Effects of withdrawal and re-application of spinal cord stimulation to restore cough.

CONTEXT: Paralysis of the expiratory muscles in cervical and high thoracic spinal cord injury (SCI) results in an impaired ability to clear airway secretions effectively and increases the risk of atelectasis and respiratory tract infections (RTI). Spinal cord stimulation (SCS) applied via the Cough Stimulation System (CSS) has been shown to restore an effective cough mechanism in subjects with SCI. In this study, we evaluated the specific impact of use of the CSS by one study participant with SCI, subsequent discontinuation of usage, and then re-institution of this modality. Airway pressure generation (P) and peak expiratory airflow rate (F) achieved with CSS and clinical assessment questionnaires were assessed. FINDINGS: With the CSS, this subject was able to generate P and F rates of 103 cmH2O and 7.1 l/s, respectively, with associated significant clinical benefits, including, much greater ease in raising secretions and reduction in the incidence of RTIs. However, following a 2-year period of regular use, the CSS became non-functional and a 2-year period elapsed before it could be replaced. During this time, he again experienced great difficulty managing airway secretions and an increased frequency of RTIs. Re-institution of the CSS system resulted in the restoration of an effective cough mechanism and similar clinical benefits. CONCLUSION/CLINICAL RELEVANCE: This report demonstrates the very high degree of the clinical utility of the CSS as it had made a substantial beneficial impact on this participant's respiratory status and life quality.

Audiological Characterization of Individuals with Cornelia de Lange Syndrome.

Introduction Cornelia de Lange Syndrome (CdLS) is a genetic disorder in which individuals may present sensorineural and/or conductive hearing loss, and the results of behavioral auditory assessments are not accurate. Objective To characterize the audiological profile of individuals with CdLS through behavioral, electroacoustic, and electrophysiological audiological assessments. Methods The study included 13 individuals of both sexes, aged between 3 and 26 years, with diagnoses confirmed through genetic studies. The following procedures were performed: medical history survey, otoscopy (pure-tone audiometry [PTA], speech audiometry, and acoustic immittance measures), and auditory brainstem response (ABR). Results In total 62.50% of the participants who underwent PTA had abnormal results (all of which were mild), with a predominance of bilateral conductive hearing loss (60%). Regarding tympanometry, 76.93% had abnormal results, most frequently type B (85.72% on the right and 88.89% on the left ear). Acoustic reflexes showed results compatible with tympanometry changes. Changes in ABR latency values compatible with middle-ear impairment were found in 8 of them (66.66%) - 3 had bilateral (37.50%), and 5 had unilateral impairments (62.50%). Conclusion Mild hearing loss was identified in 62.5% of the individuals with CdLS who underwent the behavioral audiological assessment. In the acoustic immittance measures, 76.9% of the participants presented a tympanometry curve characteristic of middle-ear changes. Acoustic reflexes were absent in 84.6% of the subjects. In the ABR, no changes were identified in auditory pathway integrity. On the other hand, changes in the absolute latency values were found, which are characteristic of conductive hearing loss.

MRI genicular nerve mapping: a novel approach to sagittal genicular nerve localization.

BACKGROUND AND OBJECTIVES: Chronic knee pain, including postarthroplasty knee pain, is a major cause of morbidity. Radiofrequency ablation of genicular nerve branches is a treatment option. The literature to date has demonstrated and recommended consistent rhizotomy targets in the coronal and axial position of the three primary genicular nerve branches (superomedial genicular nerve, superolateral genicular nerve, inferomedial genicular nerve). The debate on genicular nerve positions focuses on the anterior-posterior courses of the nerve branches. METHODS: The sagittal positions of the three primary genicular neurovascular bundles were measured in 28 consecutive knee MRI and described relative to the total anterior-posterior depth of the bony cortex. Standard radiofrequency capture radius at the classic rhizotomy targets sites was compared with identified nerve position to report proportion of observed nerves within the capture radius. RESULTS: The genicular neurovascular bundles were found further posterior than classic landmark targets. Proportion of visualized nerve branches captured by classic rhizotomy target radius varied by genicular nerve branch. CONCLUSIONS: This study supports updated guidance on genicular rhizotomy targets. Nerve localization studies using MRI data may be a promising avenue in future nerve localization research pertinent to rhizotomy.

Epidemiological characterization of rare diseases in Brazil: A retrospective study of the Brazilian Rare Diseases Network.

BACKGROUND: The Brazilian Policy for Comprehensive Care for People with Rare Diseases was implemented in 2014; however, national epidemiological data on rare diseases (RDs) are scarce and mainly focused on specific disorders. To address this gap, University Hospitals, Reference Services for Neonatal Screening, and Reference Services for Rare Diseases, all of which are public health institutions, established the Brazilian Rare Diseases Network (RARAS) in 2020. The objective of this study was to perform a comprehensive nationwide epidemiological investigation of individuals with RDs in Brazil. This retrospective survey collected data from patients receiving care in 34 healthcare facilities affiliated with RARAS in 2018 and 2019. RESULTS: The survey included 12,530 participants with a median age of 15.0 years, with women representing 50.5% of the cohort. Classification according to skin color demonstrated that 5044 (47.4%) participants were admixed. Most had a confirmed diagnosis (63.2%), with a predominance of phenylketonuria (PKU), cystic fibrosis (CF), and acromegaly. Common clinical manifestations included global developmental delay and seizures. The average duration of the diagnostic odyssey was 5.4 years (± 7.9 years). Among the confirmed diagnoses, 52.2% were etiological (biochemical: 42.5%; molecular: 30.9%), while 47.8% were clinical. Prenatal diagnoses accounted for 1.2%. Familial recurrence and consanguinity rates were 21.6% and 6.4%, respectively. Mainstay treatments included drug therapy (55.0%) and rehabilitation (15.6%). The Public Health System funded most diagnoses (84.2%) and treatments (86.7%). Hospitalizations were reported in 44.5% of cases, and the mortality rate was 1.5%, primarily due to motor neuron disease and CF. CONCLUSION: This study marks a pioneering national-level data collection effort for rare diseases in Brazil, offering novel insights to advance the understanding, management, and resource allocation for RDs. It unveils an average diagnostic odyssey of 5.4 years and a higher prevalence of PKU and CF, possibly associated with the specialized services network, which included newborn screening services.

Pediatric Outcomes After Robotic Median Arcuate Ligament Release, Celiac Ganglionectomy, and Lymphadenectomy.

BACKGROUND: Median arcuate ligament syndrome (MALS) is a neurovascular disorder characterized by gastrointestinal symptoms due to celiac artery and ganglion compression. Limited literature primarily focuses on adults. This study aims to characterize clinical and histopathologic findings in pediatric MALS. METHODS: Patients <18 years undergoing robotic MAL release, celiac ganglionectomy, and lymphadenectomy from 2020 to 2024 were evaluated. Clinical and histopathologic outcomes were analyzed. RESULTS: Twelve patients met inclusion criteria and were reviewed (15.7 ± 1.2 years, 75% female, BMI 20.9 [18.6-24.0] kg/m2). Comorbidities included depression/anxiety (83%), postural orthostatic tachycardia syndrome (POTS) (50%), gastroesophageal reflux disease (GERD) (50%), nutrition support (50%), mast cell activation syndrome (MCAS) (42%), hypermobile Ehlers-Danlos syndrome (hEDS) (42%), other vascular compression syndromes (33%). All patients who received preoperative celiac plexus block had temporary symptom relief (10/10). Mean operative time was 119.7 ± 22.4 min. No intraoperative complications, 30-day readmissions, reoperations, or complications occurred. Histopathologically, 92% had fibroadipose tissue, 100% had reactive lymph nodes, none had intraparenchymal nerves, and one had lipogranulomas. Median fibrosis scores were 1 [0.5-2] on H&E and 2 [1-2] on trichrome. Fibrosis score severity was not significantly associated with symptom improvement (χ2 = 3.67, p = 0.16). Median postoperative celiac artery velocity was 258.5 [192.5-350.5] cm/s with a median change of -80.5 [-106.1-+82.8] cm/s from preoperative 308.0 [229.3-344.0] cm/s (S = -5.0, p = 0.55). Those with lower preoperative velocities were more likely to have symptom improvement postoperatively (S = 19, p = 0.04). MALS symptoms improved in 83%; however, despite reporting "MALS pain" was improved, 64% (all female) had other comorbidities such as POTS, MCAS, hEDS, and colonic dysmotility contributing to other ongoing symptoms. CONCLUSION: Robotic MALS surgery is safe and effective in pediatrics. Clinical improvement rates and fibrosis scoring are comparable to adults; however, findings reveal challenges with multiple comorbidities contributing to separate symptoms that may continue postoperatively, particularly in females. We recommend a multidisciplinary team approach in addressing comorbidities and optimizing medical and surgical care. LEVEL OF EVIDENCE: IV.

The first Brazilian clinical report of Kleefstra syndrome, including semicircular canals agenesis as a possible phenotype expansion.

OBJECTIVE: to report the first case series of Brazilian children diagnosed with Kleefstra syndrome, present a possible phenotype expansion to the syndrome and to raise physicians' awareness for this rare disease. RESULTS: seven patients with confirmed KS were evaluated, including 5 males and 2 females. Abnormal prenatal findings were observed in 4 patients. Most patients were born at term, with normal birth measurements. All patients had neurodevelopmental delay and 6 evolved with intellectual disability. Hearing loss was present in 57.1% of patients and 28.7% had congenital heart disease. In males, cryptorchidism was present in 75%. Despite the facial dysmorphisms, only 2 out of 7 patients had a pre-test clinical suspicion of KS. One specific patient presented bilateral agenesis of the semicircular canals, a very rare ear manifestation in Kleefstra syndrome, representing a possible phenotype expansion of the syndrome. CONCLUSION: this report aims to promote awareness among physicians evaluating patients in a context of neurodevelopmental delay or congenital malformations, especially congenital heart defects. We also highlight a possible phenotype expansion of the syndrome, with a case of semicircular anomaly, not reported in this syndrome so far.

Association of the Korean-specific food-based index of dietary inflammatory potential with the risk of mild cognitive impairment in Korean older adults.

OBJECTIVES: This study aimed to examine the association between the food-based index of dietary inflammatory potential (FBDI) and the risk of mild cognitive impairment (MCI) in Korean older adults. METHODS: The subjects were 798 Korean adults aged 60 years and older. The FBDI was calculated based on the intake of 7 anti-inflammatory and 3 inflammatory food groups. Cognitive function was assessed using the Korean version of the Mini-Mental State Examination. A general linear model and multiple logistic regression were applied to assess the association between FBDI and the risk of MCI. RESULTS: As the FBDI increased, the intake of white rice, cookies/candies, and sweetened drinks tended to increase, but the intake of niacin, ß-carotene, calcium, and potassium tended to decrease (p for trend<0.05). The highest FBDI group had a higher MCI risk (odds ratio [OR], 1.60; 95% confidence interval [CI], 1.01 to 2.52) than the lowest FBDI group, adjusted for gender, age, and education level; and this trend was significant in a fully adjusted model (p for trend=0.039). No significant associations were found in men after adjusting for confounding factors. Among women, MCI risk increased as the FBDI increased (p for trend=0.007); and the highest FBDI group had a higher MCI risk (OR, 2.22; 95% CI, 1.04 to 4.74) than the lowest FBDI group in a fully adjusted model. CONCLUSIONS: These results suggest that the appropriate intake of anti-inflammatory foods and nutrients may be associated with a reduced risk of MCI among older adults.

Study Design and Protocol for a Randomized Controlled Trial to Assess Long-Term Efficacy and Safety of a Triple Combination of Ezetimibe, Fenofibrate, and Moderate-Intensity Statin in Patients with Type 2 Diabetes and Modifiable Cardiovascular Risk Factors (ENSEMBLE).

BACKGRUOUND: Atherogenic dyslipidemia, which is frequently associated with type 2 diabetes (T2D) and insulin resistance, contributes to the development of vascular complications. Statin therapy is the primary approach to dyslipidemia management in T2D, however, the role of non-statin therapy remains unclear. Ezetimibe reduces cholesterol burden by inhibiting intestinal cholesterol absorption. Fibrates lower triglyceride levels and increase high-density lipoprotein cholesterol (HDL-C) levels via peroxisome proliferator- activated receptor alpha agonism. Therefore, when combined, these drugs effectively lower non-HDL-C levels. Despite this, few clinical trials have specifically targeted non-HDL-C, and the efficacy of triple combination therapies, including statins, ezetimibe, and fibrates, has yet to be determined. METHODS: This is a multicenter, prospective, randomized, open-label, active-comparator controlled trial involving 3,958 eligible participants with T2D, cardiovascular risk factors, and elevated non-HDL-C (≥100 mg/dL). Participants, already on moderate-intensity statins, will be randomly assigned to either Ezefeno (ezetimibe/fenofibrate) addition or statin dose-escalation. The primary end point is the development of a composite of major adverse cardiovascular and diabetic microvascular events over 48 months. CONCLUSION: This trial aims to assess whether combining statins, ezetimibe, and fenofibrate is as effective as, or possibly superior to, statin monotherapy intensification in lowering cardiovascular and microvascular disease risk for patients with T2D. This could propose a novel therapeutic approach for managing dyslipidemia in T2D.

Evaluation of 73 Enlisted Patients for Liver Transplant with Unknown Etiology Reveals a Late-Diagnosed Case of Lysosomal Acid Lipase Deficiency.

Lysosomal acid lipase deficiency (LALD) varies from a severe infantile-onset form (Wolman disease) to a late-onset form known as cholesteryl ester storage disease (CESD), both of which are autosomal recessive disorders caused by biallelic LIPA pathogenic variants. We evaluated seventy-three patients enlisted for liver transplant (LT) at Instituto da Criança (HCFMUSP-Brazil) who were subjected to LAL activity measurement and LIPA Sanger sequencing analysis, resulting in a positive LALD diagnosis for only one of these individuals. This LALD patient presented recurrent diarrhea, failure to thrive, hepatomegaly, and dyslipidemia at the age of 4 months and liver failure by the age of 13 years. The LALD diagnosis confirmation was conducted at 24 years old due to low levels of LAL enzyme activity. The causal homozygous variant LIPA(NM_000235.4):c.266T>C(p.Leu89Pro) was identified, but the patient had already undergone his first LT at 18 years with several rejection episodes. Despite beginning treatment with sebelipase alfa at 26 years old (total of five infusions), this patient died at 28 years from complications after his second liver transplant. LALD is an important differential diagnosis in cases presenting with hepatomegaly, elevated liver enzymes, and dyslipidemia. Detecting low/absent LAL activity and identifying the LIPA causal variant are essential for diagnosis and specific treatment, as well as for appropriate genetic counseling. Early diagnosis, along with sebelipase alfa therapy, may improve the prognosis of affected patients.

Long-term efficacy and safety of enavogliflozin in Korean people with type 2 diabetes: A 52-week extension of a Phase 3 randomized controlled trial.

AIMS: To evaluate the long-term safety and efficacy of enavogliflozin monotherapy (0.3 mg/day) in individuals with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Following a 24-week randomized, double-blind treatment period with enavogliflozin 0.3 mg/day (n = 77) or placebo (n = 69), consenting participants received enavogliflozin 0.3 mg/day for an additional 28 weeks during an open-label extension (OLE) period. The safety and efficacy of enavogliflozin were assessed at Week 52. RESULTS: A total of 37 participants continued enavogliflozin (maintenance group), and 26 participants switched from placebo to enavogliflozin (switch group). No additional adverse drug reactions related to enavogliflozin were observed during the OLE period. At Week 52, glycated haemoglobin (HbA1c) and fasting plasma glucose were significantly lower than at the baseline, by 0.9% and 24.9 mg/dL, respectively, in the maintenance group (p < 0.0001 for both), and by 0.7% and 18.0 mg/dL, respectively, in the switch group (p < 0.0001 and p = 0.002). The proportions of participants reaching HbA1c 7.0% (53 mmol/mol) at Week 52 were 69.4% in the maintenance group and 65.4% in the switch group. A significant increase in urine glucose-to-creatinine ratio was observed at Week 52, by 84.9 g/g and 67.1 g/g in the maintenance and switch groups, respectively (p < 0.0001 for both). Body weight in both groups decreased significantly (p < 0.0001) from baseline to Week 52, by 3.5 kg and 3.8 kg in the maintenance and switch groups, respectively. CONCLUSIONS: Enavogliflozin 0.3 mg monotherapy provides long-term glycaemic control in T2DM and is safe and well tolerated during a 52-week treatment period.

Impact of Body Mass Index on Opioid Prescriptions Following Lumbar Spine Surgery.

OBJECTIVE: This study aimed to evaluate the association between BMI and postoperative opioid use within two years following lumbar spine surgery using a national database. METHODS: TriNetX, a national network of de-identified patient records, was retrospectively queried from 2003 to 2021 using ICD-10, CPT, and VA codes. Propensity-score matching analysis was performed based on demographics, comorbidities, anxiety disorders, and mood disorders. RESULTS: 21,997 total patients were included in our analysis. Patients with BMI > 30 were more likely to be prescribed opioids postoperatively (OR: 1.30; 95% CI: 1.18-1.42). Patients with BMI > 40 were more likely to be prescribed opioids when compared to patients with BMI < 30 (OR: 1.94; 95% CI: 1.48-2.56), BMI 30-34.9 (OR: 2.06; 95% CI: 1.57-2.70), BMI 35-39.9 (OR: 1.50; 95% CI: 1.13-2.00), and BMI < 40 (OR: 2.06; 95% CI: 1.57-2.70). The BMI > 40 group had an increased number of opioid prescriptions within two years following lumbar surgery compared to patients with BMI 30-34.9 (p = 0.0113) and BMI < 30 (p = 0.0018). CONCLUSION: Opioid prescription following lumbar spine surgery is associated with an elevated BMI. Patients with Class III Obesity appear to be at the highest risk of increased opioid prescriptions following lumbar surgery. Physicians should consider the patient's BMI when deciding postoperative pain management.

Fasudil and viscosity of gelatin promote hepatic differentiation by regulating organelles in human umbilical cord matrix-mesenchymal stem cells.

BACKGROUND: Human mesenchymal stem cells originating from umbilical cord matrix are a promising therapeutic resource, and their differentiated cells are spotlighted as a tissue regeneration treatment. However, there are limitations to the medical use of differentiated cells from human umbilical cord matrix-mesenchymal stem cells (hUCM-MSCs), such as efficient differentiation methods. METHODS: To effectively differentiate hUCM-MSCs into hepatocyte-like cells (HLCs), we used the ROCK inhibitor, fasudil, which is known to induce endoderm formation, and gelatin, which provides extracellular matrix to the differentiated cells. To estimate a differentiation efficiency of early stage according to combination of gelatin and fasudil, transcription analysis was conducted. Moreover, to demonstrate that organelle states affect differentiation, we performed transcription, tomographic, and mitochondrial function analysis at each stage of hepatic differentiation. Finally, we evaluated hepatocyte function based on the expression of mRNA and protein, secretion of albumin, and activity of CYP3A4 in mature HLCs. RESULTS: Fasudil induced endoderm-related genes (GATA4, SOX17, and FOXA2) in hUCM-MSCs, and it also induced lipid droplets (LDs) inside the differentiated cells. However, the excessive induction of LDs caused by fasudil inhibited mitochondrial function and prevented differentiation into hepatoblasts. To prevent the excessive LDs formation, we used gelatin as a coating material. When hUCM-MSCs were induced into hepatoblasts with fasudil on high-viscosity (1%) gelatin-coated dishes, hepatoblast-related genes (AFP and HNF4A) showed significant upregulation on high-viscosity gelatin-coated dishes compared to those treated with low-viscosity (0.1%) gelatin. Moreover, other germline cell fates, such as ectoderm and mesoderm, were repressed under these conditions. In addition, LDs abundance was also reduced, whereas mitochondrial function was increased. On the other hand, unlike early stage of the differentiation, low viscosity gelatin was more effective in generating mature HLCs. In this condition, the accumulation of LDs was inhibited in the cells, and mitochondria were activated. Consequently, HLCs originated from hUCM-MSCs were genetically and functionally more matured in low-viscosity gelatin. CONCLUSIONS: This study demonstrated an effective method for differentiating hUCM-MSCs into hepatic cells using fasudil and gelatin of varying viscosities. Moreover, we suggest that efficient hepatic differentiation and the function of hepatic cells differentiated from hUCM-MSCs depend not only on genetic changes but also on the regulation of organelle states.

A Systematic Literature Review and Meta-Analysis of Primary Evidence Reporting Health-State Preference Values in Chronic Hepatitis B, C, and D.

OBJECTIVES: Chronic viral hepatitis is associated with severe impairment and reduction in patient health-related quality of life because of the substantial morbidity associated with advanced liver disease. The aim of this study was to identify and synthesize utilities for chronic hepatitis B (cHBV), C (cHCV), and D (cHDV) through a systematic literature review (SLR) and meta-analyses. METHODS: Electronic databases were searched from inception to May 2023 to identify primary studies reporting health-state utilities in English in patients aged 18 years and over, with cHBV, cHCV, or cHDV in the United States, the United Kingdom, Europe, Canada, Australia, or New Zealand. Meta-analyses were conducted for studies reporting a measure of uncertainty; model selection (fixed and random) was based on the observed levels of heterogeneity among studies. RESULTS: A total of 24 studies met the inclusion criteria and were included in the meta-analyses. More studies meeting the inclusion criteria reported utilities for cHCV (n = 20) than for cHBV (n = 8); no studies reported utility values for cHDV. Although mean utilities were higher for cHBV compared with cHCV for any given health state, utilities decreased with disease progression toward cirrhosis health states. Meta-analyses in cHCV found a utility decline of 0.1 and 0.03, based on progression from noncirrhosis to compensated cirrhosis and for decompensation in established cirrhosis, respectively. CONCLUSIONS: Chronic viral hepatitis is associated with a considerable impairment in health-related quality of life. Despite our findings, there is a need for more evidence on the lived experience in patients living with chronic hepatitis, notably in cHBV and cHDV.

Ibulocydine Inhibits Migration and Invasion of TNBC Cells via MMP-9 Regulation.

Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancer types, indicating a poor survival prognosis with a more aggressive biology of metastasis to the lung and a short response duration to available therapies. Ibulocydine (IB) is a novel (cyclin-dependent kinase) CDK7/9 inhibitor prodrug displaying potent anti-cancer effects against various cancer cell types. We performed in vitro and in vivo experiments to determine whether IB inhibits metastasis and eventually overcomes the poor drug response in TNBC. The result showed that IB inhibited the growth of TNBC cells by inducing caspase-mediated apoptosis and blocking metastasis by reducing MMP-9 expression in vitro. Concurrently, in vivo experiments using the metastasis model showed that IB inhibited metastasis of MDA-MB-231-Luc cells to the lung. Collectively, these results demonstrate that IB inhibited the growth of TNBC cells and blocked metastasis by regulating MMP-9 expression, suggesting a novel therapeutic agent for metastatic TNBC.

Evaluation of Formalin-Inactivated Vaccine Efficacy against Red Seabream Iridovirus (RSIV) in Laboratory and Field Conditions.

Red seabream iridovirus (RSIV) is a major cause of marine fish mortality in Korea, with no effective vaccine available since its first occurrence in the 1990s. This study evaluated the efficacy of a formalin-killed vaccine against RSIV in rock bream under laboratory and field conditions. For the field trial, a total of 103,200 rock bream from two commercial marine cage-cultured farms in Southern Korea were vaccinated. Farm A vaccinated 31,100 fish in July 2020 and monitored them for 18 weeks, while farm B vaccinated 30,700 fish in August 2020 and monitored them for 12 weeks. At farm A, where there was no RSIV infection, the vaccine efficacy was assessed in the lab, showing a relative percentage of survival (RPS) ranging from 40% to 80%. At farm B, where natural RSIV infections occurred, cumulative mortality rates were 36.43% in the vaccinated group and 80.32% in the control group, resulting in an RPS of 54.67%. The RSIV-infectious status and neutralizing antibody titers in serum mirrored the cumulative mortality results. This study demonstrates that the formalin-killed vaccine effectively prevents RSIV in cage-cultured rock bream under both laboratory and field conditions.

GestaltMatcher Database - A global reference for facial phenotypic variability in rare human diseases.

The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB will serve as a vital reference database for clinicians and a transparent training set for advancing NGP technology.

Brazilian growth charts for Williams-Beuren Syndrome at ages 2 to 18 years

Abstract Objective: To develop growth charts for weight-for-age, height-for-age, and body mass index (BMI)-for-age for both genders aged 2 to 18 years for Brazilian patients with Williams-Beuren Syndrome (WBS). Methods: This is a multicenter, retrospective, and longitudinal study, data were collected from the medical records of boys and girls with a confirmed diagnosis of WBS in three large university centers in the state of Sao Paulo, Brazil. Growth charts stratified by gender and age in years were developed using LMSchartmaker Pro software. The LMS (Lambda Mu Sigma) method was used to model the charts. The quality of the settings was checked by worm plots. Results: The first Brazilian growth charts for weight-for-age, height-for-age, and BMI-for-age stratified by gender were constructed for WBS patients aged 2 to 18 years. Conclusion: The growth charts developed in this study can help to guide family members and to improve the health care offered by health professionals.

The Efficacy and Tolerability of Irbesartan/Amlodipine Combination Therapy in Patients With Essential Hypertension Whose Blood Pressure Were not Controlled by Irbesartan Monotherapy.

PURPOSE: This study aimed to evaluate the efficacy and tolerability of irbesartan (IRB) and amlodipine (AML) combination therapy in patients with essential hypertension whose blood pressure (BP) was not controlled by IRB monotherapy. METHODS: Two multicenter, randomized, double-blind, placebo-controlled, phase III studies were conducted in Korea (the I-DUO 301 study and the I-DUO 302 study). After a 4-week run-in period with either 150 mg IRB (I-DUO 301 study) or 300 mg IRB (I-DUO 302 study), patients with uncontrolled BP (ie, mean sitting systolic BP [MSSBP] ≥140 mmHg to <180 mmHg and mean sitting diastolic BP <110 mmHg) were randomized to the placebo, AML 5 mg, or AML 10 mg group. A total of 428 participants were enrolled in the 2 I-DUO studies. In the I-DUO 301 study, 271 participants were randomized in a 1:1:1 ratio to receive either IRB/AML 150/5 mg, IRB/AML 150/10 mg, or IRB 150 mg/placebo. In the I-DUO 302 study, 157 participants were randomized in a 1:1 ratio to receive IRB/AML 300/5 mg or IRB 300 mg/placebo. The primary endpoint was the change in MSSBP from baseline to week 8. Tolerability was assessed according to the development of treatment-emergent adverse events (TEAEs) and clinically significant changes in physical examination, laboratory tests, pulse, and 12-lead electrocardiography. FINDINGS: In I-DUO 301, the mean (SD) changes of MSSBP at week 8 from baseline were -14.78 (12.35) mmHg, -21.47 (12.78) mmHg, and -8.61 (12.19) mmHg in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively. In I-DUO 302, the mean (SD) changes of MSSBP at week 8 from baseline were -13.30 (12.47) mmHg and -7.19 (15.37) mmHg in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively. In both studies, all combination groups showed a significantly higher reduction in MSSBP than the IRB monotherapy groups (P < 0.001 for both). TEAEs occurred in 10.00%, 10.99%, and 12.22% of participants in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively, in I-DUO 301 and in 6.33% and 10.67% of participants in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively, in I-DUO 302, with no significant between-group differences. Overall, there was one serious adverse event throughout I-DUO study. IMPLICATIONS: The combination of IRB and AML has superior antihypertensive effects compared with IRB alone over an 8-week treatment period, with placebo-like tolerability. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05476354 (I-DUO 301), NCT05475665 (I-DUO 302).