Longitudinal volumetric analysis of gray matter atrophy in metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disorder characterized by arylsulfatase A (ASA) deficiency, leading to sulfatide accumulation and myelin degeneration in the central nervous system. While primarily considered a white matter (WM) disease, gray matter (GM) is also affected in MLD, and hematopoietic stem cell transplantation (HSCT) may have limited effect on GM atrophy. We cross-sectionally and longitudinally studied GM volumes using volumetric MRI in a cohort of 36 (late-infantile, juvenile and adult type) MLD patients containing untreated and HSCT treated subjects. Cerebrum, cortical GM, (total) CSF, cerebellum, deep gray matter (DGM) (excluding thalamus) and thalamus volumes were analyzed. Longitudinal correlations with measures of cognitive and motor functioning were assessed. Cross-sectionally, juvenile and adult type patients (infantiles excluded based on limited numbers) were compared with controls at earliest scan, before possible treatment. Patients had lower cerebrum, cortical GM, DGM and thalamus volumes. Differences were most pronounced for adult type patients. Longitudinal analyses showed substantial and progressive atrophy of all regions and increase of CSF in untreated patients. Similar, albeit less pronounced, effects were seen in treated patients for cerebrum, cortical GM, CSF and thalamus volumes. Deterioration in motor performance (all patients) was related to atrophy, and increase of CSF, in all regions. Cognitive functioning (data available for treated patients) was related to cerebral, cortical GM and thalamus atrophy; and to CSF increase. Our findings illustrate the importance of recognizing GM pathology as a potentially substantial, clinically relevant part of MLD, apparently less amenable to treatment.

Synthesis of low-k SiONC thin films by plasma-assisted molecular layer deposition with tetraisocyanatesilane and phloroglucinol.

Low-k SiONC thin films with excellent thermal stabilities were deposited using plasma-assisted molecular layer deposition (PA-MLD) with a tetraisocyanatesilane (Si(NCO)4) precursor, N2plasma, and phloroglucinol (C6H3(OH)3). By adjusting the order of the N2plasma exposure steps within the PA-MLD process, we successfully developed a deposition technique that allows accurate control of thickness at the Ångström level via self-limiting reactions. The thicknesses of the thin films were measured through spectroscopic ellipsometry (SE). By tuning the N2plasma power, we facilitated the formation of -NH2sites for phloroglucinol adsorption, achieving a growth per cycle of 0.18 Å cycle-1with 300 W of N2plasma power. Consequently, the thickness of the films increased linearly with each additional cycle. Moreover, the organic linkers within the film formed stable bonds through surface reactions, resulting in a negligible decrease in thickness of approximately -11% even upon exposure to a high annealing temperature of 600 °C. This observation was confirmed by SE, distinguishing the as-prepared film from previously reported low-k films that fail to maintain their thickness under similar conditions. X-ray photoelectron spectroscopy (XPS) and current-voltage (I-V) and capacitance-voltage (C-V) measurement were conducted to evaluate the composition, insulating properties, and dielectric constant according to the deposition and annealing conditions. XPS results revealed that as the plasma power increased from 200 to 300 W, the C/Si ratio increased from 0.37 to 0.67, decreasing the dielectric constant from 3.46 to 3.12. Furthermore, there was no significant difference in the composition before and after annealing, and the hysteresis decreased from 0.58 to 0.19 V owing to defect healing, while maintaining the leakage current density, breakdown field, and dielectric constant. The low dielectric constant, accurate thickness control, and excellent thermal stability of this MLD SiONC thin film enable its application as an interlayer dielectric in back-end-of-line process.

A comprehensive assessment of the economic and technical viability of a zero liquid discharge (ZLD) hybrid desalination system for water and salt recovery.

Brine, a by-product of desalination and industrial facilities, is becoming more and more of an environmental issue. This comprehensive techno-economic assessment (TEA), focusing on the technical and economic aspects, investigates the performance and viability of a novel hybrid desalination brine treatment system known as zero liquid discharge (ZLD). Notably, this research represents the first instance of evaluating the feasibility and effectiveness of integrating three distinct desalination processes, namely brine concentrator (BC), high-pressure reverse osmosis (HPRO), and membrane-promoted crystallization (MPC), within a ZLD framework. The findings of this study demonstrate an exceptional water recovery rate of 97.04%, while the energy requirements stand at a reasonable level of 17.53 kWh/m3. Financially, the ZLD system proves to be at least 3.28 times more cost-effective than conventional evaporation ponds and offers comparable cost efficiency to alternatives such as land application and deep-well injection. Moreover, the ZLD system exhibits profitability potential by marketing both drinking water and solid salt or solely desalinated water. The daily profit from the sale of generated water varies from US$194.08 to US$281.41, with Greece and Cyprus attaining the lowest and highest profit, respectively. When considering the sale of both salt and water, the profit rises by 8% across all locations.

Prioritizing the Best Potential Regions for Brine Concentration Systems in the USA Using GIS and Multicriteria Decision Analysis.

We propose a methodology for identifying and prioritizing the best potential locations for brine concentration facilities in the contiguous United States. The methodology uses a geographic information system and multicriteria decision analysis (GIS-MCDA) to prioritize the potential locations for brine concentration facilities based on thermodynamic, economic, environmental, and social criteria. By integrating geospatial data with a computational simulation of a real brine concentration system, an objective weighting method identifies the weights for 13 subcriteria associated with the main criteria. When considering multiple dimensions for decision making, brine concentration facilities centered in Florida were consistently selected as the best location, due to the high second-law efficiency, low transportation cost, and high capacity for supplying municipal water needs to nearby populations. For inland locations, Southeast Texas outperforms all other locations for thermodynamic, economic, and environmental priority cases. A sensitivity analysis evaluates the consistency of the results as the priority of a main criterion varies relative to other decision-making criteria. Focusing on a single subcriterion misleads decision making when identifying the best location for brine concentration systems, identifying the importance of the multicriteria methodology.

Optimizing Behavioral Interventions to Regulate Gestational Weight Gain With Sequential Decision Policies Using Hybrid Model Predictive Control.

Excessive gestational weight gain is a significant public health concern that has been the recent focus of control systems-based interventions. Healthy Mom Zone (HMZ) is an intervention study that aims to develop and validate an individually-tailored and "intensively adaptive" intervention to manage weight gain for pregnant women with overweight or obesity using control engineering approaches. This paper presents how Hybrid Model Predictive Control (HMPC) can be used to assign intervention dosages and consequently generate a prescribed intervention with dosages unique to each individuals needs. A Mixed Logical Dynamical (MLD) model enforces the requirements for categorical (discrete-level) doses of intervention components and their sequential assignment into mixed-integer linear constraints. A comprehensive system model that integrates energy balance and behavior change theory, using data from one HMZ participant, is used to illustrate the workings of the HMPC-based control system for the HMZ intervention. Simulations demonstrate the utility of HMPC as a means for enabling optimized complex interventions in behavioral medicine, and the benefits of a HMPC framework in contrast to conventional interventions relying on "IF-THEN" decision rules.

Metachromatic leukodystrophy: A single-center longitudinal study of 45 patients.

In this study, we characterize the natural course of metachromatic leukodystrophy (MLD), explore intra/inter group differences, and identify biomarkers to monitor disease progression. This is a longitudinal observational study. Genotype and characteristics at disease onset were recorded. Time-to-event analyses were performed to assess time to major disease-related milestones in different subgroups. Longitudinal trajectories of nerve conduction velocities (NCV), brain MRI score, and brainstem auditory evoked responses (BAERs) were described. We recruited 22 late-infantile, 14 early-juvenile, 5 late-juvenile, and 4 adult MLD patients. Thirty-four were prospectively evaluated (median FU time 43 months). In late-infantile patients, the attainment of independent walking was associated with a later age at dysphagia. In early-juvenile, the presence of isolated cognitive impairment at onset was not a favorable prognostic factor. Late-infantile and early-juvenile subjects showed similar rapid loss of ambulation and onset of seizures, but late-infantile displayed earlier loss of trunk control, dysphagia, and death. We found significant differences in all major disease-related milestones (except death) between early-juvenile and late-juvenile patients. Late-juvenile and adult patients both presented with a predominant cognitive impairment, mild/no peripheral neuropathy, lower brain MRI score at plateau compared to LI/EJ, and later cerebellar involvement. NCV and BAER were consistently severely abnormal in late-infantile but not in older subjects, in whom both NCV and BAER were variably affected, with no deterioration over time in some cases. This study clarifies intra/inter group differences between MLD subtypes and provides additional indications regarding reliable clinical and instrumental tools to monitor disease progression and to serve as areference to evaluate the efficacy of future therapeutic interventions inthe different MLD variants.

Masking level difference among brazilian military personnel: a comparison between pilots and non-pilots.

OBJECTIVES: The aims of this study were to investigate auditory habits and binaural interaction among pilot and non-pilot military personnel from the Brazilian Air Force. DESIGN: A cross-sectional study using (1) an auditory habits questionnaire to outline the groups auditory profile and (2) the masking level difference test (MLD, Auditec, Saint Louis®) to evaluate and compare the groups. STUDY SAMPLE: Forty military male personnel aged between 30-40 years old, all with normal hearing, comprising 20 pilots in the study group (SG), and 20 non-pilots, not exposed to noise, in the control group (CG). RESULTS: There was no significant difference between groups regarding auditory habits. In the MLD test, a significantly better performance under the homophasic condition (S0N0) was found in the SG. Under the antiphasic condition (SπN0) there were no differences between groups. This combination resulted in a significantly lower MLD in the SG compared to the CG. CONCLUSIONS: Repeated exposure to conditions where active pilots have to learn to recognise speech in noisy backgrounds may lead to a better performance in the MLD's homophasic condition (S0N0).

Synthesis and structure-activity relationships of cerebroside analogues as substrates of cerebroside sulphotransferase and discovery of a competitive inhibitor.

Metachromatic leukodystrophy (MLD) is a rare genetic disease characterised by a dysfunction of the enzyme arylsulphatase A leading to the lysosomal accumulation of cerebroside sulphate (sulphatide) causing subsequent demyelination in patients. The enzyme galactosylceramide (cerebroside) sulphotransferase (CST) catalyses the transfer of a sulphate group from 3'-phosphoadenosine-5'-phosphosulphate (PAPS) to cerebrosides producing sulphatides. Substrate reduction therapy for arylsulphatase A by inhibition of CST was proposed as a promising therapeutic approach. To identify competitive CST inhibitors, we synthesised and investigated analogues of the substrate galactosylceramide with variations at the anomeric position, the acyl substituent and the carbohydrate moiety, and investigated their structure-activity relationships. While most of the compounds behaved as substrates, α-galactosylceramide 16 was identified as the first competitive CST inhibitor. Compound 16 can serve as a new lead structure for the development of drugs for the treatment of this devastating disease, MLD, for which small molecule therapeutics are currently not available.

Aerosol infection of Balb/c mice with eastern equine encephalitis virus; susceptibility and lethality.

BACKGROUND: Eastern equine encephalitis virus is an alphavirus that naturally cycles between mosquitoes and birds or rodents in Eastern States of the US. Equine infection occurs by being bitten by cross-feeding mosquitoes, with a case fatality rate of up to 75% in humans during epizootic outbreaks. There are no licensed medical countermeasures, and with an anticipated increase in mortality when exposed by the aerosol route based on anecdotal human data and experimental animal data, it is important to understand the pathogenesis of this disease in pursuit of treatment options. This report details the clinical and pathological findings of mice infected with EEEV by the aerosol route, and use as a model for EEEV infection in humans. METHODS: Mice were exposed by the aerosol route to a dose range of EEEV to establish the median lethal dose. A pathogenesis study followed whereby mice were exposed to a defined dose of virus and sacrificed at time-points thereafter for histopathological analysis and virology. RESULTS: Clinical signs of disease appeared within 2 days post challenge, culminating in severe clinical signs within 24 h, neuro-invasion and dose dependent lethality. EEEV was first detected in the lung 1 day post challenge, and by day 3 peak viral titres were observed in the brain, spleen and blood, corresponding with severe meningoencephalitis, indicative of encephalitic disease. Lethality follows severe neurological signs, and may be linked to a threshold level of virus replication in the brain. Effective medical countermeasures for EEEV may necessitate early inoculation to inhibit infection of the brain in zoonotic incidents, and be able to traverse the blood-brain barrier to sufficiently interrupt replication in the brain in cases of aerosol infection. CONCLUSIONS: There is little human data on the hazard posed by aerosol infection with encephalitic alphaviruses, and use of EEEV as a bioweapon may be by the aerosol route. A well characterized model of aerosol exposure that recapitulates some of the most severe human clinical features is necessary to evaluate the efficacy of putative medical countermeasures, and to increase our understanding about how this route of infection induces such rapid neuro-invasion and resulting disease.

Safe and Durable High-Temperature Lithium-Sulfur Batteries via Molecular Layer Deposited Coating.

Lithium-sulfur (Li-S) battery is a promising high energy storage candidate in electric vehicles. However, the commonly employed ether based electrolyte does not enable to realize safe high-temperature Li-S batteries due to the low boiling and flash temperatures. Traditional carbonate based electrolyte obtains safe physical properties at high temperature but does not complete reversible electrochemical reaction for most Li-S batteries. Here we realize safe high temperature Li-S batteries on universal carbon-sulfur electrodes by molecular layer deposited (MLD) alucone coating. Sulfur cathodes with MLD coating complete the reversible electrochemical process in carbonate electrolyte and exhibit a safe and ultrastable cycle life at high temperature, which promise practicable Li-S batteries for electric vehicles and other large-scale energy storage systems.

Myofascial-manual lymphatic drainage for burn trauma: a service evaluation.

Improving microcirculation in the area of a wound is an important aspect of wound healing. It can be improved by a new manual methodology: myofascial-manual lymphatic drainage (M-MLD). This hybrid technique uses elements of musculoskeletal medicine and manual lymphatic drainage. Through palpation, M-MLD therapeutically affects the functional pathology of soft tissues, with reflection in trigger points, and also the functional pathology of lymphatic system, namely by lymphostasis in particular regional lymph nodes. Most cases of post-traumatic and postoperative conditions lead to dynamic insufficiency of the venous system and subsequently of the lymphatic system. If this is not treated promptly, it can lead to secondary post-traumatic lymphoedema. Early M-MLD treatment eliminates the development of secondary post traumatic lymphoedema and even secondary inflammation, thus decreasing the risk of cicatrix hypertrophy and contributing to faster wound healing and better regeneration of the afflicted area. Laboratory immunological examination of circulating immune complexes support 20 years of the authors' empirical experience. The level of circulating immune complexes before M-MLD reached constant values. After manual influencing of the functional pathology of soft tissue and lymphatic system, the dynamics of circulating immune complexes levels was observed, this is the effect of the improvement of microcirculation in the wound area. M-MLD is time- and cost-saving, but it requires professional training with a very good palpation technique. In the authors' experience, its use is indicated within 2-24 hours from the time of trauma (surgery), and then once a day until healing is achieved. This early manual therapeutic treatment can be delivered not only by physiotherapists, but also nurses working to encourage wound healing, such as in traumatology, surgery and orthopaedics. Using M-MLD makes the total treatment time shorter, and has an economical, biopsychosocial and society-wide impact.

Antibacterial Properties of Tebipenem Pivoxil Tablet, a New Oral Carbapenem Preparation against a Variety of Pathogenic Bacteria in Vitro and in Vivo.

AIMS: To systemically investigate the in vitro and in vivo antibacterial properties of tebipenem pivoxil tablet. In addition, acute toxicity of this preparation was also studied. METHODS: In vitro, minimum inhibitory concentration (MIC) or minimal inhibitory concentration (MBC) were determined by using the serial 2-fold broth or agar dilution methods. Further, cumulative MIC inhibition curves were then made to assess the antibacterial effects of the drug at various concentrations. In vivo, minimum lethal dose (MLD) in combination with maximum tolerance dose (MTD) was used to measure the acute toxicity of the tebipenem pivoxil tablet in mice. After that, sepsis mouse models challenged with Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae, respectively, were established to evaluate the anti-infective effect of this preparation. RESULTS: The MIC90 values of tebipenem pivoxil against Gram-positive bacteria such as methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), methicillin-sensitive Staphylococcus epidermidis (MSSE), methicillin-resistant Staphylococcus epidermidis (MRSE), Pyogenic streptococcus, and Enterococcus faecalis were ≤ 0.125, 16, 0.5, 8, ≤ 0.125, and 32 µg/mL, respectively. Correspondingly, the MIC90 values of tebipenem pivoxil against Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Haemophilus influenzae, Pseudomonas aeruginosa, and Acinetobacter baumannii were 1, 0.5, ≤ 0.125, 0.25, 64, 64 µg/mL, respectively. The MBC values of tebipenem pivoxil against Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae were 0.016-2, 0.063-32, 0.031-32 µg/mL, respectively. The acute toxicity study showed that the MLD of the tebipenem pivoxil tablet was 4.00 g/kg and the MTD was 3.40 g/kg in mice. In all the sepsis mouse models, the simultaneous administration of the tebipenem pivoxil tablets significantly reduced mortality of the sepsis-model mice as compared with the control. Furthermore, the survival rate in the tebipenem pivoxil tablet group was remarkably higher than that in the meropenem group in all the sepsis mouse models tested. In the sepsis model challenged with Staphylococcus aureus ATCC29213, Escherichia coli ATCC25922, Pseudomonas aeruginosa ATCC27853, and Pseudomonas aeruginosa clinical strain, respectively, tebipenem pivoxil tablet (100 mg/kg) displayed a better protective effect than tebipenem pivoxil granules (100 mg/kg). CONCLUSIONS: In summary, tebipenem pivoxil displays an excellent antibacterial activity against a variety of pathogenic bacteria in vitro. Importantly, tebipenem pivoxil tablet significantly protects the sepsis mice challenged with various pathogenic bacteria, which may provide a potential approach to treating bacterial sepsis in clinic.

Improving the latency for 5G/B5G based smart healthcare connectivity in rural area.

Smart hospitals are poised to greatly enhance life quality by offering persistent health monitoring capabilities. Remote healthcare and surgery, which are highly dependent on low latency, have seen a transformative improvement with the advent of 5G technology. This has facilitated a new breed of healthcare services, including monitoring and remote surgical procedures. The enhanced features of 5G, such as Enhanced Mobile Broadband (eMBB) and Ultra-Reliable Low Latency Communications (URLLC), have enabled the development of advanced healthcare systems. These systems reduce the need for direct patient contact in hospitals, which is especially pertinent as 5G becomes more widespread. This research presents novel hybrid detection algorithms, specifically QR decomposition with M-algorithm maximum likelihood-minimum mean square error (QRM-MLD-MMSE) and QRM-MLD-ZF (zero forcing), for use in Massive MIMO (M-MIMO) technology. These methods aim to decrease the latency in MIMO-based Non-Orthogonal Multiple Access (NOMA) waveforms while ensuring optimal bit error rate (BER) performance. We conducted simulations to evaluate parameters like BER and power spectral density (PSD) over Rician and Rayleigh channels using both the proposed hybrid and standard algorithms. The study concludes that our hybrid algorithms significantly enhance BER and PSD with lower complexity, marking a substantial improvement in 5G communication for smart healthcare applications.

Manual lymphatic drainage before and after total knee arthroplasty, a randomized controlled trial.

Purpose: Manual lymphatic drainage (MLD) is a routine therapeutic technique used to decrease peripheral oedema by activating lymphatic drainage. Evidence for its efficacy remains sparse. Therefore, the purpose of this study was to evaluate the effect of MLD before and after total knee arthroplasty (TKA). Methods: This was a single-centre randomized, controlled and observer-blinded trial. 112 patients were randomly assigned to one of three groups: group 1 underwent MLD for 30 min daily on five consecutive days both before and after TKA; group 2 underwent MLD for 30 min daily on five consecutive days only after TKA; and the control group did not undergo MLD. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, range of knee motion, swelling and pain were assessed before TKA, after two days, five days and six weeks. Results: The overall age of the patients was 69.4 years (SD = 9.8, range = 41-87). The groups were well matched in terms of sex, age, height, weight, and body mass index. There was no statistically significant difference with regard to any of the outcome measures between the groups. Conclusions: The present results indicate that MLD had no significant benefits when applied either before or early after TKA. Therefore, we do not recommend the routinely use of MLD in the early period before or after TKA. Further studies should evaluate the effect of MLD after arthroscopic surgery. Level of evidence: Therapeutic Level II, Lower quality RCT with follow up <80.

Phytoconstituents of Withania somnifera (L.) Dunal (Ashwagandha) unveiled potential cerebroside sulfotransferase inhibitors: insight through virtual screening, molecular dynamics, toxicity, and reverse pharmacophore analysis.

Cerebroside sulfotransferase (CST) is considered as therapeutic target for substrate reduction therapy (SRT) for metachromatic leukodystrophy (MLD). The present study evaluates the therapeutic potential of 57 phytoconstituents of Withania somnifera against CST. Using binding score cutoff ≤-7.0 kcal/mol, top 10 compounds were screened and after ADME and toxicity-based screening, Withasomidienone, 2,4-methylene-cholesterol, and 2,3-Didehydrosomnifericin were identified as safe and potent drug candidates for CST inhibition. Key substrate binding site residues involved in interaction were LYS82, LYS85, SER89, TYR176, PHE170, PHE177. Four steroidal Lactone-based withanolide backbone of these compounds played a critical role in stabilizing their position in the active site pocket. 100 ns molecular dynamics simulation and subsequent trajectory analysis through structural deviation and compactness, principal components, free energy landscape and correlation matrix confirmed the stability of CST-2,3-Didehydrosomnifericin complex throughout the simulation and therefore is considered as the most potent drug candidate for CST inhibition and Withasomidienone as the second most potent drug candidate. The reverse pharmacophore analysis further confirmed the specificity of these two compounds towards CST as no major cross targets were identified. Thus, identified compounds in this study strongly present their candidature for oral drug and provide route for further development of more specific CST inhibitors.

Complex genotypes in family with metachromatic leukodystrophy: Effect of trans and cis mutations distribution on the phenotype variability.

Metachromatic leukodystrophy (MLD) is a severe metabolic disorder caused by the deficient activity of arylsulfatase A due to ARSA gene mutations. According to the age of onset, MLD is classified into three forms: infantile, juvenile, and adult. In our study, we aimed to perform a genetic analysis for two siblings with juvenile MLD for a better characterization of the molecular mechanisms behind the disease. A consanguineous family including two MLD patients (PII.1 and PII.2) was enrolled in our study. The diagnosis was made based on the clinical and neuroimaging investigations. The sequencing of ARSA gene was performed followed by in silico analysis. Besides, the cis/trans distribution of the variants was verified through a PCR-RFLP. The ARSA gene sequencing revealed three known variants, two exonic c.1055A > G and c.1178C > G and an intronic one (c.1524 + 95A > G) in the 3'UTR region. All variants were present at heterozygous state in the two siblings and their mother. The assessment of the cis/trans distribution showed the presence of these variants in cis within the mother, while PII.2 and PII.2 present the c.1055A > G/c.1524 + 95A > G and the c.1178C > G in trans. Additionally, PII.1 harbored a de novo novel missense variant c.1119G > T, whose pathogenicity was supported by our predictive results. Our genetic findings, supported by a clinical examination, confirmed the affection of the mother by the adult MLD. Our results proved the implication of the variable distribution of the found variants in the age of MLD onset. Besides, we described a variable severity between the two siblings due to the de novo pathogenic variant. In conclusion, we identified a complex genotype of ARSA variants within two MLD siblings with a variable severity due to a de novo variant present in one of them. Our results allowed the establishment of an adult MLD diagnosis and highlighted the importance of an assessment of the trans/cis distribution in the cases of complex genotypes.

Evaluation of enzyme activity predictions for variants of unknown significance in Arylsulfatase A.

Continued advances in variant effect prediction are necessary to demonstrate the ability of machine learning methods to accurately determine the clinical impact of variants of unknown significance (VUS). Towards this goal, the ARSA Critical Assessment of Genome Interpretation (CAGI) challenge was designed to characterize progress by utilizing 219 experimentally assayed missense VUS in the Arylsulfatase A (ARSA) gene to assess the performance of community-submitted predictions of variant functional effects. The challenge involved 15 teams, and evaluated additional predictions from established and recently released models. Notably, a model developed by participants of a genetics and coding bootcamp, trained with standard machine-learning tools in Python, demonstrated superior performance among submissions. Furthermore, the study observed that state-of-the-art deep learning methods provided small but statistically significant improvement in predictive performance compared to less elaborate techniques. These findings underscore the utility of variant effect prediction, and the potential for models trained with modest resources to accurately classify VUS in genetic and clinical research.

Single-Level Unilateral Biportal Endoscopic versus Tubular Microdiscectomy: Comparing Surgical Outcomes and Opioid Consumption.

BACKGROUND: Unilateral biportal endoscopic (UBE) microdiscectomy is an emerging minimally invasive surgery technique for treating symptomatic lumbar disc herniation. There is limited literature regarding outcomes. Here, we assess surgical outcomes and pain medication consumption for UBE vs. tubular lumbar microdiscectomy. METHODS: This was a retrospective cohort study of adult patients undergoing primary, single-level UBE or tubular lumbar microdiscectomy surgery at a high-volume institution between 2018 and 2023. Variables of interest included operative time, complications and reoperations, as well as postoperative opioid and nonopioid pain medication consumption from discharge to 6 months. Opioid consumption was converted to morphine milligram equivalents. Standard statistical analyses were performed for comparative analyses. RESULTS: One hundred two patients-48 UBE and 54 tubular-were included. Average operative time (minutes) was higher for UBE patients (133.1 UBE vs. 86.6 tubular, P < 0.001), which trended downward over time but did not reach statistical significance (P = 0.07). There were no differences in complication or reoperation rates. Average daily MME was lower from discharge to 2-week follow-up in the UBE group (11.1 v. 14.1, P = 0.02), but were comparative thereafter. Nonopioid medication prescription was lower in the UBE cohort from discharge to 2 weeks (70.8% vs. 92.6%, P = 0.01) and 2 to 6 weeks (52.1% vs. 85.2%, P < 0.001), with no significant differences thereafter. CONCLUSIONS: UBE microdiscectomy is associated with longer operating times. Both opioid and nonopioid pain medication consumption were lower for UBE patients during the initial postoperative period, perhaps owing to the less-invasive nature of the surgery.

Exploring the Cost-Effectiveness of Newborn Screening for Metachromatic Leukodystrophy (MLD) in the UK.

Metachromatic leukodystrophy (MLD) is a fatal inherited lysosomal storage disease that can be detected through newborn bloodspot screening. The feasibility of the screening assay and the clinical rationale for screening for MLD have been previously demonstrated, so the aim of this study is to determine whether the addition of screening for MLD to the routine newborn screening program in the UK is a cost-effective use of National Health Service (NHS) resources. A health economic analysis from the perspective of the NHS and Personal Social Services was developed based on a decision-tree framework for each MLD subtype using long-term outcomes derived from a previously presented partitioned survival and Markov economic model. Modelling inputs for parameters related to epidemiology, test characteristics, screening and treatment costs were based on data from three major UK specialist MLD hospitals, structured expert opinion and published literature. Lifetime costs and quality-adjusted life years (QALYs) were discounted at 1.5% to account for time preference. Uncertainty associated with the parameter inputs was explored using sensitivity analyses. This health economic analysis demonstrates that newborn screening for MLD is a cost-effective use of NHS resources using a willingness-to-pay threshold appropriate to the severity of the disease; and supports the inclusion of MLD into the routine newborn screening programme in the UK.

The natural history and burden of illness of metachromatic leukodystrophy: a systematic literature review.

BACKGROUND: Metachromatic leukodystrophy (MLD; OMIM 250100 and 249900) is a rare lysosomal storage disease caused by deficient arylsulfatase A activity, leading to accumulation of sulfatides in the nervous system. This systematic literature review aimed to explore the effect of MLD on the lives of patients. METHODS: The Ovid platform was used to search Embase, MEDLINE, and the Cochrane Library for articles related to the natural history, clinical outcomes, and burden of illness of MLD; congress and hand searches were performed using 'metachromatic leukodystrophy' as a keyword. Of the 531 publications identified, 120 were included for data extraction following screening. A subset of findings from studies relating to MLD natural history and burden of illness (n = 108) are presented here. RESULTS: The mean age at symptom onset was generally 16-18 months for late-infantile MLD and 6-10 years for juvenile MLD. Age at diagnosis and time to diagnosis varied widely. Typically, patients with late-infantile MLD presented predominantly with motor symptoms and developmental delay; patients with juvenile MLD presented with motor, cognitive, and behavioral symptoms; and patients with adult MLD presented with cognitive symptoms and psychiatric and mood disorders. Patients with late-infantile MLD had more rapid decline of motor function over time and lower survival than patients with juvenile MLD. Commonly reported comorbidities/complications included ataxia, epilepsy, gallbladder abnormalities, incontinence, neuropathy, and seizures. CONCLUSIONS: Epidemiology of MLD by geographic regions, quantitative cognitive data, data on the differences between early- and late-juvenile MLD, and humanistic or economic outcomes were limited. Further studies on clinical, humanistic (i.e., quality of life), and economic outcomes are needed to help inform healthcare decisions for patients with MLD.