Appendicular lean mass index and motor function in ambulatory patients with Duchenne muscular dystrophy.

INTRODUCTION/AIMS: Appendicular lean mass index (ALMI) has been linked to motor function in patients with Duchenne muscular dystrophy (DMD). However, quantification of the relationship between ALMI and disease-specific clinical outcome assessment trajectories is needed. The purpose of this study was to determine associations between dual-energy x-ray absorptiometry (DXA) derived estimates of ALMI and motor function in ambulatory patients with DMD. METHODS: A retrospective analysis of longitudinal clinical visit data from 137 glucocorticoid-treated patients with DMD collected via structured motor assessment protocol evaluated associations between ALMI and motor function indexed by the North Star Ambulatory Assessment (NSAA) and 10 Meter Walk/run Test (10MWT). Body composition was assessed using DXA. ALMI was calculated by dividing arm and leg lean mass by height in m2; fat mass index (FMI) was calculated by dividing whole body fat mass by height in m2. Linear mixed-effects models were used to estimate associations between ALMI and motor function, controlling for age and FMI. RESULTS: The full prediction model (age, age,2 ALMI, and FMI) explained 57% of the variance in NSAA scores and 63% of the variance in 10MWT speed. A 1 kg/m2 higher ALMI value predicted a 5.4-point higher NSAA score (p < .001) and 0.45 m/s faster 10MWT speed (p < .001). A 1 kg/m2 higher FMI value predicted a 1.5-point lower NSAA score (p < .001) and 0.14 meters/second slower 10MWT speed (p < .001). DISCUSSION: DXA-derived estimates of ALMI and FMI are associated with motor function in DMD and may explain variation in DMD disease progression.

Development of an Infantile GM2 Clinical Rating Scale: Remote Assessment of Clinically Meaningful Health-Related Function.

GM2 gangliosidoses (GM2) are a group of rare lysosomal storage disorders in which accumulation of GM2 gangliosides results in progressive central nervous system damage. The infantile GM2 phenotype is characterized by delays in milestones by 6 months of age, followed by rapid loss of motor, cognitive, and visual function. Advancements in early diagnosis and pharmacotherapies provide promise for improved outcomes. However, the lack of feasible and clinically meaningful clinical outcome assessments for GM2 poses a challenge to characterizing GM2 natural history and selecting clinical trial endpoints. The purpose of this study was to develop a remotely administered infantile GM2 rating scale to measure health-related function in children with infantile GM2. A 2-phase mixed methods design was employed. In phase 1 of the study, 8 families of children with Infantile GM2 completed a natural history survey and a 1:1 semistructured interview to provide caregiver perspectives on the impacts of GM2 on health-related function. In phase 2 of the study, 8 expert clinicians provided feedback via surveys and participated in videoconference-hosted focus groups to refine scale administration and scoring procedures. These methods guided the development of 16 scale items to assess function in 5 health-related function domains: vision, hand and arm use, communication, gross motor, and feeding. This study used caregiver perspectives and expert clinician feedback to develop a remotely administered clinical outcome assessment of clinically meaningful health-related function in children with infantile GM2. Future studies will further evaluate the feasibility, reliability, and validity of the Infantile GM2 Clinical Rating Scale.

Analytical Validation of a Novel MicroRNA Panel for Risk Stratification of Cognitive Impairment.

We have been developing a novel approach to identify cognitive impairment-related biomarkers by profiling brain-enriched and inflammation-associated microRNA (miRNA) in plasma specimens of cognitively unimpaired and cognitively impaired patients. Here, we present an analytical validation of the novel miRNA panel, CogniMIR®, using two competing quantitative PCR technologies for the expression analysis of 24 target miRNAs. Total RNA from the plasma specimens was isolated using the MagMAX mirVana Kit, and RT-qPCR was performed using stem-loop-based TaqMan and LNA-based qPCR assays. Evaluation of RNA dilution series for our target 24 miRNAs, performed by two operators on two different days, demonstrated that all CogniMIR® panel miRNAs can be reliably and consistently detected by both qPCR technologies, with sample input as low as 20 copies in a qPCR reaction. Intra-run and inter-run repeatability and reproducibility analyses using RNA specimens demonstrated that both operators generated repeatable and consistent Cts, with R2 values of 0.94 to 0.99 and 0.96 to 0.97, respectively. The study results clearly indicate the suitability of miRNA profiling of plasma specimens using either of the qPCR technologies. However, the LNA-based qPCR technology appears to be more operationally friendly and better suited for a CAP/CLIA-certified clinical laboratory.

Development of Duchenne Video Assessment scorecards to evaluate ease of movement among those with Duchenne muscular dystrophy.

BACKGROUND: Patients with Duchenne muscular dystrophy (DMD) adopt compensatory movement patterns as muscles weaken. The Duchenne Video Assessment (DVA) measures patient ease of movement through identification of compensatory movement patterns. The DVA directs caregivers to video record patients performing specific movement tasks at home using a secure mobile application, and DVA-certified physical therapists (PTs) score the videos using scorecards with prespecified compensatory movement criteria. The goal of this study was to develop and refine the DVA scorecards. METHODS: To develop the initial scorecards, 4 PTs collaboratively created compensatory movement lists for each task, and researchers structured the lists into scorecards. A 2-round modified Delphi process was used to gather expert opinion on the understandability, comprehensiveness, and clinical meaningfulness of the compensatory movements on the scorecards. Eight PTs who had evaluated ≥50 patients with DMD and participated in ≥10 DMD clinical trials were recruited for the panel. In Round 1, panelists evaluated compensatory movement criteria understandability via questionnaire and tested the scorecards. In Round 2, panelists participated in an in-person meeting to discuss areas of disagreement from Round 1 and reach consensus (≥75% agreement) on all revisions to the scorecards. RESULTS: During the Round 1 revisions to the scorecards, there were 67 changes (44%) to the wording of 153 original compensatory movement criteria and 3 criteria were removed. During the Round 2 revisions to the scorecards, there were 47 changes (31%) to the wording of 150 compensatory movement criteria, 20 criteria were added, and 30 criteria were removed. The panel reached 100% agreement on all changes made to scorecards during Round 2. CONCLUSION: PTs with extensive experience evaluating patients with DMD confirmed that the compensatory movement criteria included in the DVA scorecards were understandable, comprehensive, and clinically meaningful.

Natural history of 10-meter walk/run test performance in spinal muscular atrophy: A longitudinal analysis.

As trials and treatments for spinal muscular atrophy (SMA) rapidly evolve, understanding the natural history and potential utility of the 10-meter walk/run test (10MWRT) in ambulant individuals is critical. Study aims were to: 1) establish change over time and across age for 10MWRT time in an untreated natural history cohort of young, ambulatory participants with SMA and 2) identify relations between 10MWRT time and age, SMA type, SMN2 copy number and anthropometrics. Untreated individuals (n = 56) age 2 to 21 years who were enrolled in a long-term natural history study between 2005 and 2014 and met inclusion criteria were included. Linear mixed effects models were used to assess changes in 10MWRT time with age and associations with SMA type, SMN2 copy number, and body mass. SMA type 3b (versus 3a), SMN2 copy number 4 (versus 3) and lower body mass were associated with faster 10MWRT. 10MWRT performance improved between 3 and 8 years of age, was stable between 9 and 10, and gradually declined from 11 to 18. Findings provide the first longitudinal natural history report of 10MWRT time in young individuals with SMA and offer a critical foundation for interpreting childhood change in short distance walking speed with pharmacologic treatment.

Implications of circulating neurofilaments for spinal muscular atrophy treatment early in life: A case series.

This longitudinal cohort study aimed to determine whether circulating neurofilaments (NFs) can monitor response to molecular therapies in newborns with spinal muscular atrophy (SMA; NCT02831296). We applied a mixed-effect model to examine differences in serum NF levels among healthy control infants (n = 13), untreated SMA infants (n = 68), and SMA infants who received the genetic therapies nusinersen and/or onasemnogene abeparvovec (n = 22). Increased NF levels were inversely associated with SMN2 copy number. SMA infants treated with either nusinersen or onasemnogene abeparvovec achieved important motor milestones not observed in the untreated cohort. NF levels declined more rapidly in the nusinersen cohort as compared with the untreated cohort. Unexpectedly, those receiving onasemnogene abeparvovec monotherapy showed a significant rise in NF levels regardless of SMN2 copy number. In contrast, symptomatic SMA infants who received nusinersen, followed by onasemnogene abeparvovec within a short interval after, did not show an elevation in NF levels. While NF cannot be used as the single marker to predict outcomes, the elevated NF levels observed with onasemnogene abeparvovec and its absence in infants treated first with nusinersen may indicate a protective effect of co-therapy during a critical period of vulnerability to acute denervation.

Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults: A Living Systematic Review.

BACKGROUND: The role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) in coronavirus disease 2019 (COVID-19) susceptibility, severity, and treatment is unclear. PURPOSE: To evaluate, on an ongoing basis, whether use of ACEIs or ARBs either increases risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or is associated with worse COVID-19 disease outcomes, and to assess the efficacy of these medications for COVID-19 treatment. DATA SOURCES: MEDLINE (Ovid) and Cochrane Database of Systematic Reviews from 2003 to 4 May 2020, with planned ongoing surveillance for 1 year; the World Health Organization database of COVID-19 publications and medRxiv.org through 17 April 2020; and ClinicalTrials.gov to 24 April 2020, with planned ongoing surveillance. STUDY SELECTION: Observational studies and trials in adults that examined associations and effects of ACEIs or ARBs on risk for SARS-CoV-2 infection and COVID-19 disease severity and mortality. DATA EXTRACTION: Single-reviewer abstraction confirmed by another reviewer, independent evaluation by 2 reviewers of study quality, and collective assessment of certainty of evidence. DATA SYNTHESIS: Two retrospective cohort studies found that ACEI and ARB use was not associated with a higher likelihood of receiving a positive SARS-CoV-2 test result, and 1 case-control study found no association with COVID-19 illness in a large community (moderate-certainty evidence). Fourteen observational studies, involving a total of 23 565 adults with COVID-19, showed consistent evidence that neither medication was associated with more severe COVID-19 illness (high-certainty evidence). Four registered randomized trials plan to evaluate ACEIs and ARBs for treatment of COVID-19. LIMITATION: Half the studies were small and did not adjust for important confounding variables. CONCLUSION: High-certainty evidence suggests that ACEI or ARB use is not associated with more severe COVID-19 disease, and moderate-certainty evidence suggests no association between use of these medications and positive SARS-CoV-2 test results among symptomatic patients. Whether these medications increase the risk for mild or asymptomatic disease or are beneficial in COVID-19 treatment remains uncertain. PRIMARY FUNDING SOURCE: None. (PROSPERO: registration number pending).

Ventriculoperitoneal Shunt Complications in the European Idiopathic Normal Pressure Hydrocephalus Multicenter Study.

BACKGROUND: Ventriculoperitoneal shunt (VP-shunt) is the standard of treatment for idiopathic normal pressure hydrocephalus (iNPH). However, a thorough investigation of VP-shunt complications in this population is lacking. OBJECTIVE: To present the analysis and the rates of complications progressively occurring during the first year after shunt surgery in the patients with iNPH included in the European multicenter (EU-iNPH) study. METHODS: Patients (n = 142) were prospectively included in the EU-iNPH study by 13 institutions. All patients received a programmable VP-shunt. One hundred fifteen patients completed the 12-mo follow-up. Reexaminations were performed 1, 3, and 12 mo after surgery. Data regarding symptomatic over- or underdrainage, infections, malposition, subdural collections, and shunt surgery were collected and analyzed. RESULTS: Thirty patients (26%) experienced symptoms due to shunt underdrainage. Symptomatic overdrainage was reported in 10 (9%). Shunt adjustments were made in 43 (37%). Shunt malposition was recognized as the primary cause of shunt malfunction in 8 (7%), while only 1 infection (0.9%) occurred. Subdural hematoma was diagnosed in 7 (6%) and was treated by increasing the opening pressure of the valve in 5 patients. Hygroma was diagnosed in 10 (9%), requiring surgery in 1 patient. Overall, 17 patients (15%) underwent 19 shunt surgeries. CONCLUSION: The advances in valve technology, a careful opening pressure setting, and rigorous follow-up allow a significant reduction of complications, which can be usually managed nonsurgically within the first 3 to 6 mo.

Progression of Ankle Plantarflexion Contractures and Functional Decline in Duchenne Muscular Dystrophy: Implications for Physical Therapy Management.

PURPOSE: This study characterizes the progressive loss of ankle dorsiflexion range of motion in boys with Duchenne muscular dystrophy (DMD), the relationship to functional decline, and the implications for physical therapy management. METHODS: Longitudinal data for 332 boys with DMD were extracted from medical records and analyzed. Summary statistics for age, number of visits, ankle dorsiflexion measures, and North Star Ambulatory Assessment (NSAA) scores were computed. RESULTS: Ankle dorsiflexion motion ranged from -32.5 to 25 degrees. Progression of ankle contractures is demonstrated by a trend line: slope -1.43 per year. NSAA score was estimated to decline approximately 0.23 points per 1 degree of ankle dorsiflexion lost. CONCLUSIONS: The results of this study describe the progression of ankle contractures and functional decline in DMD. The findings may help inform decisions regarding interventions to support participants with DMD and their families.

PROSAIKA: a prospective multicenter registry with the first programmable gravitational device for hydrocephalus shunting.

OBJECTIVE: Cerebrospinal fluid (CSF) overdrainage is a major problem in shunt therapy for hydrocephalus. The adjustable gravitational valve proSA allows for the first time a targeted compensation for overdrainage in the upright position without interfering with the differential pressure valve. To evaluate benefit, safety and reliability, the multicenter prospective registry PROSAIKA was conducted in 10 German neurosurgical centers. METHODS: Between March 2009 and July 2010, 120 hydrocephalic patients undergoing first time shunt implantation or shunt revision using proSA entered the study. 93 patients completed the 12 months follow-up. RESULTS: Hydrocephalus symptoms were improved in 86%, unchanged in 9% and deteriorated in 3%. In 51%, the proSA opening pressure was readjusted one or several times to treat suspected suboptimal shunt function, this resulted in clinical improvement in 55%, no change in 25%, and deterioration in 20% of these patients. The 1 year censored proSA shunt survival rate was 89%. Device related shunt failure was seen in two cases. CONCLUSIONS: This is the first clinical report on the implantation of the adjustable gravitational valve proSA with a follow-up of 12 months in a substantial number of patients. Irrespective of different hydrocephalus etiologies and indications for shunt surgery, the overall results after 12 months were very satisfying. The high frequency of valve readjustments underlines the fact that preoperative selection of the appropriate valve opening pressure is difficult. The low number of revisions and complications compared to other valves proves that proSA implantation adds no further risk; this valve is reliable, helpful and safe.

Regional, annual, and individual variations in the dihydroxyacetone content of the nectar of maÌ nuka (Leptospermum scoparium) in New Zealand.

A method was designed and validated for the analysis of dihydroxyacetone in the floral nectar of ma̅nuka (Leptospermum scoparium). The method was applied to samples collected from different regions of the North Island and the Nelson region of the upper South Island of New Zealand during the period 2009-2012 as well as to nectar samples from some Australian Leptospermum species. The ratio of dihydroxyacetone to total sugar (DHA/Tsugar) was classified as low (<0.001 mg/mg), moderate (0.001-0.002 mg/mg), or high (>0.002 mg/mg). Inter- and intraregional variation were observed as well as interannual variation with variation from low to high classification occurring within one region and from low to moderate between years. Australian species also demonstrated elevated levels of dihydroxyacetone in the nectar. Some garden cultivars were shown to produce very high nectar DHA/Tsugar, and a survey of cultivars was undertaken; cultivars with single-flowered red or pink flowers were the most common producers of very high nectar DHA/Tsugar.

Control of an electromechanical hydrocephalus shunt--a new approach.

Hydrocephalus is characterized by an excessive accumulation of cerebrospinal fluid (CSF). Therapeutically, an artificial pressure relief valve (so-called shunt) is implanted which opens in case of increased intracranial pressure (ICP) and drains CSF into another body compartment. Today, available shunts are of a mechanical nature and drainage depends on the pressure drop across the shunt. According to the latest data, craniospinal compliance is considered to be even more important than mean ICP alone. In addition, ICP is not constant but varies due to several influences. In fact, heartbeat-related ICP waveform patterns depend on volume changes in the cranial vessels during a heartbeat and changes its shape as a function of craniospinal compliance. In this paper, we present an electromechanical shunt approach, which changes the CSF drainage as a function of the current ICP waveform. A series of 12 infusion tests in patients were analyzed and revealed a trend between the compliance and specific features of the ICP waveform. For waveform analysis of patient data, an existing signal processing algorithm was improved (using a Moore machine) and was implemented on a low-power microcontroller within the electromechanical shunt. In a test rig, the ICP waveforms were replicated and the decisions of the ICP analysis algorithm were verified. The proposed control algorithm consists of a cascaded integral controller which determines the target ICP from the measured waveform, and a faster inner-loop integral controller that keeps ICP close to the target pressure. Feedforward control using measurement data of the patient's position was implemented to compensate for changes in hydrostatic pressure during change in position. A model-based design procedure was used to lay out controller parameters in a simple model of the cerebrospinal system. Successful simulation results have been obtained with this new approach by keeping ICP within the target range for a healthy waveform.

Rheumatoid arthritis bone fragility is associated with upregulation of IL17 and DKK1 gene expression.

Our aim was to compare bone gene expression in rheumatoid arthritis (RA) and primary osteoporosis (OP) patients. Secondary aims were to determine the association of gene expression of the Wnt/ß-catenin signaling pathway with inflammatory cytokines in the bone microenvironment and to assess the serum levels of Wnt/ß-catenin proteins in both groups. RA patients referred for hip replacement surgery were recruited. Primary OP patients were used as controls. Gene expression of Wnt pathway mediators, matrix proteins, and pro-inflammatory cytokines were analyzed in bone samples. Bone turnover markers, inflammatory cytokines, and Wnt mediators were measured in serum. Twenty-two patients were included: 10 with RA and 12 with primary OP. The expressions of Wnt10b (p = 0.034), its co-receptor LRP6 (p = 0.041), and its negative regulator DKK1 (p = 0.008) were upregulated in RA bone. IL17 gene expression in bone was upregulated in RA patients (p = 0.031) and correlated positively with Wnt10b (r = 0.810, p = 0.015), DKK2 (r = 0.800, p = 0.010), and RANKL/OPG ratio (r = 0.762, p = 0.028). DKK2 (p = 0.04) was significantly decreased in RA serum compared with primary OP. In conclusion, bone fragility in RA patients is induced by an unbalanced bone microenvironment and is associated with a specific gene expression pattern, namely, the upregulation of IL17 and DKK1, suggesting that the modulation of these two pathways might prevent RA systemic bone loss.

Predictors of subsequent overdrainage and clinical outcomes after ventriculoperitoneal shunting for idiopathic normal pressure hydrocephalus.

BACKGROUND: Little is known about variables associated with overdrainage complications and neurofunctional and health-related quality of life outcomes in idiopathic normal-pressure hydrocephalus (iNPH) patients after shunt surgery. OBJECTIVE: To identify candidate demographic and disease-specific predictors of overdrainage and patient-related outcomes, allowing for more personalized care of patients with iNPH. METHODS: This was a secondary analysis of the dataset of the SVASONA study, a multicenter randomized trial comparing gravitational and conventional gravitational valves for treating iNPH. We evaluated the association between baseline items and the incidence of overdrainage, using different endpoint definitions. RESULTS: We identified only a few variables associated with a possible increased risk of overdrainage. Apart from using conventional rather than gravitational valves, longer duration of surgery and female sex were associated with a higher risk of clinical signs and symptoms suggestive of overdrainage (hazard ratio: 1.02, 95% confidence interval: 1.01-1.04 and 1.84, 95% confidence interval: 0.81-4.16). The occurrence of clinical symptoms of overdrainage, and the need for exchanging a programmable by a gravitational valve may adversely affect disease-specific outcomes like the Kiefer score. CONCLUSION: Few, if any, baseline and treatment characteristics may be helpful in estimating the individual risk of complications and clinical outcomes after shunt surgery for iNPH. Patients should be informed that longer surgery for any reason may increase the risk of later overdrainage. Also, women should be counseled about a sex-associated increased risk of the development of clinical symptoms of overdrainage, although the latter cannot be distinguished from a generally higher prevalence of headaches in the female population.

Magnetic resonance-based estimation of intracranial pressure correlates with ventriculoperitoneal shunt valve opening pressure setting in children with hydrocephalus.

OBJECTIVES: The aim of this study was to investigate the relationship between the pressure setting of the ventriculoperitoneal (VP) shunt valve and a magnetic resonance (MR)-based estimate of intracranial pressure (ICP) in children with shunt-treated hydrocephalus without clinical signs of shunt malfunction. MATERIALS AND METHODS: Institutional review board approval was obtained before the study, and all subjects and/or their legal guardians provided written informed consent. In this prospective study, 15 consecutive patients (median age, 8.25 years; range, 2.2-18.4 years; 6 girls and 9 boys) with shunt-treated hydrocephalus without signs of shunt malfunction were examined with retrospectively gated phase contrast sequences to quantify arterial inflow, venous outflow, and cerebrospinal fluid (CSF) flow to and from the cranial vault. The ratio of the maximal intracranial volume change and the pulse pressure gradient change was used to derive MR-ICP. Spearman ρ was used to test for the association of setting of the shunt valve opening pressure and MR-ICP. RESULTS: Shunt valve opening pressure settings and MR-ICP were positively correlated (Spearman ρ = 0.64, P < 0.01). Median MR-ICP was 8.67 mm Hg (interquartile range [IQR], 1.59 mm Hg) and median setting of the VP-shunt valve was 6.62 mm Hg (IQR, 1.47 mm Hg). The median MR-ICP was 1.9 mm Hg (IQR, 0.73 mm Hg) higher than the setting of the shunt valve. CONCLUSION: There is a positive correlation between MR-ICP and VP shunt valve opening pressure setting. The systematically higher assessment of MR-ICP is most likely a result of outflow resistance within the shunt tubing system and well within the known fluctuation rates of VP shunt systems.