Optimizing the timing of an end-of-outbreak declaration: Ebola virus disease in the Democratic Republic of the Congo.

Following the apparent final case in an Ebola virus disease (EVD) outbreak, the decision to declare the outbreak over must balance societal benefits of relaxing interventions against the risk of resurgence. Estimates of the end-of-outbreak probability (the probability that no future cases will occur) provide quantitative evidence that can inform the timing of an end-of-outbreak declaration. An existing modeling approach for estimating the end-of-outbreak probability requires comprehensive contact tracing data describing who infected whom to be available, but such data are often unavailable or incomplete during outbreaks. Here, we develop a Markov chain Monte Carlo-based approach that extends the previous method and does not require contact tracing data. Considering data from two EVD outbreaks in the Democratic Republic of the Congo, we find that data describing who infected whom are not required to resolve uncertainty about when to declare an outbreak over.

CRF release from a unique subpopulation of accumbal neurons constrains action-outcome acquisition in reward learning.

Background: The nucleus accumbens (NAc) mediates reward learning and motivation. Despite an abundance of neuropeptides, peptidergic neurotransmission from the NAc has not been integrated into current models of reward learning. The existence of a sparse population of neurons containing corticotropin releasing factor (CRF) has been previously documented. Here we provide a comprehensive analysis of their identity and functional role in shaping reward learning. Methods: To do this, we took a multidisciplinary approach that included florescent in situ hybridization (N mice ≥ 3), tract tracing (N mice = 5), ex vivo electrophysiology (N cells ≥ 30), in vivo calcium imaging with fiber photometry (N mice ≥ 4) and use of viral strategies in transgenic lines to selectively delete CRF peptide from NAc neurons (N mice ≥ 4). Behaviors used were instrumental learning, sucrose preference and spontaneous exploration in an open field. Results: Here we show that the vast majority of NAc CRF-containing (NAc CRF ) neurons are spiny projection neurons (SPNs) comprised of dopamine D1-, D2- or D1/D2-containing SPNs that primarily project and connect to the ventral pallidum and to a lesser extent the ventral midbrain. As a population, they display mature and immature SPN firing properties. We demonstrate that NAc CRF neurons track reward outcomes during operant reward learning and that CRF release from these neurons acts to constrain initial acquisition of action-outcome learning, and at the same time facilitates flexibility in the face of changing contingencies. Conclusion: We conclude that CRF release from this sparse population of SPNs is critical for reward learning under normal conditions.

Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders.

PURPOSE: To identify genetic etiologies and genotype/phenotype associations for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs). METHODS: We coupled phenotyping with exome or genome sequencing of 467 probands (550 affected and 1108 total individuals) with genetically unsolved oCCDDs, integrating analyses of pedigrees, human and animal model phenotypes, and de novo variants to identify rare candidate single nucleotide variants, insertion/deletions, and structural variants disrupting protein-coding regions. Prioritized variants were classified for pathogenicity and evaluated for genotype/phenotype correlations. RESULTS: Analyses elucidated phenotypic subgroups, identified pathogenic/likely pathogenic variant(s) in 43/467 probands (9.2%), and prioritized variants of uncertain significance in 70/467 additional probands (15.0%). These included known and novel variants in established oCCDD genes, genes associated with syndromes that sometimes include oCCDDs (e.g., MYH10, KIF21B, TGFBR2, TUBB6), genes that fit the syndromic component of the phenotype but had no prior oCCDD association (e.g., CDK13, TGFB2), genes with no reported association with oCCDDs or the syndromic phenotypes (e.g., TUBA4A, KIF5C, CTNNA1, KLB, FGF21), and genes associated with oCCDD phenocopies that had resulted in misdiagnoses. CONCLUSION: This study suggests that unsolved oCCDDs are clinically and genetically heterogeneous disorders often overlapping other Mendelian conditions and nominates many candidates for future replication and functional studies.

Papillary tumor of the pineal region: analysis of DNA methylation profiles and clinical outcomes in 76 cases.

Papillary tumor of the pineal region (PTPR) is an uncommon tumor of the pineal region with distinctive histopathologic and molecular characteristics. Experience is limited with respect to its molecular heterogeneity and clinical characteristics. Here, we describe 39 new cases and combine these with 37 previously published cases for a cohort of 76 PTPR's, all confirmed by methylation profiling. As previously reported, two main methylation groups were identified (PTPR-A and PTPR-B). In our analysis we extended the subtyping into three subtypes: PTPR-A, PTPR-B1 and PTPR-B2 supported by DNA methylation profile and genomic copy number variations. Frequent loss of chromosome 3 or 14 was found in PTPR-B1 tumors but not in PTPR-B2. Examination of clinical outcome showed that nearly half (14/30, 47%) of examined patients experienced tumor progression with significant difference among the subtypes (p value = 0.046). Our analysis extends the understanding of this uncommon but distinct neuroepithelial tumor by describing its molecular heterogeneity and clinical outcomes, including its tendency towards tumor recurrence.

Rural Surgery Preparedness After Graduation From a Surgical Residency.

BACKGROUND: General surgeons in rural communities face unique challenges due to broad scopes of practice with limited support and difficulties providing training. In 1998, this academic medical center initiated a rural program consisting of senior level rotations in rural communities. We surveyed past residents to determine scope of practice, level of preparedness, and recommendations. METHODS: The survey was sent to n = 89 residents and n = 34 surveys were completed. Of those, 85% took part in the rural program, 23.5% practice in a zip code defined as rural by HRSA, and 53% had fellowship training most commonly vascular (n = 5), critical care (n = 5), cardiothoracic (n = 3), and MIS (n = 3). Most common procedures reported were MIS (64.7%), vascular (38.2%), cardiothoracic (26.5%), hepatobiliary (23.5%), and pediatric (23.5%). RESULTS: Over 97% of participants were satisfied/very satisfied with their overall program, and 94% were satisfied/very satisfied with their preparedness for rural surgery. When prompted with, "A general surgery program must have some type of rural specific specialized curriculum and extended rotations to facilitate a career path in rural general surgery," 41.2% responded strongly agree, 47.1% agree, and 11.8% neutral. Recommendations for bolstering a rural program included urology (59%), MIS (59%), vascular (56%), OBGYN (47%), and pediatrics (38%). Regarding non-surgical education, residents felt underprepared for billing (79.4%) and administration (50.0%). DISCUSSION: Although satisfaction scores were high, improvements to better prepare surgeons for rural practice include increasing residents' exposure and training in OBGYN, MIS, vascular, urology, and billing and administration. These results should direct programs to prepare surgeons for effective rural practice.

Cyprocide selectively kills nematodes via cytochrome P450 bioactivation.

Left unchecked, plant-parasitic nematodes have the potential to devastate crops globally. Highly effective but non-selective nematicides are justifiably being phased-out, leaving farmers with limited options for managing nematode infestation. Here, we report our discovery of a 1,3,4-oxadiazole thioether scaffold called Cyprocide that selectively kills nematodes including diverse species of plant-parasitic nematodes. Cyprocide is bioactivated into a lethal reactive electrophilic metabolite by specific nematode cytochrome P450 enzymes. Cyprocide fails to kill organisms beyond nematodes, suggesting that the targeted lethality of this pro-nematicide derives from P450 substrate selectivity. Our findings demonstrate that Cyprocide is a selective nematicidal scaffold with broad-spectrum activity that holds the potential to help safeguard our global food supply.

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.

Computational design of Periplasmic binding protein biosensors guided by molecular dynamics.

Periplasmic binding proteins (PBPs) are bacterial proteins commonly used as scaffolds for substrate-detecting biosensors. In these biosensors, effector proteins (for example fluorescent proteins) are inserted into a PBP such that the effector protein's output changes upon PBP-substate binding. The insertion site is often determined by comparison of PBP apo/holo crystal structures, but random insertion libraries have shown that this can miss the best sites. Here, we present a PBP biosensor design method based on residue contact analysis from molecular dynamics. This computational method identifies the best previously known insertion sites in the maltose binding PBP, and suggests further previously unknown sites. We experimentally characterise fluorescent protein insertions at these new sites, finding they too give functional biosensors. Furthermore, our method is sufficiently flexible to both suggest insertion sites compatible with a variety of effector proteins, and be applied to binding proteins beyond PBPs.

Effect of a 4-Week Telerehabilitation Program for People with Post-COVID Syndrome on Physical Function and Symptoms: Protocol for a Randomized Controlled Trial.

OBJECTIVE: COVID-19 has led to significant morbidity and mortality globally. Post-COVID sequelae can persist beyond the acute and subacute phases of infection, often termed Post-COVID Syndrome (PCS). There is limited evidence on the appropriate rehabilitation for people with PCS. The aim of this study is to evaluate the effect on exercise capacity, symptoms, cognition, anxiety, depression, health-related quality of life (HRQoL), and fatigue, of a 4-week, twice-weekly supervised pulmonary telerehabilitation program compared to usual medical care for people with PCS with persistent respiratory symptoms. METHODS: The study will be a multi-site randomized controlled trial (RCT) with assessor blinding. Participants with confirmed previous COVID-19 infection and persistent respiratory symptoms who attend a post-COVID respiratory clinic will be randomized 1:1 to either an intervention group (IG) of 4 weeks, twice-weekly pulmonary telerehabilitation or a control group (CG) of usual medical care. Participants in the CG will be invited to cross-over into the IG after the week 4 assessment. Primary outcome: exercise capacity measured by the 1-minute sit-to-stand test. Secondary outcomes: 5 repetition sit-to-stand test; Montreal Cognitive Assessment; COVID-19 Yorkshire Rehabilitation Scale; COPD Assessment Test; 36-Item Short-Form Health Survey; Hospital Anxiety and Depression Scale; Fatigue Severity Scale; and the Kessler Psychological Distress Scale. Outcomes will be collected at baseline, after 4-weeks intervention or control period, after intervention in the cross-over group, and at 12-month follow-up. IMPACT STATEMENT: Research into effective rehabilitation programs is crucial given the substantial morbidity associated with PCS and the lack of long-term data for COVID-19 recovery. A short duration pulmonary telerehabilitation program, if effective compared to usual care, could inform practice guidelines and direct future clinical trials for the benefit of individuals with persistent respiratory symptoms post-COVID.

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.

The cochlear dose and the age at radiotherapy predict severe hearing loss after passive scattering proton therapy and cisplatin in children with medulloblastoma.

BACKGROUND: Hearing loss (HL) is associated with worse neurocognitive outcomes among patients with medulloblastoma. We aimed to identify risk factors associated with severe HL and to evaluate the generalizability of a published HL calculator among patients treated with passive scattering proton therapy (PSPT) and cisplatin. METHODS: We identified patients aged 3-21 years who were treated at our centers between 2007-2022. Audiograms were graded using the International Society of Pediatric Oncology-Boston scale. Time to grade 3-4 HL was evaluated using Kaplan-Meier and multivariable Cox models to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Seventy-nine patients were treated with PSPT at a median age of 7.5 years (range:3.1-21.1). The mean cochlear dose (Dmc) (±S.D.) was 31.5±8.5 Gy, and the cumulative cisplatin dose was 295±50 mg/m2. Fifty-nine patients (75%) received amifostine. Patients completed a median of 9 audiograms (range:4-22) with a median audiogram follow-up of 49 months (range:6-177). Twenty-seven patients (34%) had grade 3-4 HL. In adjusted Cox models, only higher Dmc (HR=1.12, 95% CI:1.06-1.18) was associated with grade 3-4 HL. The predicted 3-year incidence of grade 3-4 HL was 40.0% (95% CI: 21.3-66.3) and 66.7% (95% CI: 35.4-93.7) for children with Dmc ≥36 Gy and age at radiotherapy ≥7 and <7 years, respectively (p=0.042). It was 8.9% (95% CI: 2.3-31.6) and 15.6% (95% CI: 5.3-41.1) for children with Dmc <36 Gy and age at radiotherapy ≥7 and <7 years, respectively (p=0.78). CONCLUSIONS: Children <7 years at radiotherapy with a Dmc ≥36 Gy are at higher risk for HL.

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.

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.

ACLY alternative splicing correlates with cancer phenotypes.

ATP-citrate lyase (ACLY) links carbohydrate and lipid metabolism and provides nucleocytosolic acetyl-CoA 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 an intrinsically disordered region and includes at least one dynamically phosphorylated residue. 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 is increased in several cancers and correlated with poorer overall survival in a pan-cancer analysis, though not in individual tumor types. This 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.

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.

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.

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.