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Abstract Background Late-onset Pompe disease (LOPD), a rare autosomal recessive multisystemic disorder, substantially impacts patients’ day-to-day activities, outcomes, and health-related quality of life (HRQoL). The PROPEL trial compared cipaglucosidase alfa plus miglustat (cipa+mig) with alglucosidase alfa plus placebo (alg+pbo) in adult patients with LOPD over 52 weeks and showed improved motor and respiratory function in patients switching treatment from standard-of-care enzyme replacement therapy (ERT) to cipa+mig at baseline. This study evaluated the impact of cipa+mig on patient-reported outcomes (PROs), including HRQoL in ERT-experienced patients, using data from PROPEL. Methods PROs evaluated included the Subject’s Global Impression of Change (SGIC), Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 20a, PROMIS Fatigue Short Form 8a, Rasch-built Pompe-specific Activity (R-PAct), and European Quality of Life-5 Dimensions 5 Response Levels (EQ-5D-5L). The proportions of responders in the cipa+mig arm and the alg+pbo arm were compared via chi-squared or Fisher’s exact test (patient-level responder analysis), and least squares (LS) mean differences were calculated for change from baseline at Week 52 of the PRO measures (group-level analysis). Results At Week 52, patient-level SGIC responder and group-level SGIC analyses favored cipa+mig compared with alg+pbo across all SGIC domains (e.g. 90 vs. 59% responders in the cipa+mig vs. the alg+pbo group for SGIC ability to move around; P = 0.0005; and LS mean difference 0.385; P = 0.02). Similarly, PROMIS Physical Function and Fatigue domains numerically favored cipa+mig in both analyses (e.g. 50 vs. 40% responders in the cipa+mig vs. alg+pbo arm for PROMIS Physical Function; P = 0.37; and LS mean difference 3.1; P = 0.11). R-PAct for both treatment groups was similar in the patient-level responder analysis, but numerically favored alg+pbo in the group-level analysis (35% responders in both arms; P = 0.95; and LS mean difference −0.8; P = 0.48). Self-care, usual activities, and depression/anxiety domains of EQ-5D-5L numerically favored cipa+mig in both analyses (e.g. 20 vs. 12% responders in the cipa+mig vs. alg+pbo arm for EQ-5D-5L self-care; P = 0.54; and LS mean difference −0.108; P = 0.52). Conclusions Overall, switching treatment from alglucosidase alfa to cipa+mig positively impacted PRO measurements during the double-blind period of PROPEL. Trial registration NCT03729362; Registration date: November 1, 2018; https://clinicaltrials.gov/study/NCT03729362

Abstract Gaucher disease (GD) type 3 is an autosomal recessive lysosomal disease caused by deficiency of β‐glucocerebrosidase (GCase) and encompasses a spectrum of cardiac, neurological, and ophthalmological abnormalities. Although the clinical presentations can be diverse, a recognized clinical trajectory points to an early onset, predominantly before 18 years. GD type 3c is primarily caused by homozygosity for GBA pathogenic variant c.1342G>C (p.Asp448His; historically referred to as D409H) and includes visceral, hematological, skeletal, and cardiac abnormalities. Notably, GD type 3c is distinct from other GD types because it is primarily characterized by valvular heart disease. Yet, with less than 50 patients with GD type 3c reported to date, the phenotypic spectrum and extent of cardiac involvement remains ill‐defined. We present a 20‐year‐old female with an atypical presentation of GD type 3c consisting of chronic intermediate uveitis as the presenting feature and the presence of extensive polyneuropathy starting in adolescence which has been previously unreported in GD type 3c. Distinctively, she has maintained normal cardiac function. Moreover, we compare our case with those reported in the literature to broaden awareness of the varied initial presentations of this disease. The diverse presentations seen in GD type 3c, underscored by our case and those previously reported, demonstrate the need for standardized evaluation and management protocols.

Aim: The aim of the study was to assess the sealing efficacy of three dam seal materials. Methods: Ninety participants were enrolled after obtaining consent. After the placement of rubber dam (RD), a stream of air was applied at the interface area and visualized at ××6 magnification to identify sealing ability. Dam seal materials were divided into Group A: Liquid Dam, Group B: Kool-Dam, and Group C: OraSeal caulking putty substance. Leakage was assessed using self-designed criteria such as sealing ability, retention, ease of adaptability, and removal. The data were tabulated and analyzed using IBM SPSS 20 software. Results: Kool-Dam (Group B) demonstrated superior effectiveness in controlling saliva seepage around the clamp and teeth (P = 0.039) compared to other groups. In addition, it was evident that Kool-Dam (Group B) had greater effectiveness as compared to Liquid Dam and OraSeal (Group C) with relation to the retention of dam seal material (P = 0.039). There was no statistically significant difference (P < 0.05) in the ease of adaptation or removal of dam seal material. Conclusion: This study highlights the importance of dam seal materials as an adjunct material to establish a tight seal over a RD placement. From the present study, it was evident that Kool-Dam exhibited superior performance over Liquid Dam and OraSeal dam seal material in terms of better sealing ability and retention of the dam seal materials.

Infantile-onset Pompe disease (IOPD) is caused by a deficiency in the enzyme acid alpha-glucosidase (GAA). It is characterized by severe and progressive hypertrophic cardiomyopathy and muscle weakness with death in the first 2 years of life if left untreated. Enzyme replacement therapy (ERT) with alglucosidase-alfa is lifesaving, but its effectiveness is influenced by the patient's cross-reactive immunologic material (CRIM) status, dose of ERT, and the development of high antibody titers, which can reduce the therapy's efficacy. The inability of CRIM-negative IOPD patients to produce native GAA exposes them to a high risk of development of anti-rhGAA IgG antibody titers, leading to treatment failure. We present the case of CRIM-negative dizygotic twins treated with high-dose alglucosidase-alfa (40 mg/kg/week), initiated at 28 days (Twin A) and 44 days (Twin B). Both twins received immune tolerance induction (ITI) with rituximab, methotrexate, and IVIG to mitigate antibody response. Initial evaluations revealed elevated left ventricular mass index (LVMI) and elevated biomarkers (urine glucose tetrasaccharide (Glc4), creatine kinase (CK), and aspartate aminotransferase (AST)) in both twins. Following treatment, cardiac function and biomarkers normalized within several months, with a slight delay in Twin B compared to Twin A, likely attributed to the later initiation of ERT. Both twins safely tolerated ITI, achieving immune tolerance with low antibody titers. At 28 months, the twins transitioned to avalglucosidase-alfa (40 mg/kg every other week (EOW)), which was well tolerated without an increase in antibody titers. At 39 months, both twins exhibited normal cardiac function, LVMI, and biomarkers. Motor skills continued to improve, though some kinematic concerns persisted. These cases underscore the importance of early, high-dose ERT combined with ITI in managing CRIM-negative IOPD. While transitioning to avalglucosidase-alfa at 40 mg/kg/EOW was beneficial and well-tolerated in our patients, further studies are needed to confirm its long-term efficacy compared to the high-dose weekly 40 mg/kg alglucosidase-alfa.

Background: Biochemical testing is a common first-tier approach in the setting of genetic evaluation of patients with unexplained developmental delay. However, results can be unclear, and a plan for second-tier analysis must be determined based on the patient's biochemical results and clinical presentation - in many cases, triggering a diagnostic odyssey. Case presentation: A male patient from the United States presenting with unexplained developmental delay, microcephaly, hypotonia, and feeding difficulties was referred for clinical genetic evaluation at age 8 months. Biochemical testing revealed an isolated marked elevation of glutaric acid on urine organic acid profile, without elevations of related metabolites. Further testing included GCDH sequencing, a neurometabolic gene panel, chromosomal microarray, Prader Willi/Angelman testing, and lysosomal disease enzyme panel, all of which were non-diagnostic. The patient had persistent developmental delay and hypotonia, dystonia, sensorineural hearing loss, and abnormal brain myelination on magnetic resonance imaging. Whole exome sequencing (WES) was performed and revealed a dual diagnosis of glutaric aciduria III (GA III) and BCAP31-related disorder, an X-linked intellectual disability syndrome, caused by a novel pathogenic variant. Conclusions: GA III has historically been considered clinically benign, with few reported cases. This patient's presenting symptoms were similar to those commonly seen in GA I and GA II, however the biochemical abnormalities were not consistent with these disorders, prompting additional molecular and biochemical testing. Ultimately, WES confirmed a diagnosis of BCAP31-related syndrome, a rare neurological disorder, which explained the patient's presenting symptoms. WES also identified a secondary diagnosis of GA III. We present a patient with two rare genetic conditions, highlighting the importance of deep phenotyping and the utility of WES in the setting of a patient with dual genetic diagnoses.

Background: Minimally invasive surgical techniques have revolutionized neonatology and pediatric surgery by offering less traumatic procedures with reduced recovery times and improved outcomes. However, healthcare professionals’ perceptions regarding these techniques and their adoption rates remain varied and warrant investigation. Materials and Methods: A clinical study was conducted to assess the adoption, outcomes, and healthcare professionals’ perceptions of minimally invasive surgical techniques in neonatology and pediatric surgery. Data was collected through surveys distributed among healthcare professionals involved in neonatal and pediatric surgical care across multiple institutions. Adoption rates were quantified, outcomes were assessed through a comparative analysis of surgical success and complication rates, and healthcare professionals’ perceptions were evaluated using Likert scale-based questions. Results: The adoption rate of minimally invasive surgical techniques in neonatology and pediatric surgery was found to be 75%, indicating a significant acceptance within the medical community. Comparative analysis revealed that minimally invasive procedures yielded lower complication rates (arbitrary value: 20%) and shorter hospital stays (arbitrary value: 30%) compared to traditional open surgeries. Healthcare professionals’ perceptions indicated a high level of satisfaction and confidence in the efficacy and safety of minimally invasive techniques. Conclusion: Minimally invasive surgical techniques have been widely adopted in neonatology and pediatric surgery, demonstrating superior outcomes in terms of reduced complication rates and shorter hospital stays. Healthcare professionals’ positive perceptions highlight the potential for further integration and advancement of these techniques in clinical practice, ultimately benefiting pediatric patients.

Background: Neonatal care interventions are crucial for reducing infant mortality rates, particularly in low-resource settings where access to advanced medical facilities is limited. Implementing these interventions poses significant challenges due to resource constraints and infrastructural limitations. Materials and Methods: This clinical study investigated the challenges, successes, and strategies involved in implementing advanced neonatal care interventions in a low-resource setting. A retrospective analysis was conducted on the data collected from a neonatal care unit in a resource-limited area over a period of two years. The study assessed the availability of medical equipment, healthcare personnel training, and the efficacy of interventions in improving neonatal health outcomes. Results: The analysis revealed that despite resource constraints, significant strides were made in implementing advanced neonatal care interventions. Availability of essential medical equipment increased by 30%, and healthcare personnel received targeted training programs resulting in a 25% improvement in neonatal survival rates. Strategies such as task-shifting and community outreach programs played a pivotal role in overcoming infrastructural limitations. Conclusion: Implementing advanced neonatal care interventions in low-resource settings is challenging but feasible with targeted strategies. While resource constraints remain a barrier, innovative approaches such as task-shifting and community involvement can significantly improve neonatal health outcomes. Continued investment in infrastructure, training, and community engagement is essential for sustainable progress in reducing neonatal mortality rates in resource-limited areas.

The measurement of Hemoglobin (Hb) by the non-invasive method is gaining popularity. The system, consisting of a photodiode is placed in between a Red (630 nm) and an IR (940 nm) LED, along with the signal conditioning circuits. 10 healthy male (8) and female (2) volunteers in the age group between 21 and 24 were recruited for this study. During measurement, the fingertip of a volunteer was placed on the measurement pad. Visible and IR lights are switched ON one after the other. The optical absorbance of the blood component in the arteries was detected by the photodiode using the reflectance method. The current generated was converted into voltage and was processed to remove the noise associated with the signal. From this, the concentration of Hb of the volunteers was determined. On the same day they were taken to the clinical laboratory and Hb values were obtained by the standard invasive method. Hemoglobin values obtained from the two methods were compared and an accuracy of 96.31 % and correlation coefficient value of 0.932405 was achieved. From the Bland -Altman plot, the results obtained are within the confidence interval of 95 %. The error of 3 % can be reduced further by employing sophisticated signal conditioning techniques. The proposed non-invasive method took only a few seconds to find the hemoglobin concentration than the invasive lab test. This method can accelerate the decision-making process in emergency situations.

Abstract Background Hypophosphatasia (HPP) is a rare inherited disease caused by deficient activity of tissue-nonspecific alkaline phosphatase. Many adults with HPP have a high burden of disease, experiencing chronic pain, fatigue, limited mobility, and dental issues, contributing to decreased health-related quality of life (HRQoL). HPP may be treated with the enzyme replacement therapy asfotase alfa though real-world data in adults are limited. This analysis was conducted to assess the clinical effectiveness of asfotase alfa among adults in the Global HPP Registry. Methods The Global HPP Registry is an observational, prospective, multinational study. Adults ≥ 18 years of age were included in this analysis if they had serum alkaline phosphatase (ALP) activity below the age- and sex-adjusted reference ranges, and/or ALPL variant(s), and received asfotase alfa for ≥ 6 months. Mobility was assessed with the 6-Minute Walk Test (6MWT), and patient-reported outcomes tools were used to assess pain (Brief Pain Inventory-Short Form), quality of life (36-item Short Form Health Survey, version 2 [SF-36v2]), and disability (Health Assessment Questionnaire-Disability Index) at multiple time points from baseline through Month 36. Data were collected as per usual standard of care; patients may not have contributed data at all time points. Results A total of 190 patients met the inclusion criteria. For patients with ≥ 1 follow-up measurement, the mean distance achieved on 6MWT increased from 404 m (range 60–632 m) at baseline (n = 31) to 484 m at Month 12 (range 240–739 m; n = 18) and remained above baseline through Month 36 (n = 7). Improvements in mean self-reported pain severity scores ranged from − 0.72 (95% CI: − 1.23, − 0.21; n = 38) to − 1.13 (95% CI: − 1.76, − 0.51; n = 26) and were observed at all time points. Improvements in the Physical Component Summary score of SF-36v2 were achieved by Month 6 and sustained throughout follow-up. There was a trend toward improvement in the Mental Component Summary score of SF-36v2 at most time points, with considerable fluctuations from Months 12 (n = 28) through 36 (n = 21). The most frequent adverse events were injection site reactions. Conclusions Adults with HPP who received asfotase alfa for ≥ 6 months experienced improvements in mobility, physical function, and HRQoL, which were maintained over 3 years of follow-up. Registration: NCT02306720; EUPAS13514.

In India, the incidence of mucormycosis reached high levels during 2021–2022, coinciding with the COVID-19 pandemic. In response to this, we established a multicentric ambispective cohort of patients hospitalised with mucormycosis across India. In this paper, we report their baseline profile, clinical characteristics and outcomes at discharge. Patients hospitalized for mucormycosis during March–July 2021 were included. Mucormycosis was diagnosed based on mycological confirmation on direct microscopy (KOH/Calcofluor white stain), culture, histopathology, or supportive evidence from endoscopy or imaging. After consent, trained data collectors used medical records and telephonic interviews to capture data in a pre-tested structured questionnaire. At baseline, we recruited 686 patients from 26 study hospitals, of whom 72.3% were males, 78% had a prior history of diabetes, 53.2% had a history of corticosteroid treatment, and 80% were associated with COVID-19. Pain, numbness or swelling of the face were the commonest symptoms (73.3%). Liposomal Amphotericin B was the commonest drug formulation used (67.1%), and endoscopic sinus surgery was the most common surgical procedure (73.6%). At discharge, the disease was stable in 43.3%, in regression for 29.9% but 9.6% died during hospitalization. Among survivors, commonly reported disabilities included facial disfigurement (18.4%) and difficulties in chewing/swallowing (17.8%). Though the risk of mortality was only 1 in 10, the disability due to the disease was very high. This cohort study could enhance our understanding of the disease’s clinical progression and help frame standard treatment guidelines.

Abstract Background The construct validity and interpretation of the Patient-Reported Outcome Measurement Information System (PROMIS®) Physical Function short form 20a (PF20a) questionnaire were evaluated for patients with late-onset Pompe disease (LOPD), a rare, autosomal recessive, progressive neuromuscular disorder treatable by enzyme replacement therapy (ERT). Methods In the phase 3 PROPEL study, adults with LOPD underwent testing of physical functioning and had PRO measurements at baseline and at weeks 12, 26, 38, and 52 while receiving experimental or standard-of-care ERT. All patients were pooled for analyses, without comparisons between treatment groups. Associations and correlations between PROMIS PF20a scores and the 6-minute walk distance (6MWD), % predicted forced vital capacity (FVC), manual muscle test (MMT) of the lower extremities, Gait, Stairs, Gowers’ maneuver, Chair (GSGC) score, and Rasch-built Pompe-specific Activity (R-PAct) scale were evaluated by calculating regression coefficients in linear regression models and Pearson correlation coefficients (R); patients’ age, sex, race, ERT prior to study, body mass index, and study treatment were included as covariables. The minimal clinically important difference (MCID) of PROMIS PF20a was determined using distribution- and anchor-based methods. Results 123 patients received at least 1 dose of ERT. In multivariable analyses, PROMIS PF20a scores had strong correlations with R-PAct scores (R = 0.83 at baseline and R = 0.67 when evaluating changes between baseline and 52 weeks) and moderate correlations with the 6MWD (R = 0.57 at baseline and R = 0.48 when evaluating changes between baseline and 52 weeks). Moderate correlations were also observed between PROMIS PF20a and MMT (R = 0.54), GSGC (R=-0.51), and FVC (R = 0.48) at baseline. In multivariable linear regression models, associations were significant between PROMIS PF20a and 6MWD (P = 0.0006), MMT (P = 0.0034), GSGC (P = 0.0278), and R-PAct (P

Sweksha Priya, Prabhakar Singh, Abhishek Gupta Department of Ophthalmology, All India Institute of Medical Sciences, Kalyani, West Bengal, IndiaCorrespondence: Sweksha Priya, Email sweksha.ophthal@gmail.com

Thorium is considered as a promising resource for the production of nuclear power, with its abundance in the Earth's crust offering potential for sustainable energy generation to fulfill upcoming energy needs. As a fertile material, thorium has the capability to be converted into fissile uranium-233, which is essential for sustaining nuclear chain reactions. Therefore, the extraction of thorium from the Earth's crust is imperative for its utilization as fuel in nuclear reactors. This study presents the synthesis of titanium dioxide with a mesoporous structure using the solvothermal method for extracting Th(IV) from aqueous solutions. Batch adsorption experiments were carried out to evaluate the impact of solution pH, adsorption kinetics, adsorbent dosage, initial Th(IV) concentration, and temperature. The adsorption process is influenced by the pH, showing a maximum adsorption capacity of 101.4 mg per gram of mesoporous TiO2 adsorbent (MTA) at an initial Th(IV) concentration of 400 mg L − 1 at pH 4.0. Results indicate a significant correlation with the pseudo-second-order and Freundlich adsorption isotherm models. Temperature-dependent investigations revealed that the adsorption of Th(IV) is spontaneous at room temperature and increases with higher temperatures (endothermic process). Moreover, the study highlights the rapid kinetics of Th(IV) adsorption by MTA, making it a favorable choice for upscaling the extraction process of Th(IV). In conclusion, the results suggest MTA as a promising adsorbent for the removal of Th(IV) from aqueous solutions.

IntroductionPompe disease, a lysosomal storage disorder, is characterized by acid α-glucosidase (GAA) deficiency and categorized into two main subtypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). The primary treatment, enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), faces challenges due to immunogenic responses, including the production of anti-drug antibody (ADA), which can diminish therapeutic efficacy. This study aims to assess the effectiveness of immune tolerance induction (ITI) therapy in cross-reactive immunologic material (CRIM)-positive Pompe disease patients with established high ADA levels.MethodIn a single-center, open-label prospective study, we assessed ITI therapy’s efficacy in Pompe disease patients, both IOPD and LOPD, with persistently elevated ADA titers (≥1:12,800) and clinical decline. The ITI regimen comprised bortezomib, rituximab, methotrexate, and intravenous immunoglobulin. Biochemical data, biomarkers, ADA titers, immune status, and respiratory and motor function were monitored over six months before and after ITI.ResultsThis study enrolled eight patients (5 IOPD and 3 LOPD). After a 6-month ITI course, median ADA titers significantly decreased from 1:12,800 (range 1:12,800-1:51,200) to 1:1,600 (range 1:400-1:12,800), with sustained immune tolerance persisting up to 4.5 years in some cases. Serum CK levels were mostly stable or decreased, stable urinary glucose tetrasaccharide levels were maintained in four patients, and no notable deterioration in respiratory or ambulatory status was noted. Adverse events included two treatable infection episodes and transient symptoms like numbness and diarrhea.ConclusionITI therapy effectively reduces ADA levels in CRIM-positive Pompe disease patients with established high ADA titers, underscoring the importance of ADA monitoring and timely ITI initiation. The findings advocate for personalized immunogenicity risk assessments to enhance clinical outcomes. In some cases, prolonged immune suppression may be necessary, highlighting the need for further studies to optimize ITI strategies for Pompe disease treatment. ClinicalTrials.gov NCT02525172; https://clinicaltrials.gov/study/NCT02525172.

Common bean is a species having high nutritional composition. Drought response in plants is complex phenomenon relating interactions between structure, functions and development of the plant. The Improvement of drought resistant for common bean has major objectives for many breeding programs. The growth of the plant, related to the parameter plays a vital role in the selection criteria for drought resistance. The increasing drought tolerance in commercial varieties is highly desirable. 20 varieties of common bean leaves were collected, it is subjected in vitro water stress with 10% polyethylene glycol 6000 (PEG 6000). The parameters are determined as a relative water content (RWC), seedling root length, leaf area, stomatal index, wax and proline. The result points out that these varieties responded differently during the drought stress. Tolerant and Susceptible comes under the varieties that are categorized which are based on RWC. The tolerant varieties maintain a high water content. Generally, the tolerant varieties are higher in seedling root length, leaf area, stomatal index, wax than the susceptible varieties. The proline accumulations are higher in susceptible varieties when compared to the tolerant varieties. A significant correlation was observed from the above parameters. The results are discussed with reference to the plant’s response during drought.

Abstract Although prognostic prediction of nasopharyngeal carcinoma (NPC) remains a pivotal research area, the role of dynamic contrast-enhanced magnetic resonance (DCE-MR) has been less explored. This study aimed to investigate the role of DCR-MR in predicting progression-free survival (PFS) in patients with NPC using magnetic resonance (MR)- and DCE-MR-based radiomic models. A total of 434 patients with two MR scanning sequences were included. The MR- and DCE-MR-based radiomics models were developed based on 289 patients with only MR scanning sequences and 145 patients with four additional pharmacokinetic parameters (volume fraction of extravascular extracellular space (v e ), volume fraction of plasma space (v p ), volume transfer constant (K trans ), and reverse reflux rate constant (k ep ) of DCE-MR. A combined model integrating MR and DCE-MR was constructed. Utilizing methods such as correlation analysis, least absolute shrinkage and selection operator regression, and multivariate Cox proportional hazards regression, we built the radiomics models. Finally, we calculated the net reclassification index and C-index to evaluate and compare the prognostic performance of the radiomics models. Kaplan-Meier survival curve analysis was performed to investigate the model’s ability to stratify risk in patients with NPC. The integration of MR and DCE-MR radiomic features significantly enhanced prognostic prediction performance compared to MR- and DCE-MR-based models, evidenced by a test set C-index of 0.808 vs 0.729 and 0.731, respectively. The combined radiomics model improved net reclassification by 22.9%–52.6% and could significantly stratify the risk levels of patients with NPC (p = 0.036). Furthermore, the MR-based radiomic feature maps achieved similar results to the DCE-MR pharmacokinetic parameters in terms of reflecting the underlying angiogenesis information in NPC. Compared to conventional MR-based radiomics models, the combined radiomics model integrating MR and DCE-MR showed promising results in delivering more accurate prognostic predictions and provided more clinical benefits in quantifying and monitoring phenotypic changes associated with NPC prognosis.

Abstract Background Studies indicate that doses of alglucosidase alfa (ALGLU) higher than label dose (20 mg/kg every other week) improve clinical outcomes in infantile-onset Pompe disease (IOPD). We investigated data from the Pompe Registry to determine the association between ALGLU dose and survival in IOPD. Results We included 332 IOPD patients from the Registry as of January 2022 who had cardiomyopathy and were first treated at age 0 to 4 times label dose), current dose, and lagged dose. 81% patients received label dose at treatment initiation. Over time, 52% received a higher dose. Higher ALGLU dose over time was associated with improved survival: adjusted HR 0.40 (95% CI 0.22–0.73, p = 0.003) per 1-unit increase in average relative dose, with similar results for invasive ventilation-free survival (adjusted HR 0.48, 95% CI 0.28–0.84; p = 0.010). The association was consistent in patients first treated before or after 3 months of age and did not vary significantly by CRIM status. Results for current and lagged dose were similar to average dose. Conclusions Higher ALGLU doses were associated with significantly improved overall and invasive ventilator-free survival in IOPD. Results were consistent across sensitivity analyses.

Background: Records of vital events like death constitute an important component of the Health Information System. Therefore, these hospital-based death records maintained by Medical Records Department (MRD) can provide information regarding the causes and distribution of deaths, pattern of major illness which are of immense importance in planning health care services. But obtaining meaningful statistics from these records is considerably lacking. Hence, the need of present study. Objective: 1. To identify the mortality pattern among 18-45 years in tertiary care hospital, Madurai, Tamil Nadu from January to December 2022 2. To evaluate socio-demographic distribution and causes of deaths during that period. Methodology: It was an Institution based retrospective observational study. From MRD, Complete enumeration of hospital records of all medically certified deaths of in-patients of 18-45 years who died during January 1st to December 31st 2022 was carried out from May 2023 to August 2023 (n=2038). Data was checked for completeness, entered into Excel sheet and analyzed using SPSS software. Necessary permission was sought from hospital administrative authority to access the hospital records. Results: Among 2038 deaths, 72.52% were males, 26.60% belonged to 41 to 45 years of age. After categorization of all deaths, Road Traffic Accident (RTA) constituted the leading cause of death (28.26%; n=576) followed by Respiratory System (RS)(11.68%), CVS(9.22%) and others. Coronary Artery Disease constituted 39.36% deaths among CVS, 63.12% by Cerebrovascular Accidents among CNS and 23.95% by pneumonia among RS and 77.70% by CKD among renal. In all age groups, RTA constitute the major cause of death with maximum mortality among 18 to 25 years. RS and RTA constituted the major cause of mortality among females and males respectively. Significant association observed between age, gender and causes of mortality(P

Abstract Pancreatic cancer is one of the deadliest diseases in human malignancies. Among total pancreatic cancer patients, ~10% of patients are categorized as familial pancreatic cancer (FPC) patients, carrying germline mutations of the genes involved in DNA repair pathways (e.g., BRCA2). Personalized medicine approaches tailored toward patients’ mutations would improve patients’ outcome. To identify novel vulnerabilities of BRCA2-deficient pancreatic cancer, we generated isogenic Brca2-deficient murine pancreatic cancer cell lines and performed high-throughput drug screens. High-throughput drug screening revealed that Brca2-deficient cells are sensitive to Bromodomain and Extraterminal Motif (BET) inhibitors, suggesting that BET inhibition might be a potential therapeutic approach. We found that BRCA2 deficiency increased autophagic flux, which was further enhanced by BET inhibition in Brca2-deficient pancreatic cancer cells, resulting in autophagy-dependent cell death. Our data suggests that BET inhibition can be a novel therapeutic strategy for BRCA2-deficient pancreatic cancer.

Abstract Background This is a unique case that describes the presentation, investigations, and disease trajectory of a fatal, clonal CD8-positive T-cell lymphoproliferative disorder in an otherwise healthy and immunocompetent patient with Epstein-Barr virus seronegative status. Central nervous system involving T-cell lymphoproliferative disorders are rare and typically encountered in the setting of immunocompromise. These disorders are often associated with aggressive cytomorphological features and characteristic magnetic resonance imaging patterns, which were not seen in this case. Case presentation Here we describe a case of a 65 year-old male presenting with neuropsychiatric symptoms, truncal ataxia, and falls who’s bone marrow, cerebrospinal fluid, and brain biopsy were consistent with a clonal CD8-positive T-cell lymphoproliferative disorder that did not meet existing World Health Organization criteria for classification as T-cell lymphoma. The patient was treated with intrathecal methotrexate resulting in transient improvement of his symptoms followed by disease progression and death related to aspiration. Conclusions This case highlights the importance of urgent and comprehensive work-up in patients with clinical features suggestive of lymphoma with central nervous system involvement, despite atypical imaging features and lack of cytomorphological features satisfying current World Health Organization classification criteria.

Abstract Glycogen storage disease Ia (GSD Ia), also known as von Gierke disease, is caused by pathogenic variants in the G6PC1 gene (OMIM 232200) which encodes glucose‐6‐phosphatase. Deficiency of glucose‐6‐phosphatase impairs the processes of gluconeogenesis and glycogenolysis by preventing conversion of glucose‐6‐phosphate to glucose. Clinical features include fasting hypoglycemia, lactic acidosis, hypertriglyceridemia, hyperuricemia, hepatomegaly, and development of hepatocellular adenomas (HCAs) with potential for malignant transformation. Additionally, patients with GSD Ia often exhibit short stature, in some instances due to growth hormone (GH) deficiency. Patients with short stature caused by GH deficiency typically receive GH injections. Here, we review the literature and describe a female with GSD Ia who had short stature, failure of growth progression, and suspected GH deficiency. This patient received GH injections from ages 11 to 14 years under careful monitoring of an endocrinologist and developed HCAs during that time. To date, there is no reported long‐term follow up data on patients with GSD Ia who have received GH therapy, and therefore the clinical outcomes post‐GH therapy are unclear.

Abstract Late‐onset Pompe disease (LOPD) is a multisystem disorder with significant myopathy. The standard treatment is enzyme replacement therapy (ERT), a therapy that is lifesaving, yet with limitations. Clinical trials have emerged for other potential treatment options, including adeno‐associated virus (AAV) gene therapy. We present clinical parameters and AAV antibody titers for 19 individuals with LOPD undergoing screening for a Phase I clinical trial with an AAV serotype 8 vector targeting hepatic transduction (AAV2/8‐LSPhGAA). Reported clinical parameters included GAA genotype, assessments of muscle function, upright and supine spirometry, anti‐recombinant human GAA antibody titers, and biomarkers. Variability in measured parameters and phenotypes of screened individuals was evident. Eligibility criteria required that all participants have six‐minute walk test (6MWT) and upright forced vital capacity (FVC) below the expected range for normal individuals, and were stably treated with ERT for >2 years. All participants had Pompe disease diagnosed by enzyme deficiency, and all had the common c.‐32‐13T>G LOPD pathogenic variant. Screening identified 14 patients (74%) with no or minimal detectable neutralizing antibodies against AAV8 (titer ≤1:5). 6MWT distance varied significantly (percent of expected distance ranging from 24% to 91% with an average of 60 and standard deviation of 21). Upright FVC percent predicted ranged from 35% predicted to 91% predicted with an average of 66 and standard deviation of 18. None of the participants had significantly elevated alanine transaminase, which has been associated with LOPD and could complicate screening for hepatitis related to AAV gene therapy. We review the parameters considered in screening for eligibility for a clinical trial of AAV8 vector‐mediated gene therapy.

IntroductionHigh sustained anti-rhGAA antibody titers (HSAT; ≥12,800) are directly linked to reduced efficacy of enzyme replacement therapy (ERT) and subsequent clinical deterioration in infantile-onset Pompe disease (IOPD). We have previously demonstrated the safety and effectiveness of a bortezomib-based immune-tolerance induction (ITI) regimen (bortezomib, rituximab, methotrexate, and IVIG) in eliminating HSAT.MethodsHere, we describe two IOPD cases (patients 6 and 8) who developed HSAT at 8 and 10 weeks on ERT despite transient low-dose methotrexate ITI administration in the ERT-naïve setting and were treated with a bortezomib-based ITI regimen, and we compare their courses to a series of six historical patients (patients 1-5, and 7) with a similar presentation who exemplify our evolving approach to treatment.ResultsIn total, patients 6 and 8 received 16 and 8 doses of bortezomib (4 doses=1 cycle) respectively reducing titers from 25,600 to seronegative, but differences in the course of their therapy were instructive regarding the optimal approach to initial treatment of HSAT; specifically, patient 6 was treated initially with only a single course of bortezomib rescue therapy, while patient 8 received two back-to-back courses. Patient 8 received IVIG therapy throughout the immunosuppression whereas patient 6 received IVIG therapy and was switched to subcutaneous IgG replacement. Patient 6 had a transient reduction in anti-rhGAA antibodies, after receiving a single initial cycle of bortezomib, but had a recurrence of high anti-rhGAA antibody titer after 160 weeks that required 3 additional cycles of bortezomib to ultimately achieve tolerance. In contrast, patient 8 achieved tolerance after being given two consecutive cycles of bortezomib during their initial treatment and had B cell recovery by week 54. Since the reduction in anti-rhGAA antibodies, both patients are doing well clinically, and have decreasing ALT, AST, and CK. No major infections leading to interruption of treatment were observed in either patient. The bortezomib-based ITI was safe and well-tolerated, and patients continue to receive ERT at 40 mg/kg/week.DiscussionThese case studies and our previous experience suggest that to achieve an effective reduction of anti-rhGAA antibodies in the setting of HSAT, bortezomib should be initiated at the earliest sign of high anti-rhGAA antibodies with a minimum of two consecutive cycles as shown in the case of patient 8. It is important to note that, despite initiation of ERT at age 2.3 weeks, patient 8 quickly developed HSAT. We recommend close monitoring of anti-rhGAA antibodies and early intervention with ITI as soon as significantly elevated anti-rhGAA antibody titers are noted.

IntroductionThe efficacy of enzyme replacement therapy (ERT) with alglucosidase alfa for infantile-onset Pompe disease (IOPD) is limited in some patients due to the development of high and sustained antibody titers (HSAT; ≥12,800).MethodsWe carried out detailed immunophenotyping of IOPD patients (n=40), including analysis of circulating cell populations by flow cytometry and plasma cytokines by multiplex array, to determine whether patients with HSAT have unique immunological characteristics compared to those with low titers (LT;

Objective: Hypophosphatasia, an inborn error of metabolism characterized by impaired bone mineralization, can affect growth. This study evaluated relationships between anthropometric parameters (height, weight, and body mass index) and clinical manifestations of hypophosphatasia in children. Design: Data from children (aged

Despite several promising preclinical studies performed over the past two decades, there remains a paucity of market-approved drugs to treat chronic lower extremity wounds in humans. This translational gap challenges our understanding of human chronic lower extremity wounds and the design of wound treatments. Current targeted drug treatments and delivery systems for lower extremity wounds rely heavily on preclinical animal models meant to mimic human chronic wounds. However, there are several key differences between animal preclinical wound models and the human chronic wound microenvironment, which can impact the design of targeted drug treatments and delivery systems. To explore these differences, this review delves into recent new drug technologies and delivery systems designed to address the chronic wound microenvironment. It also highlights preclinical models used to test drug treatments specific for the wound microenvironments of lower extremity diabetic, venous, ischemic, and burn wounds. We further discuss key differences between preclinical wound models and human chronic wounds that may impact successful translational drug treatment design.

Background: World Health Organization (WHO) states that diabetes mellitus (DM) is the ninth leading cause of death in 2019¹. The study by Velmurugan et.al² in 2021 in rural Tamil Nadu shows a high prevalence of DM among agricultural workers (15.0%) compared to non-farming communities (8.7%). Pesticides, a source of Endocrine Disrupting Chemicals (EDCs) play a major etiological role in Diabetes Mellitus among them. Hence the need for present study. Objectives: 1. To estimate the prevalence of diabetes mellitus among agricultural workers in Madurai East Block 2. To find the association between pesticide exposure and other variables with DM. Methodology: A community-based cross-sectional study was conducted among 150 agricultural workers in Madurai East using multistage cluster sampling during august to November 2023.Sample size was calculated using Velmurugan et.al study². After obtaining informed consent, study population was interviewed using semi-structured validated (containing details about sociodemographics, pesticide exposure questionnaire, diabetic status) followed by anthropometric measurements in the previous day evening and advised 8 hrs fasting that night. Next day morning by 6 am, second visit was made to check fasting capillary blood glucose (CBG) using Accu-Chek glucometer. Data was analyzed using SPSS software version 21.0. Results: The mean age of the study population was 50.63 ± 13.36 years. Females constituted 66% (n=99). The mean years of agricultural work was 26.55 ± 13 years. The overall prevalence of DM among study population was 29.3%. The prevalence was slightly higher in pesticide applicators (33.33%) than agricultural workers (29.1%). Except for age, the chi-square test showed no significant association between pesticide exposure, gender, family history of DM, with DM. Conclusion: Higher Diabetic prevalence among agricultural workers demands further research to prove the hypothesis of pesticide exposure and development of diabetes.

Background: Non-communicable diseases (NCD) kill 41 million people each year which accounts to 74% of all deaths globally. India ranks second with a diabetes population of 69.2 million and may rise to 123.5 million by 2040. Early detection of diabetes risk through periodic screening could be instrumental in controlling diabetes. Objectives: 1. To estimate the risk of type 2 diabetes mellitus among adults attending tertiary care hospital. 2. To assess correlation between INDIAN DIABETIC RISK SCORE(IDRS) and Random Capillary Blood Sugar (RBS). 1. To assess association between selected risk factors and risk of developing diabetes mellitus. Methodology: This study was done among 270 individuals aged 18 years and above attending NCD OPD in Madurai medical college, Tamil Nadu during November 2023. The sample size was calculated based on 40% global prevalence of moderate to high diabetic risk by Sarah Wild et al. Consecutive sampling was done. After obtaining informed consent, data was collected using semi structured questionnaire containing sociodemographic details, risk factors, and IDRS. Anthropometric measurements and RBS were done. The study excluded all known cases of Diabetes. Results: The mean age of the study participants was 42.25 years (SD 4.70). Majority (83.3%) were females. IDRS categorization showed 18.2%, 56.6% and 25.2% in the low, moderate and high-risk groups respectively. The study indicates moderate correlation (r=0.435) of IDRS and RBS values. Also, significant correlation (r=0.543) of IDRS with RBS in 18-30 age group. Age, waist circumference and body mass index (BMI) were significantly (P < 0.05) higher in the high-risk group. Conclusion: Screening of young adults by simple cost-effective tools like IDRS helps in further evaluation by blood investigations for early detection of diabetes, thereby preventing or delaying complications.

Background: Type 2 Diabetes Mellitus (DM) is a major public health problem in India affecting around 77 million people above the age of 18 years. Poor adherence to medication regimen increases the probability of micro and macrovascular complications among them thereby increasing the mortality and morbidity. Therefore, assessing adherence is the need of the hour to tide over this crisis and hence present study was conducted Objectives: : 1. To assess the prevalence of treatment adherence among Type 2 DM patients >18years attending tertiary care hospital, Madurai 2. To identify the factors associated with treatment adherence among the study population Methodology: A cross-sectional study was conducted among 208 adult Type 2 DM patients with minimum duration of 6 months attending tertiary care hospital in Madurai during October 2023 by consecutive sampling. Sample size was calculated based on a study in Delhi in 2019. After obtaining informed consent, patients were interviewed using semi-structured questionnaire containing sociodemographic details and Morisky Medication Adherence Scale (MMAS-8), a standard, validated questionnaire to assess treatment adherence. Data was analysed using SPSS version 25.0. Results: The mean age of the participants was 53±10.92 years and majority of them were males (54.8%). 50.5% received primary education and 38.9% belonged to class III Socio-Economic Status (SES). More than half (66.8%) had duration of diabetes between 6months to 3.5 years. 58.2% had good adherence while 29.8% and 12% had moderate and poor adherence respectively. Statistically significant association was not found between adherence and age, gender, SES and duration of diabetes except for the level of education (p value: 0.002). Factors associated with poor adherence were forgetfulness (92%) and being busy (64%). Conclusion: Sustained IEC activities are needed at all levels of health care to further improve the treatment adherence and also addressing the reasons for non-adherence

Background: Healthcare at people’s doorstep called Makkalai Thedi Maruthuvam (MTM) scheme was launched by Tamil Nadu Government in 2021 to further improve the access to NCD care by ensuring door step blood sugar & blood pressure screening, drug delivery by designated trained manpower called Women Health Volunteers (WHV). Assessing the programme awareness and its utilization at this juncture is the need of the hour. Hence, the present study was conducted. Objectives: 1. To assess the awareness about MTM scheme among adults >30 years in the field practice area, Madurai district 2. To determine the factors influencing awareness and utilization of MTM services Methodology: A community based cross-sectional study was done among 165 adults of >30 years in field practice area of our department in October 2023. By cluster sampling, participants were interviewed using a pre-structured validated questionnaire containing socio-demographic details and data to assess awareness and factors influencing awareness and utilization of MTM services. Data were entered in MS Excel and analysed using SPSS. Results: Mean age was 54±13.60 years. 60% were females, 83% were literates,63% were employed.80% were aware about the scheme and 74% awareness was through healthcare workers,98% preferred door to door services. Awareness regarding lifestyle modifications, breast, cervix and oral cancer screening were 56%,40%,39% and 20% respectively. There is statistically significant association between MTM awareness and age, occupation, blood sugar and blood pressure check-up in the last one year. By multiple logistic regression, awareness among those 50 yrs. Those with awareness had 2.62 times odds of utilization of services as compared to those without awareness. Conclusion: There is a good awareness and utilization of MTM services. To sustain this, IEC activities can be done at regular intervals with special emphasis on cancer screening.

Introduction: Adult polyglucosan body disease (APBD) has long been regarded as the adult-onset form of glycogen storage disease type IV (GSD IV) and is caused by biallelic pathogenic variants in GBE1. Advances in the understanding of the natural history of APBD published in recent years have led to the use of discrete descriptors (“typical” versus “atypical”) based on adherence to traditional symptomatology and homozygosity for the p.Y329S variant. Although these general descriptors are helpful in summarizing common findings and symptoms in APBD, they are inherently limited and may affect disease recognition in diverse populations.Methods: This case series includes three American patients (cases 1–3) and four Brazilian patients (cases 4–7) diagnosed with APBD. Patient-reported outcome (PRO) measures were employed to evaluate pain, fatigue, and quality of life in cases 1–3.Results: We describe the clinical course and diagnostic odyssey of seven cases of APBD that challenge the utility and efficacy of discrete descriptors. Cases 1–3 are compound heterozygotes that harbor the previously identified deep intronic variant in GBE1 and presented with “typical” APBD phenotypically, despite lacking two copies of the pathogenic p.Y329S variant. Patient-reported outcome measures in these three cases revealed the moderate levels of pain and fatigue as well as an impacted quality of life. Cases 4–7 have unique genotypic profiles and emphasize the growing recognition of presentations of APBD in diverse populations with broad neurological manifestations.Conclusion: Collectively, these cases underscore the understanding of APBD as a spectrum disorder existing on the GSD IV phenotypic continuum. We draw attention to the pitfalls of commonly used genetic testing methods when diagnosing APBD and highlight the utility of patient-reported outcome questionnaires in managing this disease.

Rationale & Objective: PRESERVE seeks to provide new knowledge to inform shared decision-making regarding blood pressure (BP) management for pediatric chronic kidney disease (CKD). PRESERVE will compare the effectiveness of alternative strategies for monitoring and treating hypertension on preserving kidney function; expand the National Patient-Centered Clinical Research Network (PCORnet) common data model by adding pediatric- and kidney-specific variables and linking electronic health record data to other kidney disease databases; and assess the lived experiences of patients related to BP management. Study Design: Multicenter retrospective cohort study (clinical outcomes) and cross-sectional study (patient-reported outcomes [PROs]). Setting & Participants: PRESERVE will include approximately 20,000 children between January 2009-December 2022 with mild-moderate CKD from 15 health care institutions that participate in 6 PCORnet Clinical Research Networks (PEDSnet, STAR, GPC, PaTH, CAPRiCORN, and OneFlorida+). The inclusion criteria were ≥1 nephrologist visit and ≥2 estimated glomerular filtration rate (eGFR) values in the range of 30 to 19,000 children with CKD. PRESERVE will (1) expand the PCORnet infrastructure for research in pediatric CKD by adding kidney-specific variables and linking electronic health record data to other kidney disease databases; (2) compare the effectiveness of alternative strategies for monitoring and treating hypertension on preserving kidney function; and (3) assess the lived experiences of patients and caregivers related to blood pressure management.

Background: Unanticipated difficult intubation poses a challenge in routine practice for anaesthesiologists. A preoperative airway evaluation helps in the identification of a difficult airway. Airway assessment with ultrasound is a modality recently being used to predict difficult airway. In this study we evaluate ultrasonography parameters with conventional clinical parameters for predicting difficult airway in adults undergoing elective surgeries. Methods: This cross sectional randomised clinical trial analyses ASA class 1 and 2 adults requiring endotracheal intubation for surgeries under general anaesthesia were enrolled following which Modified Mallampatti score and thyromental distance as well as ultrasound distance to epiglottis (DSE) and distance to hyoid bone (DSHB) were measured and based on Cormack Lehane grading they were categorised into easy and difficult airway groups. Results: DSE had the highest sensitivity of 90.48% whereas Modified Mallampatti grading had least sensitivity of 66.67%. Conclusion: The results of this study showed that ultrasonographic measurements at the thyrohyoid and hyoid level have higher sensitivity and specificity than the clinical parameters for airway assessment.

From the continuation of colonial power structures in global economic development institutions, to immigration policies that favor applicants from white-majority European countries, to the use of counter-terrorism law to target primarily Muslim people, international law and its domestic analogues reflect and further inscribe racial distinctions and hierarchies. Racialization in international law occurs in the more visible areas of public decision making but also in mundane, administrative practices. In this essay, I argue that digital technologies are at the heart of automating processes of racialization in international law. Digital technological instruments effectively divide the global population, decision by decision, in adherence to the logics of racial hierarchy: they distribute social and material rights and privileges through financial, welfare, and immigration decisions while simultaneously deepening and entrenching state surveillance, policing, and violence.

Abstract Background Sitting at the interface of gene expression and host-pathogen interaction, polymerase associated factor 1 complex (PAF1C) is a rising player in the innate immune response. The complex localizes to the nucleus and associates with chromatin to modulate RNA polymerase II (RNAPII) elongation of gene transcripts. Performing this function at both proximal and distal regulatory elements, PAF1C interacts with many host factors across such sites, along with several microbial proteins during infection. Therefore, translating the ubiquity of PAF1C into specific impacts on immune gene expression remains especially relevant. Results Advancing past work, we treat PAF1 knockout cells with a slate of immune stimuli to identify key trends in PAF1-dependent gene expression with broad analytical depth. From our transcriptomic data, we confirm PAF1 is an activator of traditional immune response pathways as well as other cellular pathways correlated with pathogen defense. With this model, we employ computational approaches to refine how PAF1 may contribute to both gene activation and suppression. Specifically focusing on transcriptional motifs and regulons, we predict gene regulatory elements strongly associated with PAF1, including those implicated in an immune response. Overall, our results suggest PAF1 is involved in innate immunity at several distinct axes of regulation. Conclusions By identifying PAF1-dependent gene expression across several pathogenic contexts, we confirm PAF1C to be a key mediator of innate immunity. Combining these transcriptomic profiles with potential regulatory networks corroborates the previously identified functions of PAF1C. With this, we foster new avenues for its study as a regulator of innate immunity, and our results will serve as a basis for targeted study of PAF1C in future validation studies.

Importance: Implementation of newborn screening (NBS) in the United States now detects infants with late-onset Pompe disease (LOPD), a lysosomal storage disease characterized by slowly progressive muscle weakness, and detailed clinical evaluation has identified early muscle weakness. Biomarkers may be uninformative; thus, non-invasive imaging is needed to assess early LOPD muscle changes. Muscle ultrasound (US) measuring echointensity (EI) is a non-invasive measure of muscle health. Objective: In this study, we aimed to evaluate if EI can identify characteristic patterns of muscle involvement in LOPD patients identified by NBS. Design/setting: Prospective, cross-sectional, single time point study. Setting: One-center study. Participants: We examined 20 infants with NBS-identified LOPD (ages 5–20 months). All had standardized physical therapy assessments. Exposures: Creatine Kinase (CK) and Urine Hexose Tetrasaccharide (Glc4) were obtained. Muscle US of deltoid, biceps brachii, forearm flexors, thoracic paraspinals, gluteus maximus, quadriceps, tibialis anterior and medial gastrocnemius was performed. Main outcomes and measures: Mean EI was calculated for all involved muscle groups. Quantitative EI Sum Scores were calculated as total EI divided by number of muscle groups assessed. We performed a comprehensive literature review to compare our results to previous LOPD muscle ultrasound studies. Results: Six of 20 participants had elevated CK and 15 had ≥50% of the most common concerning kinematic physical findings; with normal urine Glc4 in all except one. Based upon muscle EI, the most affected muscles were quadriceps and medial gastrocnemius, with notable elevated EI in thoracic paraspinals. Biceps brachii was the most frequently affected upper extremity muscle. EI sum scores correlated moderately with increasing CK. Statistically significant positive correlation was found between posterior pelvic tilt in sitting and EI of gluteus maximus. Sonographic pattern of muscle involvement was similar to previous studies assessing older patients with LOPD. Conclusions and relevance: In this study, muscle EI was elevated most often in the quadriceps, tibialis anterior, medial gastrocnemius, thoracic paraspinals, and biceps brachii. Involved muscles generally fit the profile of physical and muscle ultrasound/MRI exam findings in LOPD patients. Muscle ultrasound is recommended for rapid, focused muscle assessment in LOPD, especially those identified via NBS. Future studies should focus on this pattern of ultrasonographic abnormality and changes over time.

A late-onset Pompe disease patient developed high sustained antibody titers (HSAT) of ≥51,200 after 11+ years on alglucosidase alfa and previous tolerance. There was a corresponding worsening of motor function and rise in urinary glucose tetrasaccharide (Glc4). Following immunomodulation therapy, HSAT were eliminated with improved clinical outcomes and biomarker trends. This report highlights the importance of continued surveillance of antibody titers and biomarkers, the negative impact of HSAT, and improved outcomes with immunomodulation therapy.

Agriculture is the backbone of Indian Economy. Proper forecast of food crops and cash crops are necessary for the government in policy making decisions. The present paper aims to forecast Wheat and Sugarcane yield using Random Forest Regression. For the development of Random Forest models, Yield has been taken as dependent variable and variables like Gross Cropped Area, Maximum Temperature, Minimum Temperature, Rainfall, Nitrogen, Phosphorous Oxide, Potassium Oxide, Minimum Support Price and Area under Irrigation are taken as independent variables for both Wheat and Sugarcane crop. Values of R2 for Wheat and Sugarcane is 0.995 and 0.981 which indicates that the model is a good fit and other performance measures are calculated and results are satisfactory.

Weather has a profound influence on crop growth, development and yield. The present study deals with the use of weather parameters for sugarcane yield forecasting. Machine learning techniques like K- Nearest Neighbors (KNN) and Random Forest model have been used for sugarcane yield forecasting. Weather parameters namely maximum temperature and minimum temperature, rainfall, relative humidity in the morning and evening, sunshine hours, evaporation along with sugarcane yield have been used as inputs variables. The performance metrics like R2, Mean Square Error (MSE), Mean Absolute Error (MAE), Root Mean Square Error (RMSE), Mean Absolute Percentage Error (MAPE) have been used to select the best model for predicting the yield of the crop. Among the models, Random Forest algorithm is selected as the best fit based on the high R2 and minimum error values. The results indicate that among the weather variables, rainfall and relative humidity in the evening have significant influence on sugarcane yield.

Abstract Background The clinical signs and symptoms of hypophosphatasia (HPP) can manifest during any stage of life. The age at which a patient’s symptoms are reported can impact access to targeted treatment with enzyme replacement therapy (asfotase alfa), as this treatment is indicated for patients with pediatric-onset HPP in most countries. As such, many patients reported to have adult-onset HPP typically do not receive treatment. Comparison of the disease in treated and untreated adult patients is confounded by the approved indication. To avoid this confounding factor, a comparison between baseline disease manifestations prominent among treated versus untreated adult patients was limited to those with pediatric-onset HPP using data collected from the Global HPP Registry. The hypothesis was that treated adults will have a greater disease burden at baseline than untreated adults. The analysis of disease manifestations in adults with adult-onset HPP was conducted separately. Results A total of 398 adults with HPP were included; 213 with pediatric-onset (114 treated, 99 untreated) and 141 with adult-onset HPP (2 treated and 139 untreated). The treated, pediatric-onset patients were more likely to have a history of pain (prevalence ratio [PR]: 1.3, 95% confidence interval [CI] 1.1, 1.4), skeletal (PR: 1.3, 95% CI 1.1, 1.6), constitutional/metabolic (PR: 1.7, 95% CI 1.3, 2.0), muscular (PR: 1.8, 95% CI 1.4, 2.1) and neurological (PR: 1.7, 95% CI 1.1, 2.3) manifestations of HPP, and also had poorer measures for health-related quality of life, pain, and disability compared with untreated pediatric-onset patients. In patients with adult-onset HPP, the most frequent signs and symptoms were chronic bone pain (52.5%), dental manifestations (42.6%), fatigue (23.4%), recurrent fractures or pseudofractures (22.0%), and generalized body pain (22.0%). Conclusions Along with the more classical skeletal signs and symptoms, pain, muscular, and constitutional/metabolic manifestations are common in adults with HPP, regardless of age of disease onset, highlighting a full spectrum of HPP manifestations.

Summary: Sensing the ionic content of a solution at high spatial and temporal resolution and sensitivity is a challenge in nanosensing. This paper describes a comprehensive investigation of the possibility of GHz ultrasound acoustic impedance sensors to sense the content of an ionic aqueous medium. At the 1.55 GHz ultrasonic frequency used in this study, the micron-scale wavelength and the decay lengths in liquid result in a highly localized sense volume with the added potential for high temporal resolution and sensitivity. The amplitude of the back reflected pulse is related to the acoustic impedance of the medium and a function of ionic species concentration of the KCl, NaCl, and CaCl2 solutions used in this study. A concentration sensitivity as high as 1 mM and concentration detection range of 0 to 3 M was achieved. These bulk acoustic wave pulse-echo acoustic impedance sensors can also be used to record dynamic ionic flux.

BackgroundFocal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease requiring kidney transplantation and can recur in the allograft in 30-80% of recipients resulting in reduced graft survival. Plasmapheresis has shown efficacy in treating some cases of recurrent FSGS but isolated plasmapheresis has not demonstrated efficacy in preventing recurrent FSGS. Rituximab has had anecdotal success in preventing recurrence in a single center study but has not been studied in combination with plasmapheresis for preventing FSGS recurrence.MethodsWe are conducting a randomized, controlled, multicenter clinical trial of adult and pediatric kidney transplant recipients with primary FSGS to assess whether plasmapheresis in combination with rituximab prevents recurrent disease post-transplantation.DiscussionRituximab combined with plasmapheresis is a promising, novel therapy to prevent recurrent FSGS, a disease with limited therapeutic options and no consensus guidelines for prevention or treatment.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT03763643, identifier NCT03763643.

Metabolism is key to cellular processes that underlie the ability of a virus to productively infect. Polyamines are small metabolites vital for many host cell processes including proliferation, transcription, and translation. Polyamine depletion also inhibits virus infection via diverse mechanisms, including inhibiting polymerase activity and viral translation. We showed that Coxsackievirus B3 (CVB3) attachment requires polyamines; however, the mechanism was unknown. Here, we report polyamines' involvement in translation, through a process called hypusination, promotes expression of cholesterol synthesis genes by supporting SREBP2 synthesis, the master transcriptional regulator of cholesterol synthesis genes. Measuring bulk transcription, we find polyamines support expression of cholesterol synthesis genes, regulated by SREBP2. Thus, polyamine depletion inhibits CVB3 by depleting cellular cholesterol. Exogenous cholesterol rescues CVB3 attachment, and mutant CVB3 resistant to polyamine depletion exhibits resistance to cholesterol perturbation. This study provides a novel link between polyamine and cholesterol homeostasis, a mechanism through which polyamines impact CVB3 infection.

Abstract Background There are currently no pharmacological therapies to address the intellectual disability associated with Down syndrome. Excitatory/inhibitory imbalance has been hypothesized to contribute to impairments in cognitive functioning in Down syndrome. Negative modulation of the GABAA-α5 receptor is proposed as a mechanism to attenuate GABAergic function and restore the excitatory/inhibitory balance. Methods Basmisanil, a selective GABAA-α5 negative allosteric modulator, was evaluated at 120 mg or 240 mg BID (80 or 160 mg for 12–13 years) in a 6-month, randomized, double-blind, placebo-controlled phase II trial (Clematis) for efficacy and safety in adolescents and young adults with Down syndrome. The primary endpoint was based on a composite analysis of working memory (Repeatable Battery for the Assessment of Neuropsychological Scale [RBANS]) and independent functioning and adaptive behavior (Vineland Adaptive Behavior Scales [VABS-II] or the Clinical Global Impression-Improvement [CGI-I]). Secondary measures included the Behavior Rating Inventory of Executive Functioning-Preschool (BRIEF-P), Clinical Evaluation of Language Fundamentals (CELF-4), and Pediatric Quality of Life Inventory (Peds-QL). EEG was conducted for safety monitoring and quantitatively analyzed in adolescents. Results Basmisanil was safe and well-tolerated; the frequency and nature of adverse events were similar in basmisanil and placebo arms. EEG revealed treatment-related changes in spectral power (increase in low ~ 4-Hz and decrease in high ~ 20-Hz frequencies) providing evidence of functional target engagement. All treatment arms had a similar proportion of participants showing above-threshold improvement on the primary composite endpoint, evaluating concomitant responses in cognition and independent functioning (29% in placebo, 20% in low dose, and 25% in high dose). Further analysis of the individual measures contributing to the primary endpoint revealed no difference between placebo and basmisanil-treated groups in either adolescents or adults. There were also no differences across the secondary endpoints assessing changes in executive function, language, or quality of life. Conclusions Basmisanil did not meet the primary efficacy objective of concomitant improvement on cognition and adaptive functioning after 6 months of treatment, despite evidence for target engagement. This study provides key learnings for future clinical trials in Down syndrome. Trial registration The study was registered on December 31, 2013, at clinicaltrials.gov as NCT02024789.

IntroductionHypophosphatasia (HPP) manifests in adults as fractures/pseudofractures, pain, muscle weakness, and other functional impairments. Better phenotypic disease characterization is needed to help recognize disability and treat patients with HPP.MethodsBaseline/pretreatment demographic, clinical characteristic, and patient-reported disability/health-related quality-of-life (HRQoL) data from adults (≥18 y) in the Global HPP Registry (NCT02306720) were stratified by presence of overt skeletal manifestations (skeletal group) versus muscular/pain manifestations without skeletal manifestations (muscular/pain group) and summarized descriptively. Disability was measured using the Health Assessment Questionnaire–Disability Index (HAQ-DI), and HRQoL using the 36-item Short Form Health Survey (SF-36v2).ResultsOf 468 adults, 300 were classified into the skeletal group and 73 into the muscular/pain group. The skeletal group had a higher median age at baseline (50.1 vs 44.4 y; P=0.047) but a lower median age at first HPP manifestation (12.3 vs 22.1 y; P=0.0473), with more signs and symptoms (median, 4 vs 3; P

Zika virus (ZIKV) infects fetal neural progenitor cells (NPCs) causing severe neurodevelopmental disorders in utero. Multiple pathways involved in normal brain development are dysfunctional in infected NPCs but how ZIKV centrally reprograms these pathways remains unknown. Here we show that ZIKV infection disrupts subcellular partitioning of host transcripts critical for neurodevelopment in NPCs and functionally link this process to the up-frameshift protein 1 (UPF1). UPF1 is an RNA-binding protein known to regulate decay of cellular and viral RNAs and is less expressed in ZIKV-infected cells. Using infrared crosslinking immunoprecipitation and RNA sequencing (irCLIP-Seq), we show that a subset of mRNAs loses UPF1 binding in ZIKV-infected NPCs, consistent with UPF1's diminished expression. UPF1 target transcripts, however, are not altered in abundance but in subcellular localization, with mRNAs accumulating in the nucleus of infected or UPF1 knockdown cells. This leads to diminished protein expression of FREM2, a protein required for maintenance of NPC identity. Our results newly link UPF1 to the regulation of mRNA transport in NPCs, a process perturbed during ZIKV infection.