Table-mounted Versus Self-retaining Retraction: An Assessment of Postoperative Dysphagia Following Anterior Cervical Spine Surgery.

STUDY DESIGN: Retrospective study. OBJECTIVE: To determine whether there are significant differences in postoperative dysphagia when using table-mounted versus self-retaining retractor tools. SUMMARY OF BACKGROUND DATA: Retraction of prevertebral structures during anterior cervical spine surgery (ACSS) is commonly associated with postoperative dysphagia or dysphonia. Retractors commonly used include nonfixed self-retaining retraction devices or fixed table-mounted retractor arms. However, there is a paucity of literature regarding differences in dysphagia between retractor types. METHODS: Patients who underwent ACSS and adhered to a minimum of 6-month follow-up were retrospectively evaluated. Patient-reported outcomes (PROs) were compared between table-mounted and self-retaining retractor groups at the preoperative and final postoperative time points, including the SWAL-QOL survey for dysphagia. Categorical dysphagia was assessed using previously defined values for the minimum clinically important difference (MCID). RESULTS: Overall, 117 and 75 patients received self-retaining or table-mounted retraction. Average follow-up was significantly longer in the self-retaining cohort (14.8±15.0 mo) than in the table-mounted group (9.4±7.8, P=0.005). No differences were detected in swallowing function (P=0.918) or operative time (P=0.436), although 3-level procedures were significantly shortened with table-mounted retraction (P=0.005). Multivariate analysis trended toward worse swallow function with increased operative levels (P=0.072) and increased retraction time (P=0.054), although the retractor used did not predict swallowing function (P=0.759). However, categorical rates of postoperative dysphagia were lower with table-mounted retraction (13.3% vs. 27.4%, P=0.033). CONCLUSIONS: There was no significant difference observed in long-term swallowing dysfunction between patients who underwent ACSS with self-retaining and table-mounted retractors, although the rate of dysphagia was lower with table-mounted retraction. In addition, the greater number of operated levels per case in the table-mounted group at a similar time suggests improved efficiency.

Omic-signature of bronchopulmonary dysplasia associated pulmonary hypertension in <1500g-birth-weight-infants with hemodynamically significant intracardiac shunt.

BACKGROUND: PDA and ASD are common intracardiac shunts noted in prematurely born infants. While there is evidence of persistent PDA and ASD associated with a higher risk for developing bronchopulmonary dysplasia (ICS-BPD) and pulmonary hypertension (ICS-BPD-PH), the underlying pathogenesis is poorly understood and hence challenging to identify at-risk infants. Our study goal was to evaluate transcriptomic expression and associated pathways in tracheal aspirates (TAs) of low-birth-weight infants with hemodynamically significant cardiac shunt (ICS) that develop bronchopulmonary dysplasia (ICS-BPD) and pulmonary hypertension (ICS-BPD-PH). METHODS: TAs were collected from preterm infants with ICS and a diagnosis of BPD or BPD-PH from a single center. 36 TA samples including 19 ICS-BPD and 17 ICS-BPD-PH were analyzed. MiRNA expression was determined via PCR arrays, and mRNA expression via RNA seq. Data were analyzed using limma. RESULTS: 11 miRNAs and 10 mRNAs were differentially expressed (adjusted p < 0.05) in ICS-BPD-PH group when compared to ICS-BPD. Ingenuity Pathway Analysis identified associations with cellular growth, proliferation, death, and cell function pathways. CONCLUSION: TAs from preterm infants show differentially expressed miRNAs and mRNAs in ICS-BPD-PH when compared to ICS-BPD, an in-silico model identified target molecules that could be playing a role in BPD-PH pathogenesis in low-birth-weight infants with ICS. IMPACT: Pulmonary hypertension associated with severe BPD (BPD-PH) is a distinct disease in preterm infants with severe BPD and the role of intracardiac shunt (ICS) in its development is controversial and often challenging for clinical management. Our pilot study, researching specific endotyping of infants with pulmonary hypertension associated with BPD using multiomics approach has identified molecular markers and potential underlying pathways associated with this condition. These markers could aid in stratifying high risk infants with ICS that are at risk for developing BPD-PH and aid clinical management.

Quantification of Gleason Pattern 4 Metrics Identifies Pathologic Progression in Patients With Grade Group 2 Prostate Cancer on Active Surveillance.

BACKGROUND: During active surveillance (AS) for Grade Group (GG) 2 prostate cancer, pathologic progression to GG3 on surveillance biopsy is a trigger for intervention. However, this ratio of GP3:GP4, may be obscured by increases of relatively indolent disease. We aimed to explore changes in GP4 quantity during AS and propose alternative definitions for progression based on GP4 changes. DESIGN, SETTING, AND PARTICIPANTS: We assessed patients enrolled on AS between November 2014 and March 2020 with GG2 disease on diagnostic biopsy and subsequent surveillance biopsy approximately 1 year later. Outcome measures included change in overall %GP4 and total length GP4 (mm). RESULTS AND LIMITATIONS: 61 patients met the inclusion criteria, the median change in total length of GP4 and %GP4 was -0.12 mm (IQR -0.31, 0.09) and -2.5% (IQR -8.6, 0.0), respectively. Excluding the 35 patients with no evidence of GP4 on surveillance biopsy, median change in total GP4 length and %GP4 was 0.19 mm (IQR -0.04, 0.67) and 1.2% (IQR -1.6, 6.6), respectively. Three patients progressed to GG3 disease on surveillance biopsy, one of whom had only a small increase in %GP4. Conversely, an additional 2 patients who did not meet the criterion for GG3 had a large increase (> 1 mm) in total GP4 length. CONCLUSIONS: Presence of GG3 disease on surveillance biopsy as a trigger for treatment in men on AS is of questionable use alone; we suggest including other measures that do not depend on a ratio, such as an increase in total GP4 length.

Phenotypic and genotypic evaluation of bleeding diagnostic dilemmas: Two case studies.

Inherited platelet disorders (IPDs) are a heterogeneous group of conditions that present significant challenges in diagnosis and management. Here, we report two cases of patients presenting with clinically significant bleeding but with unclear etiologies by conventional clinical laboratory testing. Further evaluation, utilizing a combination of high-dimensional multiplexed mass cytometry and genetic sequencing, revealed the underlying causes of bleeding in both cases, leading to definitive diagnoses. These cases underscore the potential utility of combined multimodal approaches in evaluating patients with bleeding disorders. Moreover, these high-parameter methods can offer substantial mechanistic insights and can enhance our understanding of the molecular pathogenesis of IPDs. Future studies involving larger patient cohorts are needed to further validate this strategy, directly comparing its diagnostic yield and accuracy with current clinical laboratory testing approaches, which can ultimately improve patient care.

Trends in Payments for Facility and Surgeon Professional Fees for Shoulder Surgeries Performed at Ambulatory Surgery Centers.

BACKGROUND: It has previously been demonstrated that utilization of ambulatory surgery centers (ASCs) results in cost savings and improved outcomes. Despite these benefits, Medicare reimbursement for professional fees at ASCs are decreasing over time. In this study, we sought to analyze the discrepancy between facility fee and professional fee reimbursements for ASCs by Medicare for common shoulder procedures over time. We hypothesized that professional fees for shoulder procedures would decrease over the study period while facility fees kept pace with inflation. METHODS: Current Procedural Terminology (CPT) codes were used to identify shoulder specific procedures approved for ASCs by Centers for Medicare and Medicaid Services (CMS). Procedures were grouped into arthroscopic and open categories. Publicly available data from CMS was accessed via the Medicare Physician Fee Schedule Lookup Tool and used to determine professional fee payments from 2018-2024. Additionally, Medicare ASC Payment Rates files were accessed to determine facility fee reimbursements to ASCs from 2018-2024. Descriptive statistics were used to calculate means and percent change over time. Compound annual growth rates (CAGR) were calculated and discrepancies in inflation were corrected for using the Consumer Price Index. The Benjamini and Hochberg method was used to correct P values in the setting of multiple comparisons. RESULTS: A total of 33 common shoulder procedures were included for analysis (10 arthroscopic codes and 23 open codes). Reimbursements for facility fees have remained significantly higher than corresponding professional fees for both open and arthroscopic procedures (p<0.01). On average, facility fee reimbursements for common shoulder surgeries have risen on an annual basis in a manner consistent with inflation (p=0.838). However, professional fees for these procedures have experienced a nearly uniform decline over the study period both nominally and in inflation-adjusted dollars (p=0.064 and p=0.005, respectively). CONCLUSION: Facility fee payments for outpatient approved shoulder surgeries have matched or outpaced inflation. Over the same time period, professional fee reimbursements for surgeons are consistently decreasing, both in absolute and inflation-adjusted dollars. Reform to the physician fee schedule is necessary to ensure that Medicare patients retain access to high-quality physician care.

Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy-number variations contribute to CDH in the population. However, most individuals with CDH remain genetically undiagnosed. Here, we perform integrated de novo and common-variant analyses using 1,469 CDH individuals, including 1,064 child-parent trios and 6,133 ancestry-matched, unaffected controls for the genome-wide association study. We identify candidate CDH variants in 15 genes, including eight novel genes, through deleterious de novo variants. We further identify two genomic loci contributing to CDH risk through common variants with similar effect sizes among Europeans and Latinx. Both loci are in putative transcriptional regulatory regions of developmental patterning genes. Estimated heritability in common variants is ∼19%. Strikingly, there is no significant difference in estimated polygenic risk scores between isolated and complex CDH or between individuals harboring deleterious de novo variants and individuals without these variants. The data support a polygenic model as part of the CDH genetic architecture.

Disappearance and dissemination of sleep symptoms: the importance of sleep medicine expertise for psychiatry. A comment on Forbes et al.

Commentary of 'Elemental psychopathology: distilling constituent symptoms and patterns of repetition in the diagnostic criteria of the DSM-5' Vincent P. Martin 1, Régis Lopez 2,3, Jean-Arthur Micoulaud-Franchi 4,5, Christophe Gauld 4,6,.

Transitive inference in a clinical childhood sample with a focus on autism spectrum disorder.

Transitive inference (TI) has a long history in the study of human development. There have, however, few pediatric studies that report clinical diagnoses have tested trial-and-error TI learning, in which participants infer item relations, rather than evaluate them explicitly from verbal descriptions. Children aged 8-10 underwent a battery of clinical assessments and received a range of diagnoses, potentially including autism spectrum disorder (ASD), attention-deficit hyperactive disorder (ADHD), anxiety disorders (AD), specific learning disorders (SLD), and/or communication disorders (CD). Participants also performed a trial-and-error learning task that tested for TI. Response accuracy and reaction time were assessed using a statistical model that controlled for diagnostic comorbidity at the group level. Participants in all diagnostic categories showed evidence of TI. However, a model comparison analysis suggested that those diagnosed with ASD succeeded in a qualitatively different way, responding more slowly to each choice and improving faster across trials than their non-ASD counterparts. Additionally, TI performance was not associated with IQ. Overall, our data suggest that superficially similar performance levels between ASD and non-ASD participants may have resulted from a difference in the speed-accuracy tradeoff made by each group. Our work provides a preliminary profile of the impact of various clinical diagnoses on TI performance in young children. Of these, an ASD diagnosis resulted in the largest difference in task strategy.

The influence of preoperative 12-item veterans rand physical component scores on outcomes following cervical disc replacement.

PURPOSE: To evaluate the influence of preoperative VR-12 physical component scores (PCS) on outcomes following cervical disc replacement (CDR). METHODS: Patients undergoing elective CDR were retrospectively identified. Patient-reported outcomes (PROs) of interest included VR-12 PCS/VR-12 Mental Component Score (MCS)/9-Item Patient Health Questionnaire (PHQ-9)/Short Form-12 (SF-12) PCS and MCS/Patient-Reported Outcome Measurement Information System-Physical Function (PROMIS-PF)/Visual Analog Scale-Neck Pain (VAS-NP)/VAS-Arm Pain (VAS-AP)/Neck Disability Index (NDI). Baseline up to two-year postoperative scores were obtained (average follow-up: 9.2 ± 6.8months). Two cohorts were created: VR-12 PCS < 35 or VR-12 PCS ≥ 35. Improvements in scores from baseline to six weeks postoperatively and to final follow-up were calculated. Changes in scores were compared to previously reported thresholds to determine rates of minimum clinically important difference (MCID). RESULTS: Of 127 patients, 64 were in the worse VR-12 PCS group. Patients with better VR-12 PCS were more likely to have private insurance (p = 0.034). When accounting for insurance differences, the worse VR-12 PCS group reported inferior NDI/VAS-NP/PHQ-9/PROMIS-PF/VR-12 PCS/SF-12 PCS at six weeks and final follow-up (p ≤ 0.015, all). The worse VR-12 PCS group reported greater improvements in VAS-AP and VR-12 PCS by six weeks and in NDI/VR-12 MCS/VR-12 PCS/SF-12 PCS by final follow-up (p ≤ 0.026, all). Patients with worse VR-12 PCS reported greater MCID achievement for VR-12 MCS and SF-12 PCS (p ≤ 0.034, both). CONCLUSION: Following surgery, patients with worse VR-12 PCS report greater improvements in PROs, highlighting the increased relative impact of surgery for patients with worse baseline physical function. These findings can be used to optimize patient experience perioperatively and inform postoperative expectations.

Transcriptomic Analysis Reveals the Heterogeneous Role of Conducting Films Upon Electrical Stimulation.

Central nervous system (CNS) injuries and neurodegenerative diseases have markedly poor prognoses and can result in permanent dysfunction due to the general inability of CNS neurons to regenerate. Differentiation of transplanted stem cells has emerged as a therapeutic avenue to regenerate tissue architecture in damaged areas. Electrical stimulation is a promising approach for directing the differentiation outcomes and pattern of outgrowth of transplanted stem cells, however traditional inorganic bio-electrodes can induce adverse effects such as inflammation. This study demonstrates the implementation of two organic thin films, a polymer/reduced graphene oxide nanocomposite (P(rGO)) and PEDOT:PSS, that have favorable properties for implementation as conductive materials for electrical stimulation, as well as an inorganic indium tin oxide (ITO) conductive film. Transcriptomic analysis reveals that electrical stimulation improves neuronal differentiation of SH-SY5Y cells on all three films, with the greatest effect for P(rGO). Unique material- and electrical stimuli-mediated effects are observed, associated with differentiation, cell-substrate adhesion, and translation. The work demonstrates that P(rGO) and PEDOT:PSS are highly promising organic materials for the development of biocompatible, conductive scaffolds that will enhance electrically-aided stem cell therapeutics for CNS injuries and neurodegenerative diseases.

Fluid Management in Critically Ill Children: Single-Center Retrospective Comparison of Trauma and Postoperative Patients, 2020-2022.

OBJECTIVE: Injury and surgery both represent well-defined starting points of a predictable inflammatory response, but the consequent response to IV fluids has not been studied. We aimed to review and compare our single-center fluid management strategies in these two populations. DESIGN: Retrospective cohort study from January 2020 to July 2022. The primary outcome was total IV fluid volume administered. Net fluid balances and select clinical outcomes were also evaluated. SETTING: Single tertiary academic center and level 1 pediatric trauma center in New York. PATIENTS: A dataset of critically ill trauma and surgical patients aged 0-18 years who were admitted to the PICU, 2020-2022. Trauma patients had at least moderate traumatic injuries (Injury Severity Score ≥ 9) and surgical patients had at least a 1-hour operation time. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified 25 trauma and 115 surgical patients. During the first 5 days of hospitalization, we did not identify an association between grouping and total IV fluids administered and fluid balance in the prehospital, emergency department, and operating room (p = 0.90 and p = 0.79), even when adjusted for weight (p = 0.96). Time trend graphs of net fluid balance and IV fluid administered illustrated analogous fluid requirement and response with the transition from net positive to net negative fluid balance between 48 and 72 hours. There was an association between total IV fluid and ventilator requirement (p = 0.003). CONCLUSIONS: Critically ill pediatric trauma and postoperative patients seem to have similar fluid management and balance after injury or surgery. In our opinion, these two critically ill populations could be combined in large prospective studies on optimal fluid therapy in critically ill children.

HIV Infection and Exposure Increases Cariogenic Taxa, Reduces Taxonomic Turnover, and Homogenizes Spatial Differentiation for the Supragingival Microbiome.

Background: The oral microbiome comprises distinct microbial communities that colonize diverse ecological niches across the oral cavity, the composition of which are influenced by nutrient and substrate availability, host genetics, diet, behavior, age, and other diverse host and environmental factors. Unlike other densely populated human-associated microbial ecosystems (e.g., gut, urogenital), the oral microbiome is regularly and directly exposed to the external environment and is therefore likely less stable over time. Cross sectional studies of the oral microbiome capture a glimpse of this temporal dynamism, yet a full appreciation of the relative stability, robusticity, and spatial structure of the oral environment is necessary to understand the role of microbial communities in promoting health or disease. Results: Here we investigate the spatial and temporal stability of the oral microbiome over three sampling time points in the context of HIV infection and exposure. Individual teeth were sampled from a cohort of 565 Nigerian children with varying levels of tooth decay severity (i.e., caries disease). We collected 1,960 supragingival plaque samples and characterized the oral microbiome using a metataxonomic approach targeting an approximately 478 bp region of the bacterial rpoC gene. We found that both infection and exposure to HIV have significant effects on the stability of the supragingival plaque microbiome at both the spatial and temporal scale. Specifically, we detect (1) significantly lower taxonomic turnover of the oral community among exposed and infected children compared to unexposed children, (2) we find that HIV infection homogenizes the oral community across the anterior and posterior dentition, and (3) that impaired immunity (i.e., low CD4 count) and low taxonomic turnover over time in children living with HIV is associated with higher frequency of cariogenic taxa including Streptococcus mutans. Conclusions: Our results document substantial community fluctuations over time in children unexposed to HIV independent of oral health status. This suggests that the oral community, under typical conditions, rapidly adapts to environmental perturbations to maintain homeostasis and that long-term taxonomic rigidity is a signal of community dysfunction, potentially leading to a higher incidence of oral disease including caries.

Genotype-by-Environment Interactions in Nonalcoholic Fatty Liver Disease and Chronic Illness among Mexican Americans: The Role of Acculturation Stress.

This study examines the complex interplay of genetic and environmental interactions that shape chronic illness risk. Evidence is mounting for the role of genetic expression and the immune response in the pathogenesis of chronic disease. In the Rio Grande Valley of south Texas, where 90% of the population is Mexican American, chronic illnesses (including obesity, diabetes, nonalcoholic liver disease, and depression) are reaching epidemic proportions. This study leverages an ongoing family study of the genetic determinants of risk for obesity, diabetes, hypertension, hyperlipidemia, and depression in a Mexican American population. Data collected included blood pressure, BMI, hepatic transaminases, HbA1c, depression (BDI-II), acculturation/marginalization (ARSMA-II), and liver health as assessed by elastography. Heritability and genotype-by-environment (G×E) interactions were analyzed, focusing on the marginalization/separation measure of the ARSMA-II. Significant heritabilities were found for traits such as HbA1c (h2 = 0.52), marginalization (h2 = 0.30), AST (h2 = 0.25), ALT (h2 = 0.41), and BMI (h2 = 0.55). Genotype-by-environment interactions were significant for HbA1c, AST/ALT ratio, BDI-II, and CAP, indicating that genetic factors interact with marginalization to influence these traits. This study found that acculturation stress exacerbates the genetic response to chronic illness. These findings underscore the importance of considering G×E interactions in understanding disease susceptibility and may inform targeted interventions for at-risk populations. Further research is warranted to elucidate the underlying molecular pathways and replicate these findings in diverse populations.

Evaluating three-dimensional lung reconstructions for thoracoscopic lung resections using open-source software: a pilot study.

Background: Preoperative three-dimensional (3D) lung reconstructions can reduce intraoperative blood loss, conversion rate, and operation duration. These 3D reconstructions are predominantly provided by commercial expensive products, hence we aimed to assess the usability and performance of preoperative 3D lung reconstructions created with open-source software. Methods: Patients were invited to participate in this prospective pilot study if they were planned for uniportal video-assisted thoracoscopic surgery (VATS) lobectomy or segmentectomy between January and February 2023. Participants were excluded if a two-dimensional (2D) late-arterial-phase computed tomography (CT) scan contained motion artifacts, another surgical procedure was performed, or the surgery was canceled. After informed consent was obtained, 3D lung reconstructions were constructed using open-source 3D Slicer software. The system usability score (SUS) questionnaire assessed the usability of these reconstructions, whilst performance was evaluated based on anatomical validity compared to prior 2D CT assessment as well as operative findings. Descriptive statistics were reported. Results: Thirteen patients were included, of whom one underwent a segmentectomy. Eighty-three percent of the 3D lung reconstructions scored above average (SUS >68). Compared to 2D CT scans, 38% of lung nodule segmental locations were detected more accurately through 3D lung reconstructions. Furthermore, 3D lung reconstructions revealed anatomical variations in 62%, which were not recognized on 2D CT scans, and provided surgeons with insights that would change the procedure and/or transection planes in 62%. One 3D lung reconstruction failed to demonstrate an intraoperative recognized segmental pulmonary artery (A6) branch. Conclusions: Three-dimensional lung reconstructions created with open-source software were usable and effective for uniportal VATS anatomical resections. Trial Registration: ClinicalTrials.gov/NCT06132607.

Impact of preoperative back pain severity on PROMIS outcomes following minimally invasive lumbar decompression.

PURPOSE: To evaluate the effect of baseline back pain severity on PROMIS mental health outcomes following minimally invasive lumbar decompression (LD). METHODS: Patients undergoing elective, primary, single-level LD were retrospectively reviewed from a prospective single spine surgeon registry. Perioperative characteristics, demographics, and the following patient-reported outcomes (PROs) were extracted: Oswestry Disability Index (ODI)/Patient-Health Questionnaire-9 /PROMIS-Physical Function/Anxiety/Pain Interference/Sleep Disturbance (PROMIS-PF/A/PI/SD). Two cohorts were created: preoperative VAS-B < 7 and VAS-B ≥ 7. Change in PROs (ΔPROs) from baseline to six weeks/final follow-up were determined. Average patient follow-up was 13.4 ± 8.8 months. Minimal clinically important difference (MCID) achievement rates were calculated and compared through multivariable logistic regression. Postoperative scores and ΔPROs, were compared with multivariable linear regression while all other data was compared between groups with inferential statistics. RESULTS: Altogether, 347 patients were included, with 190 in the VAS-B < 7 group. VAS-B ≥ 7 reported worse outcomes preoperatively (p ≤ 0.013, all). At six weeks, VAS-B ≥ 7 reported worse VAS-B (p = 0.017), with no other significant differences. At final follow-up, patients with worse VAS-B reported worse ODI (p = 0.040) and VAS-B while all other PROs were similar (p ≥ 0.078, all). VAS-B ≥ 7 experienced greater 6-week improvements in VAS-B/ODI/PROMIS-PI/PROMIS-SD (p ≤ 0.009, all), greater VAS-B/ODI/PROMIS-SD improvement by final follow-up (p ≤ 0.009, all) and greater MCID achievement in ODI/VAS-B (p ≤ 0.027). CONCLUSION: Patients with worse baseline back pain report inferior baseline scores that converge with those with milder preoperative back pain by 6 weeks after LD and reported greater 6-week improvements in disability, pain interference, and sleep disturbance by 6 weeks, and greater improvements in disability and sleep disturbance by final follow-up.

Designing Coiled Coils for Heterochiral Complexation to Enhance Binding and Enzymatic Stability.

Coiled coils, commonly found in native proteins, are helical motifs important for mediating intermolecular interactions. While coiled coils are attractive for use in new therapies and biomaterials, the lack of enzymatic stability of naturally occurring l-peptides may limit their implementation in biological environments. d-peptides are of interest for biomedical applications as they are resistant to enzymatic degradation and recent reports indicate that stereochemistry-driven interactions, achieved by blending d- and l-peptides, yield access to a greater range of binding affinities and a resistance to enzymatic degradation compared to l-peptides alone. To our knowledge, this effect has not been studied in coiled coils. Here, we investigate the effects of blending heterochiral E/K coiled coils, which are a set of coiled coils widely used in biomaterials. We found that we needed to redesign the coiled coils from a repeating pattern of seven amino acids (heptad) to a repeating pattern of 11 amino acids (hendecad) to make them more amenable to heterochiral complex formation. The redesigned hendecad coiled coils form both homochiral and heterochiral complexes, where the heterochiral complexes have stronger heats of binding between the constituent peptides and are more enzymatically stable than the analogous homochiral complexes. Our results highlight the ability to design peptides to make them amenable to heterochiral complexation, so as to achieve desirable properties like increased enzymatic stability and stronger binding. Looking forward, understanding how to engineer peptides to utilize stereochemistry as a materials design tool will be important to the development of next-generation therapeutics and biomaterials.

Brain-age prediction: Systematic evaluation of site effects, and sample age range and size.

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain-age has highlighted the need for robust and publicly available brain-age models pre-trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain-age model. Here we expand this work to develop, empirically validate, and disseminate a pre-trained brain-age model to cover most of the human lifespan. To achieve this, we selected the best-performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain-age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5-90 years; 53.59% female). The pre-trained models were tested for cross-dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8-80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9-25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age-bins (5-40 and 40-90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain-age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain (https://centilebrain.org/#/brainAGE2), an open-science, web-based platform for individualized neuroimaging metrics.

Microsatellite Instability, Tumor Mutational Burden, and Response to Immune Checkpoint Blockade in Patients with Prostate Cancer.

PURPOSE: Patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab. We define the genomic features, clinical course, and response to immune checkpoint blockade (ICB) in patients with MSI-H/dMMR and TMB-H prostate cancers without MSI [TMB-H/microsatellite stable (MSS)]. EXPERIMENTAL DESIGN: We sequenced 3,244 tumors from 2,257 patients with prostate cancer. MSI-H/dMMR prostate cancer was defined as an MSIsensor score ≥10 or MSIsensor score ≥3 and <10 with a deleterious MMR alteration. TMB-H was defined as ≥10 mutations/megabase. PSA50 and RECIST responses were assigned. Overall survival and radiographic progression-free survival (rPFS) were compared using log-rank test. RESULTS: Sixty-three (2.8%) men had MSI-H/dMMR, and 33 (1.5%) had TMB-H/MSS prostate cancers. Patients with MSI-H/dMMR and TMB-H/MSS tumors more commonly presented with grade group 5 and metastatic disease at diagnosis. MSI-H/dMMR tumors had higher TMB, indel, and neoantigen burden compared with TMB-H/MSS. Twenty-seven patients with MSI-H/dMMR and 8 patients with TMB-H/MSS tumors received ICB, none of whom harbored polymerase epsilon (polE) catalytic subunit mutations. About 45% of patients with MSI-H/dMMR had a RECIST response, and 65% had a PSA50 response. No patient with TMB-H/MSS had a RECIST response, and 50% had a PSA50 response. rPFS tended to be longer in patients with MSI-H/dMMR than in patients with TMB-H/MSS who received immunotherapy. Pronounced differences in genomics, TMB, or MSIsensor score were not detected between MSI-H/dMMR responders and nonresponders. CONCLUSIONS: MSI-H/dMMR prostate cancers have greater TMB, indel, and neoantigen burden than TMB-H/MSS prostate cancers, and these differences may contribute to profound and durable responses to ICB.

Correlation between anxiety, sleep disturbance and clinical outcomes in a lumbar decompression cohort.

BACKGROUND: Patients with lumbar spinal pathology often suffer from anxiety and sleep disturbance, but correlations between anxiety and sleep disturbance and other patient-reported outcome measures (PROMs) before and after surgical intervention have not been explored. The purpose of this study is to analyze the correlations between patient-reported anxiety, sleep disturbance, and PROMs before and after lumbar decompression. METHODS: All patients undergoing elective, primary, lumbar decompression were retrospectively queried from a prospectively-maintained single spine surgeon database. Demographic and perioperative data and pre- and postoperative PROMs were extracted. Patient-Reported Outcome Measure Information System (PROMIS)-Anxiety, PROMIS-Sleep Disturbance (SD), PROMIS-Physical Function (PF), 9-Item Patient Health Questionnaire (PHQ-9), Visual Analog Scale (VAS)-Back, VAS-Leg, Oswestry Disability Index (ODI) were obtained preoperatively and through two years postoperatively. Pearson's correlation coefficients were calculated between PROMIS-Anxiety, PROMIS-SD, and the other PROMs of interest. RESULTS: PROMIS-Anxiety was positively correlated with PROMIS-SD (range: r = 0.473-0.828, p ≤ 0.006, all), PHQ-9 (range: r = 0.613--0.890, p ≤ 0.006, all), VAS-Back (range: r = -0.410-0.798, p ≤ 0.039, all), and ODI (range: r = 0.503-0.732, p ≤ 0.033, all) at all timepoints. PROMIS-Anxiety was negatively correlated with PROMIS-PF through 1 year postoperatively (range: r = -0.323- -0.729p ≤ 0.033, all). PROMIS-Anxiety was positively correlated to VAS-Leg at preoperative, 6-week, 12-week, and 2-year postoperative timepoints (range: r = 0.333--0.707, p ≤ 0.022, all). PROMIS-SD was positively correlated with PHQ-9 (range: r = 0.600-0.836), VASBack (range: r = 0.383-0.734), VAS-Leg (range: r = 0.399-0.811), and ODI (range: r = 0.404-0.812) at all timepoints (p ≤ 0.031, all). PROMIS-SD was negatively correlated with PROMIS-PF at all timepoints (range: r = -0.339-0.665, p ≤ 0.035, all). CONCLUSION: Patient-reported anxiety and sleep disturbance are significantly correlated with depressive burden, back pain, disability, and physical function, before and after lumbar decompression. Future studies should aim to determine the directionality of the associations and test interventions to improve health-related quality of life following lumbar decompression.