Neurodevelopment at 24 months corrected age in extremely preterm infants treated with dexamethasone alternatives during the late postnatal period: a cohort study.

The administration of dexamethasone has been associated with suboptimal neurodevelopment. We aimed to compare the development of extremely premature infants treated or not with alternatives to dexamethasone: betamethasone, hydrocortisone hemisuccinate. This retrospective cohort study included infants born before 29 weeks of gestational age, treated or not with late (day ≥ 7) postnatal steroids (betamethasone, hydrocortisone hemisuccinate). The neurodevelopment outcome was evaluated at 24 months corrected age, after adjustment on comorbidities of extreme prematurity. In order to analyse their overall development, data about growth and respiratory outcomes were collected. Among the 192 infants included, 59 (30.7%) received postnatal steroids. Suboptimal neurodevelopment concerned 37/59 (62.7%) postnatal steroid-treated and 43/133 (38.1%; p = 0.002) untreated infants. However, in multivariable analysis, only severe neonatal morbidity (p = 0.007) and male gender (p = 0.027) were associated with suboptimal neurodevelopment outcome at 24 months.  Conclusions: Betamethasone or hydrocortisone hemisuccinate treatment was not an independent risk for suboptimal neurological development, growth and respiratory outcomes assessed at 24 months corrected age in extremely premature infants.  Registration number: The study was registered on the ClinicalTrials.gov register: NCT05055193. What is Known: • Late postnatal steroids are used to treat bronchopulmonary dysplasia • Meta-analyses warned against the neurological risk of dexamethasone use during neonatal period. Early or late hydrocortisone hemisuccinate has been evaluated in multiple studies, none of which have reported an adverse effect on neurodevelopment at least to 2 years. Data about the use of betamethasone are scarce. What is New: • The risk of suboptimal neurodevelopment was higher among extremely premature infants who received postnatal steroids when compared to those who did not. • Betamethasone and hydrocortisone hemisuccinate treatment was not an independent risk factor for suboptimal neurodevelopment at 24 months corrected age.

Long Intervals between Intravitreal Injections Using a Treat-and-Extend Protocol in a Real-Life Context in AMD: The LIRE Study.

INTRODUCTION: The aim of the study was to assess the outcome of long treat-and-extend (TE) anti-VEGF intravitreal injection (IVI) intervals (≥every 12 weeks [Q12W]) in neovascular age-related macular degeneration (nAMD). The aims of this retrospective study were to determine the proportion of nAMD eyes treated ≥ Q12W, to analyze their longitudinal, functional, and anatomical outcomes, and to compare functional and anatomical outcomes between eyes that rapidly versus slowly reached a Q12W regimen and between eyes directly treated with versus initiating lately the TE regimen. METHODS: All patients receiving IVIs for nAMD were screened. The longitudinal, functional, and anatomical characteristics of Q12W-treated eyes were reported at different timepoints. RESULTS: Ninety-one eyes were included (38% of our total nAMD cohort). The mean TE regimen time to reach a Q12W interval was 20.1 ± 16.2 months. During this time, a mean number of 12.1 ± 9.3 IVIs were needed. The mean best-corrected visual acuity was 68 letters at the time of diagnosis and was maintained (p > 0.05). Eyes that rapidly reached a Q12W interval had a shorter follow-up before TE regimen initiation (p = 0.04) and received fewer IVIs (p = 0.02) than eyes that slowly reached a Q12W interval. Eyes directly treated with the TE regimen reached a Q12W interval more rapidly than eyes with late TE initiation. The neovascularization subtype was not a predictor of outcome in TE-treated eyes. CONCLUSION: ≥Q12W eyes represent an important part of the nAMD population in our real-life study. No baseline anatomical characteristics were associated with the outcome under a TE regimen, although early TE regimen initiation allowed extending more rapidly the IVI interval.

Promises and pitfalls of imaging-based biomarkers in motor neuron diseases.

PURPOSE OF REVIEW: Although neuroimaging in motor neuron diseases (MNDs) continues to generate important novel academic insights, the translation of novel radiological protocols into viable biomarkers remains challenging. RECENT FINDINGS: A multitude of technological advances contribute to the success of academic imaging in MND such as the availability of high-field MRI platforms, novel imaging techniques, quantitative spinal cord protocols to whole-brain spectroscopy. International collaborations, protocol harmonization efforts, open-source image analysis suites also fuel developments in the field. Despite the success of academic neuroimaging in MND, the meaningful interpretation of radiological data from single patients and accurate classification into relevant diagnostic, phenotypic and prognostic categories remain challenging. Appraising accruing disease burden over the short follow-up intervals typically used in pharmacological trials is also notoriously difficult. SUMMARY: Although we acknowledge the academic achievements of large descriptive studies, an unmet priority of neuroimaging in MND is the development of robust diagnostic, prognostic and monitoring applications to meet the practical demands of clinical decision-making and pharmacological trials. A paradigm shift from group-level analyses to individual-level data interpretation, accurate single-subject classification and disease-burden tracking is therefore urgently needed to distil raw spatially coded imaging data into practical biomarkers.

Profile of patients with a positive HCV viral load in a large French psychiatric hospital (2019-2021): A case-control study.

Hepatitis C virus (HCV) is highly prevalent in people with mental disorders (PWMDs). However, in the international context of HCV elimination, no previous study has explored the features of seropositive PWMDs with vs. without a positive viral load (VL). We retrospectively retrieved all HCV serology results of patients hospitalized in 2019, 2020 and 2021 in the second-largest psychiatric hospital of France. Using the medical records of all patients found seropositive for HCV, the following data were collected: sex (male, female), age (in years), previous history of illicit drug use except cannabis (yes or no) and previous history of incarceration (yes or no). We conducted a case-control comparison of these variables between the PWMDs who had and did not have a positive VL, thus providing odds ratios and 95% confidence intervals (ORs [95% CI]). In a total of 13,276 inpatients, 2540 (19.1%) underwent at least one HCV serology; 55 of them (2.16%) were found positive. A VL count was performed for 48 of them, finding 15 (31.3%) individuals with active HCV. Compared with those with a negative VL, these 15 individuals were less likely to have previous documented illicit drug use (OR = 0.18; 95% CI [0.05-0.68]) and to have been previously incarcerated (OR = 0.23; 95% CI [0.06-0.99]); age and sex did not statistically differ. In the context of HCV elimination, PWMDs yet to be treated for HCV are more likely to be those with no identified risk factor for HCV, which supports a strategy of systematic screening for HCV among PWMDs.

Surgical resection versus transarterial chemoembolization followed by moderately hypofractionated radiotherapy in hepatocellular carcinoma.

BACKGROUND AND OBJECTIVE: Transarterial chemoembolization (TACE) is the gold standard treatment in intermediate hepatocellular carcinoma (HCC), but long-term disease control rates remain low. Herein, we compared results of TACE followed by hypofractionated radiotherapy (TACE-hRT) to surgical resection (SR) in early single or paucinodular intrahepatic HCC. METHODS: Between June 2004 and November 2016, data on 160 consecutive patients with Barcelona Clinic Liver Cancer (BCLC) stage A Child-Pugh A HCC treated with SR or TACE-hRT in our expert center were retrospectively reviewed. Time to progression (TTP), progression-free survival (PFS), and overall survival (OS) were evaluated. Clinical outcomes were compared using the stabilized-weights inverse probability of treatment weighting propensity score. RESULTS: Ninety-eight patients underwent SR and 62 were treated by TACE-hRT. Median total dose of RT was 54 Gy (interquartile range [IQR] 54-54) in 3­Gy fractions. Median OS follow-up was 93 months. TTP did not significantly differ between patients following SR and TACE-hRT, with 1­year rates of 68.2% and 82.6% (p = 0.17), respectively. In contrast, PFS and OS were lower in the TACE-hRT group (p = 0.015 and p = 0.006), with a median OS of 37 vs. 63 months for patients with surgery and TACE-hRT, respectively. In multivariate analysis, a significant negative impact on PFS and OS was seen for age at diagnosis, on TTP for alcohol-related liver disease, and on OS for total number of HCC nodules. Symptomatic grade ≥ 3 adverse events were presented by 42 (42.9%) SR and 19 (30.6%) TACE-hRT patients (p = 0.17). CONCLUSION: In patients presenting Child-Pugh A BCLC­A HCC with high risk for surgical complications, TACE-hRT can be an effective and safe treatment. However, surgical management remains the standard of care whenever possible.

Time for optimism in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is among the most common motor neuron diseases in adults. Nevertheless, ALS remains fatal, despite decades of research and clinical trials, which has led to negative conclusions until recently in regard to four specific treatments. It is well known that we can learn from failures, and we consider that the time has come to present positive insight on this disease. METHODS: We did a literature search using PubMed and Scopus for articles published in English from 1 January 2016, to 30 June 2022 dealing with "amyotrophic lateral sclerosis", diagnosis, treatment, and biomarkers. RESULTS: A comprehensive review of the literature on diagnosis, monitoring, and treatment of this condition showed convincing evidence that we are now able to diagnose earlier as well as to better monitor and treat ALS. CONCLUSIONS: Although ALS is often difficult to diagnose and remains incurable, there are many indications that an optimistic view of ALS management in the coming years is now realistic.

Postnatal growth and body composition in extremely low birth weight infants fed with individually adjusted fortified human milk: a cohort study.

This cohort study aimed to evaluate the impact of an individualised nutritional care approach combining standardised fortification with adjustable fortification on postnatal growth and body composition in extremely low birth weight (ELBW) infants. We included ELBW infants admitted to a neonatal intensive care unit and still hospitalised at 35 weeks postmenstrual age (PMA). The fortification of human milk was standardised (multicomponent fortifier) between 70 mL/kg/day and full enteral feeding, and then individualised using adjustable fortification. When weight gain was below 20 g/kg/day, protein or energy was added when serum urea was below or above 3.5 mmol/L, respectively. Postnatal growth failure (PNGF) was defined as being small for gestational age at discharge and/or when the Z-score loss between birth and discharge was higher than 1. Body composition was assessed between 35 and 41 weeks of PMA. Among the 310 ELBW infants included, the gestational age of birth was 26.7 ± 1.8 weeks, and the birth weight was 800 ± 128 g. The mean Z-score difference between birth and discharge was moderately negative for the weight (-0.32), more strongly negative for length (-1.21), and almost nil for head circumference (+ 0.03). Only 27% of infants presented PNGF. At discharge, fat mass was 19.8 ± 3.6%. Multivariable analysis showed that the proportion of preterm formula received and gestational age at birth were independently associated with the percentage of fat mass.  Conclusion: The individualised nutritional care approach applied herein prevented postnatal weight loss in most infants, limited length growth deficit, and supported excellent head circumference growth. What is Known: • At least half of extremely low birth weight infants are small for gestational age at discharge and postnatal growth deficit has been associated with impaired neurocognitive and renal development. • Human milk is the main milk used in neonatology and, although fortification of human milk is a standard of care, there is no consensus regarding the optimal fortification strategy to be adopted. What is New: • Using an approach combining standardised fortification followed by individualised adjustable fortification limited postnatal growth deficit for body weight and head circumference. Postnatal growth failure is not a fatality in extremely low birth weight infants. • Each additional gestational age week at birth resulted in a decrease in fat mass percentage at discharge, which was higher than in foetuses of the same gestational age, likely representing a necessary adaptation to extra-uterine life.

The Effects of Treatment Regimen on the Initial Management of Macular Neovascularization Subtypes in Age-Related Macular Degeneration.

INTRODUCTION: The aim of this study was to evaluate the effect of initial treatment regimen individualization (pro re nata or treat-and-extend [TAE]), according to macular neovascularization (MNV) subtype, on the functional and anatomical response in neovascular age-related macular degeneration (nAMD). The secondary objective was to compare the treatment burden between each MNV subtype. METHODS: Consecutive treatment-naïve nAMD patients were retrospectively included. MNV subtype was graded by 2 independent blinded investigators on multimodal imaging. Functional and anatomical outcomes were analysed according to treatment regimen and MNV subtypes. RESULTS: A total of 281 eyes from 243 patients were included in the study. According to the treatment regimen, there was no significant difference in best-corrected visual acuity gain within the first 2 years of treatment for type 1 (p = 0.106) and type 3 MNV (p = 0.704). Conversely, there was a significant difference in favour of TAE regimen for type 2 (p = 0.017) and type 4 MNV (p = 0.047). Type 1 MNV had a higher proportion of visits with subretinal fluid (p = 0.0007) but not with intraretinal fluid (p = 0.22). The mean interval between the last 2 injections was significantly shorter for type 1 MNV (p = 0.0045). CONCLUSION: The individualization of the initial treatment protocol according to MNV subtype can improve the functional outcome and may decrease the treatment burden.

Willingness to use a drug consumption room among people who use drugs in Lyon, France, a city with no open scene of drug use (the TRABOUL survey).

BACKGROUND: Drug consumption rooms (DCRs) have been developed in cities with open drug scenes, with the aim to reduce drug-related harm. In Lyon, France's second-largest city, there is no distinct drug use area, which raised doubts regarding the need for a DCR. METHODS: We conducted a face-to-face survey of 264 people who use drugs (PWUDs), recruited in harm reduction or addiction treatment centers, in the streets or in squats. We assess their willingness to use a DCR, and we collected sociodemographic and medical features. Bivariable comparisons and analyses adjusted for sociodemographic parameters explored the association between willing to use a DCR and other variables, thus providing crude (ORs) and adjusted odds ratios (aORs) and 95% confidence intervals (95% CI). RESULTS: In total, 193 (73.1%) PWUDs accepted to participate (mean age 38.5 ± 9.3 years; 80.3% men). Among them, 64.2% declared willing to use a DCR. Being treatment-seeker (aOR 0.20, 95% CI [0.08-0.51]; p < 0.001) and not living alone (aOR 0.29; 95% CI [0.10-0.86], p = 0.025) were negatively associated with willing to use a DCR. By contrast, receiving precarity social insurance (aOR 4.12; 95% CI [1.86-9.14], p < 0.001), being seropositive for hepatitis C (aOR 3.60; 95% CI [1.20-10.84], p = 0.022), being cannabis user (aOR 2.45; 95% CI [1.01-5.99], p = 0.049), and reporting previous problems with residents (aOR 5.99; 95% CI [2.16-16.58], p < 0.001) or with the police (aOR = 4.85; 95% CI [1.43-16.39], p = 0.011) were positively associated. CONCLUSIONS: PWUDs, especially the most precarious ones, largely supported the opening of a DCR in Lyon, a city with no open drug scene.

Necrotizing external otitis: analysis of relapse risk factors in 66 patients managed during a 12 year period.

BACKGROUND: Necrotizing external otitis (NEO) is a severe infection of the skull base that occurs generally in the elderly and/or in diabetic recipients. There are few data in the literature about the therapeutic management of this complex bone infection. OBJECTIVES: To analyse relapses after NEO treatment completion, and to describe the clinical features of NEO. METHODS: We performed a retrospective cohort study in the Lyon regional reference centre for the management of complex bone and joint infections. Consecutive cases of NEO from 1 January 2006 to 31 December 2018 were included. The primary outcome was the relapse of NEO. Variables were analysed using Cox regression survival analysis with adjusted hazard ratio (aHR) and Kaplan-Meier curve. RESULTS: Sixty-six patients were included. Median age was 75 (IQR 69-81) years and 46 (70%) patients were diabetic. Eleven patients (17%) had temporomandibular arthritis, 10 (15%) cranial nerve paralysis, 2 (3%) cerebral thrombophlebitis, and 2 (3%) contiguous abscess. Microbiological documentation was obtained in 56 patients and revealed Pseudomonas aeruginosa in 44/56 patients (79%). Nine (14%) cases had no microbiological documentation. Antibiotic therapy was dual for 63 (95%) patients. During a median follow-up of 27 (IQR 12-40) months, 16 out of 63 (25%) patients experienced a relapse. Fungal infection was significantly associated with relapse [aHR 4.1 (95% CI 1.1-15); P = 0.03]. CONCLUSIONS: NEO is a severe bone infection, mainly (but not exclusively) caused by P. aeruginosa, which occurs in elderly and diabetic recipients. Fungal infections at baseline significantly impact the outcome.

In situ normothermic regional perfusion versus ex situ normothermic machine perfusion in liver transplantation from donation after circulatory death.

In situ normothermic regional perfusion (NRP) and ex situ normothermic machine perfusion (NMP) aim to improve the outcomes of liver transplantation (LT) using controlled donation after circulatory death (cDCD). NRP and NMP have not yet been compared directly. In this international observational study, outcomes of LT performed between 2015 and 2019 for organs procured from cDCD donors subjected to NRP or NMP commenced at the donor center were compared using propensity score matching (PSM). Of the 224 cDCD donations in the NRP cohort that proceeded to asystole, 193 livers were procured, resulting in 157 transplants. In the NMP cohort, perfusion was commenced in all 40 cases and resulted in 34 transplants (use rates: 70% vs. 85% [p = 0.052], respectively). After PSM, 34 NMP liver recipients were matched with 68 NRP liver recipients. The two cohorts were similar for donor functional warm ischemia time (21 min after NRP vs. 20 min after NMP; p = 0.17), UK-Donation After Circulatory Death risk score (5 vs. 5 points; p = 0.38), and laboratory Model for End-Stage Liver Disease scores (12 vs. 12 points; p = 0.83). The incidence of nonanastomotic biliary strictures (1.5% vs. 2.9%; p > 0.99), early allograft dysfunction (20.6% vs. 8.8%; p = 0.13), and 30-day graft loss (4.4% vs. 8.8%; p = 0.40) were similar, although peak posttransplant aspartate aminotransferase levels were higher in the NRP cohort (872 vs. 344 IU/L; p < 0.001). NRP livers were more frequently allocated to recipients suffering from hepatocellular carcinoma (HCC; 60.3% vs. 20.6%; p < 0.001). HCC-censored 2-year graft and patient survival rates were 91.5% versus 88.2% (p = 0.52) and 97.9% versus 94.1% (p = 0.25) after NRP and NMP, respectively. Both perfusion techniques achieved similar outcomes and appeared to match benchmarks expected for donation after brain death livers. This study may inform the design of a definitive trial.

Impact of COVID-19 pandemic on antifungal consumption: a multicenter retrospective analysis.

BACKGROUND: In the context of COVID-19 pandemic, antifungal overuse may have occurred in our hospitals as it has been previously reported for antibacterials. METHODS: To investigate the impact of COVID-19 on antifungal consumption, a multicenter retrospective study including four medical sites and 14 intensive care units (ICU) was performed. Antifungal consumption and incidences of invasive fungal diseases before and during COVID-19 pandemic, for non-COVID-19 patients and COVID-19 patients, were described. RESULTS: An increase in voriconazole consumption was observed in 2020 compared with 2019 for both the whole hospital and the ICU (+ 40.3% and + 63.7%, respectively), whereas the incidence of invasive aspergillosis significantly increased in slightly lower proportions in the ICU (+ 46%). Caspofungin consumption also increased in 2020 compared to 2019 for both the whole hospital and the ICU (+ 34.9% and + 17.0%, respectively) with an increased incidence of invasive candidiasis in the whole hospital and the ICU but in lower proportions (+ 20.0% and + 10.9%, respectively). CONCLUSIONS: We observed an increased consumption of antifungals including voriconazole and caspofungin in our hospital during the COVID-19 pandemic and explained in part by an increased incidence of invasive fungal diseases in COVID-19 patients. These results are of utmost importance as it raises concern about the urgent need for appropriate antifungal stewardship activities to control antifungal consumption.

Nephrocalcinosis in very low birth weight infants: incidence, associated factors, and natural course.

BACKGROUND: Preterm kidney is exposed to various exogenous factors that may impact its function such as nephrotoxic drugs or nephrocalcinosis. We investigated prevalence and risk factors of nephrocalcinosis (NC) in recently born very low birth weight (VLBW) infants submitted to improved biological monitoring. METHODS: Retrospective, case-control study in very preterm infants (< 32 + 6 weeks, ≤ 1500 g) admitted to a tertiary care unit during a 6-year period. Each case (ultrasound-diagnosed NC) was matched with two controls (no NC). Data were collected at days 15 and 30 of life and 35 weeks corrected age, with follow-up at 18 months and 3 years. RESULTS: Of 525 eligible infants, overall prevalence of NC was 17.1% at 35 weeks corrected age. Prevalence was halved between 2012 (26.1%) and 2017 (11.8%). We included 265 infants, more than half being born before 28 weeks. Cases presented with more severe morbidity than controls, but reached statistical significance only in infants born < 28 weeks (88.2% vs. 68.3%, P = 0.01). Protein, energy, calcium, phosphorus, and vitamin D intakes were similar in the two groups and did not change significantly over the study period. Weight gain was similar in the two groups. Exposure to furosemide (OR [IC95%]: 1.26 [1.02; 1.57]) and postnatal growth (1.65 [1.04; 2.67]) were independent risk factors of NC. NC resolved 12-18 months after diagnosis in 61% of infants. CONCLUSION: Prevalence of NC is significant but can be reduced. Furosemide should be cautiously prescribed in VLBW infants, and nutritional support must be well monitored to support postnatal growth and limit risk of nephrocalcinosis. TRIAL REGISTRATION: ClinicalTrials.gov: NCT 04,860,583. A higher resolution version of the Graphical abstract is available as Supplementary information.

Screening of telangiectatic capillaries in chronic macular edema based on multimodal imaging: a study of 101 eyes. LyoMAC1 study.

PURPOSE: To estimate the prevalence of telangiectatic capillaries (TCs) in patients followed for chronic macular edema (CME) (diabetic ME [DME] and ME associated with retinal vein occlusion [RVO]). METHODS: Real-life, prospective, bi-centric cohort study including all consecutive patients followed for a clinically significant CME secondary to diabetic retinopathy or RVO. Inclusion criteria were patients treated with intravitreal injection for their ME for at least 12 months who had to undergo follow-up angiography. Multimodal imaging with color retinophotography, spectral-domain optical coherence tomography (SD-OCT), OCT angiography, and en face OCT was performed in all patients. RESULTS: A total of 101 eyes of 71 patients were included between November 2019 and June 2020. Of the 101 eyes analyzed, indocyanine green angiography found at least one TC in 67 eyes (66.3%). No significant differences were found between the groups with and without TC except for the distribution of DME and RVO (p < 0.008). In 83.6% of eyes with TCs, TCs contributed to the formation of the ME. SD-OCT sensitivity for TC detection was 94%. CONCLUSION: In our study, the estimated prevalence of TCs in CME (DME and ME associated with RVO) was 66.3%, i.e., two-thirds of patients. SD-OCT was an excellent screening examination with a sensitivity of 94%.

A retrospective analysis of all-cause and cause-specific mortality rates in French male professional footballers.

This study retrospectively compared all-cause and cause-specific mortality in French male professional football players with data from France's national population. Altogether, 6114 individuals born in Metropolitan France or in one of its overseas territories who played at least one competitive match in France's professional football championships between January 1, 1968 and December 31, 2015, were identified and followed up for vital status obtained from a national reference database until December 31, 2015. Data on all-cause and cause-specific mortality were subsequently compared to the expected number of deaths for the national population after standardization for the year, age, and sex. Ratios between observed and expected deaths provided standardized mortality ratios (SMR) along with 95% confidence intervals (95% CI). Linear trends were investigated using the Poisson trend test. Altogether, 662 player deaths were observed. All-cause mortality overall was lower than that of the national population (SMR: 0.69, 95% CI 0.64-0.75). An excess of deaths from dementia was observed in the players (SMR: 3.38, 95% CI: 2.49-4.50) whereas mortality from diseases of the nervous (SMR: 0.64, 95% CI: 0.35-1.08) and cardiovascular systems (SMR: 0.82, 95% CI: 0.70-0.96), and cancer (SMR: 0.67, 95% CI: 0.58-0.76) was lower. Lower overall mortality and that owing to common cardiovascular and cancer-related diseases were reported in French professional football players compared to France's national population. In line with previous studies, however, excess mortality from dementia was observed in the players. Career length was not associated with all-cause or cause-specific mortality. Prospective matched-cohort studies are necessary to identify the neurologic impact of participation in professional football.

The Amyotrophic Lateral Sclerosis M114T PFN1 Mutation Deregulates Alternative Autophagy Pathways and Mitochondrial Homeostasis.

Mutations in profilin 1 (PFN1) have been identified in rare familial cases of Amyotrophic Lateral Sclerosis (ALS). PFN1 is involved in multiple pathways that could intervene in ALS pathology. However, the specific pathogenic role of PFN1 mutations in ALS is still not fully understood. We hypothesized that PFN1 could play a role in regulating autophagy pathways and that PFN1 mutations could disrupt this function. We used patient cells (lymphoblasts) or tissue (post-mortem) carrying PFN1 mutations (M114T and E117G), and designed experimental models expressing wild-type or mutant PFN1 (cell lines and novel PFN1 mice established by lentiviral transgenesis) to study the effects of PFN1 mutations on autophagic pathway markers. We observed no accumulation of PFN1 in the spinal cord of one E117G mutation carrier. Moreover, in patient lymphoblasts and transfected cell lines, the M114T mutant PFN1 protein was unstable and deregulated the RAB9-mediated alternative autophagy pathway involved in the clearance of damaged mitochondria. In vivo, motor neurons expressing M114T mutant PFN1 showed mitochondrial abnormalities. Our results demonstrate that the M114T PFN1 mutation is more deleterious than the E117G variant in patient cells and experimental models and suggest a role for the RAB9-dependent autophagic pathway in ALS.

Microelimination or Not? The Changing Epidemiology of Human Immunodeficiency Virus-Hepatitis C Virus Coinfection in France 2012-2018.

BACKGROUND: The arrival of highly effective, well-tolerated, direct-acting antiviral agents (DAA) led to a dramatic decrease in hepatitis C virus (HCV) prevalence. Human immunodeficiency virus (HIV)-HCV-coinfected patients are deemed a priority population for HCV elimination, while a rise in recently acquired HCV infections in men who have sex with men (MSM) has been described. We describe the variations in HIV-HCV epidemiology in the French Dat'AIDS cohort. METHODS: This was a retrospective analysis of a prospective cohort of persons living with HIV (PLWH) from 2012 to 2018. We determined HCV prevalence, HCV incidence, proportion of viremic patients, treatment uptake, and mortality rate in the full cohort and by HIV risk factors. RESULTS: From 2012 to 2018, 50 861 PLWH with a known HCV status were followed up. During the period, HCV prevalence decreased from 15.4% to 13.5%. HCV prevalence among new HIV cases increased from 1.9% to 3.5% in MSM but remained stable in other groups. Recently acquired HCV incidence increased from 0.36/100 person-years to 1.25/100 person-years in MSM. The proportion of viremic patients decreased from 67.0% to 8.9%. MSM became the first group of viremic patients in 2018 (37.9%). Recently acquired hepatitis represented 59.2% of viremic MSM in 2018. DAA treatment uptake increased from 11.4% to 61.5%. More treatments were initiated in MSM in 2018 (41.2%) than in intravenous drug users (35.6%). In MSM, treatment at the acute phase represented 30.0% of treatments in 2018. CONCLUSIONS: A major shift in HCV epidemiology was observed in PLWH in France from 2012 to 2018, leading to a unique situation in which the major group of HCV transmission in 2018 was MSM. Clinical Trials Registration. NCT02898987.

Split-hand and split-limb phenomena in amyotrophic lateral sclerosis: pathophysiology, electrophysiology and clinical manifestations.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting the upper and lower motor neurons. A key clinical feature of ALS is the absence of accurate, early-stage diagnostic indicators. 'Split-hand syndrome' was first described in ALS at the end of the last century and a considerable body of literature suggests that the split-hand phenomenon may be an important clinical feature of ALS. Considering the published investigations, it is conceivable that the 'split-hand syndrome' results from the associated upper and lower motor neuron degeneration, whose interaction remains to be fully clarified. Additionally, other split syndromes have been described in ALS involving upper or lower limbs, with a nuanced description of clinical and neurophysiological manifestations that may further aid ALS diagnosis. In this review, we endeavour to systematically present the spectrum of the 'split syndromes' in ALS from a clinical and neurophysiology perspective and discuss their diagnostic and pathogenic utility.

Effect of familial clustering in the genetic screening of 235 French ALS families.

OBJECTIVES: To determine whether the familial clustering of amyotrophic lateral sclerosis (ALS) cases and the phenotype of the disease may help identify the pathogenic genes involved. METHODS: We conducted a targeted next-generation sequencing analysis on 235 French familial ALS (FALS), unrelated probands to identify mutations in 30 genes linked to the disease. The genealogy, that is, number of cases and generations with ALS, gender, age, site of onset and the duration of the disease were analysed. RESULTS: Regarding the number of generations, 49 pedigrees had only one affected generation, 152 had two affected generations and 34 had at least three affected generations. Among the 149 pedigrees (63.4%) for which a deleterious variant was found, an abnormal G4C2 expansion in C9orf72 was found in 98 cases as well as SOD1, TARBP or FUS mutations in 30, 9 and 7 cases, respectively. Considering pedigrees from the number of generations, abnormal G4C2 expansion in C9orf72 was more frequent in pedigrees with pairs of affected ALS cases, which represented 65.2% of our cohort. SOD1 mutation involved all types of pedigrees. No TARDBP nor FUS mutation was present in monogenerational pedigrees. TARDBP mutation predominated in bigenerational pedigrees with at least three cases and FUS mutation in multigenerational pedigrees with more than seven cases, on average, and with an age of onset younger than 45 years. CONCLUSION: Our results suggest that familial clustering, phenotypes and genotypes are interconnected in FALS, and thus it might be possible to target the genetic screening from the familial architecture and the phenotype of ALS cases.

Neural Correlates of Motor Imagery of Gait in Amyotrophic Lateral Sclerosis.

BACKGROUND: Gait impairment is poorly characterized in amyotrophic lateral sclerosis (ALS), despite increasing evidence of extrapyramidal and cerebellar dysfunction. Gait impairment adds to the considerable motor disability of ALS patients and requires targeted multidisciplinary interventions. PURPOSE: To assess gait imagery-specific networks and functional adaptation in ALS. STUDY TYPE: Prospective. POPULATION: Seventeen ALS patients with lower motor neuron predominant (LMNp) disability, 14 patients with upper motor neurons predominant (UMNp) disease, and 14 healthy controls were included. FIELD STRENGTH/SEQUENCES: 3T / gradient echo echo planar (GE-EPI). ASSESSMENT: Subjects performed a dual motor imagery task: normal and precision gait. The Movement Imagery Questionnaire - Revised Second Version (MIQ-rs) was used to appraise movement imagery in each participant. Study group-specific activation patterns were evaluated during motor imagery of gait. Additional generalized psychophysiological interaction analyses were carried out using the supplementary motor area, caudate, cerebellum, and superior parietal lobule as seed regions. STATISTICAL TESTS: Repeated-measures analysis of variance (ANOVA) was used to compare time imagery and MIQ-rs scores between groups. Size effects were also reported as partial eta squared (η2). One-way ANOVA was performed to explore differences in terms of connexions during motor imagery tasks. RESULTS: A significant increase in imagery time in UMNp patients compared to controls (P < 0.05) and LMNp (P < 0.05) during imagined gait was demonstrated. UMNp patients exhibited altered supplementary motor area, precentral gyrus, superior parietal lobule, and dorsolateral prefrontal cortex activation and increased orbitofrontal (pFDR(False Discovery Rate) < 0.05), posterior parietal (pFDR < 0.05) caudate (pFDR < 0.05), and cerebellar (pFDR < 0.05) signal during imagined locomotion. Increased effective connectivity of the striato-cerebellar and parieto-cerebellar circuits was also demonstrated. Additional activation was detected in the insula and cingulate cortex. DATA CONCLUSION: Enhanced striato- and parieto-cerebellar networks in UMNp ALS patients are likely to represent a compensatory response to impaired postural control. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 5.