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This single-arm phase II non-randomised trial (ACTRN12619001265167) evaluated trastuzumab emtansine in solid cancers with HER2 amplification or mutation detected by comprehensive genomic profiling. The primary objective was objective response (OR), while secondary objectives included the time to progression (TTP) on study to TTP on prior therapy ratio, progression-free survival (PFS) and overall survival (OS). The cohort included 16 tumours with HER2 mutations (group 1) and 16 with HER2 amplification (group 2). After 17 months median follow-up, ORs occurred in 19% of group 1 (1 salivary gland carcinoma (SGC), 2 lung cancers) and 25% of group 2 (3 SGCs, 1 uterine carcinoma). Fourteen of 29 TTP-evaluable patients achieved a TTP ratio ≥1.3, including 10 without an OR. Median PFS and OS were 4.5 (95% CI 2.1-7.0) and 18.2 months (95% CI 8.1-not reached) respectively. Trastuzumab emtansine showed modest ORs and a favourable change in disease trajectory in select HER2-altered solid cancers.

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Coral reef ecosystems are highly threatened and can be extremely sensitive to the effects of climate change. Multiple shark species rely on coral reefs as important habitat and, as such, play a number of significant ecological roles in these ecosystems. How environmental stress impacts routine, site-attached reef shark behavior, remains relatively unexplored. Here, we combine 8 years of acoustic tracking data (2013-2020) from grey reef sharks resident to the remote coral reefs of the Chagos Archipelago in the Central Indian Ocean, with a satellite-based index of coral reef environmental stress exposure. We show that on average across the region, increased stress on the reefs significantly reduces grey reef shark residency, promoting more diffuse space use and increasing time away from shallow forereefs. Importantly, this impact has a lagged effect for up to 16 months. This may have important physiological and conservation consequences for reef sharks, as well as broader implications for reef ecosystem functioning. As climate change is predicted to increase environmental stress on coral reef ecosystems, understanding how site-attached predators respond to stress will be crucial for forecasting the functional significance of altering predator behavior and the potential impacts on conservation for both reef sharks and coral reefs themselves.

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BACKGROUND: Microsatellite Instability (MSI) and Tumor Mutational Burden (TMB) are associated with immune checkpoint inhibitor (ICI) efficacy. We examined the association between TMB and MSI status with survival in patients with urothelial carcinoma (UC) treated with ICI. METHODS: Patients from 15 institutions were treated with ICI monotherapy. Primary endpoint was overall survival and secondary endpoints included observed response rate (ORR), and progression-free (PFS) calculated from ICI initiation. TMB was analyzed as dichotomous (≥10 vs. <10 mut/Mb) and continuous variable. RESULTS: We identified 411 patients: 203 were treated with ICI 1L/upfront; 104 with 2 + L. For the 1L/upfront: median [m] OS was numerically longer in patients with TMB ≥10 versus TMB <10: mOS 35 versus 26 months (HR = 0.6) and with MSI-H and MSI-S (mOS NR vs. 22 months), though neither association was statistically significant. A statistically significant association was found between TMB (continuous variable) and OS (HR = 0.96, P = .01). For 2 + L: mOS was numerically longer in patients with TMB ≥10 versus TMB <10: (20 vs. 12 months; HR = 0.9); mOS was 12 and 17 months for patients with MSI-H and MSI-S, respectively. Eighty-nine patients received maintenance avelumab (mAV): mOS was longer in patients with TMB ≥10 versus TMB <10: 61 versus 17 months; (HR = 0.2, P = .02) and with MSI-H and MSI-S (NR vs. 24 months). CONCLUSIONS: Although not reaching statistical significance in several subsets, patients with high TMB and MSI-H had numerically longer OS with ICI, especially with mAV. Further validation is needed.

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INTRODUCTION: Diabetes disparities exist based on socioeconomic status, race, and ethnicity. The aim of this study is to compare two cohorts with diabetes from California and Florida to better elucidate how health outcomes are stratified within underserved communities according to state location, race, and ethnicity. RESEARCH DESIGN AND METHODS: Two cohorts were recruited for comparison from 20 Federally Qualified Health Centers as part of a larger ECHO Diabetes program. Participant-level data included surveys and HbA1c collection. Center-level data included Healthcare Effectiveness Data and Information Set metrics. Demographic characteristics were summarized overall and stratified by state (frequencies, percentages, means (95% CIs)). Generalized linear mixed models were used to compute and compare model-estimated rates and means. RESULTS: Participant-level cohort: 582 adults with diabetes were recruited (33.0% type 1 diabetes (T1D), 67.0% type 2 diabetes (T2D)). Mean age was 51.1 years (95% CI 49.5, 52.6); 80.7% publicly insured or uninsured; 43.7% non-Hispanic white (NHW), 31.6% Hispanic, 7.9% non-Hispanic black (NHB) and 16.8% other. Center-level cohort: 32 796 adults with diabetes were represented (3.4% with T1D, 96.6% with T2D; 72.7% publicly insured or uninsured). Florida had higher rates of uninsured (p<0.0001), lower continuous glucose monitor (CGM) use (18.3% Florida; 35.9% California, p<0.0001), and pump use (10.2% Florida; 26.5% California, p<0.0001), and higher proportions of people with T1D/T2D>9% HbA1c (p<0.001). Risk was stratified within states with NHB participants having higher HbA1c (mean 9.5 (95% CI 8.9, 10.0) compared with NHW with a mean of 8.4 (95% CI 7.8, 9.0), p=0.0058), lower pump use (p=0.0426) and CGM use (p=0.0192). People who prefer to speak English were more likely to use a CGM (p=0.0386). CONCLUSIONS: Characteristics of medically underserved communities with diabetes vary by state and by race and ethnicity. Florida's lack of Medicaid expansion could be a factor in worsened risks for vulnerable communities with diabetes.

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Despite the increasing burden of dengue, the regional emergence of the virus in Kenya has not been examined. This study investigates the genetic structure and regional spread of dengue virus-2 in Kenya. Viral RNA from acutely ill patients in Kenya was enriched and sequenced. Six new dengue-2 genomes were combined with 349 publicly available genomes and phylogenies used to infer gene flow between Kenya and other countries. Analyses indicate two dengue-2 Cosmopolitan genotype lineages circulating in Kenya, linked to recent outbreaks in coastal Kenya and Burkina Faso. Lineages circulating in Western, Southern, and Eastern Africa exhibiting similar evolutionary features are also reported. Phylogeography suggests importation of dengue-2 into Kenya from East and Southeast Asia and bidirectional geneflow. Additional lineages circulating in Africa are also imported from East and Southeast Asia. These findings underscore how intermittent importations from East and Southeast Asia drive dengue-2 circulation in Kenya and Africa more broadly.

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BACKGROUND: Sclerosing epithelioid fibrosarcoma (SEF) is a very rare soft tissue sarcoma that most commonly presents in middle-aged and elderly adults but has been rarely seen in children. SEF is a very aggressive tumor with over 50% of patients experiencing local recurrence and 40% to 80% of patients experiencing distant metastatic spread. This disease has been shown to be resistant to chemotherapy and is classically treated with surgical excision. CASE: We describe the case of a 10-year-old girl with Graves' disease who presented with protruding eyes (to a greater extent on the left side) and was found to have a large mass in her left inferior rectus muscle that was diagnosed as SEF. After treatment with incomplete resection, due to the benign-appearing nature of the tumor on imaging, and proton radiation therapy, she remains disease-free at 18 months post-therapy. DISCUSSION: SEF is typically identified via genetic testing and recognition of the EWSR1-CREB3L1 gene fusion as well as MUC4 expression via immunohistochemistry. DNA methylation profiling, which has traditionally been used in brain tumors, can also efficiently identify this tumor, and we recommend expanding the use of this technology for difficult to classify pediatric sarcomas.

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PURPOSE: The purpose of this study was to compare the effect of varying screw lengths on load to failure and retention of the dorsal ulnar corner fragment after fixation of comminuted intra-articular distal radius fractures in a cadaveric model. METHODS: Twenty-four fresh frozen cadaveric forearms were subjected to a standardized distal radius osteotomy to mimic an intra-articular fracture pattern. Dual X-ray absorptiometry scans were performed to ensure minimal variability in bone density. All fractures were fixed with a volar locking plate and distal locking screws. Three different lengths of distal locking screws were used in each group of eight specimens to simulate the clinical decision of different distal screw lengths. The screw lengths tested were bicortical, 100% of the width of the bone but unicortical, and 75% of the width of the bone and unicortical. All specimens were preconditioned with cyclic axial loading and then axially loaded using matching acrylic resin molds to clinical failure and fragment displacement as detected by a motion analysis system. Retention or loss of the dorsal ulnar corner fragment during loading was recorded as a binary variable. RESULTS: Between the three groups, there were no statistically significant differences in precycling stiffness, postcycling stiffness, load at 2 mm displacement of the dorsal ulnar corner, or force at failure. The group with 75% length screws had a significantly higher loss of reduction of the dorsal ulnar corner (86%) compared with the other groups (0%). CONCLUSIONS: Varying screw lengths did not affect the stiffness or overall loads to failure of axially loaded specimens. However, the 75% length screws did not reliably secure the dorsal ulnar corner fragments. Although this did not significantly affect the overall load to failure of the construct, displacement of this fragment may have implications for rotation of the forearm through the distal radioulnar joint. CLINICAL RELEVANCE: Surgeons should consider the utilization of full-length unicortical locking screws to ensure adequate fixation of the dorsal ulnar corner. TYPE OF STUDY/LEVEL OF EVIDENCE: Biomechanical study V.

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INTRODUCTION: Numerous studies have identified diabetes mellites (DM) as a significant risk factor for postoperative wound morbidity, with suboptimal preoperative glycemic control (GC) posing an even greater risk. However, this data largely excludes ventral hernia patients. Our study examined the association between diabetes and preoperative GC and postoperative outcomes following open complex abdominal wall reconstruction (AWR). METHODS: We identified diabetic patients who had undergone open, elective, clean VHR with transversus abdominis release (TAR) and permanent synthetic mesh at the Cleveland Clinic Foundation between January 2014 and December 2023. Their 30-day outcomes were compared to non-diabetic patients undergoing the same procedure. Subsequently, diabetic patients were categorized based on GC. status: "Optimal GC" (HbA1c < 7%), "Sub-optimal GC" (HbA1c 7-8.4%), and "Poor GC" (HbA1c ≥ 8.5%) and their outcomes were compared. RESULTS: 514 patients with DM who underwent clean elective TAR were identified, of which 431 met the inclusion criteria. GC was deemed optimal in 255 patients, sub-optimal in 128, and poor in 48 patients. Demographics were similar, except for anticoagulation treatment (p = 0.014). The entire study population exhibited significantly higher rates of wound morbidities and overall complications compared to non-diabetic patients. However, rates of surgical site infection (SSI), surgical site occurrence (SSO), SSO requiring procedural intervention (SSOPI), and reoperation did not differ significantly among the three cohorts of presurgical glycemic control (p = 0.82, p = 0.46, p = 0.51, p = 0.78), respectively. No occurrence of mesh removal was documented. CONCLUSION: In general, diabetes is a marker for increased wound morbidity and complications following complex abdominal wall reconstruction. However, we could not establish a hard cutoff to justify withholding surgery in symptomatic patients based on an arbitrary HbA1C level. We believe this data is important for shared decision-making when considering AWR for symptomatic ventral hernias in diabetic patients.

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Importance: Kidney disease is common in infants admitted to the neonatal intensive care unit (NICU). Despite the risk of chronic kidney disease (CKD) in infants discharged from the NICU, neither evidence- nor expert-based recommendations exist to guide clinical care after discharge. Objective: To develop recommendations for risk stratification and kidney health monitoring among infants after discharge from the NICU. Evidence Review: At the National Institute of Health-supported Consensus Workshop to Address Kidney Health in Neonatal Intensive Care Unit Graduates meeting conducted in February 2024, a panel of 51 neonatal nephrology experts focused on 3 at-risk groups: (1) preterm infants, (2) critically ill infants with acute kidney injury (AKI), and (3) infants with critical cardiac disease. Using established modified Delphi processes, workgroups derived consensus recommendations. Findings: In this modified Delphi consensus statement, the panel developed 10 consensus recommendations, identified gaps in knowledge, and prioritized areas of future research. Principal suggestions include risk stratification at time of hospital discharge, family and clinician education and counseling for subsequent kidney health follow-up, and blood pressure assessment as part of outpatient care. Conclusions and Relevance: Preterm infants, critically ill infants with AKI, and infants with critical cardiac disease are at increased risk of CKD. We recommend (1) risk assessment at the time of discharge, (2) clinician and family education, and (3) kidney health assessments based on the degree of risk. Future work should focus on improved risk stratification, identification of early kidney dysfunction, and development of interventions to improve long-term kidney health.

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The IQ Consortium's DruSafe Leadership Group previously reported results of a nonclinical to clinical translational database for First-In-Human (FIH)-enabling animal toxicology studies. We have completed an additional translational database populated with longer duration (>1 month) animal toxicology studies and longer duration (Phase 2 and beyond) clinical trials. The blinded database was composed of 127 molecules. Animal and clinical data were categorized by organ system and animal model (e.g. rodent, dog). The 2 × 2 contingency table (true positive, false positive, true negative, false negative) was used for statistical analysis and both the positive predictive value (PPV) and negative predictive value (NPV) were determined. As also reported in the FIH database, the NPV was the strongest predictive performance measure at 96 %. The PPV was lower than the FIH database with the rodent at 29 %, dog at 21 % and NHP at 20 %. No new additional target organs were observed in 62 % of the entries. A new target organ was identified in 38 % of the entries, with the majority in a rodent (26 %) and fewer in the dog (8 %) or NHP (12 %). However, new target organ data resulted in only a PPV of 13 %, suggesting that current ICH requirements for longer duration animal general toxicology studies should be re-evaluated and better aligned with the 3Rs. A newer paradigm could include an appropriately justified single animal model for longer duration studies, in addition to utilizing New Approach Methods (NAMs) that would provide translational safety data, but additional research is needed.

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Regulatory genetic toxicology testing is essential for identifying potentially mutagenic hazards. Duplex Sequencing (DS) is an error-corrected next-generation sequencing technology that provides substantial advantages for mutation analysis over conventional mutagenicity assays including: improved accuracy of mutation detection, ability to measure changes in mutation spectrum, and applicability across diverse biological models. To apply DS for regulatory toxicology testing, power analyses are required to determine suitable sample sizes and study designs. In this study, we explored study designs to achieve sufficient power for various effect sizes in chemical mutagenicity assessment. We collected data from MutaMouse bone marrow and liver samples that were analyzed by DS using TwinStrand's Mouse Mutagenesis Panel. Average duplex reads achieved in two separates studies on liver and bone marrow were 8.4 × 108 (± 7.4 × 107) and 9.5 × 108 (± 1.0 × 108), respectively. Baseline mean mutation frequencies (MF) were 4.6 × 10-8 (± 6.7 × 10-9) and 4.6 × 10-8 (± 1.1 × 10-8), with estimated standard deviations for the animal-to-animal random effect of 0.15 and 0.20, for liver and bone marrow, respectively. We conducted simulation analyses based on these empirically derived parameters. We found that a sample size of four animals per group is sufficient to obtain over 80% power to detect a two-fold change in MF relative to baseline. In addition, we estimated the minimal total number of informative duplex bases sequenced with different sample sizes required to retain power for various effect sizes. Our work provides foundational data for establishing suitable study designs for mutagenicity testing using DS.

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Cosmic radiation experienced during space travel may increase the risk of cognitive impairment. While simulated galactic cosmic radiation (GCRsim) has led to memory deficits in wildtype (WT) mice, it has not been investigated whether GCRsim in combination with genetic risk factors for Alzheimer's disease (AD) worsens memory further in aging mice. Here, we investigated the central nervous system (CNS) effects of 0 Gy (sham) or 0.75 Gy five-ion GCRsim or 2 Gy gamma radiation (IRR) in 14-month-old female and male APPNL-F/NL-F knock-in (KI) mice bearing humanized ApoE3 or ApoE4 (APP;E3F and APP;E4F). As travel to a specialized facility was required for irradiation, both traveled sham-irradiated C57BL/6J WT and KI mice and non-traveled (NT) KI mice acted as controls for potential effects of travel. Mice underwent four behavioral tests at 20 months of age and were euthanized for pathological and biochemical analyses 1 month later. Fecal samples were collected pre- and post-irradiation at four different time points. GCRsim seemed to impair memory in male APP;E3F mice compared to their sham counterparts. Travel tended to improve cognition in male APP;E3F mice and lowered total Aß in female and male APP;E3F mice compared to their non-traveled counterparts. Sham-irradiated male APP;E4F mice accumulated more fibrillar amyloid than their APP;E3F counterparts. Radiation exposure had only modest effects on behavior and brain changes, but travel-, sex-, and genotype-specific effects were seen. Irradiated mice had immediate and long-term differences in their gut bacterial composition that correlated to Alzheimer's disease phenotypes.

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Background: Reducing the dose of psychosis drugs in a gradual hyperbolic manner may minimise withdrawal effects and risk of relapse. There is presently limited guidance on tapering decanoate-based long-acting injectable dopamine antagonists (LIDAs). Objectives: We aimed to apply hyperbolic principles of tapering to the decanoate-based LIDAs flupentixol, zuclopenthixol and haloperidol to develop withdrawal regimens. Design: We used in silico methodology to predict plasma drug levels and D2 occupancy for different LIDA regimens. Methods: Existing pharmacokinetic and receptor occupancy data from nuclear neuroimaging studies were used to power modelling. Abrupt discontinuation was examined as a potential strategy, and dose reduction was modelled with pre-defined constraints used in similar work of 10 (fast regimens), 5 (moderate) and 2.5 (slow) percentage points of D2 occupancy change per month. Results: Abrupt discontinuation of decanoate-based LIDAs leads to excessive change in D2 occupancy which violated our pre-defined constraints, potentially resulting in withdrawal symptoms and increased risk of relapse. Reduction of LIDA dose allowed hyperbolic reduction in plasma level consistent with imposed constraints on receptor occupancy reduction rate. For equivalent per-weekly LIDA dosing, more frequent administration allowed a more gradual reduction of D2 occupancy. However, switching to oral forms is required to continue hyperbolic tapering to full discontinuation; reduction to zero using only LIDA produces too large a reduction in D2 occupancy. Guidance for reduction and cessation of LIDAs according to slow, moderate and fast criteria is provided. Conclusion: Abrupt cessation of decanoate LIDAs is not consistent with gradual hyperbolic tapering, despite their longer half-lives compared with oral formulations. Reduction to the point of full discontinuation can only be achieved by switching to oral therapy to complete the taper. These results are limited by the in silico and theoretical nature of the study, and there is a need to confirm these findings through real-world observational and interventional studies.

Computer-based research on the best way to reduce the dose and eventually stop three depot antipsychotics What is the problem? Psychosis affects how someone experiences reality. Antipsychotics are used to treat psychosis. They work by blocking a chemical called dopamine. Stopping these too rapidly can cause psychosis to occur again. This might be because the dopamine block is removed suddenly. Sometimes antipsychotics are given by injection. Injections stay in the body for a longer time than tablets. The best way to reduce these injections is currently unknown. What did we do? We explored the best way to reduce and stop antipsychotic injections. We looked at three different types of psychosis injection. We used existing data to assess how these drugs affect the brain. We examined what would happen if an antipsychotic injection was suddenly stopped. We then evaluated the effect of reducing the dose gradually. What did we find? Stopping antipsychotic injections suddenly would lead to rapid changes at brain receptors. This might lead to symptoms of withdrawal and a high risk of psychosis recurring. Reducing the dose of injections leads to less change than stopping suddenly. Switching to a tablet allows for more control when reducing dose. Having injections more often also reduce the changes occurring between injections. We outline three different rates of dose reduction. What does this mean? Antipsychotic injections stay in the body longer than tablets. However, stopping injections suddenly may still not be safe. We recommend that people reduce the dose of their injection instead. We also recommend people switch to tablets or liquid before stopping. It should be noted that our research is computer-based. We would like to see our recommendations tested in the real world.

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An advantage of treated implant surfaces is their increased degree of hydrophilicity and wettability compared with untreated, machined, smooth surfaces that are hydrophobic. The present preclinical in vivo study aimed to compare the two implant surface types, namely SLActive (Straumann, Basel, Switzerland) and nanohydroxyapatite (Hiossen, Englewood Cliffs, NJ, USA), in achieving early osseointegration. The authors hypothesised that the nanohydroxyapatite surface is comparable to SLActive for early bone-implant contact. Six male mixed foxhounds underwent mandibular premolar and first molar extraction, and the sockets healed for 42 days. The mandibles were randomised to receive implants with either SLActive (control group) or nanohydroxyapatite surfaces (test group). A total of 36 implants were placed in 6 animals, and they were sacrificed at 2 weeks (2 animals), 4 weeks (2 animals) and 6 weeks (2 animals) after implant surgery. When radiographic analysis was performed, the difference in bone level between the two groups was statistically significant at 4 weeks (P = 0.024) and 6 weeks (P = 0.008), indicating that the crestal bone level was better maintained for the test group versus the control group. The bone-implant contact was also higher for the test group at 2 (P = 0.012) and 4 weeks (P = 0.011), indicating early osseointegration. In conclusion, this study underscored the potential of implants with nanohydroxyapatite surfaces to achieve early osseointegration.

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Background: This study follows published associations in BC to 2014 (updated in 2019) to model the predicted incidence of asthma in BC children attributable to antibiotic use within the context of reduced antibiotic use and increased breastfeeding in BC infants from 2000 to 2019. Methods: A population-based ecological study was conducted in BC from 2000 to 2019, using outpatient antibiotic prescription data from BC PharmaNet and asthma diagnoses from the Chronic Disease Registry. Breastfeeding estimates were calculated using the Canadian Community Health Survey (CCHS). Population attributable risk (PAR) was calculated using a blended relative risk (RR) of asthma in antibiotic-exposed children who were and were not breastfed. PAR was used to calculate predicted vs. actual asthma incidence in 2019. Negative binomial regression was used to estimate the association between the average antibiotic prescription rate in infants under 1 and asthma incidence in 1-4 year olds, stratified by periods between 2000-2014 and 2015-2019. Results: In BC, antibiotic prescribing decreased by 77% in infants under 1 and asthma incidence decreased by 41% in children 1-4 years from 2000 to 2019. BC breastfeeding rates increased from 46% in the 2005 CCHS to 71% in the 2017/18 CCHS. After calculating the PAR using a blended RR, the predicted asthma incidence in 2019 was 18.8/1,000 population. This was comparable to the observed asthma incidence in children 1-4 years of 16.6/1,000 population in 2019. During 2000-2014, adjusted incidence risk ratio (aIRR) for children under Quintile 5 of average antibiotic prescribing was 1.75 (95% CI: 1.63-1.88, P < 0.0001) times higher than that for Quintile 1. However, between 2015 and 2019, this association weakened (as expected because of increasing prevalence of breastfeeding), with the expected asthma incidence for Quintile 5 only 11% (aIRR 1.11, 95% CI: 0.78-1.57) higher than for Quintile 1. Conclusion: We identified that over the past 20 years, antibiotic exposure in infants under 1 and asthma incidence in children 1-4 years has decreased significantly. Decreasing antibiotic exposure and increasing breastfeeding (which further mitigates risk associated with antibiotics) are of sufficient scale to explain much of this population trend. Changes in environmental, social and other exposures remain relevant to this complicated etiological pathway.

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Background: Patients with alcohol use disorder (AUD) and high-risk opioid use are at risk of serious complications. The purpose of this study was to estimate the prevalence of and factors associated with high-risk opioid use in patients with an alcohol use problem from 2005 to 2018. Methods: This repeated cross-sectional study analyzed data from first admissions for alcohol treatment (2005-2018) to the NYS Office of Addiction Services and Supports merged with Medicaid Claims Data. High-risk opioid use was defined as opioid dose ≥50 morphine mg equivalents (MME) per day; opioid prescriptions overlapping ≥7 days; opioids for chronic pain >90 days or opioids for acute pain >7 days. Results: Patients receiving ≥50 MME increased from 690 to 3226 from 2005 to 2010; then decreased to 2330 in 2018. From 2005-2011, patients with opioid prescriptions overlapping ≥7 days increased from 226 to 1594 then decreased to 892 in 2018. From 2005-2010, opioid use >7 days for acute pain increased from 133 to 970 and plateaued after 2010. From 2005-2018, patients who received opioids >90 days for chronic pain trended from 186 to 1655. White patients, females, age 36-55, patients with chronic and acute pain diagnoses had the highest rates of high-risk use. Conclusions: The prevalence of high-risk opioid use in patients with alcohol use problems increased from 2005 to 2011, and generally decreased after 2010. However, prevalence of opioids >90 days for chronic pain trended up from 2005 to 2018. High-risk opioid use among patients with AUD emphasizes the need to develop interventional strategies to improve patient care.

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Neurodegenerative disorders comprise a series of heterogeneous conditions that affect millions of people worldwide, representing a significant health burden in both developed and developing countries. Without disease-modifying treatments currently available, the development of effective neurotherapeutics is a health priority. In this work, a new series of peptide-conjugates of the Glypromate neuropeptide is reported to determine the interplay of annular constriction and neuroprotective activity. To this end, (1R,3S,4S)-2-azanorbornane-3-carboxylic acid was used as an l-proline and l-pipecolic acid surrogate in addition to functionalization of the glutamate residue with relevant active pharmaceutical ingredients (APIs), namely amantadine, memantine, and (R)-1-aminoindane. Using non-differentiated SH-SY5Y cells, conjugates 14a and 15a, functionalized with amantadine, significantly reduced protein aggregation, with 15a outperforming both Glypromate (2-fold enhancement, p < 0.05) and an equimolar mixture of Glypromate and amantadine (p < 0.0001). On the other hand, in SH-SY5Y differentiated cells, conjugate 18c functionalized with (R)-1-aminoindane counteracted the toxicity elicited by paraquat (p < 0.0001), while Glypromate was found to exacerbate the neurotoxicity. Altogether, this work adds new insights into Glypromate research by demonstrating that chemical conjugation and annular constriction are effective strategies to tune neuroprotective responses against different neurotoxic stimuli, paving the way for the development of new neurotherapeutics.

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This article evaluated the effectiveness of using generative AI to simplify science communication and enhance the public's understanding of science. By comparing lay summaries of journal articles from PNAS, yoked to those generated by AI, this work first assessed linguistic simplicity differences across such summaries and public perceptions in follow-up experiments. Specifically, study 1a analyzed simplicity features of PNAS abstracts (scientific summaries) and significance statements (lay summaries), observing that lay summaries were indeed linguistically simpler, but effect size differences were small. Study 1b used a large language model, GPT-4, to create significance statements based on paper abstracts and this more than doubled the average effect size without fine-tuning. Study 2 experimentally demonstrated that simply-written generative pre-trained transformer (GPT) summaries facilitated more favorable perceptions of scientists (they were perceived as more credible and trustworthy, but less intelligent) than more complexly written human PNAS summaries. Crucially, study 3 experimentally demonstrated that participants comprehended scientific writing better after reading simple GPT summaries compared to complex PNAS summaries. In their own words, participants also summarized scientific papers in a more detailed and concrete manner after reading GPT summaries compared to PNAS summaries of the same article. AI has the potential to engage scientific communities and the public via a simple language heuristic, advocating for its integration into scientific dissemination for a more informed society.

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Background: Despite widespread usage of the SRS-22r questionnaire (Scoliosis Research Society Questionnaire-22r), the English version has only sparingly been subjected to analysis using modern psychometric techniques for patients with adolescent idiopathic scoliosis (AIS). The study purpose was to improve interpretation and clinical utility of the SRS-22r for adolescents with AIS by generating additional robust evidence, using modern statistical techniques. Questions about (1) Structure and (2) Item and Scale Functioning are addressed and interpreted for clinicians and researchers. Methods: This retrospective case review analyzed SRS-22r data collected from 1823 patients (mean age 14.9±2.2years) with a primary diagnosis of AIS who clinically completed an SRS-22r questionnaire.Individual SRS-22r questions and domain scores were retrieved through data queries. Patient information collected through chart review included diagnosis, age at assessment, sex, race and radiographic parameters. From 6044 SRS-22r assessments, 1 assessment per patient was randomly selected. Exploratory structural equation modeling (ESEM) and item response theory (IRT) techniques were used for data modeling, item calibration, and reliability assessment. Results: ESEM demonstrated acceptable fit to the data: χ2 (130)=343.73, p<.001; RMSEA=0.035; CFI=0.98; TLI=0.96; SRMR=0.02. Several items failed to adequately load onto their assigned factor. Item fit was adequate for all items except SRSq10 (Self-Image), SRSq16 (Mental Health), and SRSq20 (Mental Health). IRT models found item discriminations are within normal levels for items in psychological measures, except items SRSq1 (pain), SRSq2 (pain), and SRSq16 (mental health). Estimated reliability of the Function domain (ρ=0.69) was low, however, Pain, Self-Image and Mental Health domains exhibited high (ρ>0.80) reliability. Conclusions: Modern psychometric assessment of the SRS-22r, in adolescent patients with AIS, are presented and interpreted to assist clinicians and researchers in understanding its strengths and limitations. Overall, the SRS-22r demonstrated good psychometric properties in all domains except function. Cautious interpretation of the total score is suggested, as it does not reflect a single HRQoL construct.

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Magnetic resonance-guided, focused ultrasound thalamotomy is a neurosurgical treatment for refractory essential tremor. This study examined cognitive outcomes following unilateral magnetic resonance-guided, focused ultrasound thalamotomy, targeting the ventral intermediate nucleus of the thalamus for essential tremor. The research was conducted at two sites: Sunnybrook Research Institute in Toronto, Canada, and West Virginia University School of Medicine Rockefeller Neuroscience Institute in West Virginia, USA. The study focused on cognitive changes at both the group and individual levels. Patients with refractory essential tremor completed cognitive testing before and after magnetic resonance-guided, focused ultrasound thalamotomy at both sites. The cognitive testing assessed domains of attention, processing speed, working memory, executive function, language and learning/memory. Postoperative changes in cognition were examined using paired t-tests and Wilcoxon signed-rank tests, as appropriate. Reliable change indices were calculated to assess clinically significant changes at the individual level. A total of 33 patients from Toronto and 22 patients from West Virginia were included. Following magnetic resonance-guided, focused ultrasound thalamotomy, there was a significant reduction in tremor severity in both cohorts. At the group level, there were no significant declines in postoperative cognitive performance in either cohort. The reliable change analyses revealed some variability at the individual level, with most patients maintaining stable performance or showing improvement. Taken together, the results from these two independent cohorts demonstrate that unilateral magnetic resonance-guided, focused ultrasound thalamotomy significantly reduces tremor severity without negatively impacting cognition at both the group and individual levels, highlighting the cognitive safety of magnetic resonance-guided focused ultrasound thalamotomy for essential tremor.