. The purpose of this study was to assess how TSA utilization, reimbursement, surgeon practices, and patient populations have evolved within the Medicare population from 2013 to 2021 at a national and regional level. METHODS: The Medicare Physician and Other Practitioners dataset was queried for all episodes of primary TSA (CPT-23472), both anatomic and reverse, between years 2013 and 2021. TSA utilization was assessed as volume per 10,000 Medicare beneficiaries. Average inflation-adjusted reimbursement, physician practice styles, and patient demographics of each TSA surgeon were extracted each year. Data was stratified geographically based on US census classifications and rural-urban commuting codes. Kruskal-Wallis and multivariate regressions were utilized to determine differences between regions. RESULTS: Between 2013 and 2021, TSA utilization increased by 121.8% nationally. The increase was greatest in the Northeast (+147.2%) and least in the Midwest (+115.5%). Average TSA reimbursement declined by 8.8% nationally, with the least decline in the Northeast (6.4%) and the greatest decline in the Midwest (-11.9%). In 2021, the Midwest had the highest TSA utilization (18.1/10,000), while having the lowest average reimbursement ($1,108.59; p<0.001). The Northeast had the lowest utilization (11.5/10,000) and highest reimbursement ($1,223.44; p<0.001) in 2021. Nationally, the number of Medicare beneficiaries per surgeon performing shoulder arthroplasty declined by 5.9%, while the average number of TSAs per surgeon (+8.5%) and average number of billable services per beneficiary (+16.6%) both increased. Surgeons in the South performed the most services per beneficiary in 2021 (9.0; p<0.001). The average comorbidity burden of patients decreased by 4.8% between 2013 and 2021, with the West having the healthiest patients in 2021. Higher patient comorbidities were associated with lower physician reimbursement nationally (p<0.001). CONCLUSION: This study demonstrates that TSA utilization in the Medicare population has more than doubled between 2013 and 2021, while average inflation-adjusted reimbursement has declined by nearly 10%. The Midwest has the highest per-capita TSA utilization, while simultaneously having the lowest average reimbursement per TSA. Over time, TSA surgeons are seeing fewer and healthier beneficiaries but performing more services per beneficiary. Additionally, increased patient complexity may be associated with lower reimbursement. Together, these findings are concerning for long-term equitable access to care within shoulder surgery.

ACLY alternative splicing correlates with cancer phenotypes.

ATP-citrate lyase (ACLY) links carbohydrate and lipid metabolism and provides nucleocytosolic acetyl-CoA necessary for protein acetylation. ACLY has two major splice isoforms: the full-length canonical "long" isoform and an uncharacterized "short" isoform in which exon 14 is spliced out. Exon 14 encodes 10 amino acids within a disordered region of the protein and includes at least 1 site that is dynamically phosphorylated. Both isoforms are expressed in healthy tissues to varying degrees. Analysis of human transcriptomic data revealed that the Percent Spliced In (PSI) of exon 14, i.e., the proportion of long isoform, is increased in several cancers and correlated with poorer overall survival in a pan-cancer analysis, though not in individual tumor types, which prompted us to explore potential biochemical and functional differences between ACLY isoforms. Here, we show that there are no discernible differences in enzymatic activity or stability between isoforms or phosphomutants of ACLY in vitro. Similarly, both isoforms and phosphomutants were able to rescue ACLY functions, including fatty acid synthesis and bulk histone acetylation, when re-expressed in Acly knockout cells. Deletion of Acly exon 14 in mice did not overtly impact development or metabolic physiology, nor did it attenuate tumor burden in a genetic model of intestinal cancer. Notably, expression of epithelial splicing regulatory protein 1 (ESRP1) is highly correlated with ACLY PSI. We report that ACLY splicing is regulated by ESRP1. In turn, both ESRP1 expression and ACLY PSI are correlated with specific immune signatures in tumors. Despite these intriguing patterns of ACLY splicing in healthy and cancer tissues, functional differences between the isoforms remain elusive.

Investigating the Reading Profiles of Middle School Emergent Bilinguals with Significant Reading Comprehension Difficulties.

Purpose: This study investigated the reading profiles of middle school Spanish-speaking emergent bilinguals (EBs) with significantly below grade level reading comprehension and whether these profiles varied in their reading comprehension performance over time. Method: Latent profile analyses were used to classify Grade 6 and 7 Hispanic EBs (n = 340; 39% female) into subgroups based on their word reading and vocabulary knowledge. Growth models were then fit within each profile to evaluate reading comprehension performance over time. Results: Analyses revealed four latent profiles emerged: (a) very low word reading and low vocabulary (10%), (b) low word reading and low vocabulary (71%), (c) average word reading and low vocabulary (16%), and (d) high word reading and low vocabulary (3%). Subgroups varied in their reading comprehension initially and over one year. Students in the subgroup marked by very low word reading and low vocabulary showed the lowest reading comprehension performance initially; however, they also showed the greatest growth over one year. Conclusion: These findings suggest there is heterogeneity in the reading skill profiles of Spanish-speaking EBs with reading comprehension difficulties. They also underscore the prevalence of word reading difficulties among these students. These may be important factors to consider when developing interventions to prevent and remediate these difficulties.

Body Composition in Advanced Non-Small Cell Lung Cancer Treated With Immunotherapy.

Importance: The association between body composition (BC) and cancer outcomes is complex and incompletely understood. Previous research in non-small-cell lung cancer (NSCLC) has been limited to small, single-institution studies and yielded promising, albeit heterogeneous, results. Objectives: To evaluate the association of BC with oncologic outcomes in patients receiving immunotherapy for advanced or metastatic NSCLC. Design, Setting, and Participants: This comprehensive multicohort analysis included clinical data from cohorts receiving treatment at the Dana-Farber Brigham Cancer Center (DFBCC) who received immunotherapy given alone or in combination with chemotherapy and prospectively collected data from the phase 1/2 Study 1108 and the chemotherapy arm of the phase 3 MYSTIC trial. Baseline and follow-up computed tomography (CT) scans were collected and analyzed using deep neural networks for automatic L3 slice selection and body compartment segmentation (skeletal muscle [SM], subcutaneous adipose tissue [SAT], and visceral adipose tissue). Outcomes were compared based on baseline BC measures or their change at the first follow-up scan. The data were analyzed between July 2022 and April 2023. Main Outcomes and Measures: Hazard ratios (HRs) for the association of BC measurements with overall survival (OS) and progression-free survival (PFS). Results: A total of 1791 patients (878 women [49%]) with NSCLC were analyzed, of whom 487 (27.2%) received chemoimmunotherapy at DFBCC (DFBCC-CIO), 825 (46.1%) received ICI monotherapy at DFBCC (DFBCC-IO), 222 (12.4%) were treated with durvalumab monotherapy on Study 1108, and 257 (14.3%) were treated with chemotherapy on MYSTIC; median (IQR) ages were 65 (58-74), 66 (57-71), 65 (26-87), and 63 (30-84) years, respectively. A loss in SM mass, as indicated by a change in the L3 SM area, was associated with worse oncologic outcome across patient groups (HR, 0.59 [95% CI, 0.43-0.81] and 0.61 [95% CI, 0.47-0.79] for OS and PFS, respectively, in DFBCC-CIO; HR, 0.74 [95% CI, 0.60-0.91] for OS in DFBCC-IO; HR, 0.46 [95% CI, 0.33-0.64] and 0.47 [95% CI, 0.34-0.64] for OS and PFS, respectively, in Study 1108; HR, 0.76 [95% CI, 0.61-0.96] for PFS in the MYSTIC trial). This association was most prominent among male patients, with a nonsignificant association among female patients in the MYSTIC trial and DFBCC-CIO cohorts on Kaplan-Meier analysis. An increase of more than 5% in SAT density, as quantified by the average CT attenuation in Hounsfield units of the SAT compartment, was associated with poorer OS in 3 patient cohorts (HR, 0.61 [95% CI, 0.43-0.86] for DFBCC-CIO; HR, 0.62 [95% CI, 0.49-0.79] for DFBCC-IO; and HR, 0.56 [95% CI, 0.40-0.77] for Study 1108). The change in SAT density was also associated with PFS for DFBCC-CIO (HR, 0.73; 95% CI, 0.54-0.97). This was primarily observed in female patients on Kaplan-Meier analysis. Conclusions and Relevance: The results of this multicohort study suggest that loss in SM mass during systemic therapy for NSCLC is a marker of poor outcomes, especially in male patients. SAT density changes are also associated with prognosis, particularly in female patients. Automated CT-derived BC measurements should be considered in determining NSCLC prognosis.

The prison-based Therapeutic Community: Resident recommendations for program improvement.

INTRODUCTION: The prison-based Therapeutic Community (TC) is widely used within correctional institutions to address substance use disorders (SUDs). While most evaluations of the prison-based TC find the program to be effective, recent mixed evidence and the continued surge of the opioid crisis call for deeper investigation into program operations, barriers to engagement, and sources of treatment effect heterogeneity. Notably lacking from prior evaluations, and critical to our understanding of variable program engagement, is first-hand experiences and perceptions from program participants. METHODS: To assess prison-based TC resident perceptions of the program and their recommendations for improvement, we utilize data from the Therapeutic Community Prison Inmate Network Study (TC-PINS), a longitudinal data collection effort conducted in one prison-based TC unit within a Pennsylvania state prison. Specifically, we assess resident responses to the open-ended item "What can the TC do better?" Analyzing 470 responses to this question by 177 residents, two independent coders identified seven substantive categories of recommended changes or improvements to their TC program. RESULTS: Residents provided tangible recommendations for improvement of their prison-based TC program based on their experiences and perceptions. Importantly, a number of their recommendations directly counter the intended model of the TC, which highlights imperative issues underlying the translation of the TC model within the prison environment. Resident suggestions include enhanced structure, increased individualization, expanded curriculum, stricter enforcement of rules, and improved or more experienced staff. Additionally, many question the coercive nature of TC program participation within this prison system. CONCLUSIONS: Resident recommendations for program improvement unveil important sources of treatment effect heterogeneity and highlight tangible program changes that can be implemented to reduce barriers to treatment engagement. We provide suggested changes to this prison-based TC based on resident perceptions and discuss both the importance and relative ease of eliciting this critical participant feedback.

JNJ-7184, a respiratory syncytial virus inhibitor targeting the connector domain of the viral polymerase.

Respiratory syncytial virus (RSV) can cause pulmonary complications in infants, elderly and immunocompromised patients. While two vaccines and two prophylactic monoclonal antibodies are now available, treatment options are still needed. JNJ-7184 is a non-nucleoside inhibitor of the RSV-Large (L) polymerase, displaying potent inhibition of both RSV-A and -B strains. Resistance selection and hydrogen-deuterium exchange experiments suggest JNJ-7184 binds RSV-L in the connector domain. JNJ-7184 prevents RSV replication and transcription by inhibiting initiation or early elongation. JNJ-7184 is effective in air-liquid interface cultures and therapeutically in neonatal lambs, acting to drastically reverse the appearance of lung pathology.

Functional annotation and meta-analysis of maize transcriptomes reveal genes involved in biotic and abiotic stress.

BACKGROUND: Environmental stress factors, such as biotic and abiotic stress, are becoming more common due to climate variability, significantly affecting global maize yield. Transcriptome profiling studies provide insights into the molecular mechanisms underlying stress response in maize, though the functions of many genes are still unknown. To enhance the functional annotation of maize-specific genes, MaizeGDB has outlined a data-driven approach with an emphasis on identifying genes and traits related to biotic and abiotic stress. RESULTS: We mapped high-quality RNA-Seq expression reads from 24 different publicly available datasets (17 abiotic and seven biotic studies) generated from the B73 cultivar to the recent version of the reference genome B73 (B73v5) and deduced stress-related functional annotation of maize gene models. We conducted a robust meta-analysis of the transcriptome profiles from the datasets to identify maize loci responsive to stress, identifying 3,230 differentially expressed genes (DEGs): 2,555 DEGs regulated in response to abiotic stress, 408 DEGs regulated during biotic stress, and 267 common DEGs (co-DEGs) that overlap between abiotic and biotic stress. We discovered hub genes from network analyses, and among the hub genes of the co-DEGs we identified a putative NAC domain transcription factor superfamily protein (Zm00001eb369060) IDP275, which previously responded to herbivory and drought stress. IDP275 was up-regulated in our analysis in response to eight different abiotic and four different biotic stresses. A gene set enrichment and pathway analysis of hub genes of the co-DEGs revealed hormone-mediated signaling processes and phenylpropanoid biosynthesis pathways, respectively. Using phylostratigraphic analysis, we also demonstrated how abiotic and biotic stress genes differentially evolve to adapt to changing environments. CONCLUSIONS: These results will help facilitate the functional annotation of multiple stress response gene models and annotation in maize. Data can be accessed and downloaded at the Maize Genetics and Genomics Database (MaizeGDB).

Risk Versus Reward: Hospitals Incentivized More Than Surgeons to Care for Riskier Arthroplasty Patients.

BACKGROUND: The purpose of this study was to assess the relationship between risk and reimbursement for both surgeons and hospitals among Medicare patients undergoing primary total joint arthroplasty (TJA). METHODS: The "2021 Medicare Physician and Other Provider" and "2021 Medicare Inpatient Hospitals" files were used. Patient comorbidity profiles were collected, including the mean patient hierarchal condition category (HCC) risk score. Surgeon data included all primary TJA procedures (inpatient and outpatient) billed to Medicare in 2021, while hospital data included all such inpatient episodes. Surgeon and hospital reimbursements were collected. All episodes were split into a "sicker cohort" with an HCC risk score of 1.5 or more and a "healthier cohort" with HCC risk scores less than 1.5. Variables were compared across cohorts. RESULTS: In 2021, 386,355 primary total hip and knee arthroplasty procedures were billed to Medicare and were included. The mean surgeon reimbursement among the sicker cohort was $1,021.91, which was less than for the healthier cohort of $1,060.13 (P < .001). Meanwhile, for the hospital analysis, 112,012 Medicare TJA patients were admitted as inpatients and included. The mean reimbursement to hospitals was significantly greater for the sicker cohort at $13,950.66, compared to the healthier cohort of $8,430.46. For both analyses, the sicker patient cohorts had a significantly higher rate of all comorbidities assessed (P < .001). CONCLUSIONS: This study demonstrates that mean surgeon reimbursement was lower for primary TJA among sicker patients in comparison to their healthier counterparts, while hospital reimbursement was higher for sicker patients. This represents a discrepancy in the incentivization of care for complex patients, as hospitals receive increased remuneration for taking on extra risk, while surgeons get paid less on average for performing TJA on sicker patients. Such data should inform future policy to assure continued access to arthroplasty care among complex patients.

Differences in Reimbursements, Procedural Volumes, and Patient Characteristics Based on Surgeon Gender in Total Hip Arthroplasty.

BACKGROUND: Prior studies have suggested there may be differences in reimbursement and practice patterns by gender. The purpose of this study was to comprehensively evaluate differences in reimbursement, procedural volume, and patient characteristics in total hip arthroplasty (THA) between men and women surgeons from 2013 to 2021. METHODS: The Medicare Physician and Other Practitioners database from 2013 to 2021 was queried. Inflation-adjusted reimbursement, procedural volume, surgeon information, and patient demographics were extracted for surgeons performing over 10 primary THAs each year. Wilcoxon, t-tests, and multivariate linear regressions were utilized to compare men and women surgeons. RESULTS: Only 1.4% of THAs billed to Medicare between 2013 and 2021 were billed by women surgeons. Men surgeons earned significantly greater reimbursement nationally in 2021 compared to women surgeons per THA ($1,018.56 versus $954.17, P = .03), but no difference was found when assessing each region separately. Reimbursement declined at similar rates for both men and women surgeons (-18.3 versus -19.8%, P = .38). An increase in the proportion of women surgeons performing THA between 2013 and 2021 was seen in all regions except the South. In 2021, the proportion of all THAs performed by women surgeons was highest in the West (3.5%) and lowest in the South (1.0%). Women surgeons had comparable patient populations in terms of age, race, comorbidity status, and Medicaid eligibility to their men counterparts, but performed significantly fewer services per beneficiary (5.6 versus 8.1, P < .001) and fewer unique services (51.1 versus 69.6, P < .001). CONCLUSIONS: Average reimbursement per THA has declined at a similar rate for men and women physicians between 2013 and 2021. Women's representation in THA surgery nationwide has nearly doubled between 2013 and 2021, with the greatest increase in the West. However, there are notable differences in billing practices between genders.

How do implants overlying the spine influence "The Law of Diminishing Returns" in early-onset scoliosis patients?

PURPOSE: The "law of diminishing returns" (LODR) in early-onset scoliosis (EOS) is well-known. We hypothesized that previously observed variations between constructs may be related to the lateral distance that each construct lies from the spine. We therefore sought to determine whether the curve magnitude improvement and spinal length gains for distraction-based constructs in EOS are positively correlated with the collinearity of the spine and the convex-sided implant on posteroanterior radiographs. METHODS: A prospectively-collected, multicenter EOS registry was queried for all patients who underwent non-fusion, distraction-based instrumentation surgery. Post-index radiographs were graded from 1 to 5 based on amount of overlap between the convex-sided rod and the apical vertebra. Grade 1: convex rod is lateral to convex-sided pedicle; Grade 2: overlaps the convex-sided pedicle; Grade 3: lies between pedicles; Grade 4: overlaps concave-sided pedicle; Grade 5: medial to concave-sided pedicle. ANOVA assessed the correlations between post-index overlap grade and change in (a) curve magnitude and (b) T1-T12 height. Multivariable regression modeling further assessed these associations. RESULTS: 284 patients met all selection criteria and were included. On ANOVA, post-index grade was associated with curve magnitude (p <0.001) and T1-12 height (p = 0.028) change. Better curve correction and height change were associated with higher grade. On regression modeling, curve correction (R = 0.574) and T1-T12 height change (R = 0.339) remained significantly associated with grade when controlling for time, anchor locations, age, underlying diagnosis, and pre-index curve magnitude. CONCLUSION: More apical overlap by the convex rod was associated with better spinal deformity control and improved height gain. LEVEL OF EVIDENCE III: Therapeutic.

MRI Accurately Predicts Quadrupled Semitendinosus Autograft Size Using Posterior Hamstring Harvest for ACL Reconstruction.

Purpose: To determine the effectiveness of preoperative magnetic resonance imaging (MRI) measurements of the cross-sectional area (CSA) of the semitendinosus tendon in predicting the intraoperative quadrupled semitendinosus graft diameter of a posteriorly harvested hamstring autograft for anterior cruciate ligament (ACL) reconstruction. Methods: A retrospective review of patients who underwent ACL reconstruction with autograft using a posterior hamstring harvest was performed. Patient demographics and operative reports were reviewed, and measurements of the CSA of the semitendinosus on MRI were performed. Multiple linear regression was used to analyze the predictors for graft diameter. A P value < .05 was considered statistically significant. Interrater and intrarater reliability were calculated. Results: 280 patients were included. Patient height (P < .0001), and CSA of the semitendinosus (P < .0001) were significant predictors. Patients shorter than 63 inches had an average graft diameter of 7.89 mm compared to 8.69 mm for patients above 63 in (P < .001). The formula for the model is as follows: Graft diameter (mm2) = 2.74 + .067·Height (in) + .00009 · Weight (lbs) + .0018 · Age (years) +.12·Gender (1 if M, 0 if F) + 8.56 · CSA (cm2). The R2 for the model (0.5620), was greater than models using only height (R2 = .4092) or only CSA Semitendinosus (R2 = .3932). None of the interaction terms between covariates (e.g., height, weight, age, gender) were significant. Age (P =.6400), weight (P = .9970), and gender (P = .6700) were not significant predictors. Both intraclass (ICC = 0.864, 95% CI=[0.791, 0.912]) and interclass correlation (ICC=0.827, 95% CI=[0.715, 0.894]) showed good reliability. Conclusion: CSA semitendinosus tendon and patient height independently perform similarly as predictors of graft diameter. When used together, CSA and height accurately predict the graft diameter. In particular, for patients under 63 in tall who demonstrated an average graft diameter below the minimum 8 mm, as suggested by the literature, this may be a useful tool for preoperative planning of patients intending to undergo ACL reconstruction with posterior hamstring harvest. Level of Evidence: Level III, diagnostic: retrospective cohort study.

Regional Differences in Reimbursement, Volume, and Patient Characteristics Exist for Rotator Cuff Repairs: A Temporal Analysis from 2013 to 2021.

BACKGROUND: Prior studies have demonstrated declining reimbursement and changing procedural utilization across multiple orthopedic subspecialties, yet a comprehensive examination of this has not been performed for rotator cuff repair, particularly at a geographic level. The purpose of this study was to evaluate changes in reimbursement, utilization, and patient populations for open and arthroscopic rotator cuff repairs (RCR) from 2013 to 2021 at a national and regional level. METHODS: The Medicare Physician and Other Practitioners database from years 2013 to 2021 were queried to extract all episodes of open chronic RCR, open acute RCR, and arthroscopic RCR. Utilization was measured as procedural volume per 10,000 Medicare beneficiaries. Inflation-adjusted reimbursement, utilization, surgeon information, and patient characteristics were extracted for each procedure for each year. Data was stratified geographically based on US Census regions and rural-urban commuting codes. Kruskal-Wallis tests and linear regressions were performed to compare geographical areas. RESULTS: Between 2013 and 2021, arthroscopic RCR utilization increased by 9.4% (11.0/10,000 to 12.0/10,000), while open chronic RCR utilization decreased by 58.8% (2.0/10,000 to 0.8/10,000). During that time, average inflation-adjusted reimbursement declined by 10.0% and 11.3% for arthroscopic and open chronic RCR, respectively. The increase in utilization and decrease in reimbursement was greatest in the Midwest. In 2021, arthroscopic RCR utilization was 12.0/10,000, while average reimbursement for was $846.87, nationally. Utilization was highest in the South (14.5/10,000) and lowest in the Northeast (8.1/10,000) (p<0.001). Alternatively, reimbursement was highest in the Northeast ($904.60) and lowest in the South ($830.80) (p<0.001). The proportion of patients who were male, Medicaid eligible, or non-White was highest in the West (p<0.001). Patients in the West also had the fewest comorbidities. Increased patient comorbidities, when controlling patient demographics, was associated with lower reimbursement nationally and within the Northeast (p<0.001). CONCLUSION: Geographical discrepancies in rotator cuff repair utilization and reimbursement exist. The South consistently demonstrates the highest utilization of RCR, while also having the lowest reimbursement. Alternatively, the Northeast has the lowest utilization but the highest reimbursement. Increased patient population comorbidities were associated with reduced RCR reimbursement for surgeons in the Northeast, but not in other regions.

Fragment-based drug discovery for disorders of the central nervous system: designing better drugs piece by piece.

Fragment-based drug discovery (FBDD) has emerged as a powerful strategy to confront the challenges faced by conventional drug development approaches, particularly in the context of central nervous system (CNS) disorders. FBDD involves the screening of libraries that comprise thousands of small molecular fragments, each no greater than 300 Da in size. Unlike the generally larger molecules from high-throughput screening that limit customisation, fragments offer a more strategic starting point. These fragments are inherently compact, providing a strong foundation with good binding affinity for the development of drug candidates. The minimal elaboration required to transition the hit into a drug-like molecule is not only accelerated, but also it allows for precise modifications to enhance both their activity and pharmacokinetic properties. This shift towards a fragment-centric approach has seen commercial success and holds considerable promise in the continued streamlining of the drug discovery and development process. In this review, we highlight how FBDD can be integrated into the CNS drug discovery process to enhance the exploration of a target. Furthermore, we provide recent examples where FBDD has been an integral component in CNS drug discovery programs, enabling the improvement of pharmacokinetic properties that have previously proven challenging. The FBDD optimisation process provides a systematic approach to explore this vast chemical space, facilitating the discovery and design of compounds piece by piece that are capable of modulating crucial CNS targets.

Direct Implantation of Patient Brain Tumor Cells into Matching Locations in Mouse Brains for Patient-Derived Orthotopic Xenograft Model Development.

Background: Despite multimodality therapies, the prognosis of patients with malignant brain tumors remains extremely poor. One of the major obstacles that hinders development of effective therapies is the limited availability of clinically relevant and biologically accurate (CRBA) mouse models. Methods: We have developed a freehand surgical technique that allows for rapid and safe injection of fresh human brain tumor specimens directly into the matching locations (cerebrum, cerebellum, or brainstem) in the brains of SCID mice. Results: Using this technique, we successfully developed 188 PDOX models from 408 brain tumor patient samples (both high-and low-grade) with a success rate of 72.3% in high-grade glioma, 64.2% in medulloblastoma, 50% in ATRT, 33.8% in ependymoma, and 11.6% in low-grade gliomas. Detailed characterization confirmed their replication of the histopathological and genetic abnormalities of the original patient tumors. Conclusions: The protocol is easy to follow, without a sterotactic frame, in order to generate large cohorts of tumor-bearing mice to meet the needs of biological studies and preclinical drug testing.

Mental health outcomes, literacy and service provision in low- and middle-income settings: a systematic review of the Democratic Republic of the Congo.

In the Democratic Republic of the Congo (DRC), the prevalence of mental health issues could be greater than in other low-income and middle-income countries because of major risk factors related to armed conflicts and poverty. Given that mental health is an essential component of health, it is surprising that no systematic evaluation of mental health in the DRC has yet been undertaken. This study aims to undertake the first systematic review of mental health literacy and service provision in the DRC, to bridge this gap and inform those who need to develop an evidence base. This could support policymakers in tackling the issues related to limited mental health systems and service provision in DRC. Following Cochrane and PRISMA guidelines, a systematic (Web of Science, Medline, Public Health, PsycINFO, and Google Scholar) search was conducted (January 2000 and August 2023). Combinations of key blocks of terms were used in the search such as DRC, war zone, mental health, post-traumatic stress disorder (PTSD), anxiety, depression, sexual violence, war trauma, resilience, mental health systems and service provision. We followed additional sources from reference lists of included studies. Screening was completed in two stages: title and abstract search, and full-text screening for relevance and quality. Overall, 50 studies were included in the review; the majority of studies (n = 31) were conducted in the Eastern region of the DRC, a region devastated by war and sexual violence. Different instruments were used to measure participants' mental health such as the Hopkins Symptoms Checklist (HSCL-25), The Harvard Trauma Questionnaire, Patient Health Questionnaire (PHQ-9); General Anxiety Disorder (GAD-7), and Positive and Negative Symptoms Scale (PANSS). Our study found that wartime sexual violence and extreme poverty are highly traumatic, and cause multiple, long-term mental health difficulties. We found that depression, anxiety, and PTSD were the most common problems in the DRC. Psychosocial interventions such as group therapy, family support, and socio-economic support were effective in reducing anxiety, depression, and PTSD symptoms. This systematic review calls attention to the need to support sexual violence survivors and many other Congolese people affected by traumatic events. This review also highlights the need for validating culturally appropriate measures, and the need for well-designed controlled intervention studies in low-income settings such as the DRC. Better public mental health systems and service provision could help to improve community cohesion, human resilience, and mental wellbeing. There is also an urgent need to address wider social issues such as poverty, stigma, and gender inequality in the DRC.

Rasch validation of the short form (8 item) PC-QoL questionnaire and applicability of use as a health state classification system for a new preference-based measure.

BACKGROUND: The parent-proxy paediatric chronic cough quality of life questionnaire (PC-QoL) is a commonly used measure of spillover quality of life in parents of children with chronic cough. To date, spillover health utility in these parents is not routinely estimated largely due to the lack of a suitable instrument. Their perspective is not included in economic evaluations of interventions for their children. We explored developing a health state classification system based on the PC-QoL for measuring health utility spill over in this population. METHODS: This study included PC-QoL 8-item responses of 653 parents participating in a prospective cohort study about paediatric chronic cough. Exploratory factor analysis (EFA) and Rasch analysis were used to examine dimensionality and select potential items and level structure. RESULTS: EFA indicated that the PC-QoL had one underlying domain. Rasch analysis indicated threshold disordering in all items which improved when items were collapsed from seven to four levels. Two demonstrated differential item functioning (DIF) by diagnosis or ethnicity and were excluded from the final scale. This scale satisfied Rasch assumptions of local independence and unidimensionality and demonstrated acceptable fit to the Rasch model. It was presented to and modified by an expert panel and a consumer panel. The resulting classification system had six items, each with four levels. DISCUSSION: The PC-QoL can conform to a Rasch model with minor modifications. It may be a good basis for the classification system of a child cough-specific PBM. A valuation study is required to estimate preference weights for each item and to estimate health utility in parents of children with chronic cough.