Wilhelm Keller MD (1818-1877) and the emergence of xenobiochemistry.

Although there had been many previous inklings, the field of xenobiotic metabolism (as we know it today) began with an experiment reported in the 1841 literature proclaiming that the ingestion of benzoic acid led to the subsequent excretion of hippuric acid in human urine. A metabolic transformation undertaken by a living organism. One worker involved in the early stages of this discovery was Wilhelm Keller, although very little information about him is readily available. Hopefully, this article will go some way to counter this dearth and also highlight Keller's pioneering contribution in the development of the fields of drug metabolism and xenobiochemistry.

A Systematic Literature Review of the Natural History of Respiratory, Swallowing, Feeding, and Speech Functions in Spinal Muscular Atrophy (SMA).

Background: Respiratory and bulbar dysfunctions (including swallowing, feeding, and speech functions) are key symptoms of spinal muscular atrophy (SMA), especially in its most severe forms. Demonstrating the long-term efficacy of disease-modifying therapies (DMTs) necessitates an understanding of SMA natural history. Objective: This study summarizes published natural history data on respiratory, swallowing, feeding, and speech functions in patients with SMA not receiving DMTs. Methods: Electronic databases (Embase, MEDLINE, and Evidence-Based Medicine Reviews) were searched from database inception to June 27, 2022, for studies reporting data on respiratory and/or bulbar function outcomes in Types 1-3 SMA. Data were extracted into a predefined template and a descriptive summary of these data was provided. Results: Ninety-one publications were included: 43 reported data on respiratory, swallowing, feeding, and/or speech function outcomes. Data highlighted early loss of respiratory function for patients with Type 1 SMA, with ventilatory support typically required by 12 months of age. Patients with Type 2 or 3 SMA were at risk of losing respiratory function over time, with ventilatory support initiated between the first and fifth decades of life. Swallowing and feeding difficulties, including choking, chewing problems, and aspiration, were reported in patients across the SMA spectrum. Swallowing and feeding difficulties, and a need for non-oral nutritional support, were reported before 1 year of age in Type 1 SMA, and before 10 years of age in Type 2 SMA. Limited data relating to other bulbar functions were collated. Conclusions: Natural history data demonstrate that untreated patients with SMA experience respiratory and bulbar function deterioration, with a more rapid decline associated with greater disease severity. This study provides a comprehensive repository of natural history data on bulbar function in SMA, and it highlights that consistent assessment of outcomes in this area is necessary to benefit understanding and approval of new treatments.

Computer Hexapod-assisted Orthopaedic Surgery for the Correction of Multiplanar Deformities throughout the Lower Limb.

Introduction: Computerised hexapod-assisted orthopaedic surgery (CHAOS) is a method by which complex multiplanar, multilevel deformity can be corrected with a high degree of accuracy utilising minimally invasive techniques within a single operative event. This study's aim was to report the reliability, accuracy and magnitude of correction achieved, alongside patient-reported outcomes and risk factors for complications when using the CHAOS technique throughout the lower limb. Materials and methods: Retrospective review of medical records and radiographs for consecutive patients who underwent CHAOS for lower limb deformity correction at a tertiary centre between 2012 and 2020. Results: There were 70 cases in 56 patients, with the site of surgery being the femur in 48 cases, proximal tibia in 17 and distal tibia in 5 cases. Multiplanar correction was performed in 43 cases, and multilevel osteotomy was undertaken in 23 cases. Fixation was undertaken with intramedullary nailing (IMN) in 49 cases and locked plates in 21.The maximum corrections were 40° rotation, 20° coronal angulation, 51° sagittal angulation and 62-mm mechanical axis deviation (MAD). Deformity correction was mechanically satisfactory in all patients bar one who was undercorrected requiring revision. The mean patient global impression of change (PGIC) score was 6.2 out of 7.Overall complication rate was 12/70 (17%). Complications from femoral surgery included two nonunions, one case of undercorrection, one case of stiffness, one muscle hernia and one pulmonary embolism. Complications from tibial surgery were one compartment syndrome, one pseudoaneurysm of the anterior tibial artery requiring stenting, one transient neurapraxia of the common peroneal nerve, one locking plate fatigue failure, one seroma and one superficial wound infection. Conclusion: Computerised hexapod-assisted orthopaedic surgery can be used for accurate correction of complex multilevel and multiplanar deformities of both the femur and tibia. The risk profile appears to differ between femoral and tibial surgeries, and also to that of traditional circular frame correction. Patients remain highly satisfied with both the functional and symptomatic outcomes. How to cite this article: French JMR, Filer J, Hogan K, et al. Computer Hexapod-assisted Orthopaedic Surgery for the Correction of Multiplanar Deformities throughout the Lower Limb. Strategies Trauma Limb Reconstr 2024;19(1):9-14.

Non-invasive methods of monitoring Fe3O4 magnetic nanoparticle toxicity in human liver HepaRG cells using impedance biosensing and Coherent anti-Stokes Raman spectroscopic (CARS) microscopy.

Functionalized nanoparticles have been developed for use in nanomedicines for treating life threatening diseases including various cancers. To ensure safe use of these new nanoscale reagents, various assays for biocompatibility or cytotoxicity in vitro using cell lines often serve as preliminary assessments prior to in vivo animal testing. However, many of these assays were designed for soluble, colourless materials and may not be suitable for coloured, non-transparent nanoparticles. Moreover, cell lines are not always representative of mammalian organs in vivo. In this work, we use non-invasive impedance sensing methods with organotypic human liver HepaRG cells as a model to test the toxicity of PEG-Fe3O4 magnetic nanoparticles. We also use Coherent anti-Stokes Raman Spectroscopic (CARS) microscopy to monitor the formation of lipid droplets as a parameter to the adverse effect on the HepaRG cell model. The results were also compared with two commercial testing kits (PrestoBlue and ATP) for cytotoxicity. The results suggested that the HepaRG cell model can be a more realistic model than commercial cell lines while use of impedance monitoring of Fe3O4 nanoparticles circumventing the uncertainties due to colour assays. These methods can play important roles for scientists driving towards the 3Rs principle - Replacement, Reduction and Refinement.

SAGA1 and SAGA2 promote starch formation around proto-pyrenoids in Arabidopsis chloroplasts.

The pyrenoid is a chloroplastic microcompartment in which most algae and some terrestrial plants condense the primary carboxylase, Rubisco (ribulose-1,5-bisphosphate carboxylase/oxygenase) as part of a CO2-concentrating mechanism that improves the efficiency of CO2 capture. Engineering a pyrenoid-based CO2-concentrating mechanism (pCCM) into C3 crop plants is a promising strategy to enhance yield capacities and resilience to the changing climate. Many pyrenoids are characterized by a sheath of starch plates that is proposed to act as a barrier to limit CO2 diffusion. Recently, we have reconstituted a phase-separated "proto-pyrenoid" Rubisco matrix in the model C3 plant Arabidopsis thaliana using proteins from the alga with the most well-studied pyrenoid, Chlamydomonas reinhardtii [N. Atkinson, Y. Mao, K. X. Chan, A. J. McCormick, Nat. Commun. 11, 6303 (2020)]. Here, we describe the impact of introducing the Chlamydomonas proteins StArch Granules Abnormal 1 (SAGA1) and SAGA2, which are associated with the regulation of pyrenoid starch biogenesis and morphology. We show that SAGA1 localizes to the proto-pyrenoid in engineered Arabidopsis plants, which results in the formation of atypical spherical starch granules enclosed within the proto-pyrenoid condensate and adjacent plate-like granules that partially cover the condensate, but without modifying the total amount of chloroplastic starch accrued. Additional expression of SAGA2 further increases the proportion of starch synthesized as adjacent plate-like granules that fully encircle the proto-pyrenoid. Our findings pave the way to assembling a diffusion barrier as part of a functional pCCM in vascular plants, while also advancing our understanding of the roles of SAGA1 and SAGA2 in starch sheath formation and broadening the avenues for engineering starch morphology.

Systematic Literature Review of the Natural History of Spinal Muscular Atrophy: Motor Function, Scoliosis, and Contractures.

BACKGROUND AND OBJECTIVES: Spinal muscular atrophy (SMA) is a progressive neuromuscular disorder associated with continuous motor function loss and complications, such as scoliosis and contractures. Understanding the natural history of SMA is key to demonstrating the long-term outcomes of SMA treatments. This study reviews the natural history of motor function, scoliosis, and contractures in patients with SMA. METHODS: Electronic databases were searched from inception to June 27, 2022 (Embase, MEDLINE, and Evidence-Based Medicine Reviews). Observational studies, case-control studies, cross-sectional studies, and case series reporting on motor function (i.e., sitting, standing, and walking ability), scoliosis, and contracture outcomes in patients with types 1-3 SMA were included. Data on study design, baseline characteristics, and treatment outcomes were extracted. Data sets were generated from studies that reported Kaplan-Meier (KM) curves and pooled to generate overall KM curves. RESULTS: Ninety-three publications were included, of which 68 reported on motor function. Of these, 10 reported KM curves (3 on the probability of sitting in patients with types 2 and 3 SMA and 8 on the probability of walking/ambulation in patients with type 3 SMA). The median time to loss of sitting (95% CI) was 14.5 years (14.1-31.5) for the type 2 SMA sitter population (their maximum ability was independent sitting). The median time to loss of ambulation (95% CI) was 13.4 years (12.5-14.5) for type 3a SMA (disease onset at age younger than 3 years) and 44.2 years (43.0-49.4) for type 3b SMA (disease onset at age 3 years or older). Studies including scoliosis and contracture outcomes mostly reported non-time-to-event data. DISCUSSION: The results demonstrate that a high degree of motor function loss is inevitable, affecting patients of all ages. In addition, data suggest that untreated patients with types 2 and 3 SMA remain at risk of losing motor milestones during late adulthood, and patients with types 3a and 3b SMA are at risk of loss of ambulation over time. These findings support the importance of stabilization of motor function development even at older ages. Natural history data are key for the evaluation of SMA treatments as they contextualize the assessment of long-term outcomes.

Return on investment from service transformation for young people experiencing mental health problems: Approach to economic evaluations in ACCESS Open Minds (Esprits ouverts), a multi-site pan-Canadian youth mental health project.

Introduction: Mental health problems are common globally, and typically have their onset in adolescence and early adulthood-making youth (aged 11-25) an optimal target for prevention and early intervention efforts. While increasing numbers of youth mental health (YMH) initiatives are now underway, thus far few have been subject to economic evaluations. Here we describe an approach to determining the return on investment of YMH service transformation via the pan-Canadian ACCESS Open Minds (AOM) project, for which a key focus is on improving access to mental health care and reducing unmet need in community settings. Approach: As a complex intervention package, it is hoped that the AOM transformation will: (i) enable early intervention through accessible, community-based services; (ii) shift care away toward these primary/community settings and away from acute hospital and emergency services; and (iii) offset at least some of the increased costs of primary care/community-based mental health services with reductions in the volume of more resource-intensive acute, emergency, hospital or specialist services utilized. Co-designed with three diverse sites that represent different Canadian contexts, a return on investment analysis will (separately at each site) compare the costs generated by the intervention, including volumes and expenditures associated with the AOM service transformation and any contemporaneous changes in acute, emergency, hospital or service utilization (vs. historical or parallel comparators). Available data from health system partners are being mobilized to assess these hypotheses. Anticipated results: Across urban, semi-urban and Indigenous sites, the additional costs of the AOM transformation and its implementation in community settings are expected to be at least partially offset by a reduction in the need for acute, emergency, hospital or specialist care. Discussion: Complex interventions such as AOM aim to shift care "upstream": away from acute, emergency, hospital and specialist services and toward community-based programming which is more easily accessible, often more appropriate for early-stage presentations, and more resource-efficient. Carrying out economic evaluations of such interventions is challenging given the constraints of available data and health system organization. Nonetheless, such analyses can advance knowledge, strengthen stakeholder engagement, and further implementation of this public health priority.

Microglia regulate central nervous system myelin growth and integrity.

Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health1, it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFß1-TGFßR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease2,3.

A systematic review of the cost-effectiveness of renal replacement therapies, and consequences for decision-making in the end-stage renal disease treatment pathway.

OBJECTIVES: Comparative economic assessments of renal replacement therapies (RRT) are common and often used to inform national policy in the management of end-stage renal disease (ESRD). This study aimed to assess existing cost-effectiveness analyses of dialysis modalities and consider whether the methods applied and results obtained reflect the complexities of the real-world treatment pathway experienced by ESRD patients. METHODS: A systematic literature review (SLR) was conducted to identify cost-effectiveness studies of dialysis modalities from 2005 onward by searching Embase, MEDLINE, EBM reviews, and EconLit. Economic evaluations were included if they compared distinct dialysis modalities (e.g. in-centre haemodialysis [ICHD], home haemodialysis [HHD] and peritoneal dialysis [PD]). RESULTS: In total, 19 cost-effectiveness studies were identified. There was considerable heterogeneity in perspectives, time horizon, discounting, utility values, sources of clinical and economic data, and extent of clinical and economic elements included. The vast majority of studies included an incident dialysis patient population. All studies concluded that home dialysis treatment options were cost-effective interventions. CONCLUSIONS: Despite similar findings across studies, there are a number of uncertainties about which dialysis modalities represent the most cost-effective options for patients at different points in the care pathway. Most studies included an incident patient cohort; however, in clinical practice, patients may switch between different treatment modalities over time according to their clinical need and personal circumstances. Promoting health policies through financial incentives in renal care should reflect the cost-effectiveness of a comprehensive approach that considers different RRTs along the patient pathway; however, no such evidence is currently available.

Semaglutide 2.4 Mg for the Management of Overweight and Obesity: Systematic Literature Review and Meta-Analysis.

Purpose: Semaglutide has demonstrated safe and effective weight loss for overweight and obesity, including participants with concomitant type 2 diabetes mellitus (T2DM), in randomized placebo-controlled trials (RCTs). We conducted a systematic literature review (SLR) and network meta-analyses (NMA) to compare weekly semaglutide 2.4 mg with pharmacological comparators for weight management in overweight or obesity. Methods: The SLR was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist. NMAs were performed to compare weight change for semaglutide 2.4 mg with comparators using data identified in the SLR. The populations of interest were total population, normal glucose tolerance, non-T2DM, pre-diabetes, and T2DM. Included outcomes were weight change from baseline (CFB, %) at 52 weeks and proportion of participants losing ≥5% baseline fasting body weight at 12 weeks (at full therapeutic dose). Results: The SLR identified 108 RCTs examining non-surgical interventions, of which 41 were considered for inclusion in the NMAs. In all populations, semaglutide 2.4 mg was associated with a greater percentage weight CFB with 52 weeks of treatment versus all available comparators. In all populations, semaglutide was associated with a higher likelihood of participants losing ≥5% of baseline fasting body weight at 12 weeks versus all available comparators. Conclusion: In NMA, semaglutide 2.4 mg demonstrated effective weight loss (≥5%) in the total population and all subpopulations of glucose tolerance versus active comparators. Semaglutide is an effective treatment that may address unmet need in the management of overweight and obesity.

Total Hip Replacement Interrupted by Intraoperative Arrest with a Final Component in Place: A Case Report.

No consensus recommendations exist as to the management of implants exposed during an interrupted total hip arthroplasty (THA). Given the infrequency of such events, documentation of successful outcomes in single case reports aids in decision-making. A 71-year-old male with a history of coronary artery disease and a BMI of 39.5 went into ventricular fibrillation half-way through a THA, after placement of a cementless acetabular component but before femoral preparation could begin. Continuation of the planned arthroplasty was aborted, the patient's wound was packed with sterile sponges and covered with an iodoform dressing, and he was flipped supine for CPR. He returned to the OR 6-hours following his arrest and his arthroplasty was completed with the original acetabular implant left in place. The patient was placed empirically on 2 weeks of IV vancomycin and 3 months of oral doxycycline based on infectious disease recommendations, and healed uneventfully. While validation of our strategy is challenging due to the infrequent nature of this event, it is hoped that this description and discussion may provide a template to those who encounter a similar challenging situation.

Efficacy and safety of VNS therapy or continued medication management for treatment of adults with drug-resistant epilepsy: systematic review and meta-analysis.

Vagus nerve stimulation (VNS) Therapy® is an adjunctive neurostimulation treatment for people with drug-resistant epilepsy (DRE) who are unwilling to undergo resective surgery, have had unsuccessful surgery or are unsuitable for surgery. A systematic review and meta-analysis were conducted to determine the treatment effects of VNS Therapy as an adjunct to anti-seizure medications (ASMs) for the management of adults with DRE. A literature search was performed in August 2020 of the Medline®, Medline® Epub Ahead of Print, Embase, and the Cochrane library databases. Outcomes examined included reduction in seizure frequency, seizure freedom, ASM load, discontinuations, and serious adverse events (SAEs). Comparators included best medical practice, ASMs, low-stimulation or sham VNS Therapy. Four RCTs and six comparative observational studies were identified for inclusion. Against comparators, individuals treated with VNS had a significantly better odds of experiencing a ≥ 50% reduction in seizure frequency (OR: 2.27 [95% CI 1.47, 3.51]; p = 0.0002), a ≥ 75% reduction in seizure frequency (OR: 3.56 [95% CI 1.59, 7.98]; p = 0.002) and a reduced risk for increased ASM load (risk ratio: 0.36 [95% CI 0.21, 0.62]; p = 0.0002). There was no difference in the odds of discontinuation or the rate of SAEs between VNS versus comparators. This meta-analysis demonstrated the benefits of VNS Therapy in people with DRE, which included improvement in seizure frequency without an increase in the rate of SAEs or discontinuations, thereby supporting the consideration of VNS Therapy for people who are not responding to ASMs and those unsuitable or unwilling to undergo surgery.

Systematic Literature Review to Identify Utility Values in Patients with Spinal Muscular Atrophy (SMA) and Their Caregivers.

BACKGROUND: Spinal muscular atrophy (SMA) is a progressive neuromuscular disorder that has a substantial impact on health-related quality of life for patients with SMA and their caregivers. Utility values ('utilities') are used in health economic analyses to incorporate individual or societal perspectives regarding the desirability of health outcomes such as a certain health state or change in health states over time. OBJECTIVES: The primary objective of this systematic literature review (SLR) was to identify published utilities associated with patients with SMA and their caregivers and to determine the extent to which Health Technology Assessment (HTA) requirements of methods used to generate utilities are met. A secondary objective was to broaden the scope to identify utilities associated with other (non-SMA) neuromuscular disorders. METHODS: A comprehensive search to capture published utilities associated with patients with SMA and their caregivers was performed in 2019 and updated in 2021 using several electronic databases in addition to supplementary sources. As we anticipated that few published utilities associated with SMA would be identified, the search also captured utilities for other (non-SMA) neuromuscular disorders that may serve as useful surrogate values for studies of SMA and other rare diseases. Electronic searches were performed in Embase, MEDLINE, Evidence-Based Medicine Reviews, and EconLit via the Ovid platform and were supplemented by searches of the grey literature (reference lists, conference proceedings, global HTA body websites, and other relevant sources). Study eligibility criteria were based on the population, interventions, comparators, and outcomes (PICO) framework. The quality of the full-text publications was assessed using a checklist based on UK National Institute for Health and Care Excellence technical support documents. RESULTS: In total, 14 publications that reported SMA-related patient or caregiver utilities or disutilities met the eligibility criteria to be included in the SLR; the included studies demonstrate the substantial health-related quality-of-life burden of SMA on both patients with SMA and their caregivers. A variety of preference-based measures were used to derive utilities for patients with SMA and their caregivers. Different methods for collecting utility data included patient and proxy assessment of health states using questionnaires, vignette methodologies, structured forms of expert elicitation, and mapped data from results of clinical trials. A range of utilities was reported from both patient- and proxy-reported data, which reflects the degree of disability associated with early- and later-onset SMA. Methods for deriving utilities were assessed with respect to three reference cases from HTA bodies in the UK, the USA, and Canada. None of the 14 publications met the requirements of all three HTA bodies because of differing tariff requirements between countries; one study met the requirements of HTA bodies in Canada and the UK. Also, six studies did not report the method of valuation, which precluded analysis with respect to the HTA reference cases. CONCLUSIONS: This SLR provides a comprehensive repository of the currently available utilities relevant to patients with SMA and their caregivers. This SLR provides recommendations for establishing consensus on the approach to generating utility values for the SMA patient population and their caregivers for health economic decisions.

Meta-Analysis Comparing Apixaban Versus Rivaroxaban for Management of Patients With Nonvalvular Atrial Fibrillation.

To compare the efficacy and safety of apixaban and rivaroxaban for the prevention of stroke in patients with nonvalvular atrial fibrillation (NVAF) by way of a meta-analysis informed by real-world evidence. Systematic review and meta-analysis of observational studies including patients with NVAF on apixaban and rivaroxaban, which reported stroke/systemic embolism and/or major bleeding. Prospero registration number: CRD42021251719. Estimates of relative treatment effect (based on hazard ratios[HRs]) were pooled using the inverse variance method. Fixed-effects and random effect analyses were conducted. Exploratory meta-regression analyses that included study-level covariates were conducted using the metareg (meta-regression) command of Stata Statistical Software: Release 15.1 (College Station, Texas. StataCorp LLC.). Study level covariates explored in the meta-regression analyses were CHA2DS2-VASc and HAS-BLED scores. A total of 10 unique retrospective real-world evidence studies reported comparative estimates for apixaban versus rivaroxaban in patients with NVAF and were included in the meta-analysis. Adjusted HR was 0.88 (95% [confidence interval] CI 0.81 to 0.95), indicating a significantly lower hazard of stroke/systemic embolism associated with apixaban versus rivaroxaban. Pairwise meta-analysis for a major bleeding episode was significantly lower with apixaban compared with rivaroxaban (HR 0.62; 95% CI 0.56 to 0.69), whereas apixaban was associated with a lower risk of gastrointestinal bleeding compared with rivaroxaban (HR 0.57; 95% CI 0.50 to 0.64). In conclusion, this study suggests that patient CHA2DS2-VASc and HAS-BLED scores might be an important factor when selecting which direct oral anticoagulants to use, given the relation these scores have on treatment outcomes. Apixaban is associated with lower rates of both major and gastrointestinal bleeding than rivaroxaban, with no loss of efficacy.

Systematic Literature Review to Assess the Cost and Resource Use Associated with Spinal Muscular Atrophy Management.

BACKGROUND: Spinal muscular atrophy (SMA) is a severe neuromuscular disease that is inherited in an autosomal recessive manner with an estimated incidence of 1 in 10,000 live births. The traditional classification of SMA includes five types (Types 0-4 SMA) based on patient age at disease onset and the highest motor milestone achieved. Spinal muscular atrophy leads to progressive muscle denervation, skeletal muscle atrophy and loss of motor function and ambulation, though phenotypes vary along a disease continuum. Regardless of disease severity, or access to treatment, a multidisciplinary approach to care is required to ease the burden of disease. To date, limited global data exist regarding the cost and resource use associated with SMA management. OBJECTIVE: We planned to perform a systematic literature review to identify studies on cost and healthcare resource use associated with SMA. METHODS: A comprehensive search was conducted in 2019 using several electronic databases in addition to supplementary sources and updated in 2021 in order to capture recently published studies. Electronic searches performed in Embase, MEDLINE, Evidence-Based Medicine Reviews and EconLit via the Ovid platform were supplemented by searches of the grey literature (reference lists, conference proceedings, global Health Technology Assessment body websites and other relevant sources). Study eligibility criteria were based on the population, interventions, comparators and outcomes (PICO) framework. Quality assessment of full-text publications was evaluated with reference to a published checklist. To accommodate heterogeneity across studies including countries, currencies, populations, time units and methods of reporting used, costs were reported in Euros in 2019. RESULTS: A total of 51 publications, comprising 49 unique studies of patients with SMA that met all eligibility criteria were included in the final selection. The publications comprised data from 14 countries and seven additional studies that reported multi-national data. Because of the heterogeneity between the different types of SMA, data were frequently reported separately for individuals with Type 1 or early-onset SMA and for Types 2, 3, and 4 SMA or later-onset SMA. Generally, direct medical costs and resource use were reported to be highest for patients with Type 1 SMA, decreasing incrementally for patients with Type 2 and Type 3 disease. Where cost categories were similar, direct costs were much lower in Europe than in the USA. Indirect costs were primarily associated with informal care, which was a substantial burden on patients and families in terms of both cost and time. Cost drivers were generally found to be dependent on SMA type. CONCLUSIONS: Long-term robust studies are required to fully elucidate the economic burden of SMA. Considering that motor function can vary broadly, especially in Type 2 SMA, it would be beneficial to understand how costs and resource use are affected by different degrees of ambulation. Reporting data in terms of achieved motor function could also mitigate the challenges of comparing global data studies of small populations. Global, regional, and/or local data collection platforms and disease registry networks could play an important role in helping to address current data gaps.

Efficacy of Early Preventive Dental Services in Primary Medical Care Setting: Results From Alabama's 1st Look Program.

Purpose: To evaluate early preventive dental services (PDS) provided by primary care providers (PCPs) in reducing future caries treatments among Alabama Medicaid recipients. Methods: Data from 2009 to 2019 Alabama Medicaid were used to evaluate effectiveness of 1st Look Program on PDS before age three years and incidence of caries treatments after age three years. PDS groups consisted of 1st Look-involved (PDS claims from PCPs), dentist-only (PDS claims from dental providers), and no early fluoride treatment participants (no PDS claims before age three years). Outcomes included frequency and expenditures of fluoride applications, simple restorations, and extensive treatments. Regression models were used to evaluate associations between PDS groups and outcomes while controlling for covariates. Results: Children in 1st Look- involved received more fluoride (3.0 versus 2.1 times; P<0.001) and were applied earlier (12.1 versus 22.9 months old; P<0.001) than dentist-only group. After adjusting for covariates, compared to dentist-only, 1st Look-involved group received earlier fluoride (beta value equals -11.1 months; 95 percent confidence interval [95% CI] equals -11.25 to -10.97) with greater frequency (incident rate ratio equals 1.49; 95% CI equals 1.47 to 1.51). Caries treatment counts were highest in dentist-only followed by 1st Look-involved and no early fluoride treatment groups in both simple restorations (2.7 versus 2.0 versus 0.2 times; P<0.001) and extensive treatments (2.8 versus 2.3 versus 0.2 times; P<0.001), which were consistent after adjusting for covariates. Conclusions: PDS were provided earlier by PCPs in Medicaid-qualified children, with reduced caries treatments on primary teeth, compared to PDS by dental providers only.