Individualized Dose-Response to Statins Associated with Cardiovascular Disease Outcomes.

Background: Statins reduce low-density lipoprotein cholesterol (LDL-C) and are efficacious in the prevention of atherosclerotic cardiovascular disease (ASCVD). Dose-response to statins varies among patients and can be modeled using three distinct pharmacological properties: (1) E0 (baseline LDL-C), (2) ED50 (potency: median dose achieving 50% reduction in LDL-C); and (3) Emax (efficacy: maximum LDL-C reduction). However, individualized dose-response and its association with ASCVD events remains unknown. Objective: We analyze the relationship between ED50 and Emax with real-world cardiovascular disease outcomes. Method: We leveraged de-identified electronic health record data to identify individuals exposed to multiple doses of the three most commonly prescribed statins (atorvastatin, simvastatin, or rosuvastatin) within the context of their longitudinal healthcare. We derived ED50 and Emax to quantify the relationship with a composite outcome of ASCVD events and all-cause mortality. Results: We estimated ED50 and Emax for 3,033 unique individuals (atorvastatin: 1,632, simvastatin: 1,089, and rosuvastatin: 312) using a nonlinear, mixed effects dose-response model. Time-to-event analyses revealed that ED50 and Emax are independently associated with the primary endpoint. Hazard ratios were 0.85 (p < 0.01), 0.83 (p < 0.01), and 0.87 (p = 0.10) for ED50 and 1.13 (p < 0.001), 1.06 (p < 0.001), and 1.15 (p = 0.009) for Emax in the atorvastatin, simvastatin, and rosuvastatin cohorts, respectively. Conclusion: The class-wide association of ED50 and Emax with clinical outcomes indicates that these measures influence the risk for ASCVD events in patients on statins.

High-performance GeSi/Ge multi-quantum well photodetector on a Ge-buffered Si substrate.

This work demonstrates a high-performance photodetector with a 4-cycle Ge0.86Si0.14/Ge multi-quantum well (MQW) structure grown by reduced pressure chemical vapor deposition techniques on a Ge-buffered Si (100) substrate. At -1 V bias, the dark current density of the fabricated PIN mesa devices is as low as 3 mA/cm2, and the optical responsivities are 0.51 and 0.17 A/W at 1310 and 1550 nm, respectively, corresponding to the cutoff wavelength of 1620 nm. At the same time, the device has good high-power performance and continuous repeatable light response. On the other hand, the temperature coefficient of resistance (TCR) of the device is as high as -5.18%/K, surpassing all commercial thermal detectors. These results indicate that the CMOS-compatible and low-cost Ge0.86Si0.14/Ge multilayer structure is promising for short-wave infrared and uncooled infrared imaging.

Evaluating post-rhinoplasty nasal obstruction treatment: The efficacy of VivAer radiofrequency ablation.

PURPOSE: Nasal obstruction is a prevalent issue affecting up to one-third of adults, often requiring surgical intervention. Low-temperature radiofrequency (RF) treatment, specifically VivAer, has emerged as a promising alternative, especially for the treatment of nasal valve collapse (NVC). However, its efficacy in patients with a history of rhinoplasty or nasal valve repair remains unexplored. METHODS: A single-center retrospective chart review was conducted on 37 patients with a history of rhinoplasty or nasal valve repair who underwent VivAer RF treatment. Treatment outcomes were assessed using the Nasal Obstruction Symptom Evaluation (NOSE) scale. The primary outcome was defined as a decrease in NOSE score by at least one severity category or a 20 % reduction in total NOSE score. RESULTS: The study found a statistically significant average reduction in NOSE score of 22.4 points or 36.6 %. Among patients with a positive treatment response (21 patients or 56.8 %), the average NOSE score reduction was 34.7 points or 55.6 %. Repeat RF treatment in non-responders resulted in a 50 % response rate. No significant difference was observed in treatment outcomes based on the type of prior rhinoplasty or NVC. CONCLUSIONS: Temperature-controlled RF treatment with VivAer can effectively alleviate nasal obstruction in patients with a history of rhinoplasty or nasal valve repair, offering a viable alternative to revision surgery. The study also highlights the potential benefit of repeat RF treatment in non-responders. Further research, including randomized controlled trials, is needed to validate these promising results and expand the treatment options for this complex patient population.

Factors Associated with Obstetric Anal Sphincter Injury During Vacuum-Assisted Vaginal Delivery.

INTRODUCTION AND HYPOTHESIS: Obstetric anal sphincter injury (OASI) is a major complication associated with vacuum-assisted vaginal delivery (VAVD). The aim of this study was to evaluate risk factors related to vacuum extraction that are associated with OASI. METHODS: This was a case-control study performed at a tertiary university teaching hospital. Included were patients aged 18-45 years who had a singleton pregnancy resulting in a live, term, VAVD. The study group consisted of women diagnosed with OASI following vacuum extraction. The control group included women following VAVD without OASI. Matching at a ratio of 1:2 was performed. Groups were compared regarding demographic, obstetric. and labor-related parameters, specifically focusing on variables related to the vacuum procedure itself. RESULTS: One hundred and ten patients within the study group and 212 within the control group were included in the final analysis. Patients in the OASI group were more likely to undergo induction of labor, use of oxytocin during labor, increased second stage of labor, higher likelihood of the operator being a resident, increased number of pulls, procedure lasting under 10 min, occipito-posterior head position at vacuum initiation, episiotomy, increased neonatal head circumference, and birthweight. Multivariate logistic regression analysis revealed that increased week of gestation (OR 1.67, 95% CI 1.25-2.22, p < 0.001), unsupervised resident performing the procedure (OR 4.63, 95% CI 2.17-9.90), p < 0.001), indication of VAVD being fetal distress (OR 2.72, 95% CI 1.04-7.10, p = 0.041), and length of procedure under 10 min (OR 4.75, 95% CI 1.53-14.68, p = 0.007) were associated with OASI. Increased maternal age was associated with lower risk of OASI (OR 0.9, 95% CI 0.84-0.98, p = 0.012). CONCLUSIONS: When performing VAVD, increased week of gestation, unsupervised resident performing the procedure, fetal distress as vacuum indication, and vacuum procedure under 10 min were associated with OASI. In contrast, increased maternal age was shown to be a protective factor.

CMOS Scaling for the 5 nm Node and Beyond: Device, Process and Technology.

After more than five decades, Moore's Law for transistors is approaching the end of the international technology roadmap of semiconductors (ITRS). The fate of complementary metal oxide semiconductor (CMOS) architecture has become increasingly unknown. In this era, 3D transistors in the form of gate-all-around (GAA) transistors are being considered as an excellent solution to scaling down beyond the 5 nm technology node, which solves the difficulties of carrier transport in the channel region which are mainly rooted in short channel effects (SCEs). In parallel to Moore, during the last two decades, transistors with a fully depleted SOI (FDSOI) design have also been processed for low-power electronics. Among all the possible designs, there are also tunneling field-effect transistors (TFETs), which offer very low power consumption and decent electrical characteristics. This review article presents new transistor designs, along with the integration of electronics and photonics, simulation methods, and continuation of CMOS process technology to the 5 nm technology node and beyond. The content highlights the innovative methods, challenges, and difficulties in device processing and design, as well as how to apply suitable metrology techniques as a tool to find out the imperfections and lattice distortions, strain status, and composition in the device structures.

A review of the topical management of acne and its associated sequelae in the Asia-Pacific region with a spotlight on trifarotene.

Acne, a highly prevalent skin disease, can be particularly bothersome for patients of Asian background because of its impact on self-confidence and social interactions. In addition to active acne lesions, some patients may develop sequelae such as scarring, macular/postinflammatory hyperpigmentation, or erythema. The tendency of Asian skin to develop sequelae because of its increased susceptibility to irritation, cultural preferences for lighter skin phototypes, and differences in skincare regimens may all contribute to the increased burden of acne. Moreover, many Asia-Pacific countries do not have their own guidelines for acne management, and those that do often have no schedule in place for regular updates. In this article, we provide a critical review of the published guidance for the management of acne and its sequelae in the Asia-Pacific region, identifying gaps in current recommendations that could be addressed to enhance standards of acne care in Asia-Pacific countries. Along with highlighting the importance of a comprehensive skincare regimen to increase treatment efficacy and adherence, we discuss topical retinoids and retinoid combination options in the acne armamentarium that may be beneficial for sequelae prevention and management, such as adapalene 0.3% ± benzoyl peroxide 2.5%, tretinoin 0.05%, tazarotene 0.1%, and trifarotene 0.005%. In particular, trifarotene 0.005% has been observed to significantly reduce acne scar counts in a Phase 4 study. The recent data highlight the need to establish up-to-date guidance for acne and acne sequelae management in Asia-Pacific countries to provide optimal care to Asian patients.

The role of surgical disconnection for posterior fossa pial arteriovenous fistulas and dural fistulas with pial supply: an illustrative case series.

BACKGROUND: Pial arteriovenous fistulas (pAVFs) are rare vascular malformations characterized by high-flow arteriovenous shunting involving a cortical arterial supply directly connecting to venous drainage without an intermediate nidus. Dural arteriovenous fistulas (dAVFs) can infrequently involve additional pial feeders which can introduce higher flow shunting and increase the associated treatment risk. In the posterior fossa, arteriovenous fistula (AVF) angioarchitecture tends to be particularly complex, involving either multiple arterial feeders-sometimes from both dural and pial origins-or small caliber vessels that are difficult to catheterize and tend to be intimately involved with functionally critical brainstem or upper cervical cord structures. Given their rarity, published experience on microsurgical or endovascular treatment strategies for posterior fossa pAVFs and dAVFs with pial supply remains limited. METHODS: Retrospective chart review from 2019-2023 at a high-volume center identified six adult patients with posterior fossa pAVFs that were unable to be fully treated endovascularly and required microsurgical disconnection. These cases are individually presented with a technical emphasis and supported by comprehensive angiographic and intraoperative images. RESULTS: One vermian (Case 1), three cerebellopontine angle (Cases 2-4) and two craniovertebral junction (Cases 5-6) posterior fossa pAVFs or dAVFs with pial supply are presented. Three cases involved mixed dural and pial arterial supply (Cases 1, 4, and 6), and one case involved a concomitant microAVM (Case 2). Endovascular embolization was attempted in four cases (Cases 1-4): The small caliber and tortuosity of the main arterial feeder prevented catheterization in two cases (Cases 1 and 3). Partial embolization was achieved in Cases 2 and 4. In Cases 5 and 6, involvement of the lateral spinal artery or anterior spinal artery created a prohibitive risk for endovascular embolization, and surgical clip ligation was pursued as primary management. In all cases, microsurgical disconnection resulted in complete fistula obliteration without evidence of recurrence on follow-up imaging (mean follow-up 27.1 months). Two patients experienced persistent post-treatment sensory deficits without significant functional limitation. CONCLUSIONS: This illustrative case series highlights the technical difficulties and anatomical limitations of endovascular management for posterior fossa pAVFs and dAVFs with pial supply and emphasizes the relative safety and utility of microsurgical disconnection in this context. A combined approach involving partial preoperative embolization-when the angioarchitecture is permissive-can potentially decrease surgical morbidity. Larger studies are warranted to better define the role for multimodal intervention and to assess associated long-term AVF obliteration rates in the setting of pial arterial involvement.

Valacyclovir or valganciclovir for cytomegalovirus prophylaxis: A randomized controlled trial in adult and pediatric kidney transplant recipients.

BACKGROUND: Valganciclovir (valG), a cytomegalovirus (CMV) prophylactic agent, has dose-limiting side effects. The tolerability and effectiveness of valacyclovir (valA) as CMV prophylaxis is unknown. METHODS: We conducted a randomized, open-label, single-center trial of valA versus valG for all posttransplant CMV prophylaxis in adult and pediatric kidney recipients. Participants were randomly assigned to receive valA or valG. Primary endpoints were the incidence of CMV viremia and side-effect related drug reduction with secondary assessment of incidence of EBV viremia. RESULTS: Of the 137 sequential kidney transplant recipients enrolled, 26 % were positive and negative for CMV antibody in donor and recipient respectively. The incidence of CMV viremia (4 of 71 [6 %]; 8 of 67 [12 %] P = 0.23), time to viremia (P = 0.16) and area under CMV viral load time curve (P = 0.19) were not significantly different. ValG participants were significantly more likely to require side-effect related dose reduction (15/71 [21 %] versus 1/66 [2 %] P = 0.0003). Leukopenia was the most common reason for valG dose reduction and granulocyte-colony stimulating factor was utilized for leukopenia recovery more frequently (25 % in valG vs 5 % in valA: P = 0.0007). Incidence of EBV viremia was not significantly different. CONCLUSIONS: ValA has significantly less dose-limiting side effects than valG. In our study population, a significant increase in CMV viremia was not observed, in adults and children after kidney transplant, compared to valG. TRIAL REGISTRATION NUMBER: NCT01329185.

Gene replacement therapies for inherited disorders of neurotransmission: Current progress in succinic semialdehyde dehydrogenase deficiency.

Neurodevelopment is a highly organized and complex process involving lasting and often irreversible changes in the central nervous system. Inherited disorders of neurotransmission (IDNT) are a group of genetic disorders where neurotransmission is primarily affected, resulting in abnormal brain development from early life, manifest as neurodevelopmental disorders and other chronic conditions. In principle, IDNT (particularly those of monogenic causes) are amenable to gene replacement therapy via precise genetic correction. However, practical challenges for gene replacement therapy remain major hurdles for its translation from bench to bedside. We discuss key considerations for the development of gene replacement therapies for IDNT. As an example, we describe our ongoing work on gene replacement therapy for succinic semialdehyde dehydrogenase deficiency, a GABA catabolic disorder.

Sinus rhythm activation signature indicates reentrant ventricular tachycardia inducibility and approximate isthmus location.

BACKGROUND: Sinus rhythm activation time is useful to assess infarct border zone substrate. OBJECTIVE: We sought to further investigate sinus activation in ventricular tachycardia (VT). METHODS: Canine postinfarction data were analyzed retrospectively. In each experiment, an infarct was created in the left ventricular wall by left anterior descending coronary artery ligation. At 3 to 5 days after ligation, 196-312 bipolar electrograms were recorded from the anterior left ventricular epicardium overlapping the infarct border zone. Sustained monomorphic VT was induced by premature electrical stimulation in 50 experiments and was noninducible in 43 experiments. Acquired sinus rhythm and VT electrograms were marked for electrical activation time, and activation maps of representative sinus rhythm and VT cycles were constructed. The sinus rhythm activation signature was defined as the cumulative number of multielectrode recording sites that had activated per time epoch, and its derivative was used to predict VT inducibility and to define the sinus rhythm slow/late activation sequence. RESULTS: Plotting mean activation signature derivative, a best cutoff value was useful to separate experiments with reentrant VT inducibility (sensitivity, 42/50) vs noninducibility (specificity, 39/43), with an accuracy of 81 of 93. For the 50 experiments with inducible VT, recording sites overlying a segment of isochrone encompassing the sinus rhythm slow/late activation sequence spanned the VT isthmus location in 32 cases (64%), partially spanned it in 15 cases (30%), but did not span it in 3 cases (6%). CONCLUSION: The sinus rhythm activation signature derivative is assistive to differentiate substrate supporting reentrant VT inducibility vs noninducibility and to identify slow/late activation for targeting isthmus location.

A practical guide for the use of apalutamide for non-metastatic castration-resistant prostate cancer in Australia.

Studies of patients with castrate-resistant prostate cancer at high risk of developing overt metastases but with no current evidence of evaluable disease on computed tomography or bone scan non-metastatic castrate-resistant prostrate cancer have demonstrated increased metastasis-free survival and overall survival following treatment with the next-generation oral anti-androgen apalutamide (in addition to therapies that aim to lower testosterone to castrate levels) or luteinizing hormone-releasing hormone antagonist or surgical castration. Patients receiving apalutamide can be managed by medical oncologists, radiation oncologists, or urologists, preferably as part of a multidisciplinary team. However, the importance of additional safety monitoring for significant adverse effects and drug interactions should not be underestimated. The toxicities of apalutamide are manageable with experience and should be managed proactively to minimize their impact on patients. Monitoring of patients for apalutamide-specific toxicities, including skin rash, hypothyroidism, and QT prolongation should be carried out regularly, particularly in the first few months following initiation. Monitoring should continue alongside monitoring for toxicities of androgen deprivation, including cardiovascular risk, hot flashes, weight gain, bone health, muscle wasting, and diabetic risk. This review is a practical guide to the use of apalutamide describing the management of patients including dosing and administration, toxicities, potential drug interactions, and safety monitoring requirements.

Large language models facilitate the generation of electronic health record phenotyping algorithms.

OBJECTIVES: Phenotyping is a core task in observational health research utilizing electronic health records (EHRs). Developing an accurate algorithm demands substantial input from domain experts, involving extensive literature review and evidence synthesis. This burdensome process limits scalability and delays knowledge discovery. We investigate the potential for leveraging large language models (LLMs) to enhance the efficiency of EHR phenotyping by generating high-quality algorithm drafts. MATERIALS AND METHODS: We prompted four LLMs-GPT-4 and GPT-3.5 of ChatGPT, Claude 2, and Bard-in October 2023, asking them to generate executable phenotyping algorithms in the form of SQL queries adhering to a common data model (CDM) for three phenotypes (ie, type 2 diabetes mellitus, dementia, and hypothyroidism). Three phenotyping experts evaluated the returned algorithms across several critical metrics. We further implemented the top-rated algorithms and compared them against clinician-validated phenotyping algorithms from the Electronic Medical Records and Genomics (eMERGE) network. RESULTS: GPT-4 and GPT-3.5 exhibited significantly higher overall expert evaluation scores in instruction following, algorithmic logic, and SQL executability, when compared to Claude 2 and Bard. Although GPT-4 and GPT-3.5 effectively identified relevant clinical concepts, they exhibited immature capability in organizing phenotyping criteria with the proper logic, leading to phenotyping algorithms that were either excessively restrictive (with low recall) or overly broad (with low positive predictive values). CONCLUSION: GPT versions 3.5 and 4 are capable of drafting phenotyping algorithms by identifying relevant clinical criteria aligned with a CDM. However, expertise in informatics and clinical experience is still required to assess and further refine generated algorithms.

TARGETING SOLUBLE AMYLOID-BETA OLIGOMERS WITH A NOVEL NANOBODY.

The classical amyloid cascade hypothesis postulates that the aggregation of amyloid plaques and the accumulation of intracellular hyperphosphorylated Tau tangles, together, lead to profound neuronal death. However, emerging research has demonstrated that soluble amyloid-ß oligomers (SAßOs) accumulate early, prior to amyloid plaque formation. SAßOs induce memory impairment and disrupt cognitive function independent of amyloid-ß plaques, and even in the absence of plaque formation. This work describes the development and characterization of a novel anti-SAßO (E3) nanobody generated from an alpaca immunized with SAßO. In-vitro assays and in-vivo studies using 5XFAD mice indicate that the fluorescein (FAM)-labeled E3 nanobody recognizes both SAßOs and amyloid-ß plaques. The E3 nanobody traverses across the blood-brain barrier and binds to amyloid species in the brain of 5XFAD mice. Imaging of mouse brains reveals that SAßO and amyloid-ß plaques are not only different in size, shape, and morphology, but also have a distinct spatial distribution in the brain. SAßOs are associated with neurons, while amyloid plaques reside in the extracellular matrix. The results of this study demonstrate that the SAßO nanobody can serve as a diagnostic agent with potential theragnostic applications in Alzheimer's disease.

The potential of historical spy-satellite imagery to support research in ecology and conservation.

Remote sensing data are important for assessing ecological change, but their value is often restricted by their limited temporal coverage. Major historical events that affected the environment, such as those associated with colonial history, World War II, or the Green Revolution are not captured by modern remote sensing. In the present article, we highlight the potential of globally available black-and-white satellite photographs to expand ecological and conservation assessments back to the 1960s and to illuminate ecological concepts such as shifting baselines, time-lag responses, and legacy effects. This historical satellite photography can be used to monitor ecosystem extent and structure, species' populations and habitats, and human pressures on the environment. Even though the data were declassified decades ago, their use in ecology and conservation remains limited. But recent advances in image processing and analysis can now unlock this research resource. We encourage the use of this opportunity to address important ecological and conservation questions.

Assessment of Urinary Dysfunction After Midurethral Sling Placement: A Comparison of Two Voiding Trial Methods.

STUDY OBJECTIVE: Temporary urinary retention after midurethral sling (MUS) surgery requiring indwelling catheter or self-catheterization usage is common. Different methods for assessment of immediate postoperative urinary retention have been described. This study aimed to compare postoperative voiding trial (VT) success after active vs passive VT in women undergoing MUS surgery. DESIGN: Comparative retrospective cohort study. SETTING: Female pelvic medicine and reconstructive surgery practice at a university-affiliated tertiary medical center. PATIENTS: Patients with stress urinary incontinence who underwent surgical treatment during the study period were eligible for inclusion. Excluded were patients younger than the age of 18 years, combined cases with other surgical services, planned laparotomy, and a history of urinary retention and patients for whom their VT was performed on postoperative day 1. The cohort was divided into 2 groups: (1) patients who underwent an active retrofill of their bladder using a Foley catheter and (2) patients who were allowed to have a spontaneous void. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 285 patients met the inclusion criteria for the study. Of these subjects, 94 underwent an active VT and 191 underwent a passive VT. There were no statistically significant differences in immediate postoperative urinary retention (30.8% vs 29.3%; p = .79) or time from surgery end to VT (233.0 ± 167.6 minutes vs 203.1 ± 147.8 minutes; p = .13) between groups. Urinary retention, as defined by a failed VT, increased from 10% to 29.3% when MUS placement was accompanied by concomitant prolapse repair procedure. Multivariate logistic regression analysis revealed that undergoing a combined anterior and posterior colporrhaphy (odds ratio [OR], 5.13; p <.001) and undergoing an apical prolapse procedure (OR, 2.75; p = .004) were independently associated with immediate postoperative urinary retention whereas increased body mass index (OR, 0.89; p <.001) lowered likelihood of retention. CONCLUSION: The method used to assess immediate postoperative urinary retention did not affect VT success. Concomitant combined anterior and posterior colporrhaphy and apical suspension were correlated with greater likelihood of VT failure whereas increased body mass index decreased odds of retention.

Maternal Recall of Obstetric Office-Based Activities That Promote Antepartum Tetanus-Diphtheria-Acellular-Pertussis Vaccination.

Objective: To explore associations between maternal characteristics and recall of obstetric provider actions in promoting antepartum tetanus-diphtheria-acellular-pertussis (Tdap) vaccination. Methods: A convenience sample of 1,682 postpartum women was surveyed in this cross-sectional study. Maternal characteristics and recall of four obstetric provider actions (recommending antepartum Tdap vaccine, offering it in clinic, providing written information, and referring patients elsewhere for vaccination) were collected. Univariate and multivariable logistic regression analyses were performed to characterize the association between maternal characteristics and each provider action. Results: Among 1,604 surveys (95% of total collected), maternal recall of an obstetric provider recommending Tdap vaccination, offering it in clinic, providing written information, or referring patients elsewhere was 68%, 59%, 53%, and 15%, respectively. Multivariable analysis revealed specific maternal characteristics that increased odds of recalling at least one obstetric provider action promoting Tdap vaccination, including receipt of first trimester prenatal care (adjusted odds ratio [aOR] 1.77, 95% confidence interval [CI] = 1.06-2.97), primiparity (aOR 1.35, 95% CI = 1.05-1.75), private health insurance (aOR 1.56, 95% CI = 1.16-2.04), higher household income (aOR ranging from 1.71 to 2.10 for ≥$150,000 for two actions), and non-White, non-Hispanic race/ethnicity (aOR ranging from 1.49 to 1.74 for Asian non-Hispanic for two actions and aOR 1.71 for Black non-Hispanic). Conclusion: Prenatal care, parity, insurance type, household income, and race/ethnicity are associated with recall of obstetric provider activities that impact antepartum Tdap vaccine promotion. Obstetric providers should recommend this potentially life-saving vaccine with each pregnancy, irrespective of differences in maternal characteristics, and policymakers should work to combat systemic factors that may cause disparities in uptake.

Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder.

BACKGROUND: Succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a model neurometabolic disease at the fulcrum of translational research within the Boston Children's Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC), including the NIH-sponsored natural history study of clinical, neurophysiological, neuroimaging, and molecular markers, patient-derived induced pluripotent stem cells (iPSC) characterization, and development of a murine model for tightly regulated, cell-specific gene therapy. METHODS: SSADHD subjects underwent clinical evaluations, neuropsychological assessments, biochemical quantification of γ-aminobutyrate (GABA) and related metabolites, electroencephalography (standard and high density), magnetoencephalography, transcranial magnetic stimulation, magnetic resonance imaging and spectroscopy, and genetic tests. This was parallel to laboratory molecular investigations of in vitro GABAergic neurons derived from induced human pluripotent stem cells (hiPSCs) of SSADHD subjects and biochemical analyses performed on a versatile murine model that uses an inducible and reversible rescue strategy allowing on-demand and cell-specific gene therapy. RESULTS: The 62 SSADHD subjects [53% females, median (IQR) age of 9.6 (5.4-14.5) years] included in the study had a reported symptom onset at ∼ 6 months and were diagnosed at a median age of 4 years. Language developmental delays were more prominent than motor. Autism, epilepsy, movement disorders, sleep disturbances, and various psychiatric behaviors constituted the core of the disorder's clinical phenotype. Lower clinical severity scores, indicating worst severity, coincided with older age (R= -0.302, p = 0.03), as well as age-adjusted lower values of plasma γ-aminobutyrate (GABA) (R = 0.337, p = 0.02) and γ-hydroxybutyrate (GHB) (R = 0.360, p = 0.05). While epilepsy and psychiatric behaviors increase in severity with age, communication abilities and motor function tend to improve. iPSCs, which were differentiated into GABAergic neurons, represent the first in vitro neuronal model of SSADHD and express the neuronal marker microtubule-associated protein 2 (MAP2), as well as GABA. GABA-metabolism in induced GABAergic neurons could be reversed using CRISPR correction of the pathogenic variants or mRNA transfection and SSADHD iPSCs were associated with excessive glutamatergic activity and related synaptic excitation. CONCLUSIONS: Findings from the SSADHD Natural History Study converge with iPSC and animal model work focused on a common disorder within our IDDRC, deepening our knowledge of the pathophysiology and longitudinal clinical course of a complex neurodevelopmental disorder. This further enables the identification of biomarkers and changes throughout development that will be essential for upcoming targeted trials of enzyme replacement and gene therapy.

Incidence, Risk Factors, and Outcomes of De Novo Malignancy following Kidney Transplantation.

Introduction: Post-transplant malignancy is a significant cause of morbidity and mortality following kidney transplantation often emerging after medium- to long-term follow-up. To understand the risk factors for the development of de novo post-transplant malignancy (DPTM), this study aimed to assess the incidence, risk factors, and outcomes of DPTM at a single nephrology centre over two decades. Methods: This retrospective cohort study included 963 kidney transplant recipients who underwent kidney transplantation between January 2000 and December 2020 and followed up over a median follow-up of 7.1 years (IQR 3.9-11.4). Cox regression models were used to identify the significant risk factors of DPTM development, the association of DPTM with graft survival, and mortality with a functioning graft. Results: In total, 8.1% of transplant recipients developed DPTM, and the DPTM incidence rate was 14.7 per 100 patient-years. There was a higher mean age observed in the DPTM group (53 vs. 47 years, p < 0.001). The most affected organ systems were genitourinary (32.1%), gastrointestinal (24.4%), and lymphoproliferative (20.5%). Multivariate Cox analysis identified older age at transplant (aHR 9.51, 95%CI: 2.60-34.87, p < 0.001) and pre-existing glomerulonephritis (aHR 3.27, 95%CI: 1.10-9.77, p = 0.03) as significant risk factors for DPTM. Older age was significantly associated with poorer graft survival (aHR 8.71, 95%CI: 3.77-20.20, p < 0.001). When age was excluded from the multivariate Cox model, DPTM emerged as a significant risk factor for poor survival (aHR 1.76, 95%CI: 1.17-2.63, p = 0.006). Conclusion: These findings underscore the need for tailored screening, prevention, and management strategies to address DPTM in an aging and immunosuppressed kidney transplant population.

Multiscale calculations reveal new insights into the reaction mechanism between KRASG12C and α, ß-unsaturated carbonyl of covalent inhibitors.

Utilizing α,ß-unsaturated carbonyl group as Michael acceptors to react with thiols represents a successful strategy for developing KRASG12C inhibitors. Despite this, the precise reaction mechanism between KRASG12C and covalent inhibitors remains a subject of debate, primarily due to the absence of an appropriate residue capable of deprotonating the cysteine thiol as a base. To uncover this reaction mechanism, we first discussed the chemical reaction mechanism in solvent conditions via density functional theory (DFT) calculation. Based on this, we then proposed and validated the enzymatic reaction mechanism by employing quantum mechanics/molecular mechanics (QM/MM) calculation. Our QM/MM analysis suggests that, in biological conditions, proton transfer and nucleophilic addition may proceed through a concerted process to form an enolate intermediate, bypassing the need for a base catalyst. This proposed mechanism differs from previous findings. Following the formation of the enolate intermediate, solvent-assisted tautomerization results in the final product. Our calculations indicate that solvent-assisted tautomerization is the rate-limiting step in the catalytic cycle under biological conditions. On the basis of this reaction mechanism, the calculated kinact/ki for two inhibitors is consistent well with the experimental results. Our findings provide new insights into the reaction mechanism between the cysteine of KRASG12C and the covalent inhibitors and may provide valuable information for designing effective covalent inhibitors targeting KRASG12C and other similar targets.

Consensus guidelines for the diagnosis and management of succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) (OMIM #271980) is a rare autosomal recessive metabolic disorder caused by pathogenic variants of ALDH5A1. Deficiency of SSADH results in accumulation of γ-aminobutyric acid (GABA) and other GABA-related metabolites. The clinical phenotype of SSADHD includes a broad spectrum of non-pathognomonic symptoms such as cognitive disabilities, communication and language deficits, movement disorders, epilepsy, sleep disturbances, attention problems, anxiety, and obsessive-compulsive traits. Current treatment options for SSADHD remain supportive, but there are ongoing attempts to develop targeted genetic therapies. This study aimed to create consensus guidelines for the diagnosis and management of SSADHD. Thirty relevant statements were initially addressed by a systematic literature review, resulting in different evidence levels of strength according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. The highest level of evidence (level A), based on randomized controlled trials, was unavailable for any of the statements. Based on cohort studies, Level B evidence was available for 12 (40%) of the statements. Thereupon, through a process following the Delphi Method and directed by the Appraisal of Guidelines for Research and Evaluation (AGREE II) criteria, expert opinion was sought, and members of an SSADHD Consensus Group evaluated all the statements. The group consisted of neurologists, epileptologists, neuropsychologists, neurophysiologists, metabolic disease specialists, clinical and biochemical geneticists, and laboratory scientists affiliated with 19 institutions from 11 countries who have clinical experience with SSADHD patients and have studied the disorder. Representatives from parent groups were also included in the Consensus Group. An analysis of the survey's results yielded 25 (83%) strong and 5 (17%) weak agreement strengths. These first-of-their-kind consensus guidelines intend to consolidate and unify the optimal care that can be provided to individuals with SSADHD.