Geochemical and hydrological data from abandoned mine watersheds demonstrated that (1) point sources of pollution fail to account for total receiving watercourse metal load at higher flows and (2) an ...inverse relationship exists between river flow and pH due to peatland runoff. Quantifying the varying importance of point and diffuse pollution sources enabled prediction of treatment benefits for a major point source of pollution in one watershed. Instream zinc load increases with river flow (∼3 to 14 kg Zn/d) due to diffuse groundwater and surface runoff pollution sources at higher flows. Lab tests demonstrated that metal release from the streambed, driven by pH decreases at higher flows, also contribute to increased downstream metal loads. Predicting point source treatment benefits demonstrates major instream improvements at low flow (zinc decreases from >800 to 120 μg Zn/L). At higher flows treatment benefits diminish (Zn decreases from 240 to only 200 μg Zn/L) due to the greater influence of diffuse sources. A quantitative understanding of the variable importance of point and diffuse sources of pollution, and instream processes of metal attenuation and release, is crucial to evaluating the benefits of treatment to downstream water quality.
Wolman disease is a rare, lysosomal storage disorder in which biallelic variants in the LIPA gene result in reduced or complete lack of lysosomal acid lipase. The accumulation of the substrates; ...cholesterol esters and triglycerides, significantly impacts cellular function. Untreated patients die within the first 12 months of life. Clinically, patients present severely malnourished, with diarrhoea and hepatosplenomegaly, many have an inflammatory phenotype, including with hemophagocytic lymphohistiocytosis (HLH). Hematopoietic stem cell transplant (HCT) had been historically the only treatment available but has a high procedure-related mortality because of disease progression and disease-associated morbidities. More recently, enzyme replacement therapy (ERT) with dietary substrate reduction (DSR) has significantly improved patient survival. However, ERT is life long, expensive and its utility is limited by anti-drug antibodies (ADA) and the need for central venous access.
We describe five Wolman disease patients diagnosed in infancy that were treated at Royal Manchester Children's Hospital receiving ERT with DSR then HCT-multimodal therapy. In 3/5 an initial response to ERT was attenuated by ADA with associated clinical and laboratory features of deterioration. 1/5 developed anaphylaxis to ERT and the other patient died post HCT with ongoing HLH. All patients received allogeneic HCT. 4/5 patients are alive, and both disease phenotype and laboratory parameters are improved compared to when they were on ERT alone. The gastrointestinal symptoms are particularly improved after HCT, with reduced diarrhoea and vomiting. This allows gradual structured normalisation of diet with improved tolerance of dietary fat. Histologically there are reduced cholesterol clefts, fewer foamy macrophages and an improved villous structure. Disease biomarkers also show improvement with ERT, immunotherapy and HCT. Three patients have mixed chimerism after HCT, indicating a likely engraftment-defect in this condition.
We describe combined ERT, DSR and HCT, multimodal treatment for Wolman disease. ERT and DSR stabilises the sick infant and reduces the formerly described prohibitively high, transplant-associated mortality in this condition. HCT abrogates the problems of ERT, namely attenuating ADA, the need for continuing venous access, and continuing high cost drug treatment. HCT also brings improved efficacy, particularly evident in improved gastrointestinal function and histology. Multimodal therapy should be considered a new paradigm of treatment for Wolman disease patients where there is an attenuated response to ERT, and for all patients where there is a well-matched transplant donor, in order to improve long term gut function, tolerance of a normal diet and quality of life.
BACKGROUND:Use of outcome measures (OMs) in adult neurologic physical therapy is essential for monitoring changes in a patientʼs status over time, quantifying observations and patient-reported ...function, enhancing communication, and increasing the efficiency of patient care. OMs also provide a mechanism to compare patient and organizational outcomes, examine intervention effectiveness, and generate new knowledge. This clinical practice guideline (CPG) examined the literature related to OMs of balance, gait, transfers, and patient-stated goals to identify a core set of OMs for use across adults with neurologic conditions and practice settings.
METHODS:To determine the scope of this CPG, surveys were conducted to assess the needs and priorities of consumers and physical therapists. OMs were identified through recommendations of the Academy of Neurologic Physical Therapyʼs Evidence Database to Guide Effectiveness task forces. A systematic review of the literature on the OMs was conducted and additional OMs were identified; the literature search was repeated on these measures. Articles meeting the inclusion criteria were critically appraised by 2 reviewers using a modified version of the COnsensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) checklist. Methodological quality and the strength of statistical results were determined. To be recommended for the core set, the OMs needed to demonstrate excellent psychometric properties in high-quality studies across neurologic conditions.
RESULTS/DISCUSSION:Based on survey results, the CPG focuses on OMs that have acceptable clinical utility and can be used to assess change over time in a patientʼs balance, gait, transfers, and patient-stated goals. Strong, level I evidence supports the use of the Berg Balance Scale to assess changes in static and dynamic sitting and standing balance and the Activities-specific Balance Confidence Scale to assess changes in balance confidence. Strong to moderate evidence supports the use of the Functional Gait Assessment to assess changes in dynamic balance while walking, the 10-m walk test to assess changes in gait speed, and the 6-minute walk test to assess changes in walking distance. Best practice evidence supports the use of the 5 times sit-to-stand to assess sit to standing transfers. Evidence was insufficient to support use of a specific OM to assess patient-stated goals across adult neurologic conditions. Physical therapists should discuss the OM results with patients and collaboratively decide how the results should inform the plan of care.
DISCLAIMER:The recommendations included in this CPG are intended as a guide for clinicians, patients, educators, and researchers to improve rehabilitation care and its impact on adults with neurologic conditions. The contents of this CPG were developed with support from the APTA and the Academy of Neurologic Physical Therapy (ANPT). The Guideline Development Group (GDG) used a rigorous review process and was able to freely express its findings and recommendations without influence from the APTA or the ANPT. The authors declare no competing interest.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, available athttp://links.lww.com/JNPT/A214).This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Summary
Neurocognitive impairment is common in sickle cell disease (SCD) and is associated with significant functional limitations. In a cross‐sectional analysis, we examined the association between ...hydroxyurea (HU) treatment and neurocognitive functioning from school‐age to young adulthood in individuals with SCD. A total of 215 patients with HbSS/HbSβ0‐thalassaemia (71% HU treated) and 149 patients with HbSC/HbSβ+‐thalassaemia (20% HU treated) completed neurocognitive measures at one of four developmental stages: school‐age (age 8–9 years), early adolescence (age 12–13 years), late adolescence (age 16–17 years) and young adulthood (ages 19–24 years). For participants with multiple assessments, only the most recent evaluation was included. In multivariable analysis adjusted for social vulnerability, HU treatment and sex, older age was associated with a reduction in overall intelligence quotient (IQ) of 0·55 points per year of life standard error (SE) = 0·18, false discovery rate adjusted P value (PFDR) = 0.01 for patients with HbSS/HbSβ0‐thalassaemia. Earlier initiation of HU (n = 152) in HbSS/HbSβ0‐thalassaemia was associated with higher scores on neurocognitive measures across most domains, including IQ estimate (SE) 0·77 (0·25)/year, PFDR = 0·01, after adjusting for social vulnerability, sex and treatment duration. These results support the early use of HU to limit the detrimental neurocognitive effects of SCD, while highlighting the need for additional measures to further mitigate neurocognitive deterioration.
Objective
Women with antiphospholipid antibodies (aPL) are at risk for pregnancy complications associated with poor placentation and placental inflammation. Although these antibodies are ...heterogeneous, some anti–β2‐glycoprotein I (anti‐β2GPI) antibodies can activate Toll‐like receptor 4 (TLR‐4) and NLRP3 in human first‐trimester trophoblasts. The objective of this study was to determine the role of negative regulators of TLR and inflammasome function in aPL‐induced trophoblast inflammation.
Methods
Human trophoblasts were not treated or were treated with anti‐β2GPI aPL or control IgG in the presence or absence of the common TAM (TYRO3, AXL, and Mer tyrosine kinase MERTK) receptor ligand growth arrest–specific protein 6 (GAS6) or the autophagy‐inducer rapamycin. The expression and function of the TAM receptor pathway and autophagy were measured by quantitative reverse transcription–polymerase chain reaction (qRT‐PCR), Western blotting, and enzyme‐linked immunosorbent assay (ELISA). Antiphospholipid antibody–induced trophoblast inflammation was measured by qRT‐PCR, activity assays, and ELISA.
Results
Anti‐β2GPI aPL inhibited trophoblast TAM receptor function by reducing cellular expression of the receptor tyrosine kinases AXL and MERTK and the ligand GAS6. The addition of GAS6 blocked the effects of aPL on the TLR‐4–mediated interleukin‐8 (IL‐8) response. However, the NLRP3 inflammasome‐mediated IL‐1β response was not affected by GAS6, suggesting that another regulatory pathway was involved. Indeed, anti‐β2GPI aPL inhibited basal trophoblast autophagy, and reversing this with rapamycin inhibited aPL‐induced inflammasome function and IL‐1β secretion.
Conclusion
Basal TAM receptor function and autophagy may serve to inhibit trophoblast TLR and inflammasome function, respectively. Impairment of TAM receptor signaling and autophagy by anti‐β2GPI aPL may allow subsequent TLR and inflammasome activity, leading to a robust inflammatory response.
Abstract Plasma corticosterone concentrations increase when birds experience a stressor, and in this study we quantified variation in corticosterone responses for the first time in a species of ...free-living bird. Adelie penguins ( Pygoscelis adeliae ) nesting at Cape Bird on Ross Island in Antarctica were sampled on three occasions. Penguins with relatively low or high corticosterone responses on the first occasion had consistently low or high responses, as previously found for great tits and chickens. A model for birds is proposed in which birds with low corticosterone responses and proactive personalities are likely to be more successful (have greater fitness) in constant or predictable conditions, whilst birds with reactive personalities and high corticosterone responses will be more successful in changing or unpredictable conditions. There is thus no linear relationship between the size of a corticosterone response and fitness. Whilst the absolute magnitude of corticosterone responses varies markedly across species of birds, coefficients of variation are similar. Individual corticosterone responses are generally repeatable, with significant statistical repeatabilities for 30 min corticosterone concentrations and integrated corticosterone concentrations in the Adelie penguin, great tit and chicken. Coefficients of variation in corticosterone responses between birds and power analyses were used to provide a rule of thumb for determining differences between groups of birds in mean corticosterone concentrations to enable statistical analyses to have acceptable levels of statistical power for given sample sizes. It is suggested that power analyses and this rule of thumb be adopted in future investigations of corticosterone responses in birds.
•A subsurface flow compost wetland for Zn removal was investigated over 2 years.•The reactor had a very short hydraulic residence time of 7.5–14.5h.•Mean total Zn removal was 67.5% and mean filtered ...(0.45μm) Zn removal was 84.4%.•Aqueous geochemical modelling showed ZnS to be the main solid phase sink for Zn.•Up to 12,227mg/kg Zn, and 9066mg/kg sulfide, accumulated in the compost.
The performance of an innovative pilot-scale subsurface flow compost wetland for the attenuation of zinc in mine drainage was investigated. The particular novelty of the system, which operated under ambient environmental conditions, was the short hydraulic residence time (HRT) of 7.5–14.5h. Short HRT is crucial because it reduces absolute wetland size and construction cost, which can be major impediments to use of wetlands. Over a 2year period mean treatment efficiency was 67.5% (total Zn) and 84.4% (0.45μm filtered Zn). Mean volume-adjusted removal rates for total and filtered Zn were 0.92g/m3/day and 1.05g/m3/day respectively. Both water and compost analyses showed bacterial sulfate reduction to be the most important Zn removal process within the subsurface flow wetland: water analyses showed consistent decreases in sulfate concentration through the system, whilst Acid Volatile Sulfide − Simultaneously Extracted Metals (AVS-SEM) analysis of the compost revealed concentrations of Zn up to 12,227mg/kg and AVS up to 9066mg/kg. Geochemical modelling using PHREEQC also showed that biogeochemical conditions within the wetland favored Zn attenuation as its sulfide: ZnS was the only solid Zn phase that was super-saturated in the wetland effluent water (mean Saturation Index of +9.52). Preliminary investigation of the use of liquid waste carbon sources to further enhance performance were ambiguous, but the results of the research nevertheless show the potential of short hydraulic residence time subsurface flow compost wetlands as a low cost treatment option for metal-polluted abandoned mine drainage.
This open-label, multicenter, phase IB/II study evaluated sapanisertib, a dual inhibitor of mTOR kinase complexes 1/2, plus exemestane or fulvestrant in postmenopausal women with hormone ...receptor-positive (HR
)/HER2-negative (HER2
) advanced/metastatic breast cancer.
Eligible patients had previously progressed on everolimus with exemestane/fulvestrant and received ≤3 (phase IB) or ≤1 (phase II) prior chemotherapy regimens. Patients received sapanisertib 3 to 5 mg every day (phase IB), or 4 mg every day (phase II) with exemestane 25 mg every day or fulvestrant 500 mg monthly in 28-day cycles. Phase II enrolled parallel cohorts based on prior response to everolimus. The primary objective of phase II was to evaluate antitumor activity by clinical benefit rate at 16 weeks (CBR-16).
Overall, 118 patients enrolled in phase IB (
= 24) and II (
= 94). Five patients in phase IB experienced dose-limiting toxicities, at sapanisertib doses of 5 mg every day (
= 4) and 4 mg every day (
= 1); sapanisertib 4 mg every day was the MTD in combination with exemestane or fulvestrant. In phase II, in everolimus-sensitive versus everolimus-resistant cohorts, CBR-16 was 45% versus 23%, and overall response rate was 8% versus 2%, respectively. The most common adverse events were nausea (52%), fatigue (47%), diarrhea (37%), and hyperglycemia (33%); rash occurred in 17% of patients. Molecular analysis suggested positive association between
mutation status and best treatment response (complete + partial response;
= 0.0262).
Sapanisertib plus exemestane or fulvestrant was well tolerated and exhibited clinical benefit in postmenopausal women with pretreated everolimus-sensitive or everolimus-resistant breast cancer.
Abstract
Context
Resistance exercise training (strength training) and aerobic exercise training are both recommended for people with type 1 diabetes, but it is unknown whether adding resistance ...exercise provides incremental benefits in people with this condition who already perform aerobic exercise regularly.
Objective
This work aimed to evaluate the incremental effect of resistance training on glycated hemoglobin A1c (HbA1c), fitness, body composition, and cardiometabolic risk factors in aerobically active people with type 1 diabetes.
Methods
The Resistance Exercise in Already-active Diabetic Individuals (READI) trial (NCT00410436) was a 4-center, randomized, parallel-group trial. After a 5-week run-in period with diabetes management optimization, 131 aerobically active individuals with type 1 diabetes were randomly assigned to resistance exercise (n = 71, intervention—INT) or control (n = 60, CON) for 22 additional weeks. Both groups maintained their aerobic activities and were provided dietary counseling throughout. Exercise training was 3 times per week at community-based facilities. The primary outcome was HbA1c, and secondary outcomes included fitness (peak oxygen consumption, muscle strength), body composition (anthropometrics, dual-energy x-ray absorptiometry, computed tomography), and cardiometabolic risk markers (lipids, apolipoproteins). Assessors were blinded to group allocation.
Results
There were no significant differences in HbA1c change between INT and CON. Declines in HbA1c (INT: 7.75 ± 0.10% 61.2 ± 1.1 mmol/mol to 7.55 ± 0.10% 59 ± 1.1 mmol/mol; CON: 7.70 ± 0.11% 60.7 ± 1.2 mmol/mol to 7.57 ± 0.11% 59.6 ± 1.3 mmol/mol; intergroup difference in change −0.07 95% CI, −0.31 to 0.18). Waist circumference decreased more in INT than CON after 6 months (P = .02). Muscular strength increased more in INT than in CON (P < .001). There were no intergroup differences in hypoglycemia or any other variables.
Conclusion
Adding resistance training did not affect glycemia, but it increased strength and reduced waist circumference, in aerobically active individuals with type 1 diabetes.
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