A reporter Oropouche virus expressing ZsGreen from the M segment enables pathogenesis studies in mice.

Oropouche fever caused by Oropouche virus (OROV) is a significant zoonosis in Central and South America. Despite its public health significance, we lack high-throughput diagnostics, therapeutics, and a comprehensive knowledge of OROV biology. Reporter viruses are valuable tools to rapidly study virus dynamics and develop neutralization and antiviral screening assays. OROV is a tri-segmented bunyavirus, which makes generating a reporter virus challenging, as introducing foreign elements into the viral genome typically affects fitness. We previously demonstrated that the non-structural gene NSm on the OROV medium (M) segment is non-essential for replication in vitro. Taking advantage of this, we have now generated a recombinant OROV expressing fluorescent protein ZsGreen in place of NSm. This reporter OROV is both stable and pathogenic in IFNAR-/- mice and provides a powerful tool for OROV pathogenesis studies and assay development.IMPORTANCEEmerging and reemerging infectious agents such as zoonotic bunyaviruses are of global health concern. Oropouche virus (OROV) causes recurring outbreaks of acute febrile illness in the Central and South American human populations. Biting midges are the primary transmission vectors, whereas sloths and non-human primates are their reservoir hosts. As global temperatures increase, we will likely see an expansion in arthropod-borne pathogens such as OROV. Therefore, developing reagents to study pathogen biology to aid in identifying druggable targets is essential. Here, we demonstrate the feasibility and use of a fluorescent OROV reporter in mice to study viral dynamics and pathogenesis. We show that this reporter OROV maintains characteristics such as growth and pathogenicity similar to the wild-type virus. Using this reporter virus, we can now develop methods to assist OROV studies and establish various high-throughput assays.

Engineering Nitrogen-Doped Carbon Quantum Dots: Tailoring Optical and Chemical Properties through Selection of Nitrogen Precursors.

The process of N-doping is frequently employed to enhance the properties of carbon quantum dots. However, the precise requirements for nitrogen precursors in producing high-quality N-doped carbon quantum dots (NCQDs) remain undefined. This research systematically examines the influence of various nitrogen dopants on the morphology, optical features, and band structure of NCQDs. The dots are synthesized using an efficient, eco- friendly, and rapid continuous hydrothermal flow technique. This method offers unparalleled control over synthesis and doping, while also eliminating convention-related issues. Citric acid is used as the carbon source, and urea, trizma base, beta-alanine, L-arginine, and EDTA are used as nitrogen sources. Notably, urea and trizma produced NCQDs with excitation-independent fluorescence, high quantum yields (up to 40%), and uniform dots with narrow particle size distributions. Density functional theory (DFT) and time-dependent DFT modelling established that defects and substituents within the graphitic structure have a more significant impact on the NCQDs' electronic structure than nitrogen-containing functional groups. Importantly, for the first time, this work demonstrates that the conventional approach of modelling single-layer structures is insufficient, but two layers suffice for replicating experimental data. This study, therefore, provides essential guidance on the selection of nitrogen precursors for NCQD customization for diverse applications.

Selecting informative patients for phase 2 progressive trials in MS: Design considerations for phase 2 clinical trials in progressive MS.

While relapsing-remitting multiple sclerosis (MS) has many therapeutic options, progressive forms of MS remain largely untreatable. Phase 2 clinical trials are our main tool to advance new treatments for progressive MS. Given the complexities of progressive MS, it will likely require many phase 2 trials to improve its treatment. To conduct informative and efficient phase 2 trials, it is important that such trials are designed in a way that they can identify a successful treatment as quickly and with as few participants as possible. In this topical review, we discuss cohort selection, outcome selection, cohort enrichment, and dosing selection as strategies to optimize the efficiency of phase 2 clinical trials in progressive MS.

InterARTIC: an interactive web application for whole-genome nanopore sequencing analysis of SARS-CoV-2 and other viruses.

MOTIVATION: InterARTIC is an interactive web application for the analysis of viral whole-genome sequencing (WGS) data generated on Oxford Nanopore Technologies (ONT) devices. A graphical interface enables users with no bioinformatics expertise to analyze WGS experiments and reconstruct consensus genome sequences from individual isolates of viruses, such as SARS-CoV-2. InterARTIC is intended to facilitate widespread adoption and standardization of ONT sequencing for viral surveillance and molecular epidemiology. RESULTS: We demonstrate the use of InterARTIC for the analysis of ONT viral WGS data from SARS-CoV-2 and Ebola virus, using a laptop computer or the internal computer on an ONT GridION sequencing device. We showcase the intuitive graphical interface, workflow customization capabilities and job-scheduling system that facilitate execution of small- and large-scale WGS projects on any common virus. AVAILABILITY AND IMPLEMENTATION: InterARTIC is a free, open-source web application implemented in Python that executes best-practice command line workflows from the ARTIC network. The application can be downloaded as a set of pre-compiled binaries that are compatible with all common Linux distributions, Windows with Linux subsystems, MacOSX and ARM systems. All code can be found on GitHub at https://github.com/Psy-Fer/interARTIC/ and documentation can be found at https://github.com/Psy-Fer/interARTIC/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Association of age and inflammatory disease activity in the pivotal natalizumab clinical trials in relapsing-remitting multiple sclerosis.

BACKGROUND: Focal inflammatory disease activity in relapsing-remitting multiple sclerosis (RRMS) diminishes with increasing age. Here we use patient-level data from randomised controlled trials (RCTs) of natalizumab treatment in RRMS to investigate the association of age and inflammatory disease activity. METHODS: We used patient-level data from the AFFIRM (natalizumab vs placebo in relapsing-remitting MS, NCT00027300) and SENTINEL (natalizumab plus interferon beta vs interferon beta in relapsing remitting MS, NCT00030966) RCTs. We determined the proportion of participants developing new T2 lesions, contrast-enhancing lesions (CELs) and relapses over 2 years of follow-up as a function of age, and investigated the association of age with time to first relapse using time-to-event analyses. RESULTS: At baseline, there were no differences between age groups in T2 lesion volume and number of relapses in the year before inclusion. In SENTINEL, older participants had a significantly lower number of CELs. During both trials, the number of new CELs and the proportion of participants developing new CELs were significantly lower in older age groups. The number of new T2 lesions and the proportion of participants with any radiological disease activity during follow-up were also lower in older age groups, especially in the control arms. CONCLUSIONS: Older age is associated with a lower prevalence and degree of focal inflammatory disease activity in treated and untreated RRMS. Our findings inform the design of RCTs, and suggest that patient age should be taken into consideration when deciding on immunomodulatory treatment in RRMS.

Relapse recovery in relapsing-remitting multiple sclerosis: An analysis of the CombiRx dataset.

BACKGROUND: Clinical relapses are the defining feature of relapsing forms of multiple sclerosis (MS), but relatively little is known about the time course of relapse recovery. OBJECTIVE: The aim of this study was to investigate the time course of and patient factors associated with the speed and success of relapse recovery in people with relapsing-remitting MS (RRMS). METHODS: Using data from CombiRx, a large RRMS trial (clinicaltrials.gov identifier NCT00211887), we measured the time to recovery from the first on-trial relapse. We used Kaplan-Meier survival analyses and Cox regression models to investigate the association of patient factors with the time to unconfirmed and confirmed relapse recovery. RESULTS: CombiRx included 1008 participants. We investigated 240 relapses. Median time to relapse recovery was 111 days. Most recovery events took place within 1 year of relapse onset: 202 of 240 (84%) individuals recovered during follow-up, 161 of 202 (80%) by 180 days, and 189 of 202 (94%) by 365 days. Relapse severity was the only factor associated with relapse recovery. CONCLUSION: Recovery from relapses takes place up to approximately 1 year after the event. Relapse severity, but no other patient factors, was associated with the speed of relapse recovery. Our findings inform clinical practice and trial design in RRMS.

Threshold definitions for significant change on the timed 25-foot walk and nine-hole peg test in primary progressive multiple sclerosis.

BACKGROUND AND PURPOSE: The timed 25-foot walk (T25FW) and nine-hole peg test (NHPT) exhibit random variability in the short term. A threshold of ≥20% change from baseline has been used to indicate true disability change, but other threshold definitions may be better suited to exclude false and include true change events. The aim of this study was to use patient-level original trial data to investigate the short-term variation in T25FW and NHPT, and to compare its extent with disability change at 12-month follow-up in people with primary progressive multiple sclerosis (PPMS). METHODS: We used original patient-level data from PROMISE, a large PPMS trial. In this trial, three separate T25FW and NHPT measurements were performed 1 week apart during screening. We used these repeated measures to describe the extent of short-term variation. We used binary logistic regression models to investigate the association between screening characteristics and unacceptable short-term variation. RESULTS: The traditional 20% threshold excluded a reasonable number of false change events, while also yielding a large number of change events at follow-up. Increasing index values on the T25FW and NHPT were associated with higher short-term variation. CONCLUSIONS: The traditional ≥20% change threshold for the T25FW and NHPT represents a reasonable compromise between reducing the number of false change events and achieving the largest number of change events in people with PPMS. Our analyses inform the design of clinical trials in PPMS.

MRI brain volume loss, lesion burden, and clinical outcome in secondary progressive multiple sclerosis.

BACKGROUND: Magnetic resonance imaging (MRI) of brain volume measures are widely used outcomes in secondary progressive multiple sclerosis (SPMS), but it is unclear whether they are associated with physical and cognitive disability. OBJECTIVE: To investigate the association between MRI outcomes and physical and cognitive disability worsening in people with SPMS. METHODS: We used data from ASCEND, a large randomized controlled trial (n = 889). We investigated the association of change in whole brain and gray matter volume, contrast enhancing lesions, and T2 lesions with significant worsening on the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), Nine-Hole Peg Test (NHPT), and Symbol Digit Modalities Test (SDMT) with logistic regression models. RESULTS: We found no association between MRI measures and EDSS or SDMT worsening. T25FW worsening at 48 and 96 weeks, and NHPT worsening at 96 weeks were associated with cumulative new or newly enlarging T2 lesions at 96 weeks. NHPT worsening at 48 and 96 weeks was associated with normalized brain volume loss at 48 weeks, but not with other MRI outcomes. CONCLUSION: The association of standard MRI outcomes and disability was noticeably weak and inconsistent over 2 years of follow-up. These MRI outcomes may not be useful surrogates of disability measures in SPMS.

Impact of clinical outcomes and imaging measures on health-related quality of life in secondary progressive MS.

BACKGROUND: Health-related quality of life (HRQOL) outcomes are often included as secondary outcomes in clinical trials in secondary progressive MS (SPMS), but little is known about the longitudinal association of HRQOL and clinical and imaging outcome measures in SPMS. OBJECTIVE: To assess the association of change in clinical and imaging outcomes with HRQOL in people with SPMS. METHODS: We used data from ASCEND, a large randomized controlled trial (n = 889), to investigate the association of significant worsening on the Expanded Disability Status Scale (EDSS), Timed 25 Foot Walk (T25FW), Nine Hole Peg Test (NHPT), Symbol Digit Modalities Test (SDMT), and change in lesional and volumetric imaging outcomes with significant worsening on the 36-Item Short Form Health Survey (SF-36) and the Multiple Sclerosis Impact Scale (MSIS-29) during 2 years of follow-up using logistic regression models. RESULTS: HRQOL measures were most associated with EDSS and T25FW, less so with NHPT and SDMT, and not associated with lesional and volumetric imaging outcomes. DISCUSSION: Worsening of the EDSS and T25FW was associated with two commonly used HRQOL measures. These outcomes therefore appear to be more patient relevant than either the NHPT or SDMT in the context of a 2-year clinical trial.

The MSIS-29 and SF-36 as outcomes in secondary progressive MS trials.

BACKGROUND: Patient-reported outcome measures (PROMs) are often used in clinical research, but little is known about their performance as longitudinal outcomes. METHODS: We used data from ASCEND, a large SPMS trial (n = 889), to investigate changes on the Short Form Health Survey 36 (SF-36 v2) and the Multiple Sclerosis Impact Scale (MSIS-29) over 2 years of follow-up. RESULTS: PROM scores changed little over the 2 years of follow-up. In contrast to physical disability measures, there was no consistent trend in PROM change: significant worsening occurred about as often as improvement. Using a 6-month confirmation reduced the number of both worsening and improvement events without altering their relative balance. There was no clear difference in worsening events in groups based on population characteristics, nor was there a noticeable effect using different thresholds for clinically significant change. CONCLUSION: We found little consistent change in MSIS-29 and SF-36 over 2 years of follow-up in people with SPMS. Our findings show a disconnect between disability worsening and PROM change in this population. Our findings raise caution about the use of these PROMs as primary outcome measures in SPMS trials and call for a critical reappraisal of the longitudinal use of these measures in SPMS trials.

Early first-line treatment response and subsequent disability worsening in relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: Treatment success in relapsing-remitting multiple sclerosis (RRMS) is generally determined using relapse frequency and magnetic resonance imaging (MRI) activity in the first 6 or 12 months on treatment. The association of these definitions of short-term treatment success with disability worsening and disease activity in the longer term is unclear. In this study, we investigated risk factors associated with early first-line treatment failure in RRMS, and the association of early treatment failure with subsequent disability worsening or "no evidence of disease activity" (NEDA-3) status. METHODS: We used data from CombiRx (clinicaltrials.gov identifier NCT00211887) to investigate risk factors associated with early treatment failure, and the association of early treatment failure at 6 and 12 months with subsequent disability worsening or NEDA-3 at 36 months. RESULTS: CombiRx included 1008 treatment-naïve participants with RRMS, who were randomly assigned to treatment with glatiramer acetate, interferon beta, or the combination of both. Early treatment failure at 6 or 12 months by several definitions was associated with NEDA-3 failure at 36 months, but not with subsequent disability worsening at 36 months. Expanded Disability Status Scale (EDSS) was the only baseline characteristic associated with the risk of disability worsening at 36 months. Approximately 70% of NEDA-3 failures occurred due to MRI activity, and <10% occurred due to EDSS worsening. CONCLUSIONS: Our investigation shows that current definitions of early treatment failure in RRMS are unrelated to patient-relevant disability worsening at 36 months of follow-up. Further research into useful definitions of treatment success and failure in RRMS is needed.

Synthetic and biosynthetic methods for selective cyclisations of 4,5-epoxy alcohols to tetrahydropyrans.

Tetrahydropyrans (THPs) are common structural motifs found in natural products and synthetic therapeutic molecules. In Nature these 6-membered oxygen heterocycles are often assembled via intramolecular reactions involving either oxy-Michael additions or ring opening of epoxy-alcohols. Indeed, the polyether natural products have been particularly widely studied due to their fascinating structures and important biological properties; these are commonly formed via endo-selective epoxide-opening cascades. In this review we outline synthetic approaches for endo-selective intramolecular epoxide ring opening (IERO) of 4,5-epoxy-alcohols and their applications in natural product synthesis. In addition, the biosynthesis of THP-containing natural products which utilise IERO reactions are reviewed.

A complement-microglial axis drives synapse loss during virus-induced memory impairment.

Over 50% of patients who survive neuroinvasive infection with West Nile virus (WNV) exhibit chronic cognitive sequelae. Although thousands of cases of WNV-mediated memory dysfunction accrue annually, the mechanisms responsible for these impairments are unknown. The classical complement cascade, a key component of innate immune pathogen defence, mediates synaptic pruning by microglia during early postnatal development. Here we show that viral infection of adult hippocampal neurons induces complement-mediated elimination of presynaptic terminals in a murine WNV neuroinvasive disease model. Inoculation of WNV-NS5-E218A, a WNV with a mutant NS5(E218A) protein leads to survival rates and cognitive dysfunction that mirror human WNV neuroinvasive disease. WNV-NS5-E218A-recovered mice (recovery defined as survival after acute infection) display impaired spatial learning and persistence of phagocytic microglia without loss of hippocampal neurons or volume. Hippocampi from WNV-NS5-E218A-recovered mice with poor spatial learning show increased expression of genes that drive synaptic remodelling by microglia via complement. C1QA was upregulated and localized to microglia, infected neurons and presynaptic terminals during WNV neuroinvasive disease. Murine and human WNV neuroinvasive disease post-mortem samples exhibit loss of hippocampal CA3 presynaptic terminals, and murine studies revealed microglial engulfment of presynaptic terminals during acute infection and after recovery. Mice with fewer microglia (Il34(-/-) mice with a deficiency in IL-34 production) or deficiency in complement C3 or C3a receptor were protected from WNV-induced synaptic terminal loss. Our study provides a new murine model of WNV-induced spatial memory impairment, and identifies a potential mechanism underlying neurocognitive impairment in patients recovering from WNV neuroinvasive disease.

Inter-individual relationships within a Canadian SPOR research network: a social network study.

BACKGROUND: Efforts have been made by health research granting agencies to bring research closer to patients' concerns. In Canada, such efforts were formalized in 2011 with the funding of the Strategy for Patient-Oriented Research (SPOR)'s research networks to address research priorities identified by patients and accelerate the translation of research findings into patient care and health care policy. Among these networks, SPOR Diabetes Action Canada (DAC) has created patient-partner circles to facilitate their integration within the network. The nature of the relationships within this atypical patient-oriented research network is systematically explored in this paper. METHODS: A cross-sectional social network study was conducted among the SPOR DAC's network members to examine inter-individual interactions, and the topics discussed the most between members. Descriptive data analyses were conducted to explore which discussion topics were discussed most among members whose primary roles were research, administration, governance, and patient representation. RESULTS: The response rate was 51.9%, providing data on 76.5% of the maximum number of connections in the network. The survey captured 2763 inter-individual relationships. Responses to a sub-question inserted in the survey show that 482 of these relationships (17,4%) existed before joining the network in collaboration on a research project. Most ties captured in the survey were yearly or quarterly, while few relationships were monthly, weekly, or daily. In measured relationships, members discussed several topics, the most frequent being scientific research, patient engagement, network coordination and governance, and operations and management. The topics associated with the most significant proportion of relationships captured in the survey were scientific research (45.4%) and patient engagement (40.7%). Management & operations and governance & coordination follow, corresponding to 24.3 and 23.9% of the captured relationships. All discussion topic subnetworks were either somewhat or highly centralized, meaning that relationships were not equally distributed among members involved in these discussions. Of the 1256 relationships involving exchanges about scientific research, 647 (51.5%) involved a researcher, 419 (33.3%) an administrator, 182 (14.5%) a patient partner, and 82 (6.5%) a member whose primary role is network governance. CONCLUSIONS: Scientific research and patient engagement were the most common topics discussed, consistent with the patient-centered research at the heart of the SPOR Diabetes Action Canada network. The study identified several relationships where a patient partner has discussed scientific research with a researcher. However, relationships involving research discussions were three times more common between a researcher and an administrator than between a researcher and a patient partner, although twice as many patient partners as administrators participated in the survey. The institutionalization of patient-partner involvement in large research networks is an evolving practice for which optimal engagement methods are still being explored.

Applications and Error Ratios of Calibration Techniques in EOS, Orthoroentgenogram, and Teleoroentgenogram for Length Measurement: A Comparative Study.

BACKGROUND: Accurate length measurements of extremity bones are essential in treating limb deformities and length discrepancies in children. OBJECTIVE: This study aimed to determine errors in common techniques used to measure lower limb lengths in children. METHODS: Precision and instrument errors in length measurements were studied utilizing electro-optical system (EOS), orthoroentgenogram, and teleoroentgenogram The goal was to measure a 70-cm metallic rod phantom (average length of the lower extremity of a 10-year-old boy in the 50th percentile) in 3 phases. In Phase 1, the length measurements were performed in an EOS unit with internal calibrations, a magball/magstrip in various scan positions, and measurement with TraumaCAD software. In Phase 2, the measurements were repeated utilizing a single radiation "shot" teleoroentgenogram. In Phase 3, an orthoroentgenogram was utilized with a radiopaque ruler reference. The reliability and validity of measurements were calibrated by 4 physicians (a radiologist, senior orthopaedic attending, and 2 orthopaedic fellows). RESULTS: EOS measurements utilizing internal references had excellent accuracy (for a 700-mm real length, magnification error (ME)] of 0.09%. Teleoroentgenogram with a magball reference and measurements performed with automatic calibration by TraumaCAD program results in ME of 1.83% with insignificant intraobserver/interobserver difference. Teleoroentgenogram with a magball or magstrip reference measured manually showed that the magball has higher intraobserver/interobserver variance than magstrip, with a 6.60 and 0.33-mm SD, respectively. The length by manual measurement utilizing the magstrip has ME of 2.21%. Orthoroentgenogram is accurate with ME of 0.26%, but does not allow anatomical analysis and is also radiation-costly. CONCLUSION: EOS and orthoroentgenogram are very accurate for length measurements. Teleoroentgenogram is less accurate in measuring length; however, addition of an external reference (magball, magstrip) placed lateral to the target improves accuracy. Automatic calibration with computer-based analysis of the external reference improves the accuracy more than manual calibration. If manual calibration is utilized, the length measurement is less accurate with the magball than the magstrip. LEVEL OF EVIDENCE: Level II-comparative in vitro study.

Prevalence and Risk Factors Associated With Pelvic Rod/Screw Radiographic Lucency Following Scoliosis Surgery in Spastic Cerebral Palsy: A Longitudinal Study.

BACKGROUND: Radiographic lucency around a smooth pelvic rod (Galveston/unit rod technique) or sacroiliac/iliac screw following spinal fusion in children with nonambulatory spastic cerebral palsy (CP) has been described as a "windshield wiper" phenomenon. We evaluated demographics, radiographs, and complications in 101 cases from a single center to determine prevalence, risk factors, and complications associated with persistent radiographic lucency from 1 to 5 years following spinal fusion. METHODS: Inclusion criteria were diagnosis of nonambulatory spastic quadriplegic CP [Gross Motor Function Classification System (GMFCS) IV-V], under 18 years of age, scoliosis treated by posterior fusion from upper thoracic to sacrum with pelvic fixation (Galveston rod, iliac screw, or sacroiliac screw), adequate radiographs (preoperative, immediate postoperative, first-year, and second-year), and minimum 5-year follow-up. We evaluated demographics, radiographic parameters, comorbidities, scoliosis curve type, type of pelvic screw/rod, use of off-set connector, screw width, associated with posterior column osteotomy and/or additional anterior spinal release concurrent with posterior spine fusion, and infection over the follow-up period. Specific attention was given to the area and shape of the radiographic lucency. The logistic regression analysis was performed for continuous and categorical variables to define risk factors ( P =0.05). RESULTS: In 101 patients, data were collected at mean intervals of 1-year, 2-year, and >5-year follow-up and were 12.9±1.5, 25.8±2.5, and 81.5±23.0 months, respectively. Prevalence of pelvic rod/screw radiographic lucency was unchanged at 33%, 35%, and 24% at 1-year, 2-year, and >5-year follow-up, respectively, and radiographic parameters did not change ( P >0.05). Furthermore, no risk factors or complications were associated with radiographic lucency around pelvic rods/screws ( P >0.05). CONCLUSION: In patients with spastic nonambulatory CP who had scoliosis treated with posterior spinal fusion from upper thorax to pelvis, the prevalence of pelvic rod/screw lucency is high. Persistent lucency >2 mm around pelvic implants is not clinically significant, does not warrant advanced imaging, or indicate a complication if stable over time and wider distally than proximally. LEVEL OF EVIDENCE: Level III.

Elongation-Derotation-Flexion Casting Treatment of Early-Onset Progressive Scoliosis in Skeletal Dysplasia.

BACKGROUND: Early-onset scoliosis in children with skeletal dysplasia is progressive, contributing to cardiopulmonary restrictive disease. Serial elongation-derotation-flexion (EDF) casting, used in other etiologies of scoliosis to delay curve progression, may be beneficial in maximizing spine growth. Our hypothesis is serial EDF casting can be safely used as a temporary alternative to surgery, delaying progression and preserving growth, to treat scoliosis in skeletal dysplasia. METHODS: All patients with skeletal dysplasia treated at a single institution with serial EDF casting for scoliosis were reviewed retrospectively. Radiographic parameters: Cobb angle of major and minor curves, curve location, thoracic height, thoracolumbar height, space available for lung, and rib vertebra angle difference were measured before casting (C1), in first casting (C2), in last casting (C3), and out of last casting (C4). Peak inspiratory pressure (PIP) values were monitored and recorded during the casting application. RESULTS: Eleven patients met the inclusion criteria (mean 9.7 castings). The mean duration of EDF serial casting was 35 months. The mean major Cobb angles were 54 degrees° (C1), 30 degrees (C2), 37 degrees (C3), and 49 degrees (C4) with no statistically significant differences. The mean minor Cobb angles were 35 degrees (C1), 25 degrees (C2), 33 degrees (C3), and 51 degrees (C4) with no statistically significant differences. The mean thoracic heights were 130 mm (C1), 155 mm (C2), 173 mm (C3), and 160 mm (C4). The 19-mm mean difference between C2 and C3 represents spinal growth. The PIP-1, PIP-2, and PIP-3 mean values were 15, 27, and 18 cmH2O, respectively. Changes in PIP-1 and PIP-2 and PIP-2 and PIP-3 were statistically significant. CONCLUSION: Serial EDF casting can delay surgical scoliosis correction in children younger than 7 years with a diagnosis of skeletal dysplasia. Our study showed that serial casting controls progression of the major curve and allows longitudinal growth of the spine with possible expansion of lung volume for nearly 3 years. During cast application, PIP increased with molding and traction, and improved until windowing and trimming of the cast. LEVEL OF EVIDENCE: Level IV-retrospective study.

Is the Symbol Digit Modalities Test a useful outcome in secondary progressive multiple sclerosis?

BACKGROUND: It is unclear which cognitive outcome measure is the most useful for clinical trials in multiple sclerosis. To investigate the usefulness of the Symbol Digit Modalities Test (SDMT) as a clinical outcome measure in secondary progressive multiple sclerosis (SPMS), we describe the frequency of worsening and improvement events in a large randomized controlled trial (RCT) dataset. METHODS: Using original trial data from the ASCEND trial (n = 889), a recent large RCT in SPMS, we describe worsening and similarly defined improvement with and without 3-month confirmation on the SDMT in the whole trial cohort and unconfirmed worsening and improvement on the Paced Auditory Serial Addition Test (PASAT) in a smaller subset (n = 107). RESULTS: Somewhat unexpectedly, SDMT scores steadily increased throughout the 2 years of follow-up in this trial. There were overall few SDMT worsening events throughout the trial (generally fewer than 10% of participants), but improvement events steadily increased from around 50% of participants with improvement at 12 weeks to more than 70% at 84 weeks and beyond. PASAT scores followed a similar pattern. CONCLUSIONS: In this well-characterized clinical trial cohort, the SDMT does not reflect the steady cognitive decline that patients with SPMS experience. Both SDMT and PASAT scores improve throughout follow-up, possibly due to a practice effect. The SDMT may not be a useful outcome measure of disease progression in 2-year clinical trials in SPMS.

Ambruticins: tetrahydropyran ring formation and total synthesis.

The ambruticins are a family of polyketide natural products which exhibit potent antifungal activity. Gene knockout experiments are in accord with the proposal that the tetrahydropyran ring of the ambruticins is formed via the AmbJ catalysed epoxidation of the unsaturated 3,5-dihydroxy acid, ambruticin J, followed by regioselective cyclisation to ambruticin F. Herein, a convergent approach to the total synthesis of ambruticin J is described as well as model studies involving epoxidation and cyclisations of unsaturated hydroxy esters to give tetrahydropyrans and tetrahydrofurans. The total synthesis involves preparation of three key fragments which were united via a Suzuki-Miyaura cross-coupling and Julia-Kocienski olefination to generate the required carbon framework. Global deprotection to a triol and selective oxidation of the primary alcohol gave, after hydrolysis of the lactone, ambruticin J.

Risk Factors for Failure of Pavlik Harness Treatment in Infants With Dislocated Hips That Are Evaluated by Dynamic Sonography.

BACKGROUND: Frankly dislocated hips occur in ∼1% to 3% of infants with developmental dysplasia of the hip and are often difficult to treat. In the most severely dislocated hips, the femoral head is positioned outside the posterior/lateral rim of the acetabulum and is irreducible, that is, the femoral head will not reduce by positioning the leg. The purpose of this study was to determine risk factors, using univariate and multivariate analyses, for Pavlik harness failure in infants who initially presented with irreducible/dislocated hips (confirmed by dynamic sonography). METHODS: Following institutional review board approval, 124 infants (170 hips) with frankly dislocated hips treated using a Pavlik harness between 2000 and 2018 were evaluated. Patients' demographic characteristics, clinical findings, dynamic sonographic findings (dislocated-fixed vs. dislocated-mobile), age at onset of Pavlik harness treatment, duration of harness usage, and follow-up treatments were recorded. Univariate analyses were used to determine risk factors for treatment failure. RESULTS: In frankly dislocated hips (confirmed by dynamic sonography to be positioned outside the posterior/lateral rim of the acetabulum), Pavlik harness treatment was successful in 104 of 170 hips (61%) while it failed in 66 hips. Mean follow-up was 4.86±4.20 years. Univariate analysis determined the risk factors to be onset of treatment after the seventh week of age (P=0.049) and initial mobility (dislocated-fixed group) (P<0.001) by dynamic sonography. In addition, multivariate analysis (P=0.007) showed infants of multigravida mothers (non-firstborn) to be another risk factor for failure. Six percent of hips with no risk factors failed Pavlik harness treatment, those with 1 risk factor had 42% failure, 2 risk factors had 69% failure, and all 3 risk factors had 100% failure. CONCLUSIONS: In our patients with frankly dislocated irreducible hips, 39% of hip failed Pavlik harness treatment. Independent multivariate, logistic regression analysis, and multivariate analysis determining the risk factors for failure of Pavlik harness treatment were onset of treatment after the seventh week of age, infants of multigravida mothers, and initial hip mobility (fixed-dislocated hips) by dynamic sonography. LEVEL OF EVIDENCE: Level III.