Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.

Inhibition of the electron transport chain (ETC) prevents the regeneration of mitochondrial NAD+, resulting in cessation of the oxidative tricarboxylic acid (TCA) cycle and a consequent dependence upon reductive carboxylation for aspartate synthesis. NAD+ regeneration alone in the cytosol can rescue the viability of ETC-deficient cells. Yet, how this occurs and whether transfer of oxidative equivalents to the mitochondrion is required remain unknown. Here, we show that inhibition of the ETC drives reversal of the mitochondrial aspartate transaminase (GOT2) as well as malate and succinate dehydrogenases (MDH2 and SDH) to transfer oxidative NAD+ equivalents into the mitochondrion. This supports the NAD+-dependent activity of the mitochondrial glutamate dehydrogenase (GDH) and thereby enables anaplerosis-the entry of glutamine-derived carbon into the TCA cycle and connected biosynthetic pathways. Thus, under impaired ETC function, the cytosolic redox state is communicated into the mitochondrion and acts as a rheostat to support GDH activity and cell viability.

Predictors of unsustained measurable residual disease negativity in transplant-eligible patients with multiple myeloma.

ABSTRACT: The role of measurable residual disease (MRD) negativity as a biomarker to stop treatment is being investigated in transplant-eligible patients with multiple myeloma (MM). Thus, it is important to identify risk factors of MRD resurgence and/or progressive disease (PD) among patients achieving undetectable MRD to avoid undertreating them. Here, we studied 267 newly diagnosed transplant-eligible patients with MM enrolled in the GEM2012MENOS65 and GEM2014MAIN clinical trials who achieved MRD negativity by next-generation flow cytometry. After a median follow-up of 73 months since the first MRD negative assessment, 111 of the 267 (42%) patients showed MRD resurgence and/or PD. The only prognostic factors at diagnosis that predicted MRD resurgence and/or PD were an International Staging System (ISS) 3 and the presence of ≥0.01% circulating tumor cells (CTCs). Failure to achieve MRD negativity after induction also predicted higher risk of MRD resurgence and/or PD. Patients having 0 vs 1 vs ≥2 risk factors (ISS 3, ≥0.01% CTCs, and late MRD negativity) showed 5-year rates of MRD resurgence and/or PD of 16%, 33%, and 57%, respectively (P < .001). Thus, these easily measurable risk factors could help refine the selection of patients for whom treatment cessation after MRD negativity is being investigated in clinical trials. This trial was registered at www.clinicaltrials.gov as NCT01916252 and NCT02406144.

KRAGEN: a knowledge graph-enhanced RAG framework for biomedical problem solving using large language models.

MOTIVATION: Answering and solving complex problems using a large language model (LLM) given a certain domain such as biomedicine is a challenging task that requires both factual consistency and logic, and LLMs often suffer from some major limitations, such as hallucinating false or irrelevant information, or being influenced by noisy data. These issues can compromise the trustworthiness, accuracy, and compliance of LLM-generated text and insights. RESULTS: Knowledge Retrieval Augmented Generation ENgine (KRAGEN) is a new tool that combines knowledge graphs, Retrieval Augmented Generation (RAG), and advanced prompting techniques to solve complex problems with natural language. KRAGEN converts knowledge graphs into a vector database and uses RAG to retrieve relevant facts from it. KRAGEN uses advanced prompting techniques: namely graph-of-thoughts (GoT), to dynamically break down a complex problem into smaller subproblems, and proceeds to solve each subproblem by using the relevant knowledge through the RAG framework, which limits the hallucinations, and finally, consolidates the subproblems and provides a solution. KRAGEN's graph visualization allows the user to interact with and evaluate the quality of the solution's GoT structure and logic. AVAILABILITY AND IMPLEMENTATION: KRAGEN is deployed by running its custom Docker containers. KRAGEN is available as open-source from GitHub at: https://github.com/EpistasisLab/KRAGEN.

Lenalidomide and dexamethasone maintenance with or without ixazomib, tailored by residual disease status in myeloma.

From November 2014 to May 2017, 332 patients homogeneously treated with bortezomib, lenalidomide, and dexamethasone (VRD) induction, autologous stem cell transplant, and VRD consolidation were randomly assigned to receive maintenance therapy with lenalidomide and dexamethasone (RD; 161 patients) vs RD plus ixazomib (IRD; 171 patients). RD consisted of lenalidomide 15 mg/d from days 1 to 21 plus dexamethasone 20 mg/d on days 1 to 4 and 9 to 12 at 4-week intervals, whereas in the IRD arm, oral ixazomib at a dose of 4 mg on days 1, 8, and 15 was added. Therapy for patients with negative measurable residual disease (MRD) after 24 cycles was discontinued, whereas those who tested positive for MRD remained on maintenance with RD for 36 more cycles. After a median follow-up of 69 months from the initiation of maintenance, the progression-free survival (PFS) was similar in both arms, with a 6-year PFS rate of 61.3% and 55.6% for RD and IRD, respectively (hazard ratio, 1.136; 95% confidence interval, 0.809-1.603). After 2 years of maintenance, treatment was discontinued in 163 patients with negative MRD, whereas 63 patients with positive MRD continued with RD therapy. Maintenance discontinuation in patients tested negative for MRD resulted in a low progression rate (17.2% at 4 years), even in patients with high-risk features. In summary, our results show the efficacy of RD maintenance and support the safety of maintenance therapy discontinuation in patients with negative MRD at 2 years. This trial was registered at www.clinicaltrials.gov as #NCT02406144 and at EudraCT as 2014-00055410.

Aliro: an automated machine learning tool leveraging large language models.

MOTIVATION: Biomedical and healthcare domains generate vast amounts of complex data that can be challenging to analyze using machine learning tools, especially for researchers without computer science training. RESULTS: Aliro is an open-source software package designed to automate machine learning analysis through a clean web interface. By infusing the power of large language models, the user can interact with their data by seamlessly retrieving and executing code pulled from the large language model, accelerating automated discovery of new insights from data. Aliro includes a pre-trained machine learning recommendation system that can assist the user to automate the selection of machine learning algorithms and its hyperparameters and provides visualization of the evaluated model and data. AVAILABILITY AND IMPLEMENTATION: Aliro is deployed by running its custom Docker containers. Aliro is available as open-source from GitHub at: https://github.com/EpistasisLab/Aliro.

Selinexor, daratumumab, bortezomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma: results of the phase II, nonrandomized, multicenter GEM-SELIBORDARA study.

The treatment landscape for multiple myeloma has significantly evolved in the last decade. Notwithstanding, a large proportion of patients continue to relapse and novel combinations continue to be needed. In this phase II study, selinexor, a first-in-class inhibitor of exportin-1 was evaluated in combination with standard daratumumab-bortezomib-dexamethasone (DVd), for the treatment of relapsed and refractory multiple myeloma (RRMM). The aim of the trial was to assess the efficacy and safety of the combination of selinexor with DVd (S-DVd). A total of 57 patients were enrolled in the two parts of the study. Part 1 enrolled a heavily pretreated population with at least three prior lines (PL) of therapy and part 2 enrolled an early relapse population with at least one PL of therapy. The primary endpoint was complete response (CR) rate in part 2 and overall response rate (ORR) in part 1. In the latter, 24 patients were treated with a median of three PL. Overall response rate (ORR) was 50% with two CR. Median progression- free survival (PFS) was 7 months. In part 2, 33 patients were enrolled, with a median of one PL. ORR was 82% and CR or better was 33%. Median PFS was 24 months. In lenalidomide-refractory patients, a median PFS of 22.1 months was observed. Thrombocytopenia was the most common hematological adverse event (69%; grade 3-4: 34%) and nausea, the most frequent non-hematological adverse event (38%; grade 3-4: 6%). Sixty-two percent of the patients required dose modifications. In summary, although the primary endpoint of the study was not met, the combination of S-DVd showed encouraging clinical efficacy with a generally manageable safety profile representing a potential option for the treatment of RRMM patients.

Single-point and kinetics of peripheral residual disease by mass spectrometry to predict outcome in patients with high risk smoldering multiple myeloma included in the GEM-CESAR trial.

The value of quantitative immunoprecipitation mass spectrometry (QIP-MS) to identify the M-protein is being investigated in patients with monoclonal gammopathies but no data are yet available in high-risk smoldering myeloma (HRsMM). We have therefore investigated QIP-MS to monitor peripheral residual disease (PRD) in 62 HRsMM patients enrolled in the GEM-CESAR trial. After 24 cycles of maintenance, detecting the M-protein by MS or clonal plasma cells by NGF identified cases with a significantly shorter median PFS (mPFS; MS: not reached vs 1,4 years, p=0.001; NGF: not reached vs 2 years, p=0.0002) but reaching CR+sCR did not discriminate patients with different outcome. With NGF as a reference, the combined results of NGF and MS showed a high negative predictive value (NPV) of MS: 81% overall and 73% at treatment completion. When sequential results were considered, sustained negativity by MS or NGF was associated with a very favorable outcome with a mPFS not yet reached vs 1.66 years and 2.18 years in cases never attaining PRD or minimal residual disease (MRD) negativity, respectively. We can thus conclude that 1) the standard response categories of the IMWG do not seem to be useful for treatment monitoring in HRsMM patients, 2) MS could be used as a non-invasive, clinical valuable tool with the capacity of guiding timely bone marrow evaluations (based on its high NPV with NGF as a reference) and 3) similarly to NGF, sequential results of MS are able identify a subgroup of HRsMM patients with long-term disease control. This study was registered at www.clinicaltrials.gov (ClinicalTrials.gov identifier: NCT02415413).

Mapping Plastic and Plastic Additive Cycles in Coastal Countries: A Norwegian Case Study.

The growing environmental consequences caused by plastic pollution highlight the need for a better understanding of plastic polymer cycles and their associated additives. We present a novel, comprehensive top-down method using inflow-driven dynamic probabilistic material flow analysis (DPMFA) to map the plastic cycle in coastal countries. For the first time, we covered the progressive leaching of microplastics to the environment during the use phase of products and modeled the presence of 232 plastic additives. We applied this methodology to Norway and proposed initial release pathways to different environmental compartments. 758 kt of plastics distributed among 13 different polymers was introduced to the Norwegian economy in 2020, 4.4 Mt was present in in-use stocks, and 632 kt was wasted, of which 15.2 kt (2.4%) was released to the environment with a similar share of macro- and microplastics and 4.8 kt ended up in the ocean. Our study shows tire wear rubber as a highly pollutive microplastic source, while most macroplastics originated from consumer packaging with LDPE, PP, and PET as dominant polymers. Additionally, 75 kt of plastic additives was potentially released to the environment alongside these polymers. We emphasize that upstream measures, such as consumption reduction and changes in product design, would result in the most positive impact for limiting plastic pollution.

Subacute encephalopathy with seizures in alcoholics (SESA) syndrome: Relevant questions.

OBJECTIVE: The aim of this article is to answer three relevant issues: i/What epileptic condition is referred to as subacute encephalopathy with seizures in alcoholics (SESA) syndrome; ii/ Why it can be important to distinguish SESA syndrome in clinical practice and iii/ What do we know about its pathophysiology. METHODS: We reviewed all cases published in the English language from the initial description of the syndrome to the present. All met the previously established criteria for SESA syndrome were included in our analysis. RESULTS: We found 34 patients diagnosed with SESA syndrome Fourteen (41.1%) out of 34 patients were over 60 years of age. In 12 (35.2 %), abstinence, and in 4 (11.7 %) excessive consumption of alcohol, were considered precipitating factors, respectively. Triggering causes were unknown in 18 cases (53.0 %). All cases (100 %) presented with altered mental status. Fourteen (41.1 %) subjects had a history of epileptic seizures in the context of alcohol withdrawal syndrome (AWS). Twenty (58.8 %) patients had focal motor seizures (FMSs), 24 (70.5 %) bilateral tonic-clonic seizures (BTCSs), and 15 (44.1 %) focal impaired awareness seizures (FIASs). In 8 (23.5 %), criteria for focal nonconvulsive status epilepticus (NCSE) were met. Twenty-eight (82.3 %) subjects had transient neurological deficits. In 29 (85.2 %) subjects, lateralized periodic discharges (LPDs) were observed on the EEG. Areas of signal hyperintensities and restricted diffusion in neuroimaging were mentioned in 22 subjects (64.7 %). Transfer to the intensive care unit was necessary in 8 (23.5 %) subjects. Thirteen (38.2 %) had recurrent episodes. Enduring brain damage was mentioned in 9 (26.4 %) cases. The most used anti-seizure medication (ASM) was levetiracetam, followed by phenytoin and lacosamide. CONCLUSIONS: SESA syndrome represents a well-defined subtype of focal NCSE in patients with chronic alcoholism. Its prompt recognition can facilitate the initiation of early ASM therapy and help design appropriate video-EEG evaluation and a treatment strategy.

Assessing Full Stomach Prevalence with Ultrasound Following Preoperative Fasting in Diabetic Patients with Dysautonomia: A Comparative Observational Study.

BACKGROUND: Traditionally, diabetics have been considered patients with a high risk of aspiration due to having delayed gastric emptying; However, the evidence concerning residual gastric volume (GV) in fasting diabetic patients is inconsistent. This study aimed to compare the fasting GV of diabetic patients with or without dysautonomia with control patients scheduled for elective surgery using gastric ultrasound. METHODS: This bicentric prospective single-blinded case-control study was conducted at 2 university hospitals in Spain. Patients aged over 18 years, classified as American Society of Anesthesiologists (ASA) physical statuses I to III and having similar fasting statuses, were included in the study. The primary outcome was to compare the prevalence of risk stomach using the Perlas gastric content grading scale evaluated by ultrasound in the 3 groups. Secondary outcomes included the measurement of cross-sectional area (CSA) and GV in the right lateral decubitus (RLD) position, as well as the prevalence of solid gastric residue. RESULTS: A total of 289 patients were recruited for the study, comprising 145 diabetic patients (83 of whom had dysautonomia) and 144 patients in the control group. The percentage of patients classified as Perlas grade 2 was 13.2% in the control group, 16.1% in diabetic patients without dysautonomia, and 22.9% in diabetic patients with dysautonomia (P = .31). Antral CSA was significantly higher in diabetic patients with dysautonomia (6.5 [4.8-8.4]) compared to the control group (5.4 [4.0-7.2]; P = .04). However, no significant differences were observed between groups in residual GV. Among diabetic patients with dysautonomia, 12% exhibited solid gastric residue, which was twice the percentage observed in diabetic patients without dysautonomia (4.8%) and 3 times higher than that in the control group (3.5%; P = .03). The presence of dysautonomia was associated with an increased odds ratio of solid gastric residue (odds ratio [OR], 3.37; 95% confidence interval [CI], 1.28-8.87; P = .01) after adjusting for confounding factors. CONCLUSIONS: This study offers insights into the relationship between dysautonomia in patients with diabetes mellitus and the presence of full stomach, underscoring the significance of preoperative gastric ultrasound evaluation in managing perioperative risks in this population.

Comparison of Continuous Intracortical and Scalp Electroencephalography in Comatose Patients with Acute Brain Injury.

BACKGROUND: Depth electroencephalography (dEEG) is a recent invasive monitoring technique used in patients with acute brain injury. This study aimed to describe in detail the clinical manifestations of nonconvulsive seizures (NCSzs) with and without a surface EEG correlate, analyze their long-standing effects, and provide data that contribute to understanding the significance of certain scalp EEG patterns observed in critically ill patients. METHODS: We prospectively enrolled a cohort of 33 adults with severe acute brain injury admitted to the neurological intensive care unit. All of them underwent multimodal invasive monitoring, including dEEG. All patients were scanned on a 3T magnetic resonance imaging scanner at 6 months after hospital discharge, and mesial temporal atrophy (MTA) was calculated using a visual scale. RESULTS: In 21 (65.6%) of 32 study participants, highly epileptiform intracortical patterns were observed. A total of 11 (34.3%) patients had electrographic or electroclinical seizures in the dEEG, of whom 8 had both spontaneous and stimulus-induced (SI) seizures, and 3 patients had only spontaneous intracortical seizures. An unequivocal ictal scalp correlate was observed in only 3 (27.2%) of the 11 study participants. SI-NCSzs occurred during nursing care, medical procedures, and family visits. Subtle clinical manifestations, such as restlessness, purposeless stereotyped movements of the upper limbs, ventilation disturbances, jerks, head movements, hyperextension posturing, chewing, and oroalimentary automatisms, occurred during intracortical electroclinical seizures. MTA was detected in 18 (81.8%) of the 22 patients. There were no statistically significant differences between patients with MTA with and without seizures or status epilepticus. CONCLUSIONS: Most NCSzs in critically ill comatose patients remain undetectable on scalp EEG. SI-NCSzs frequently occur during nursing care, medical procedures, and family visits. Semiology of NCSzs included ictal minor signs and subtle symptoms, such as breathing pattern changes manifested as patient-ventilator dyssynchrony.

Targeted Expression to Liver of an antimiR-33 Sponge as a Gene Therapy Strategy against Hypercholesterolemia: In Vitro Study.

Atherosclerosis is the leading cause of cardiovascular diseases in Mexico and worldwide. The membrane transporters ABCA1 and ABCG1 are involved in the reverse transport of cholesterol and stimulate the HDL synthesis in hepatocytes, therefore the deficiency of these transporters promotes the acceleration of atherosclerosis. MicroRNA-33 (miR-33) plays an important role in lipid metabolism and exerts a negative regulation on the transporters ABCA1 and ABCG1. It is known that by inhibiting the function of miR-33 with antisense RNA, HDL levels increase and atherogenic risk decreases. Therefore, in this work, a genetic construct, pPEPCK-antimiR-33-IRES2-EGFP, containing a specific antimiR-33 sponge with two binding sites for miR-33 governed under the PEPCK promoter was designed, constructed, and characterized, the identity of which was confirmed by enzymatic restriction, PCR, and sequencing. Hep G2 and Hek 293 FT cell lines, as well as a mouse hepatocyte primary cell culture were transfected with this plasmid construction showing expression specificity of the PEPCK promoter in hepatic cells. An analysis of the relative expression of miR-33 target messengers showed that the antimiR-33 sponge indirectly induces the expression of its target messengers (ABCA1 and ABCG1). This strategy could open new specific therapeutic options for hypercholesterolemia and atherosclerosis, by blocking the miR-33 specifically in hepatocytes.

Intramuscular Anti-D treatment for immune thrombocytopenia: A single centre experience.

Intravenous Anti-Rhesus-D immunoglobulin (Anti-D) is a first-line treatment option for immune thrombocytopenia in non-splenectomised and RhD-positive patients. In this report, we retrospectively review our experience with intramuscular (IM) Anti-D treatment in 74 adult patients between 1990 and 2018. We found that 73% of patients showed a response; almost all of them had complete responses (68.9%), and 26% achieved complete responses sustained at least 6 months after treatment discontinuation. [Correction added on 02 December 2022, after first online publication: In the preceding sentence, '(68.89%)' has been corrected to '(68.9%)' in this version.] No significant side effects were observed with no cases of acute haemolysis or anaemia reported. We conclude from this study that IM Anti-D is an effective and safe treatment for immune thrombocytopenia.

Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard- and high-risk myeloma.

Patients with multiple myeloma (MM) carrying standard- or high-risk cytogenetic abnormalities (CAs) achieve similar complete response (CR) rates, but the later have inferior progression-free survival (PFS). This questions the legitimacy of CR as a treatment endpoint and represents a biological conundrum regarding the nature of tumor reservoirs that persist after therapy in high-risk MM. We used next-generation flow (NGF) cytometry to evaluate measurable residual disease (MRD) in MM patients with standard- vs high-risk CAs (n = 300 and 90, respectively) enrolled in the PETHEMA/GEM2012MENOS65 trial, and to identify mechanisms that determine MRD resistance in both patient subgroups (n = 40). The 36-month PFS rates were higher than 90% in patients with standard- or high-risk CAs achieving undetectable MRD. Persistent MRD resulted in a median PFS of âˆ¼3 and 2 years in patients with standard- and high-risk CAs, respectively. Further use of NGF to isolate MRD, followed by whole-exome sequencing of paired diagnostic and MRD tumor cells, revealed greater clonal selection in patients with standard-risk CAs, higher genomic instability with acquisition of new mutations in high-risk MM, and no unifying genetic event driving MRD resistance. Conversely, RNA sequencing of diagnostic and MRD tumor cells uncovered the selection of MRD clones with singular transcriptional programs and reactive oxygen species-mediated MRD resistance in high-risk MM. Our study supports undetectable MRD as a treatment endpoint for patients with MM who have high-risk CAs and proposes characterizing MRD clones to understand and overcome MRD resistance. This trial is registered at www.clinicaltrials.gov as #NCT01916252.

Randomized phase II study of weekly carfilzomib 70 mg/m2 and dexamethasone with or without cyclophosphamide in relapsed and/or refractory multiple myeloma patients.

In this randomized phase II study (GEM-KyCyDex, clinicaltrials gov. Identifier: NCT03336073), the combination of weekly carfilzomib 70 mg/m2, cyclophosphamide and dexamethasone (KCd) was compared to carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM) after 1-3 prior lines (PL). One hundred and ninety-seven patients were included and randomized 1:1 to receive KCd (97 patients) or Kd (100 patients) in 28-day cycles until progressive disease or unacceptable toxicity occurred. Patient median age was 70 years, and the median number of PL was one (range, 1-3). More than 90% of patients had previously been exposed to proteasome inhibitors, approximetely 70% to immunomodulators, and approximetely 50% were refractory to their last line (mainly lenalidomide) in both groups. After a median follow-up of 37 months, median progression-free survival (PFS) was 19.1 and 16.6 months in KCd and Kd, respectively (P=0.577). Of note, in the post hoc analysis of the lenalidomide-refractory population, the addition of cyclophosphamide to Kd resulted in a significant benefit in terms of PFS: 18.4 versus 11.3 months (hazard ratio =1.7, 95% confidence interval: 1.1-2.7; P=0.043). The overall response rate and the percentage of patients who achieved complete response was around 70% and 20% in both groups. The addition of cyclophosphamide to Kd did not result in any safety signal, except for severe infections (7% vs. 2%). In conclusion, the combination of cyclophosphamide with Kd 70 mg/m2 weekly does not improve outcomes as compared with Kd alone in RRMM after 1-3 PL, but a significant benefit in PFS was observed with the triplet combination in the lenalidomide-refractory population. The administration of weekly carfilzomib 70 mg/m2 was safe and convenient, and, overall, the toxicity was manageable in both arms.

Recovery of uninvolved heavy/light chain pair immunoparesis in newly diagnosed transplant-eligible myeloma patients complements the prognostic value of minimal residual disease detection.

Immunoparesis (IP) in multiple myeloma (MM) patients can be measured by classic assessment of immunoglobulin (Ig) levels or by analysis of the uninvolved heavy/light chain pair of the same immunoglobulin (uHLC) by the Hevylite® assay. In this study we evaluate the prognostic value of recovery from IP measured by classic total Ig and uHLC assessment in newly diagnosed MM transplant-eligible (NDMM-TE) patients with intensive treatment and its association with Minimal Residual Disease (MRD). Patients were enrolled and treated in the PETHEMA/GEM2012MENOS65 trial and continued in the PETHEMA/GEM2014MAIN trial. Total Ig (IgG, IgA and IgM) and uHLC were analyzed in a central laboratory at diagnosis, after consolidation treatment and after the first year of maintenance. MRD was analyzed by next generation flow cytometry after consolidation (sensitivity level 2x10-6). We found no differences in progression free survival (PFS) between patients who recovered and patients who didn't recover from IP after consolidation when examining classic total Ig and uHLC. However, after the first year of maintenance, in contrast to patients with classic IP, patients with recovery from uHLC IP had longer PFS than patients without recovery, with hazard ratio of 0.42 (CI95% 0.21-0.81; p=0.008). Multivariate analysis with Cox proportional-hazards regression models confirmed recovery from uHLC IP after the first year of maintenance as an independent prognostic factor for PFS, with an increase in C-statistic of 0.05 (-0.04-0.14; p<0.001) when adding uHLC IP recovery. Moreover, we observed that MRD status and uHLC IP recovery affords complementary information for risk stratification. In conclusion, recovery from uHLC IP after one year of maintenance is an independent prognostic factor for PFS in NDMM-TE patients who receive intensive treatment. Immune reconstitution, measured as recovery from uHLC IP, provides complementary prognostic information to MRD assessment.

Telemedicine for neurological diseases: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: The aim was to systematically review the effectiveness and safety of telemedicine combined with usual care (in-person visits) compared to usual care for the therapeutic management and follow-up assessment of neurological diseases. METHODS: The electronic databases MEDLINE, Embase, Web of Science and Cochrane Central Register of Controlled Trials were searched (June 2021). Randomized controlled trials (RCTs) on patients of any age with neurological diseases were considered. Two reviewers screened and abstracted data in duplicate and independently and assessed risk of bias using the Cochrane risk-of-bias tool for randomized trials (RoB 2). When possible, pooled effect estimates were calculated. RESULTS: Of a total of 3018 records initially retrieved, 25 RCTs (n = 2335) were included: 11 (n = 804) on stroke, four (n = 520) on Parkinson's disease, three (n = 110) on multiple sclerosis, two (n = 320) on epilepsy, one (n = 63) on dementia, one (n = 23) on spina bifida, one (n = 40) on migraine, one (n = 22) on cerebral palsy and one (n = 433) on brain damage. Types of telemedicine assessed were online visits (11 studies), tele-rehabilitation (seven studies), telephone calls (three), smartphone apps (two) and online computer software (two). The evidence was quite limited except for stroke. Compared to usual care alone, telemedicine plus usual care was found to improve depressive symptoms, functional status, motor function, executive function, generic quality of life, healthcare utilization and healthy lifestyle in patients in post-stroke follow-up. CONCLUSIONS: Well-designed and executed RCTs are needed to confirm our findings on stroke and to have more scientific evidence available for the other neurological diseases.

Tuning of Cu-Al Interactions in Complexes Derived from Tris(pyridonyl-6-methyl)aluminum Metalloligands.

A series of bioinspired polar atrane Cu-Al complexes were studied with a combined experimental and computational approach to assess the range and nature of Cu-Al interactions in these novel species. The aluminum metalloligand [Na{Me2Al(OPy-6-Me)2}] (2) was furnished in excellent yield (92%) from the nucleophilic attack of Na(OPy-6-Me) to AlMe3 and the subsequent alkane elimination reaction with 6-methyl-2-hydroxypyridine. At the same time, the metalloligand [Al(OPy-6-Me)3] (3) was isolated in an also excellent yield (95%) via alkane elimination of AlMe3 with 6-methyl-2-hydroxypyridine. The zwitterionic Cu-Al atranes [Cu{MeAl(OPy-6-Me)3}] (5Me) and [Cu{MesAl(OPy-6-Me)3}] (5Mes) were isolated (73 and 97% yields) from metalloligands 2 and 3, respectively. [(Cu{Al(OPy-6-Me)4})2(µ-Cu)]+ ([6+][B(ArCF3)4]) was isolated via a reaction that involves alkane elimination and redistribution reacting from 5Me with [H(OEt2)2][B(ArCF3)4] in benzene solution. Alkane elimination in benzene of either 5Me or 5Mes with [HNEt3][B(ArCF3)4] renders [Cu{(Et3N)Al(OPy-6-Me)3}]+ (Et3N-5+). The Lewis base-free cationic complex [Cu{Al(OPy-6-Me)3}]+ (5+) was isolated in 68% yield upon reacting 3 with [Cu(COD)2][B(ArCF3)4] in benzene. Metalloligands and complexes were fully characterized with an array of spectroscopic and analytical techniques that include multinuclear NMR, ATR-IR, ESI-spectrometry, combustion microanalysis, cyclic voltammetry (CV), and, whenever feasible, SCXRD. X-ray and DFT parameters indicate that the strength of the Cu→Al transannular interaction follows the trend 5+ > Et3N-5+ > [6+][B(ArCF3)4], 5Me, and 5Mes in a smooth transition from zwitterionic species where the Cu-Al interaction is nonexistent to moderate Cu-Al Z-type interactions. CV, in conjunction with DFT calculations of Et3N-5+ and 5+, hint at the generation in the electrochemical cell of the radical species 5rad at -1.82 V and the anionic complex 5- at -2.32 V vs Fc/Fc+, respectively. The proposed species 5rad exhibits 2-center/1-electron (2c/1e) σ bonding whereas 5- a 2-center/2-electron (2c/2e) bond.

Using pentamidine to treat cutaneous leishmaniasis in children: a 10-year study in French Guiana.

There are little data on pentamidine as a treatment for paediatric cutaneous leishmaniasis (CL). The objective of this study was to describe the effectiveness and safety of pentamidine over a 10-year period. Every child seen in French Guiana between 2010 and 2020 with proven CL and treated with pentamidine was included. In total, 55 children met the inclusion criteria - 23 girls and 32 boys. There were 38 patients (38/55, 69%) with a > 50% improvement at 1 month after pentamidine treatment and a complete cure at 3 months; 16 children had a < 50% improvement at 1 month and were given a second dose. Of these 16, 8 showed a complete cure at 3 months, 5 were lost to follow-up and 3 showed therapeutic failure at 3 months. The overall cure rate was 84% (46/55) after one or two doses. In terms of the safety of pentamidine, no severe adverse events (grade ≥ 3) were reported.

The causal effect of obesity on prediabetes and insulin resistance reveals the important role of adipose tissue in insulin resistance.

Reverse causality has made it difficult to establish the causal directions between obesity and prediabetes and obesity and insulin resistance. To disentangle whether obesity causally drives prediabetes and insulin resistance already in non-diabetic individuals, we utilized the UK Biobank and METSIM cohort to perform a Mendelian randomization (MR) analyses in the non-diabetic individuals. Our results suggest that both prediabetes and systemic insulin resistance are caused by obesity (p = 1.2×10-3 and p = 3.1×10-24). As obesity reflects the amount of body fat, we next studied how adipose tissue affects insulin resistance. We performed both bulk RNA-sequencing and single nucleus RNA sequencing on frozen human subcutaneous adipose biopsies to assess adipose cell-type heterogeneity and mitochondrial (MT) gene expression in insulin resistance. We discovered that the adipose MT gene expression and body fat percent are both independently associated with insulin resistance (p≤0.05 for each) when adjusting for the decomposed adipose cell-type proportions. Next, we showed that these 3 factors, adipose MT gene expression, body fat percent, and adipose cell types, explain a substantial amount (44.39%) of variance in insulin resistance and can be used to predict it (p≤2.64×10-5 in 3 independent human cohorts). In summary, we demonstrated that obesity is a strong determinant of both prediabetes and insulin resistance, and discovered that individuals' adipose cell-type composition, adipose MT gene expression, and body fat percent predict their insulin resistance, emphasizing the critical role of adipose tissue in systemic insulin resistance.