Are mice good models for human neuromuscular disease? Comparing muscle excursions in walking between mice and humans

The mouse is one of the most widely used animal models to study neuromuscular diseases and test new therapeutic strategies. However, findings from successful pre-clinical studies using mouse models frequently fail to translate to humans due to various factors. Differences in muscle function between the two species could be crucial but often have been overlooked. The purpose of this study was to evaluate and compare muscle excursions in walking between mice and humans

Efficacy and safety of obinutuzumab in systemic lupus erythematosus patients with secondary non-response to rituximab

OBJECTIVE: Secondary inefficacy with infusion reactions and anti-drug antibodies (secondary non-depletion nonresponse, 2NDNR) occurs in 14% of SLE patients receiving repeated rituximab courses. We evaluated baseline clinical characteristics, efficacy and safety of obinutuzumab, a next-generation humanized type-2 anti-CD20 antibody licensed for haematological malignancies in SLE patients with 2NDNR to rituximab. METHODS: We collated data from SLE patients receiving obinutuzumab for secondary non-response to rituximab in BILAG centres. Disease activity was assessed using BILAG-2004, SLEDAI-2K and serology before, and 6 months after, obinutuzumab 2× 1000 mg infusions alongside methylprednisolone 100 mg. RESULTS: All nine patients included in the study received obinutuzumab with concomitant oral immunosuppression. At 6 months post-obinutuzumab, there were significant reductions in median SLEDAI-2K from 12 to 6 (P = 0.014) and total BILAG-2004 score from 21 to 2 (P = 0.009). Complement C3 and dsDNA titres improved significantly (both P = 0.04). Numerical, but not statistically significant improvements were seen in C4 levels. Of 8/9 patients receiving concomitant oral prednisolone at baseline (all >10 mg/day), 5/8 had their dose reduced at 6 months. Four of nine patients were on 5 mg/day and were in Lupus Low Disease Activity State following obinutuzumab. After obinutuzumab, 6/9 patients with peripheral B cell data achieved complete depletion, including 4/4 assessed with highly sensitive assays. Of the nine patients, one obinutuzumab non-responder required CYC therapy. One unvaccinated patient died from COVID-19. CONCLUSIONS: Obinutuzumab appears to be effective and steroid-sparing in renal and non-renal SLE patients with secondary non-response to rituximab. These patients have severe disease with few treatment options but given responsiveness to B cell depletion, switching to humanized type-2 anti-CD20 therapy is a logical approach

A topological classification of convex bodies

The shape of homogeneous, generic, smooth convex bodies as described by the Euclidean distance with nondegenerate critical points, measured from the center of mass represents a rather restricted class M_C of Morse-Smale functions on S^2. Here we show that even M_C exhibits the complexity known for general Morse-Smale functions on S^2 by exhausting all combinatorial possibilities: every 2-colored quadrangulation of the sphere is isomorphic to a suitably represented Morse-Smale complex associated with a function in M_C (and vice versa). We prove our claim by an inductive algorithm, starting from the path graph P_2 and generating convex bodies corresponding to quadrangulations with increasing number of vertices by performing each combinatorially possible vertex splitting by a convexity-preserving local manipulation of the surface. Since convex bodies carrying Morse-Smale complexes isomorphic to P_2 exist, this algorithm not only proves our claim but also generalizes the known classification scheme in [36]. Our expansion algorithm is essentially the dual procedure to the algorithm presented by Edelsbrunner et al. in [21], producing a hierarchy of increasingly coarse Morse-Smale complexes. We point out applications to pebble shapes.Comment: 25 pages, 10 figure

Vaccination against Foot-and-mouth disease : do initial conditions affect its benefit?

When facing incursion of a major livestock infectious disease, the decision to implement a vaccination programme is made at the national level. To make this decision, governments must consider whether the benefits of vaccination are sufficient to outweigh potential additional costs, including further trade restrictions that may be imposed due to the implementation of vaccination. However, little consensus exists on the factors triggering its implementation on the field. This work explores the effect of several triggers in the implementation of a reactive vaccination-to-live policy when facing epidemics of foot-and-mouth disease. In particular, we tested whether changes in the location of the incursion and the delay of implementation would affect the epidemiological benefit of such a policy in the context of Scotland. To reach this goal, we used a spatial, premises-based model that has been extensively used to investigate the effectiveness of mitigation procedures in Great Britain. The results show that the decision to vaccinate, or not, is not straightforward and strongly depends on the underlying local structure of the population-at-risk. With regards to disease incursion preparedness, simply identifying areas of highest population density may not capture all complexities that may influence the spread of disease as well as the benefit of implementing vaccination. However, if a decision to vaccinate is made, we show that delaying its implementation in the field may markedly reduce its benefit. This work provides guidelines to support policy makers in their decision to implement, or not, a vaccination-to-live policy when facing epidemics of infectious livestock disease

The transition between stochastic and deterministic behavior in an excitable gene circuit

We explore the connection between a stochastic simulation model and an ordinary differential equations (ODEs) model of the dynamics of an excitable gene circuit that exhibits noise-induced oscillations. Near a bifurcation point in the ODE model, the stochastic simulation model yields behavior dramatically different from that predicted by the ODE model. We analyze how that behavior depends on the gene copy number and find very slow convergence to the large number limit near the bifurcation point. The implications for understanding the dynamics of gene circuits and other birth-death dynamical systems with small numbers of constituents are discussed.Comment: PLoS ONE: Research Article, published 11 Apr 201

Solitary metastatic adenocarcinoma of the sternum treated by total sternectomy and chest wall reconstruction using a Gore-Tex patch and myocutaneous flap: a case report

<p>Abstract</p> <p>Introduction</p> <p>The consequences of bone metastasis are often devastating. Although the exact incidence of bone metastasis is unknown, it is estimated that 350,000 people die of bone metastasis annually in the United States. The incidence of local recurrences after mastectomy and breast-conserving therapy varies between 5% and 40% depending on the risk factors and primary therapy utilized. So far, a standard therapy of local recurrence has not been defined, while indications of resection and reconstruction considerations have been infrequently described. This case report reviews the use of sternectomy for breast cancer recurrence, highlights the need for thorough clinical and radiologic evaluation to ensure the absence of other systemic diseases, and suggests the use of serratus anterior muscle flap as a pedicle graft to cover full-thickness defects of the anterior chest wall.</p> <p>Case presentation</p> <p>We report the case of a 70-year-old Caucasian woman who was referred to our hospital for the management of a retrosternal mediastinal mass. She had undergone radical mastectomy in 1999. Computed tomography and magnetic resonance imaging revealed a 74.23 × 37.7 × 133.6-mm mass in the anterior mediastinum adjacent to the main pulmonary artery, the right ventricle and the ascending aorta. We performed total sternectomy at all layers encompassing the skin, the subcutaneous tissues, the right pectoralis major muscle, all the costal cartilages, and the anterior part of the pericardium. The defect was immediately closed using a 0.6 mm Gore-Tex cardiovascular patch combined with a serratus anterior muscle flap. Our patient had remained asymptomatic during her follow-up examination after 18 months.</p> <p>Conclusion</p> <p>Chest wall resection has become a critical component of the thoracic surgeon's armamentarium. It may be performed to treat either benign conditions (osteoradionecrosis, osteomyelitis) or malignant diseases. There are, however, very few reports on the results of full-thickness complete chest wall resections for locally recurrent breast cancer with sufficient safety margins, and even fewer reports that describe the operative technique of using the serratus anterior muscle as a pedicled flap.</p

Breakthrough SARS-CoV-2 infections and prediction of moderate-to-severe outcomes during rituximab therapy in patients with rheumatic and musculoskeletal diseases in the UK: a single-centre cohort study

Background Concerns have been raised regarding the reduced immunogenicity of vaccines against COVID-19 in patients with autoimmune diseases treated with rituximab. However, the incidence and severity of breakthrough infections in unbiased samples of patients with specific rheumatic and musculoskeletal diseases are largely unknown. We aimed to assess the incidence of breakthrough SARS-CoV-2 infection, compare rates of moderate-to-severe COVID-19 with any severe infection event, and evaluate predictors of moderate-to-severe COVID-19 outcomes in patients treated with rituximab. Methods We did a retrospective cohort study in all rituximab-treated patients with rheumatic and musculoskeletal diseases in a single centre in Leeds, UK between March 1, 2020 (the index date), and April 1, 2022. Adults aged 18 years and older, who fulfilled classification criteria for established rheumatic and musculoskeletal diseases, and received therapy with at least one rituximab infusion between Sept 1, 2019 (6 months before the pandemic in the UK), and April 1, 2022, were eligible for inclusion in the study. SARS-CoV-2 infection was defined by antigen test or PCR. COVID-19 outcomes were categorised as mild (from ambulatory to hospitalised but not requiring oxygen support) or moderate-to-severe (hospitalised and requiring oxygen support or death). The primary outcome was breakthrough COVID-19 infection, which was defined as an infection occurring 14 days or more after the second vaccine dose. Predictors of moderate-to-severe COVID-19 outcomes were analysed using Cox regression proportional hazards. Findings Of the 1280 patients who were treated with at least one cycle of rituximab since Jan 1, 2002, 485 (38%) remained on rituximab therapy on April 1, 2022. Of these patients, 400 fulfilled all inclusion criteria and were included in our final analysis. The mean age at the index date was 58·9 years (SD 14·6), 288 (72%) of 400 patients were female and 112 (28%) were male, 333 (83%) were White, and 110 (28%) had two or more comorbidities. 272 (68%) of 400 patients had rheumatoid arthritis, 48 (12%) had systemic lupus erythematosus, 48 (12%) had anti-neutrophil cytoplasmic antibody-associated vasculitis, and 46 (12%) had other rheumatic and musculoskeletal diseases. During the study, 798 rituximab cycles were administered. Of the 398 (>99%) of 400 patients with vaccine data, 372 (93%) were fully vaccinated. Over the 774·6 patient-years of follow-up, there was an incremental increase in all SARS-CoV-2 severity types over the three pandemic phases (wild-type or alpha, delta, and omicron), but most infections were mild. The rates of moderate-to-severe COVID-19 were broadly similar across these three variant phases. Of 370 patients who were fully vaccinated and with complete data, 110 (30%) had all severity type breakthrough COVID-19, 16 (4%) had moderate-to-severe breakthrough COVID-19, and one (<1%) died. In the post-vaccination phase (after Dec 18, 2020), the incidence rates of all severity type and moderate-to-severe COVID-19 were substantially lower in those who were fully vaccinated compared with unvaccinated or partially vaccinated individuals (22·83 per 100 person-years [95% CI 18·94–27·52] in those who were fully vaccinated vs 89·46 per 100 person-years [52·98–151·05] in those who were partially vaccinated or unvaccinated for infections of all severities, and 3·32 per 100 person-years [2·03–5·42] in those who were fully vaccinated vs 25·56 per 100 person-years [9·59–68·10] in those who were partially vaccinated or unvaccinated for moderate-to-severe infections). The rate of moderate-to-severe COVID-19 was broadly similar to other severe infection events in this cohort (5·68 per 100 person-years [95% CI 4·22–7·63]). In multivariable Cox regression analysis, factors associated with an increased risk of moderate-to-severe COVID-19 were the number of comorbidities (hazard ratio 1·46 [95% CI 1·13–1·89]; p=0·0037) and hypogammaglobulinaemia (defined by a pre-rituximab IgG concentration of <6 g/L; 3·22 [1·27–8·19]; p=0·014). This risk was reduced with each vaccine dose received (0·49 [0·37–0·65]; p<0·0001). Other factors, including concomitant prednisolone use, rituximab-associated factors (eg, rituximab dose and time to vaccination since last rituximab dose), and vaccine-associated factors (eg, vaccine type and peripheral B-cell depletion) were not predictive of moderate-to-severe COVID-19 outcomes. Interpretation This study presented detailed analyses of rituximab-treated patients during various phases of the COVID-19 pandemic. In later stages of the pandemic, the SARS-CoV-2 breakthrough infection rate was high but severe COVID-19 rates were similar to any severe infection event rate in patients who were vaccinated. The risk–benefit ratio might still favour rituximab in vaccinated patients with severe rheumatic and musculoskeletal diseases who have few other treatment options. Increased vigilance is needed in the presence of comorbidities and hypogammaglobulinaemia for all infection types

Predicting Sustained Clinical Response to Rituximab in Moderate to Severe Systemic Manifestations of Primary Sjögren Syndrome

Objective To assess outcomes of repeat rituximab cycles and identify predictors of sustained clinical response in systemic manifestations of primary Sjögren syndrome (pSS). Methods An observational study was conducted in 40 rituximab-treated patients with pSS. Clinical response was defined as a 3-point or more reduction in the European League Against Rheumatism (EULAR) Sjögren Disease Activity Index (ESSDAI) at 6 months from baseline. Peripheral blood B cells were measured using highly sensitive flow cytometry. Predictors of sustained response (within two rituximab cycles) were analyzed using penalized logistic regression. Results Thirty-eight out of 40 patients had moderate to severe systemic disease (ESSDAI >5). Main domains were articular (73%), mucocutaneous (23%), hematological (20%), and nervous system (18%). Twenty-eight out of 40 (70%) patients were on concomitant immunosuppressants. One hundred sixty-nine rituximab cycles were administered with a total follow-up of 165 patient-years. In cycle 1 (C1), 29/40 (73%) achieved ESSDAI response. Of C1 responders, 23/29 received retreatment on clinical relapse, and 15/23 (65%) responded. Of the 8/23 patients who lost response, these were due to secondary non-depletion and non-response (2NDNR; 4/23 [17%] as we previously observed in systemic lupus erythematosus with antirituximab antibodies, inefficacy = 2/23, and other side effects = 2/23). Within two cycles, 13/40 (33%) discontinued therapy. In multivariable analysis, concomitant immunosuppressant (odds ratio 7.16 [95% confidence interval: 1.37–37.35]) and achieving complete B-cell depletion (9.78 [1.32–72.25]) in C1 increased odds of response to rituximab. At 5 years, 57% of patients continued on rituximab. Conclusion Our data suggest that patients with pSS should be co-prescribed immunosuppressant with rituximab, and treatment should aim to achieve complete depletion. About one in six patients develop 2NDNR in repeat cycles. Humanized or type 2 anti-CD20 antibodies may improve clinical response in extra-glandular pSS

Health-related quality of life in patients with a germline BRCA mutation and metastatic pancreatic cancer receiving maintenance olaparib

BACKGROUND: Patients with metastatic pancreatic cancer (mPC) often have a detriment in health-related quality of life (HRQoL). In the randomized, double-blind, Phase III POLO trial progression-free survival was significantly longer with maintenance olaparib, a poly(ADP-ribose) polymerase inhibitor, than placebo in patients with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and mPC whose disease had not progressed during first-line platinum-based chemotherapy. The prespecified HRQoL evaluation is reported here. PATIENTS AND METHODS: Patients were randomized to receive maintenance olaparib (300 mg bid; tablets) or placebo. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module at baseline, every 4 weeks until disease progression, at discontinuation, and 30 days after last dose. Scores ranged from 0 to 100; a ≥ 10-point change or difference between arms was considered clinically meaningful. Adjusted mean change from baseline was analysed using a mixed model for repeated measures. Time to sustained clinically meaningful deterioration (TSCMD) was analysed using a log-rank test. RESULTS: Of 154 randomized patients, 89 of 92 olaparib-arm and 58 of 62 placebo-arm patients were included in HRQoL analyses. The adjusted mean change in Global Health Status (GHS) score from baseline was less than 10 points in both arms and there was no significant between-group difference (-2.47; 95% CI - 7.27, 2.33; P=0.31). Analysis of physical functioning scores showed a significant between-group difference (-4.45 points; 95% CI - 8.75, -0.16; P=0.04). There was no difference in TSCMD for olaparib versus placebo for GHS (P=0.25; HR 0.72; 95% CI 0.41, 1.27) or physical functioning (P=0.32; HR 1.38; 95%CI 0.73, 2.63). CONCLUSIONS: HRQoL was preserved with maintenance olaparib treatment with no clinically meaningful difference compared with placebo. These results support the observed efficacy benefit of maintenance olaparib in patients with a gBRCAm and mPC. CLINCALTRIALS.GOV NUMBER: NCT02184195

A Novel Tandem Mass Spectrometry Method for Rapid Confirmation of Medium- and Very Long-Chain acyl-CoA Dehydrogenase Deficiency in Newborns

BACKGROUND:Newborn screening for medium- and very long-chain acyl-CoA dehydrogenase (MCAD and VLCAD, respectively) deficiency, using acylcarnitine profiling with tandem mass spectrometry, has increased the number of patients with fatty acid oxidation disorders due to the identification of additional milder, and so far silent, phenotypes. However, especially for VLCADD, the acylcarnitine profile can not constitute the sole parameter in order to reliably confirm disease. Therefore, we developed a new liquid chromatography tandem mass spectrometry (LC-MS/MS) method to rapidly determine both MCAD- and/or VLCAD-activity in human lymphocytes in order to confirm diagnosis. METHODOLOGY:LC-MS/MS was used to measure MCAD- or VLCAD-catalyzed production of enoyl-CoA and hydroxyacyl-CoA, in human lymphocytes. PRINCIPAL FINDINGS:VLCAD activity in controls was 6.95+/-0.42 mU/mg (range 1.95 to 11.91 mU/mg). Residual VLCAD activity of 4 patients with confirmed VLCAD-deficiency was between 0.3 and 1.1%. Heterozygous ACADVL mutation carriers showed residual VLCAD activities of 23.7 to 54.2%. MCAD activity in controls was 2.38+/-0.18 mU/mg. In total, 28 patients with suspected MCAD-deficiency were assayed. Nearly all patients with residual MCAD activities below 2.5% were homozygous 985A>G carriers. MCAD-deficient patients with one other than the 985A>G mutation had higher MCAD residual activities, ranging from 5.7 to 13.9%. All patients with the 199T>C mutation had residual activities above 10%. CONCLUSIONS:Our newly developed LC-MS/MS method is able to provide ample sensitivity to correctly and rapidly determine MCAD and VLCAD residual activity in human lymphocytes. Importantly, based on measured MCAD residual activities in correlation with genotype, new insights were obtained on the expected clinical phenotype