Measures of performance and proficiency in robotic assisted surgery: a systematic review.

Robotic assisted surgery (RAS) has seen a global rise in adoption. Despite this, there is not a standardised training curricula nor a standardised measure of performance. We performed a systematic review across the surgical specialties in RAS and evaluated tools used to assess surgeons' technical performance. Using the PRISMA 2020 guidelines, Pubmed, Embase and the Cochrane Library were searched systematically for full texts published on or after January 2020-January 2022. Observational studies and RCTs were included; review articles and systematic reviews were excluded. The papers' quality and bias score were assessed using the Newcastle Ottawa Score for the observational studies and Cochrane Risk Tool for the RCTs. The initial search yielded 1189 papers of which 72 fit the eligibility criteria. 27 unique performance metrics were identified. Global assessments were the most common tool of assessment (n = 13); the most used was GEARS (Global Evaluative Assessment of Robotic Skills). 11 metrics (42%) were objective tools of performance. Automated performance metrics (APMs) were the most widely used objective metrics whilst the remaining (n = 15, 58%) were subjective. The results demonstrate variation in tools used to assess technical performance in RAS. A large proportion of the metrics are subjective measures which increases the risk of bias amongst users. A standardised objective metric which measures all domains of technical performance from global to cognitive is required. The metric should be applicable to all RAS procedures and easily implementable. Automated performance metrics (APMs) have demonstrated promise in their wide use of accurate measures.

Single use flexible ureteroscopes: a review of current technologies and cost effectiveness analysis.

PURPOSE OF REVIEW: Flexible ureteroscopy (fURS) has evolved into both diagnostic and therapeutic modalities. Our review discusses the cost-effectiveness of single use flexible ureteroscopes (su-fURS) and the use of these instruments in routine urological practice. RECENT FINDINGS: There are studies which support the use of su-fURS with an argument of both cost and clinical utility over reusable flexible ureteroscopes (ru-fURS). However, the cost may vary across countries, hence is difficult to compare the results based on the current literature. Perhaps therefore there is a role for hybrid strategy incorporating ru- and su-fURS, where su-fURS are employed in complex endourological cases with a high risk of scope damage or fracture to preserve ru-fURS, with the ability to maintain clinical activity in such an event. SUMMARY: While there seems to be some cost advantages with su-fURS with reduced sterilization and maintenance costs, the data supporting it is sparse and limited. This choice of scope would depend on the durability of ru-fURS, procedural volumes, limited availability of sterilization units in some centers and potential risk of infectious complications. It is time that cost-benefit analysis is conducted with defined outcomes for a given healthcare set-up to help with the decision making on the type of scope that best serves their needs.

CHARIOT: a phase I study of berzosertib with chemoradiotherapy in oesophageal and other solid cancers using time to event continual reassessment method.

BACKGROUND: Berzosertib (M6620) is a highly potent (IC50 = 19 nM) and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. This trial assessed the safety, preliminary efficacy, and tolerance of berzosertib in oesophageal cancer (A1 cohort) with RT and advanced solid tumours (A2 cohort) with cisplatin and capecitabine. METHODS: Single-arm, open-label dose-escalation (Time-to-Event Continual Reassessment Method) trial with 16 patients in A1 and 18 in A2. A1 tested six dose levels of berzosertib with RT (35 Gy over 15 fractions in 3 weeks). RESULTS: No dose-limiting toxicities (DLTs) in A1. Eight grade 3 treatment-related AEs occurred in five patients, with rash being the most common. The highest dose (240 mg/m2) was determined as the recommended phase II dose (RP2D) for A1. Seven DLTs in two patients in A2. The RP2D of berzosertib was 140 mg/m2 once weekly. The most common grade ≥3 treatment-related AEs were neutropenia and thrombocytopenia. No treatment-related deaths were reported. CONCLUSIONS: Berzosertib combined with RT is feasible and well tolerated in oesophageal cancer patients at high palliative doses. Berzosertib with cisplatin and capecitabine was well tolerated in advanced cancer. Further investigation is warranted in a phase 2 setting. CLINICAL TRIALS IDENTIFIER: EU Clinical Trials Register (EudraCT) - 2015-003965-27 ClinicalTrials.gov - NCT03641547.

Relationships between growth indicators, liver and kidney function markers, and blood concentrations of essential and potentially toxic elements in environmentally exposed young children.

Environmental exposure to multiple metals and metalloids is widespread, leading to a global concern relating to the adverse health effects of mixed-metals exposure, especially in young children living around industrial areas. This study aimed to quantify the concentrations of essential and potentially toxic elements in blood and to examine the potential associations between multiple elements exposures, growth determinants, and liver and kidney function biomarkers in children living in several industrial areas in Dhaka, Bangladesh. The blood distribution of 20 trace elements As, Ag, Bi, Br, Cd, Co, Cr, Cu, I, Mn, Hg, Mo, Ni, Pb, Se, Sb, Tl, V, U, and Zn, growth determinants such as body mass index and body fats, blood pressure, liver and kidney injury biomarkers including serum alanine aminotransferase and alkaline phosphatase activities, serum calcium, and creatinine levels, blood urea nitrogen, and hemoglobin concentrations, and glomerular filtration rate were measured in 141 children, aged six to 16 years. Among these elements, blood concentrations of Ag, U, V, Cr, Cd, Sb, and Bi were measured below LOQs and excluded from subsequent statistical analysis. This comprehensive study revealed that blood concentrations of these elements in children, living in industrial areas, exceeded critical reference values to varying extents; elevated exposure to As, Pb, Br, Cu, and Se was found in children living in multiple industrial areas. A significant positive association between elevated blood Tl concentration and obesity (ß = 0.300, p = 0.007) and an inverse relationship between lower As concentration and underweight (ß = -0.351, p < 0.001) compared to healthy weight children indicate that chronic exposure to Tl and As may influence the metabolic burden and physical growth in children. Concentration-dependent positive associations were observed between the blood concentrations of Cu, Se, and Br and hepatic- and renal dysfunction biomarkers, an inverse association with blood Mo and I level, however, indicates an increased risk of Cu, Se, and Br-induced liver and kidney toxicity. Further in-depth studies are warranted to elucidate the underlying mechanisms of the observed associations. Regular biomonitoring of elemental exposures is also indispensable to regulate pollution in consideration of the long-term health effects of mixed-elements exposure in children.

Luminescence-based detection and identification of illicit drugs.

Luminescence-based sensing is capable of being used for the sensitive, rapid, and in some cases selective detection of chemicals. Furthermore, the method is amenable to incorporation into handheld low-power portable detectors that can be used in the field. Luminescence-based detectors are now commercially available for explosive detection with the technology built on a strong foundation of science. In contrast, there are fewer examples of luminescence-based detection of illicit drugs, despite the pervasive and global challenge of combating their manufacture, distribution and consumption and the need for handheld detection systems. This perspective describes the relatively nascent steps that have been reported in the use of luminescent materials for the detection of illicit drugs. Much of the published work has focused on detection of illicit drugs in solution with less work on vapour detection using thin luminescent sensing films. The latter are better suited for handheld sensing devices and detection in the field. Illicit drug detection has been achieved via different mechanisms, all of which change the luminescence of the sensing material. These include photoinduced hole transfer (PHT) leading to quenching of the luminescence, disruption of Förster energy transfer between different chromophores by a drug, and chemical reaction between the sensing material and a drug. The most promising of these is PHT, which can be used for rapid and reversible detection of illicit drugs in solution and film-based sensing of drugs in the vapour phase. However, there are still significant knowledge gaps, for example, how vapours of illicit drugs interact with the sensing films, and how to achieve selectivity for specific drugs.

A feasibility study of perioperative vitamin D supplementation in patients undergoing colorectal cancer resection.

Background: Vitamin D supplementation improves colorectal cancer (CRC) survival outcomes in randomized trials. The aim of this study was to test the feasibility, safety and efficacy of vitamin D supplementation in the pre- and perioperative period in patients undergoing CRC surgery. Methods: Patients were given 3200IU oral cholecalciferol (D3) per day perioperatively. Serial serum 25-hydroxyvitamin (25OHD) was measured by liquid chromatography tandem mass spectrometry and compared to untreated CRC controls. 25OHD and C-reactive protein (CRP) levels were compared using adjusted generalized linear mixed-effects models. Results: A total of 122 patients underwent serial perioperative sampling, including 41 patients given high-dose perioperative supplementation. Supplementation was well-tolerated with no adverse or serious adverse events related to supplementation reported. Pre-operative supplementation increased 25OHD levels on the day of surgery (103.9 vs. 42.5 nmol/l, P = 8.2E-12). Supplementation increased 25OHD levels at all post-operative timepoints (P < 0.001) and attenuated the post-operative drop in 25OHD (46 vs. 24% drop, P = 3.0E-4). Rate of vitamin D peri-operative insufficiency was significantly less in those on supplementation (e.g., day 3-5, 14 vs. 84%, P = 1.41E-08), with multivariate modeling across all timepoints indicating a ∼59 nmol/l higher 25OHD compared to control patients (P = 3.7E-21). Post-operative CRP was lower in patients taking supplementation (e.g., day 3-5 timepoint; 129 vs. 81 mg/l, P = 0.04). Conclusion: High dose pre-operative vitamin D supplementation is associated with higher perioperative 25OHD levels, lower rates of vitamin D insufficiency and reduced early post-operative CRP. Alongside published evidence for a beneficial effect of vitamin D on CRC survival outcomes, these novel findings provide strong rationale for early initiation of vitamin D supplementation after a diagnosis of CRC.

Analysis of brain and spinal MRI measures in a common domain to investigate directional neurodegeneration in motor neuron disease.

BACKGROUND: Magnetic resonance imaging (MRI) of the brain and cervical spinal cord is often performed in diagnostic evaluation of suspected motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). Analysis of MRI-derived tissue damage metrics in a common domain facilitates group-level inferences on pathophysiology. This approach was applied to address competing hypotheses of directionality of neurodegeneration, whether anterograde, cranio-caudal dying-forward from precentral gyrus or retrograde, dying-back. METHODS: In this cross-sectional study, MRI was performed on 75 MND patients and 13 healthy controls. Precentral gyral thickness was estimated from volumetric T1-weighted images using FreeSurfer, corticospinal tract fractional anisotropy (FA) from diffusion tensor imaging using FSL, and cross-sectional cervical cord area between C1-C8 levels using Spinal Cord Toolbox. To analyse these multimodal data within a common domain, individual parameter estimates representing tissue damage at each corticospinal tract level were first converted to z-scores, referenced to healthy control norms. Mixed-effects linear regression models were then fitted to these z-scores, with gradients hypothesised to represent directionality of neurodegeneration. RESULTS: At group-level, z-scores did not differ significantly between precentral gyral and intracranial corticospinal tract tissue damage estimates (regression coefficient - 0.24, [95% CI - 0.62, 0.14], p = 0.222), but step-changes were evident between intracranial corticospinal tract and C1 (1.14, [95% CI 0.74, 1.53], p < 0.001), and between C5 and C6 cord levels (0.98, [95% CI 0.58, 1.38], p < 0.001). DISCUSSION: Analysis of brain and cervical spinal MRI data in a common domain enabled investigation of pathophysiological hypotheses in vivo. A cranio-caudal step-change in MND patients was observed, and requires further investigation in larger cohorts.

Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.

Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation.

Association study of candidate DNA-repair gene variants and acute graft versus host disease in pediatric patients receiving allogeneic hematopoietic stem-cell transplantation.

Acute Graft versus Host Disease (aGvHD) grades 2-4 occurs in 15-60% of pediatric patients undergoing allogeneic haematopoietic stem-cell transplantation (allo-HSCT). The collateral damage to normal tissue by conditioning regimens administered prior to allo-HSCT serve as an initial trigger for aGvHD. DNA-repair mechanisms may play an important role in mitigating this initial damage, and so the variants in corresponding DNA-repair protein-coding genes via affecting their quantity and/or function. We explored 51 variants within 17 DNA-repair genes for their association with aGvHD grades 2-4 in 60 pediatric patients. The cumulative incidence of aGvHD 2-4 was 12% (n = 7) in the exploratory cohort. MGMT rs10764881 (G>A) and EXO rs9350 (c.2270C>T) variants were associated with aGvHD 2-4 [Odds ratios = 14.8 (0 events out of 40 in rs10764881 GG group) and 11.5 (95% CI: 2.3-191.8), respectively, multiple testing corrected p ≤ 0.001]. Upon evaluation in an extended cohort (n = 182) with an incidence of aGvHD 2-4 of 22% (n = 40), only MGMT rs10764881 (G>A) remained significant (adjusted HR = 2.05 [95% CI: 1.06-3.94]; p = 0.03) in the presence of other clinical risk factors. Higher MGMT expression was seen in GG carriers for rs10764881 and was associated with higher IC50 of Busulfan in lymphoblastoid cells. MGMT rs10764881 carrier status could predict aGvHD occurrence in pediatric patients undergoing allo-HSCT.

Oral vitamin D supplementation induces transcriptomic changes in rectal mucosa that are linked to anti-tumour effects.

BACKGROUND: The risk for several common cancers is influenced by the transcriptomic landscape of the respective tissue-of-origin. Vitamin D influences in vitro gene expression and cancer cell growth. We sought to determine whether oral vitamin D induces beneficial gene expression effects in human rectal epithelium and identify biomarkers of response. METHODS: Blood and rectal mucosa was sampled from 191 human subjects and mucosa gene expression (HT12) correlated with plasma vitamin D (25-OHD) to identify differentially expressed genes. Fifty subjects were then administered 3200IU/day oral vitamin D3 and matched blood/mucosa resampled after 12 weeks. Transcriptomic changes (HT12/RNAseq) after supplementation were tested against the prioritised genes for gene-set and GO-process enrichment. To identify blood biomarkers of mucosal response, we derived receiver-operator curves and C-statistic (AUC) and tested biomarker reproducibility in an independent Supplementation Trial (BEST-D). RESULTS: Six hundred twenty-nine genes were associated with 25-OHD level (P < 0.01), highlighting 453 GO-term processes (FDR<0.05). In the whole intervention cohort, vitamin D supplementation enriched the prioritised mucosal gene-set (upregulated gene-set P < 1.0E-07; downregulated gene-set P < 2.6E-05) and corresponding GO terms (P = 2.90E-02), highlighting gene expression patterns consistent with anti-tumour effects. However, only 9 individual participants (18%) showed a significant response (NM gene-set enrichment P < 0.001) to supplementation. Expression changes in HIPK2 and PPP1CC expression served as blood biomarkers of mucosal transcriptomic response (AUC=0.84 [95%CI 0.66-1.00]) and replicated in BEST-D trial subjects (HIPK2 AUC=0.83 [95%CI 0.77-0.89]; PPP1CC AUC=0.91 [95%CI 0.86-0.95]). CONCLUSIONS: Higher plasma 25-OHD correlates with rectal mucosa gene expression patterns consistent with anti-tumour effects, and this beneficial signature is induced by short-term vitamin D supplementation. Heterogenous gene expression responses to vitamin D may limit the ability of randomised trials to identify beneficial effects of supplementation on CRC risk. However, in the current study blood expression changes in HIPK2 and PPP1CC identify those participants with significant anti-tumour transcriptomic responses to supplementation in the rectum. These data provide compelling rationale for a trial of vitamin D and CRC prevention using easily assayed blood gene expression signatures as intermediate biomarkers of response.

Earthworm-Collembola interactions affecting water-soluble nutrients, fauna and physiochemistry in a mesocosm manure-straw composting experiment.

A mesocosm fermentation experiment was undertaken to investigate interactions between Eisenia fetida and Collembola affecting composting processes. Earthworms, Collembola, respiration, water soluble nutrients and compost characteristics (near infrared spectra - NIRS) were monitored on four occasions over 136 days. Earthworms were the main drivers of early changes in composts, increasing the general abundance of Collembola, although responses varied with species. Earthworms accelerated substrate mineralisation and release of soluble nutrients whilst also changing compost characteristics. Collembola alone had little direct effect on soluble nutrient concentrations or respiration; they did however alter compost characteristics (NIR spectra). Earthworm-Collembola interactions affecting respiration and soluble nutrients were mainly antagonistic in the early stages of composting but synergistic in later stages. In the later stages of composting, the higher abundance of Collembola when combined with earthworms resulted in greater concentrations of soluble nitrate and phosphate. These findings emphasise the importance in vermicomposting practice of different invertebrate groups having access to feedstock at appropriate stages of the process. The high concentrations of soluble nutrients released during vermicomposting indicate the need for control measures to avoid off-site pollution and loss of this resource.

NRF2 as a therapeutic opportunity to impact in the molecular roadmap of ALS.

Amyotrophic Lateral Sclerosis (ALS) is a devastating heterogeneous disease with still no convincing therapy. To identify the most strategically significant hallmarks for therapeutic intervention, we have performed a comprehensive transcriptomics analysis of dysregulated pathways, comparing datasets from ALS patients and healthy donors. We have identified crucial alterations in RNA metabolism, intracellular transport, vascular system, redox homeostasis, proteostasis and inflammatory responses. Interestingly, the transcription factor NRF2 (nuclear factor (erythroid-derived 2)-like 2) has significant effects in modulating these pathways. NRF2 has been classically considered as the master regulator of the antioxidant cellular response, although it is currently considered as a key component of the transduction machinery to maintain coordinated control of protein quality, inflammation, and redox homeostasis. Herein, we will summarize the data from NRF2 activators in ALS pre-clinical models as well as those that are being studied in clinical trials. As we will discuss, NRF2 is a promising target to build a coordinated transcriptional response to motor neuron injury, highlighting its therapeutic potential to combat ALS.

Effects of storage conditions on the stability and distribution of clinical trace elements in whole blood and plasma: Application of ICP-MS.

BACKGROUND: Knowledge of trace element stability during sample handling and preservation is a prerequisite to produce reliable test results in clinical trace element analysis. METHOD: An alkaline dissolution method has been developed using inductively coupled plasma mass spectrometry to quantify eighteen trace element concentrations: vanadium, chromium, manganese, cobalt, nickel, copper, zinc, arsenic, selenium, bromine, molybdenum, cadmium, antimony, iodine, mercury, thallium, lead, and bismuth in human blood, using a small sample volume of 0.1 mL. The study evaluated the comparative effects of storage conditions on the stability of nutritionally essential and non-essential elements in human blood and plasma samples stored at three different temperatures (4 °C, -20 °C and -80 °C) over a one-year period, and analysed at multiple time points. The distribution of these elements between whole blood and plasma and their distribution relationships are illustrated using blood samples from 66 adult donors in Queensland. RESULTS: The refrigeration and freezing of blood and plasma specimens proved to be suitable storage conditions for many of the trace elements for periods up to six months, with essentially unchanged concentrations. Substantially consistent recoveries were obtained by preserving specimens at -20 °C for up to one year. Ultra-freezing of the specimens at -80 °C did not improve stability; but appeared to result in adsorption and/or precipitation of some elements, accompanied by a longer sample thawing time. A population sample study revealed significant differences between the blood and plasma concentrations of six essential elements and their relationships also varied significantly for different elements. CONCLUSION: Blood and plasma specimens can be reliably stored at 4 °C for six months or kept frozen at -20 °C up to one year to obtain high quality test results of trace elements.

The fractionation of phosphorus in UK chalk stream surface waters and its relevance to the regulation and management of water quality.

The regulatory management of river water quality requires measurements of phosphorus that are operationally viable and meaningful in terms of insight into its effects. This need is a particular concern in globally rare and ecologically sensitive chalk streams. P data pertaining to rivers are commonly limited to soluble reactive P; other fractions of P may be of concern but are not routinely monitored. This study seeks to establish the nature and extent of non-regulated forms of P in UK chalk streams. Whilst soluble reactive P in two southern English chalk streams was found to comprise the majority of reactive P in surface waters in the majority of samples, 15-20% of the total reactive P was within other size fractions greater than 0.22 µm. The contribution of reactive P to the total P was highly variable. We conclude that, with some adjustments, the established method of regulatory monitoring of P in UK rivers is viable and valuable. In cases where the levels of reactive P are not consistent with ecological status and/or expected outcomes of programmes of measures, we recommend that targeted analysis of non-regulated forms of P is undertaken as a means to guide and focus management interventions.

Development and Validation of an ICP-MS Method and Its Application to Determine Multiple Trace Elements in Small Volumes of Whole Blood and Plasma.

Essential and nonessential element concentrations in human blood provide important information on the nutritional status of individuals and can assist in the screening or diagnosis of certain disorders and their association with other causative factors. A simple and sensitive method, suitable for use with small sample volumes, for quantification of multiple trace element concentrations in whole blood and plasma has been developed using inductively coupled plasma-mass spectrometry. Method validation was performed using standard reference materials of whole blood and serum using varying sample treatments with nitric acid, water and hydrogen peroxide. The method was applied to quantify the trace element concentrations in whole blood and plasma samples (0.1 mL) from 50 adult blood donors in Queensland. The whole blood sample (5 mL) was collected in Vacutainer tubes with K2EDTA as anticoagulant. The developed method was able to quantify, in blood and plasma samples over a wide range of concentrations, several essential elements: cobalt, copper, zinc, iron, manganese and selenium; the nutritionally probably essential elements vanadium and strontium; and nonessential elements including lead, cadmium, arsenic, caesium, barium, thallium and uranium. Significant differences (P < 0.0001) were observed between whole blood and plasma concentrations for 13 elements; 5 of the measured elements, cobalt (0.49 vs. 0.36 µg/L), copper (1.0 vs. 0.75 mg/L), strontium (28 vs. 16 µg/L), barium (1.5 vs. 0.64 µg/L) and thallium (0.06 vs. 0.03 µg/L), had higher mean concentrations in plasma than in blood. Whole blood concentrations of nine trace elements were significantly correlated (P < 0.0001) with plasma concentrations. The distribution of the trace elements between human blood and plasma varied considerably for the different elements. These results indicate that, using a small sample volume, this assay is suitable for the evaluation of nutritional status as well as in monitoring human toxic elemental exposures.

TDP43 proteinopathy is associated with aberrant DNA methylation in human amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neurone (MN) degeneration and death. ALS can be sporadic (sALS) or familial, with a number of associated gene mutations, including C9orf72 (C9ALS). DNA methylation is an epigenetic mechanism whereby a methyl group is attached to a cytosine (5mC), resulting in gene expression repression. 5mC can be further oxidized to 5-hydroxymethylcytosine (5hmC). DNA methylation has been studied in other neurodegenerative diseases, but little work has been conducted in ALS. AIMS: To assess differences in DNA methylation in individuals with ALS and the relationship between DNA methylation and TDP43 pathology. METHODS: Post mortem tissue from controls, sALS cases and C9ALS cases were assessed by immunohistochemistry for 5mC and 5hmC in spinal cord, motor cortex and prefrontal cortex. LMNs were extracted from a subset of cases using laser capture microdissection. DNA from these underwent analysis using the MethylationEPIC array to determine which molecular processes were most affected. RESULTS: There were higher levels of 5mC and 5hmC in sALS and C9ALS in the residual lower motor neurones (LMNs) of the spinal cord. Importantly, in LMNs with TDP43 pathology there was less nuclear 5mC and 5hmC compared to the majority of residual LMNs that lacked TDP43 pathology. Enrichment analysis of the array data suggested RNA metabolism was particularly affected. CONCLUSIONS: DNA methylation is a contributory factor in ALS LMN pathology. This is not so for glia or neocortical neurones.

Epidermolysis bullosa acquisita as an adverse effect from rituximab therapy: A case report.

RATIONALE: Rituximab is a monoclonal antibody directed against B cells and is a first-line agent for the treatment of B cell lymphoma and a second-line agent for the treatment of idiopathic thrombocytopenic purpura (ITP). It has also been used for the treatment of several other autoimmune diseases. Epidermolysis bullosa acquisita (EBA) has never been reported as an adverse effect resulted from rituximab therapy. PATIENT CONCERNS: A 54-year-old female presented with relapse of the ITP for around eight months. She was treated with rituximab. Intramuscular chlorpheniramine and intravenous methylprednisolone and cimetidine were used as premedication before rituximab infusion. The infusion was initially started at 50 mg/h for 1 h followed by 100 mg/h till the end of infusion. The day after rituximab infusion, the patient noticed pruritic blisters on both arms and chest skin. The next day, the lesions increased in severity and extent. DIAGNOSIS: The skin biopsy established the diagnosis of EBA. H&E staining revealed subepidermal blisters infiltrated by inflammatory cells, including eosinophils and lymphocytes. Direct immunofluorescence (DIF) showed linear deposition of IgG and C3 at the dermoepidermal junction. Indirect immunofluorescence with the patient's serum on salt-split skin revealed exclusive dermal binding of circulating IgG antibasement membrane antibodies at a titer of 1:160. INTERVENTIONS: She was treated with intravenous methylprednisolone and was continued on oral prednisolone. OUTCOMES: The lesions regressed. Six weeks later, she had a recurrence of similar lesions but in milder form. This episode subsided in 4 to 5 days with topical steroid application. LESSONS: Physicians should consider this diagnosis when a patient develops bullous skin eruptions while undergoing Rituximab therapy.