TRPV4 neuromuscular disease registry highlights bulbar, skeletal and proximal limb manifestations.

Dominant missense mutations of the calcium-permeable cation channel TRPV4 cause Charcot-Marie-Tooth disease (CMT) type 2C and two forms of distal spinal muscular atrophy. These conditions are collectively referred to as TRPV4-related neuromuscular disease and share features of motor greater than sensory dysfunction and frequent vocal fold weakness. Pathogenic variants lead to gain of ion channel function that can be rescued by TRPV4 antagonists in cellular and animal models. As small molecule TRPV4 antagonists have proven safe in trials for other disease indications, channel inhibition is a promising therapeutic strategy for TRPV4 patients. However, the current knowledge of the clinical features and natural history of TRPV4-related neuromuscular disease is insufficient to enable rational clinical trial design. To address these issues, we developed a TRPV4 patient database and administered a TRPV4-specific patient questionnaire. Here, we report demographic and clinical information, including CMT examination scores (CMTES), from 68 patients with known pathogenic TRPV4 variants, 40 of whom also completed the TRPV4 patient questionnaire. TRPV4 patients showed a bimodal age of onset, with the largest peak occurring in the first 2 years of life. Compared to CMT1A patients, TRPV4 patients showed distinct symptoms and signs, manifesting more ambulatory difficulties and more frequent involvement of proximal arm and leg muscles. Although patients reported fewer sensory symptoms, sensory dysfunction was often detected clinically. Many patients were affected by vocal fold weakness (55%) and shortness of breath (55%), and 11% required ventilatory support. Skeletal abnormalities were common, including scoliosis (64%), arthrogryposis (33%), and foot deformities. Strikingly, patients with infantile onset of disease showed less sensory involvement and less progression of symptoms. These results highlight distinctive clinical features in TRPV4 patients, including motor-predominant disease, proximal arm and leg weakness, severe ambulatory difficulties, vocal fold weakness, respiratory dysfunction, and skeletal involvement. In addition, patients with infantile onset of disease appeared to have a distinct phenotype with less apparent disease progression based on CMTES. These collective observations indicate that clinical trial design for TRPV4-related neuromuscular disease should include outcome measures that reliably capture non-length dependent motor dysfunction, vocal fold weakness, and respiratory disease.

GLA/DRST real-world outcome analysis of CAR T-cell therapies for large B-cell lymphoma in Germany.

CD19-directed chimeric antigen receptor (CAR) T cells have evolved as a new standard-of-care (SOC) treatment in patients with relapsed/refractory (r/r) large B-cell lymphoma (LBCL). Here, we report the first German real-world data on SOC CAR T-cell therapies with the aim to explore risk factors associated with outcomes. Patients who received SOC axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for LBCL and were registered with the German Registry for Stem Cell Transplantation (DRST) were eligible. The main outcomes analyzed were toxicities, response, overall survival (OS), and progression-free survival (PFS). We report 356 patients who received axi-cel (n = 173) or tisa-cel (n = 183) between November 2018 and April 2021 at 21 German centers. Whereas the axi-cel and tisa-cel cohorts were comparable for age, sex, lactate dehydrogenase (LDH), international prognostic index (IPI), and pretreatment, the tisa-cel group comprised significantly more patients with poor performance status, ineligibility for ZUMA-1, and the need for bridging, respectively. With a median follow-up of 11 months, Kaplan-Meier estimates of OS, PFS, and nonrelapse mortality (NRM) 12 months after dosing were 52%, 30%, and 6%, respectively. While NRM was largely driven by infections subsequent to prolonged neutropenia and/or severe neurotoxicity and significantly higher with axi-cel, significant risk factors for PFS on the multivariate analysis included bridging failure, elevated LDH, age, and tisa-cel use. In conclusion, this study suggests that important outcome determinants of CD19-directed CAR T-cell treatment of LBCL in the real-world setting are bridging success, CAR-T product selection, LDH, and the absence of prolonged neutropenia and/or severe neurotoxicity. These findings may have implications for designing risk-adapted CAR T-cell therapy strategies.

D-2-hydroxyglutarate supports a tolerogenic phenotype with lowered major histocompatibility class II expression in non-malignant dendritic cells and acute myeloid leukemia cells.

D-2-hydroxyglutarate (D-2-HG) accumulates in primary acute myeloid leukemia (AML) patients with mutated isocitrate dehydrogenase (IDH) and other malignancies. D-2-HG suppresses antitumor T cell immunity but little is known about potential effects on non-malignant myeloid cells. Here we show that D-2-HG impairs human but not murine dendritic cell (DC) differentiation, resulting in a tolerogenic phenotype with low major histocompatibility (MHC) class II expression. In line, IDH-mutated AML blasts exhibited lower expression of HLA-DP and were less susceptible to lysis by HLA-DP-specific T cells. Interestingly, D-2-HG reprogrammed metabolism towards increased lactate production in DCs and AML besides its expected impact on DNA demethylation. Vitamin C accelerated DNA demethylation, but only the combination of vitamin C and glycolytic inhibition lowered lactate levels and supported MHC class II expression. Our results indicate an unexpected link between the immunosuppressive metabolites 2-HG and lactic acid and suggest a potentially novel therapeutic strategy with combinations of anti-glycolytic drugs and epigenetic modulators (hypomethylating agents) or other therapeutics for the treatment of AML.

Plasma proteomic analysis on neuropathic pain in idiopathic peripheral neuropathy patients.

BACKGROUND AND AIMS: Why only half of the idiopathic peripheral neuropathy (IPN) patients develop neuropathic pain remains unknown. By conducting a proteomics analysis on IPN patients, we aimed to discover proteins and new pathways that are associated with neuropathic pain. METHODS: We conducted unbiased mass-spectrometry proteomics analysis on blood plasma from 31 IPN patients with severe neuropathic pain and 29 IPN patients with no pain, to investigate protein biomarkers and protein-protein interactions associated with neuropathic pain. Univariate modeling was done with linear mixed modeling (LMM) and corrected for multiple testing. Multivariate modeling was performed using elastic net analysis and validated with internal cross-validation and bootstrapping. RESULTS: In the univariate analysis, 73 proteins showed a p-value <.05 and 12 proteins showed a p-value <.01. None were significant after Benjamini-Hochberg adjustment for multiple testing. Elastic net analysis created a model containing 12 proteins with reasonable discriminatory power to differentiate between painful and painless IPN (false-negative rate 0.10, false-positive rate 0.18, and an area under the curve 0.75). Eight of these 12 proteins were clustered into one interaction network, significantly enriched for the complement and coagulation pathway (Benjamini-Hochberg adjusted p-value = .0057), with complement component 3 (C3) as the central node. Bootstrap validation identified insulin-like growth factor-binding protein 2 (IGFBP2), complement factor H-related protein 4 (CFHR4), and ferritin light chain (FTL), as the most discriminatory proteins of the original 12 identified. INTERPRETATION: This proteomics analysis suggests a role for the complement system in neuropathic pain in IPN.

Considerations for establishing and maintaining international research collaboration: the example of chemotherapy-induced peripheral neurotoxicity (CIPN)-a white paper.

PURPOSE: This white paper provides guidance regarding the process for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research. METHODS: An international multidisciplinary group of CIPN scientists, clinicians, research administrators, and legal experts have pooled their collective knowledge regarding recommendations for establishing and maintaining international collaboration to foster advancement of CIPN science. RESULTS: Experts provide recommendations in 10 categories: (1) preclinical and (2) clinical research collaboration; (3) collaborators and consortiums; (4) communication; (5) funding; (6) international regulatory standards; (7) staff training; (8) data management, quality control, and data sharing; (9) dissemination across disciplines and countries; and (10) additional recommendations about feasibility, policy, and mentorship. CONCLUSION: Recommendations to establish and maintain international CIPN research collaboration will promote the inclusion of more diverse research participants, increasing consideration of cultural and genetic factors that are essential to inform innovative precision medicine interventions and propel scientific discovery to benefit cancer survivors worldwide. RELEVANCE TO INFORM RESEARCH POLICY: Our suggested guidelines for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research set forth a challenge to multinational science, clinical, and policy leaders to (1) develop simple, streamlined research designs; (2) address logistical barriers; (3) simplify and standardize regulatory requirements across countries; (4) increase funding to support international collaboration; and (5) foster faculty mentorship.

Siglec-6 is a novel target for CAR T-cell therapy in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an attractive entity for the development of chimeric antigen receptor (CAR) T-cell immunotherapy because AML blasts are susceptible to T-cell-mediated elimination. Here, we introduce sialic acid-binding immunoglobulin-like lectin 6 (Siglec-6) as a novel target for CAR T cells in AML. We designed a Siglec-6-specific CAR with a targeting domain derived from the human monoclonal antibody JML-1. We found that Siglec-6 is commonly expressed on AML cell lines and primary AML blasts, including the subpopulation of AML stem cells. Treatment with Siglec-6 CAR T cells confers specific antileukemia reactivity that correlates with Siglec-6 expression in preclinical models, including induction of complete remission in a xenograft AML model in immunodeficient mice (NSG/U937). In addition, we confirmed Siglec-6 expression on transformed B cells in chronic lymphocytic leukemia (CLL), and specific anti-CLL reactivity of Siglec-6 CAR T cells in vitro. Of particular interest, we found that Siglec-6 is not detectable on normal hematopoietic stem and progenitor cells (HSPCs) and that treatment with Siglec-6 CAR T cells does not affect their viability and lineage differentiation in colony-formation assays. These data suggest that Siglec-6 CAR T-cell therapy may be used to effectively treat AML without the need for subsequent allogeneic hematopoietic stem cell transplantation. In mature normal hematopoietic cells, we detected Siglec-6 in a proportion of memory (and naïve) B cells and basophilic granulocytes, suggesting the potential for limited on-target/off-tumor reactivity. The lack of expression of Siglec-6 on normal HSPCs is a key to differentiating it from other Siglec family members (eg, Siglec-3 [CD33]) and other CAR target antigens (eg, CD123) that are under investigation in AML, and it warrants the clinical investigation of Siglec-6 CAR T-cell therapy.

Apheresis for chimeric antigen receptor T-cell production in adult lymphoma patients.

BACKGROUND: To date, in-depth analysis of leukapheresis products as starting material for CAR T-cell manufacturing, specifically Tisagenlecleucel production, are scarce. In this study, we report on lymphapheresis data for production of Tisagenlecleucel for elderly and pretreated lymphoma patients. STUDY DESIGN AND METHODS: Spectra Optia from Terumo BCT, Lakewood, CO, was employed for apheresis using the cMNC program. Apheresis success was defined as meeting a target total nucleated cell (TNC) count of ≥2 × 109 , a CD3-positive lymphocyte count of ≥1 × 109 and an overall viability of ≥70% in the lymphapheresis product. RESULTS: Twenty-three patients (age 37-77 years) and 24 apheresis runs were evaluated. The median CD3-positive lymphocyte count in peripheral blood at the beginning of apheresis was 565 cells/µl (range: 70-1345 cells/µl). Circulating lymphoma cells were detected in one patient prior to apheresis. Target criteria were met in 21 of 23 patients. The median TNC count in the apheresate was 11.2 × 109 (range: 2.9 × 109 -47.4 × 109 ). The median CD3-positive lymphocyte count in the apheresate was 2.55 × 109 (range: 0.370 × 109 -6.915 × 109 ), which resulted in a median collection efficiency for CD3-positive lymphocytes of 63.7% (range: 9.56%-93.6%). No adverse events associated with the apheresis process were observed. CONCLUSIONS: Lymphapheresis with the Spectra Optia cMNC program provided a sufficient quantity of CD3-positive lymphocytes for CAR T-cell manufacturing for the majority of patients despite their heavy pretreatment and advanced age. Moreover, we are the first to advocate early pre-emptive lymphocyte collection in DLBCL-NOS patients intended to undergo treatment with Tisagenlecleucel.

Vitamin B6 levels do not correlate with severity of neuropathy in chronic idiopathic axonal polyneuropathy.

Pyridoxine (vitamin B6) toxicity is known to cause a length-dependent, sensory predominant axonal polyneuropathy. There is debate regarding the threshold at which intake levels can cause neurological symptoms through pyridoxine toxicity. We asked if elevated plasma vitamin B6 levels were related to outcome measures in a well-characterized cohort of patients with chronic idiopathic axonal polyneuropathy (CIAP). We included 261 patients enrolled in the Peripheral Neuropathy Research Registry who had a complete dataset including a plasma vitamin B6 value. Patients with vitamin B6 deficiency (0-4.9 µg/L) were excluded. We performed a chi-square test for independence and analyzed the logistic relation of elevated plasma B6 level to nerve conduction studies (NCS), neurological examination findings, and patient-reported symptoms controlling for age and time elapsed since neuropathy symptom onset. Plasma B6 level was not related to neuropathy severity. There was no logistic relation of elevated plasma B6 level to NCS results, examination features including toe strength, vibration sense, and deep tendon reflexes, or patient-reported numbness or pain intensity. This study suggests that moderately elevated plasma B6 levels, even in the 100 to 200 µg/L range, are not associated with significantly worse neuropathy signs or symptoms. Although standard supplementation of B6 does not appear to have a major negative affect on CIAP, this study does not directly answer whether stopping supplementation will have a beneficial effect. Very few patients in the study had vitamin B6 levels >300 µg/L, suggesting that screening for vitamin B6 toxicity may be left to the discretion of the physician.

LDHB Overexpression Can Partially Overcome T Cell Inhibition by Lactic Acid.

Accelerated glycolysis leads to secretion and accumulation of lactate and protons in the tumor environment and determines the efficacy of adoptive T cell and checkpoint inhibition therapy. Here, we analyzed effects of lactic acid on different human CD4 T cell subsets and aimed to increase CD4 T cell resistance towards lactic acid. In all CD4 T cell subsets analyzed, lactic acid inhibited metabolic activity (glycolysis and respiration), cytokine secretion, and cell proliferation. Overexpression of the lactate-metabolizing isoenzyme LDHB increased cell respiration and mitigated lactic acid effects on intracellular cytokine production. Strikingly, LDHB-overexpressing cells preferentially migrated into HCT116 tumor spheroids and displayed higher expression of cytotoxic effector molecules. We conclude, that LDHB overexpression might be a promising strategy to increase the efficacy of adoptive T cell transfer therapy.

Relation of exercise and pain in patients with idiopathic distal axonal polyneuropathies.

Although exercise is associated with better outcomes in patients with some peripheral neuropathies, data in idiopathic peripheral neuropathies is lacking. This study was completed to do a comprehensive data analysis about the benefits of regular exercise in a well-characterized cohort of patients with idiopathic distal, symmetrical, axonal polyneuropathy enrolled in the Peripheral Neuropathy Research Registry (PNRR) at Johns Hopkins University School of Medicine. From the patient-reported exercise habits, metabolic equivalents (METs) were calculated and the patient information was grouped into four categories. The PNRR data set, including patient reported pain, numbness, and weakness, was analyzed using the METs categories to evaluate for the benefits of exercise. We controlled for the components of metabolic syndrome including Hemoglobin A1c (HbA1c), systolic and diastolic blood pressure (BP), high density lipids (HDL) and triglyceride level, and body mass index (BMI) as defined by the Adult Treatment Panel III Guidelines. Lower METs were associated with neuropathic pain, but not with other peripheral neuropathy symptoms. Patients with IPN who exercised were less likely to have painful neuropathy independent of the average METs per week (P < .01). No significant differences were seen for patient reported numbness, weakness, or balance issues. The data suggests that patients with idiopathic neuropathy benefit from exercises even if performed on a low intensity level or less frequently, and patients are less likely to have severe pain symptoms when exercising on a regular basis.

Electromechanical-assisted training for walking after stroke.

BACKGROUND: Electromechanical- and robot-assisted gait-training devices are used in rehabilitation and might help to improve walking after stroke. This is an update of a Cochrane Review first published in 2007 and previously updated in 2017. OBJECTIVES: Primary • To determine whether electromechanical- and robot-assisted gait training versus normal care improves walking after stroke Secondary • To determine whether electromechanical- and robot-assisted gait training versus normal care after stroke improves walking velocity, walking capacity, acceptability, and death from all causes until the end of the intervention phase SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched 6 January 2020); the Cochrane Central Register of Controlled Trials (CENTRAL; 2020 Issue 1), in the Cochrane Library; MEDLINE in Ovid (1950 to 6 January 2020); Embase (1980 to 6 January 2020); the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 20 November 2019); the Allied and Complementary Medicine Database (AMED; 1985 to 6 January 2020); Web of Science (1899 to 7 January 2020); SPORTDiscus (1949 to 6 January 2020); the Physiotherapy Evidence Database (PEDro; searched 7 January 2020); and the engineering databases COMPENDEX (1972 to 16 January 2020) and Inspec (1969 to 6 January 2020). We handsearched relevant conference proceedings, searched trials and research registers, checked reference lists, and contacted trial authors in an effort to identify further published, unpublished, and ongoing trials. SELECTION CRITERIA: We included all randomised controlled trials and randomised controlled cross-over trials in people over the age of 18 years diagnosed with stroke of any severity, at any stage, in any setting, evaluating electromechanical- and robot-assisted gait training versus normal care. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed methodological quality and risk of bias, and extracted data. We assessed the quality of evidence using the GRADE approach. The primary outcome was the proportion of participants walking independently at follow-up. MAIN RESULTS: We included in this review update 62 trials involving 2440 participants. Electromechanical-assisted gait training in combination with physiotherapy increased the odds of participants becoming independent in walking (odds ratio (random effects) 2.01, 95% confidence interval (CI) 1.51 to 2.69; 38 studies, 1567 participants; P < 0.00001; I² = 0%; high-quality evidence) and increased mean walking velocity (mean difference (MD) 0.06 m/s, 95% CI 0.02 to 0.10; 42 studies, 1600 participants; P = 0.004; I² = 60%; low-quality evidence) but did not improve mean walking capacity (MD 10.9 metres walked in 6 minutes, 95% CI -5.7 to 27.4; 24 studies, 983 participants; P = 0.2; I² = 42%; moderate-quality evidence). Electromechanical-assisted gait training did not increase the risk of loss to the study during intervention nor the risk of death from all causes. Results must be interpreted with caution because (1) some trials investigated people who were independent in walking at the start of the study, (2) we found variation between trials with respect to devices used and duration and frequency of treatment, and (3) some trials included devices with functional electrical stimulation. Post hoc analysis showed that people who are non-ambulatory at the start of the intervention may benefit but ambulatory people may not benefit from this type of training. Post hoc analysis showed no differences between the types of devices used in studies regarding ability to walk but revealed differences between devices in terms of walking velocity and capacity. AUTHORS' CONCLUSIONS: People who receive electromechanical-assisted gait training in combination with physiotherapy after stroke are more likely to achieve independent walking than people who receive gait training without these devices. We concluded that eight patients need to be treated to prevent one dependency in walking. Specifically, people in the first three months after stroke and those who are not able to walk seem to benefit most from this type of intervention. The role of the type of device is still not clear. Further research should consist of large definitive pragmatic phase 3 trials undertaken to address specific questions about the most effective frequency and duration of electromechanical-assisted gait training, as well as how long any benefit may last. Future trials should consider time post stroke in their trial design.

Efficient Delivery of Human Cytomegalovirus T Cell Antigens by Attenuated Sendai Virus Vectors.

Human cytomegalovirus (HCMV) represents a major cause of clinical complications during pregnancy as well as immunosuppression, and the licensing of a protective HCMV vaccine remains an unmet global need. Here, we designed and validated novel Sendai virus (SeV) vectors delivering the T cell immunogens IE-1 and pp65. To enhance vector safety, we used a replication-deficient strain (rdSeV) that infects target cells in a nonproductive manner while retaining viral gene expression. In this study, we explored the impact that transduction with rdSeV has on human dendritic cells (DCs) by comparing it to the parental, replication-competent Sendai virus strain (rcSeV) as well as the poxvirus strain modified vaccinia Ankara (MVA). We found that wild-type SeV is capable of replicating to high titers in DCs while rdSeV infects cells abortively. Due to the higher degree of attenuation, IE-1 and pp65 protein levels mediated by rdSeV after infection of DCs were markedly reduced compared to those of the parental Sendai virus recombinants, but antigen-specific restimulation of T cell clones was not negatively affected by this. Importantly, rdSeV showed reduced cytotoxic effects compared to rcSeV and MVA and was capable of mediating DC maturation as well as secretion of alpha interferon and interleukin-6. Finally, in a challenge model with a murine cytomegalovirus (MCMV) strain carrying an HCMV pp65 peptide, we found that viral replication was restricted if mice were previously vaccinated with rdSeV-pp65. Taken together, these data demonstrate that rdSeV has great potential as a vector system for the delivery of HCMV immunogens.IMPORTANCE HCMV is a highly prevalent betaherpesvirus that establishes lifelong latency after primary infection. Congenital HCMV infection is the most common viral complication in newborns, causing a number of late sequelae ranging from impaired hearing to mental retardation. At the same time, managing HCMV reactivation during immunosuppression remains a major hurdle in posttransplant care. Since options for the treatment of HCMV infection are still limited, the development of a vaccine to confine HCMV-related morbidities is urgently needed. We generated new vaccine candidates in which the main targets of T cell immunity during natural HCMV infection, IE-1 and pp65, are delivered by a replication-deficient, Sendai virus-based vector system. In addition to classical prophylactic vaccine concepts, these vectors could also be used for therapeutic applications, thereby expanding preexisting immunity in high-risk groups such as transplant recipients or for immunotherapy of glioblastomas expressing HCMV antigens.

Peripheral Neuropathy Research Registry: A prospective cohort.

The Peripheral Neuropathy Research Registry (PNRR) is a prospective cohort of peripheral neuropathy (PN) patients focused on idiopathic axonal peripheral neuropathy. Patients with diabetic, human immunodeficiency virus-, and chemotherapy-induced peripheral neuropathies are enrolled as comparison groups. The PNRR is a multi-center collaboration initiated and funded by the Foundation for Peripheral Neuropathy (FPN) with the objective to recruit a well characterized cohort of patients with different phenotypes and symptoms in each diagnostic category, and to advance research through development of biomarkers and identification of previously unknown causes of PN. The overall goal of the initiative is to find disease-altering treatments and better symptom relief for patients. We present the study design, types of data collected, and characteristics of the first 1150 patients enrolled. We also discuss ongoing analyses on this dataset, including untargeted-omics methodologies.

Self-Reported Skin Changes by a Selected Number of Astronauts after Long-Duration Mission on ISS as Part of the Skin B Project.

BACKGROUND: One of the most challenging and important factors of manned space missions is to keep astronauts healthy on orbit. In a study on 46 ISS crew members who were on 6-month (average) missions, skin rashes were the most self-reported event. Furthermore, among notable events, 40% were classified as skin rashes/hypersensitivities. Thus, especially skin conditions during space travel are of major clinical interest and require further research. AIMS: The aim of the study was to determine skin conditions in space flight among US and European astronauts, especially taking into account the terrestrial skin conditions as well as on-orbit skin care habits. METHODS: A preflight questionnaire was given to the astronauts asking about their terrestrial skin care habits and skin conditions/atopy before launch. In addition, they were asked to fill out a postflight questionnaire asking about their on-orbit skin care routine and whether any special observations regarding the skin were made during flight. RESULTS: A total of 23 skin symptoms were recorded by 8 nonatopic astronauts (mean age: 41 years) during the mission. The symptoms were peeling (21.74%), rash (17.39%), dryness (13.04%), severe dryness (8.70%), reddening (8.70%), itchiness (8.70%), bruising (4.35%), skin sensitivity (4.34%), bumps (4.35%), acne (4.35%) and slow healing of contusions and lacerations (4.35%). Especially the hands and feet were affected by skin problems. As a result of this examination, it was shown that the skin symptoms correlate with poor hygiene on orbit, whereas the factor "environment" on the ISS plays a minor role. Surprisingly, 2 astronauts even experienced positive effects on their skin. CONCLUSION: Based on these preliminary data, it is important to pay more attention to skin hygiene and maintenance in space.

Evaluating Human T-Cell Therapy of Cytomegalovirus Organ Disease in HLA-Transgenic Mice.

Reactivation of human cytomegalovirus (HCMV) can cause severe disease in recipients of hematopoietic stem cell transplantation. Although preclinical research in murine models as well as clinical trials have provided 'proof of concept' for infection control by pre-emptive CD8 T-cell immunotherapy, there exists no predictive model to experimentally evaluate parameters that determine antiviral efficacy of human T cells in terms of virus control in functional organs, prevention of organ disease, and host survival benefit. We here introduce a novel mouse model for testing HCMV epitope-specific human T cells. The HCMV UL83/pp65-derived NLV-peptide was presented by transgenic HLA-A2.1 in the context of a lethal infection of NOD/SCID/IL-2rg-/- mice with a chimeric murine CMV, mCMV-NLV. Scenarios of HCMV-seropositive and -seronegative human T-cell donors were modeled by testing peptide-restimulated and T-cell receptor-transduced human T cells, respectively. Upon transfer, the T cells infiltrated host tissues in an epitope-specific manner, confining the infection to nodular inflammatory foci. This resulted in a significant reduction of viral load, diminished organ pathology, and prolonged survival. The model has thus proven its potential for a preclinical testing of the protective antiviral efficacy of HCMV epitope-specific human T cells in the evaluation of new approaches to an immunotherapy of CMV disease.

Treadmill training and body weight support for walking after stroke.

BACKGROUND: Treadmill training, with or without body weight support using a harness, is used in rehabilitation and might help to improve walking after stroke. This is an update of the Cochrane review first published in 2003 and updated in 2005 and 2014. OBJECTIVES: To determine if treadmill training and body weight support, individually or in combination, improve walking ability, quality of life, activities of daily living, dependency or death, and institutionalisation or death, compared with other physiotherapy gait-training interventions after stroke. The secondary objective was to determine the safety and acceptability of this method of gait training. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched 14 February 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) and the Database of Reviews of Effects (DARE) (the Cochrane Library 2017, Issue 2), MEDLINE (1966 to 14 February 2017), Embase (1980 to 14 February 2017), CINAHL (1982 to 14 February 2017), AMED (1985 to 14 February 2017) and SPORTDiscus (1949 to 14 February 2017). We also handsearched relevant conference proceedings and ongoing trials and research registers, screened reference lists, and contacted trialists to identify further trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled and cross-over trials of treadmill training and body weight support, individually or in combination, for the treatment of walking after stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted data, and assessed risk of bias and methodological quality. The primary outcomes investigated were walking speed, endurance, and dependency. MAIN RESULTS: We included 56 trials with 3105 participants in this updated review. The average age of the participants was 60 years, and the studies were carried out in both inpatient and outpatient settings. All participants had at least some walking difficulties and many could not walk without assistance. Overall, the use of treadmill training did not increase the chances of walking independently compared with other physiotherapy interventions (risk difference (RD) -0.00, 95% confidence interval (CI) -0.02 to 0.02; 18 trials, 1210 participants; P = 0.94; I² = 0%; low-quality evidence). Overall, the use of treadmill training in walking rehabilitation for people after stroke increased the walking velocity and walking endurance significantly. The pooled mean difference (MD) (random-effects model) for walking velocity was 0.06 m/s (95% CI 0.03 to 0.09; 47 trials, 2323 participants; P < 0.0001; I² = 44%; moderate-quality evidence) and the pooled MD for walking endurance was 14.19 metres (95% CI 2.92 to 25.46; 28 trials, 1680 participants; P = 0.01; I² = 27%; moderate-quality evidence). Overall, the use of treadmill training with body weight support in walking rehabilitation for people after stroke did not increase the walking velocity and walking endurance at the end of scheduled follow-up. The pooled MD (random-effects model) for walking velocity was 0.03 m/s (95% CI -0.05 to 0.10; 12 trials, 954 participants; P = 0.50; I² = 55%; low-quality evidence) and the pooled MD for walking endurance was 21.64 metres (95% CI -4.70 to 47.98; 10 trials, 882 participants; P = 0.11; I² = 47%; low-quality evidence). In 38 studies with a total of 1571 participants who were independent in walking at study onset, the use of treadmill training increased the walking velocity significantly. The pooled MD (random-effects model) for walking velocity was 0.08 m/s (95% CI 0.05 to 0.12; P < 0.00001; I2 = 49%). There were insufficient data to comment on any effects on quality of life or activities of daily living. Adverse events and dropouts did not occur more frequently in people receiving treadmill training and these were not judged to be clinically serious events. AUTHORS' CONCLUSIONS: Overall, people after stroke who receive treadmill training, with or without body weight support, are not more likely to improve their ability to walk independently compared with people after stroke not receiving treadmill training, but walking speed and walking endurance may improve slightly in the short term. Specifically, people with stroke who are able to walk (but not people who are dependent in walking at start of treatment) appear to benefit most from this type of intervention with regard to walking speed and walking endurance. This review did not find, however, that improvements in walking speed and endurance may have persisting beneficial effects. Further research should specifically investigate the effects of different frequencies, durations, or intensities (in terms of speed increments and inclination) of treadmill training, as well as the use of handrails, in ambulatory participants, but not in dependent walkers.

Electromechanical-assisted training for walking after stroke.

BACKGROUND: Electromechanical- and robotic-assisted gait-training devices are used in rehabilitation and might help to improve walking after stroke. This is an update of a Cochrane Review first published in 2007. OBJECTIVES: To investigate the effects of automated electromechanical- and robotic-assisted gait-training devices for improving walking after stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched 9 August 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 8), MEDLINE in Ovid (1950 to 15 August 2016), Embase (1980 to 15 August 2016), CINAHL (1982 to 15 August 2016), AMED (1985 to 15 August 2016), Web of Science (1899 to 16 August 2016), SPORTDiscus (1949 to 15 September 2012), the Physiotherapy Evidence Database (PEDro) (searched 16 August 2016), and the engineering databases COMPENDEX (1972 to 16 November 2012) and Inspec (1969 to 26 August 2016). We handsearched relevant conference proceedings, searched trials and research registers, checked reference lists, and contacted authors in an effort to identify further published, unpublished, and ongoing trials. SELECTION CRITERIA: We included all randomised controlled trials and randomised controlled cross-over trials in people over the age of 18 years diagnosed with stroke of any severity, at any stage, in any setting, evaluating electromechanical- and robotic-assisted gait training versus normal care. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed methodological quality and risk of bias, and extracted the data. The primary outcome was the proportion of participants walking independently at follow-up. MAIN RESULTS: We included 36 trials involving 1472 participants in this review update. Electromechanical-assisted gait training in combination with physiotherapy increased the odds of participants becoming independent in walking (odds ratio (random effects) 1.94, 95% confidence interval (CI) 1.39 to 2.71; P < 0.001; I² = 8%; moderate-quality evidence) but did not significantly increase walking velocity (mean difference (MD) 0.04 m/s, 95% CI 0.00 to 0.09; P = 0.08; I² = 65%; low-quality evidence) or walking capacity (MD 5.84 metres walked in 6 minutes, 95% CI -16.73 to 28.40; P = 0.61; I² = 53%; very low-quality evidence). The results must be interpreted with caution because 1) some trials investigated people who were independent in walking at the start of the study, 2) we found variations between the trials with respect to devices used and duration and frequency of treatment, and 3) some trials included devices with functional electrical stimulation. Our planned subgroup analysis suggested that people in the acute phase may benefit, but people in the chronic phase may not benefit from electromechanical-assisted gait training. Post hoc analysis showed that people who are non-ambulatory at intervention onset may benefit, but ambulatory people may not benefit from this type of training. Post hoc analysis showed no differences between the types of devices used in studies regarding ability to walk, but significant differences were found between devices in terms of walking velocity. AUTHORS' CONCLUSIONS: People who receive electromechanical-assisted gait training in combination with physiotherapy after stroke are more likely to achieve independent walking than people who receive gait training without these devices. We concluded that seven patients need to be treated to prevent one dependency in walking. Specifically, people in the first three months after stroke and those who are not able to walk seem to benefit most from this type of intervention. The role of the type of device is still not clear. Further research should consist of large definitive pragmatic phase III trials undertaken to address specific questions about the most effective frequency and duration of electromechanical-assisted gait training as well as how long any benefit may last.

Toward Early Identification of Sensory Over-Responsivity (SOR): A Construct for Predicting Difficulties With Sleep and Feeding in Infants.

Sensory over-responsivity (SOR) is a type of sensory modulation disorder in which heightened sensitivity to non-noxious sensations interrupts daily life. In this preliminary study within a larger investigation, we used infants with sleep/feeding difficulties as a proxy for later development of SOR. We tested evidence for construct validity and internal reliability of preand perinatal factors that, together, could predict infant sleep/feeding difficulties. We obtained retrospective data on 360 mother-infant dyads on 38 pre- and perinatal variables and linked the data with infant referral for sleep/feeding difficulties. We analyzed the data with Rasch analysis to examine evidence for a unidimensional construct. Our results show good evidence for a construct comprising 18 of the 38 pre- and perinatal variables examined. This construct may represent a step toward early identification of SOR and provide therapists with evidence to support the use of pre- and perinatal information as predictors of infant sleep/feeding difficulties.