The Association Between Infant Sleep, Cognitive, and Psychomotor Development: A Systematic Review.

STUDY OBJECTIVES: To synthesize findings of original articles examining the association between sleep-wake patterns of typically developing infants aged 0-to-18 months and cognitive and psychomotor development. METHODS: A systematic search strategy was used to identify articles assessing the association between infant sleep (0-to-18 months) and cognitive/psychomotor development (Medline, PsycINFO, SCOPUS). Of 7,136 articles screened, 22 articles met inclusion criteria, and the results were subsequently synthesized. A quality assessment was conducted, and studies were categorized as "poor", "fair", or "good". RESULTS: Out of 22 studies, two found exclusively significant associations between infant sleep and cognitive/psychomotor development, three found no significant associations and 17 found mixed results. Studies with exclusively significant results used a single sleep variable and single timepoint designs. Studies finding mixed results or no significant associations used multiple sleep, developmental variables, or multi-timepoint designs. Eight out of 10 studies and seven out of eight studies investigating nocturnal and total sleep duration, respectively, found no significant association with developmental outcomes. While 63% of studies were rated as having good methodological quality, all studies but one had estimated power of less than 0.80. CONCLUSION: Findings of this review do not support conclusive associations between sleep-wake patterns in infancy and cognitive/psychomotor development. This conclusion contrasts with the literature in older populations, questioning if the association between sleep and development is of a different nature in infancy, potentially because of brain maturation. More studies including larger samples will be needed to clarify the presence or absence of such an association.

Identification of novel small molecule-based strategies of COL7A1 upregulation and readthrough activity for the treatment of recessive dystrophic epidermolysis bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disease caused by loss of function mutations in the gene coding for collagen VII (C7) due to deficient or absent C7 expression. This disrupts structural and functional skin architecture, leading to blistering, chronic wounds, inflammation, important systemic symptoms affecting the mouth, gastrointestinal tract, cornea, and kidney function, and an increased skin cancer risk. RDEB patients have an extremely poor quality of life and often die at an early age. A frequent class of mutations in RDEB is premature termination codons (PTC), which appear in homozygosity or compound heterozygosity with other mutations. RDEB has no cure and current therapies are mostly palliative. Using patient-derived keratinocytes and a library of 8273 small molecules and 20,160 microbial extracts evaluated in a phenotypic screening interrogating C7 levels, we identified three active chemical series. Two of these series had PTC readthrough activity, and one upregulated C7 mRNA, showing synergistic activity when combined with the reference readthrough molecule gentamicin. These compounds represent novel potential small molecule-based systemic strategies that could complement topical-based treatments for RDEB.

Pustular mycosis fungoides has a poor outcome: a multicentric clinico-pathological and molecular case series study.

BACKGROUND: Mycosis fungoides (MF) has usually an indolent course. However, some patients develop a more aggressive disease and few prognostic parameters have been identified. Isolated cases of pustular MF (pMF) suggest an unfavourable prognosis. OBJECTIVES: We aim to describe the clinico-pathological characteristics and prognostic value of pMF. METHODS: We retrospectively collected data of all cases of MF with histological pustules diagnosed from 2009 to 2020. The outcomes and clinico-pathological characteristics of pMF at diagnosis (pMFD) were compared to those of a cohort of non-pustular MF (NpMF). RESULTS: 33 pMF (including 22 pMFD) and 86 NpMF cases were included. The median age at diagnosis of pMF was 61 years [IQR=50-75]. The median follow-up of pMFD was 32 months [IQR=14-49]. Clinically, 33% of pMF had pustules. Large-cell transformation (LCT) occurred in 17 cases. pMFD were at a significantly more advanced-stage and more showed LCT at diagnosis than NpMF (50% vs 7%, p<0.001 and 23% vs 0%, p<0.001, respectively). In multivariate Cox analysis, the presence of histological pustule at diagnostic was associated with shorter OS in all patients (HR=13.90, CI95%[2.43-79]; p=0.003), and in early-stage patients (HR=11.09, CI95%[1.56-78.82]; p=0.02). In multivariate Fine and Gray model analysis, pMFD was associated with a higher cumulative incidence of LCT (SHR=13.90, CI95% [2.43-79]; p=0.003) in all patients. Median OS after the occurrence of histological pustules during follow-up of all pMF patients was 37 months, with a five-year OS of 25% (CI95% [0.06-0.5]). CONCLUSION: pMF often follows an aggressive course, with a high risk of LCT and shorter survival, even for early-stage patients. Histological pustules at diagnostic of MF might represent an independent poor prognostic factor, to be confirmed by further studies. Because pustules are not always clinically identified, histological pustules should be mentioned in pathology reports of MF and prompt discussion of a closer follow-up.

Comparison of subconjunctival TRIamcinolone acetonide injection and intravitreal dexamethasone (OZurdex) injection for uveitic and postoperative macular oedema: the TRIOZ study.

AIMS: To compare effectiveness of subconjunctival triamcinolone acetonide injections and intravitreal injections of dexamethasone 700 µg implants in reducing central macular thickness (CMT) in uveitic and postoperative macular oedema (ME). METHODS: We conducted an open-label, French multicentre randomised comparative trial with a logarithmic CMT non-inferiority margin set at 0.06. Patients were adults with non-infectious inflammatory ME, without any contraindication to the treatments. They were randomised 1:1 to receive either triamcinolone or dexamethasone. The primary endpoint was the difference in CMT among treated eyes between baseline and 2 months, measured with spectral-domain optical coherence tomography. Secondary outcomes included visual acuity, laser flare, vitreous haze, duration of action, tolerance to injections and adverse events. RESULTS: Between January 2016 and January 2020, 106 patients were enrolled (54 in the triamcinolone group and 52 in the dexamethasone group). Subconjunctival triamcinolone injections seemed to be non-inferior to intravitreal dexamethasone injections, especially at month 3 (and nearly at month 1). Nevertheless, we could not demonstrate it, with a treatment effect at month 2 of 0.05 (0.01 ; 0.09) (p value=0.001). This was corroborated by post hoc analyses in the postoperative subgroup, for whom the non-inferiority was nearly demonstrated at month 2 with a treatment effect of 0.02 (-0.03 ; 0.08) (p=0.37). There was no significant difference in the occurrence of adverse effects. CONCLUSION: We could not demonstrate the non-inferiority of triamcinolone injections at month 2. Nevertheless, they showed some efficacity, particularly in treating postoperative ME, being as safe as dexamethasone injections, without any loss of chance if a therapeutic switch is necessary.

Radioactivity as a driver of bacterial community composition in naturally radioactive mineral springs in the French Massif Central.

Some natural environments on Earth are characterised by high levels of radiation, including naturally radioelement enriched mineral springs in the French Massif Central. Therefore, naturally radioactive mineral springs are interesting ecosystems for understanding how bacterial populations in these springs have adapted to high levels of natural and chronic radioactivity over the very long term. The aim of this study was to analyse the bacterial communities of sediments from five naturally radioactive mineral springs in the French Massif Central, sampled in autumn 2019 and spring 2020, and to observe whether radionuclides, compared to other physicochemical parameters, are drivers of the bacterial community structuring in these extreme environments. Physicochemical measurements showed that two springs, Dourioux and Montagne had high radioelement concentrations/activities (uranium, thorium and radon). Analysis of the structure of the bacterial communities, by next generation sequencing based on 16S rRNA gene sequencing, showed that the presence of radionuclides in Dourioux and Montagne, did not lead to a reduction in bacterial diversity and richness compared to the other springs. However, Dourioux and Montagne were characterised by specific bacterial populations, whose presence correlates with the radioelement concentrations/activities measured in these springs. This suggests that radioelements could partly explain the structuring of bacterial communities in these springs. In addition, several of these operational taxonomic units (OTUs) specific to Dourioux and Montagne, mainly affiliated to Proteobacteria, Firmicutes, Acidobacteria, Actinobacteria, and Bacteroidetes, could be involved in the biogeochemistry of radionuclides through different mechanisms (biosorption, biomineralisation, bioaccumulation, and bioreduction), which would allow the development of other bacterial species sensitive to these metals/radioelements. In particular, the co-occurrence of sulphate and/or iron-reducing bacteria, capable of bioreducing uranium, with fermentative bacteria, releasing sources of organic carbons, reflects associations of bacteria with complementary functions that allow them to grow in this peculiar environment and maintain a high diversity in these extreme environments. This study has provided a better understanding of the structuring of bacterial communities exposed to ionising radiation for thousands of years in naturally radioactive environments.

The early communication stages between serine proteases and enterovirus capsids in the race for viral disintegration.

Serine proteases are important environmental contributors of enterovirus biocontrol. However, the structural features of molecular interaction accounting for the susceptibility of enteroviruses to proteases remains unexplained. Here, we describe the molecular mechanisms involved in the recruitment of serine proteases to viral capsids. Among the virus types used, coxsackievirus A9 (CVA9), but not CVB5 and echovirus 11 (E11), was inactivated by Subtilisin A in a host-independent manner, while Bovine Pancreatic Trypsin (BPT) only reduced CVA9 infectivity in a host-dependent manner. Predictive interaction models of each protease with capsid protomers indicate the main targets as internal disordered protein (IDP) segments exposed either on the 5-fold vertex (DE loop VP1) or at the 5/2-fold intersection (C-terminal end VP1) of viral capsids. We further show that a functional binding protease/capsid depends on both the strength and the evolution over time of protease-VP1 complexes, and lastly on the local adaptation of proteases on surrounding viral regions. Finally, we predicted three residues on CVA9 capsid that trigger cleavage by Subtilisin A, one of which may act as a sensor residue contributing to enzyme recognition on the DE loop. Overall, this study describes an important biological mechanism involved in enteroviruses biocontrol.

Canadian colorectal cancer screening programs: How do they measure up using the International Agency for Research on Cancer criteria for organized screening?

Background: Canada has one of the highest incidences of colorectal cancer (CRC) worldwide. CRC screening improves CRC outcomes and is cost-effective. This study compares Canadian CRC screening programs using essential elements of an organized screening program outlined by the International Agency for Research on Cancer (IARC). Methods: We collaborated with the Cancer Screening in 5 continents (CanScreen5) program, an initiative of IARC. Standardized data collection forms were sent to representatives of provincial and territorial CRC screening programs. Twenty-five questions were selected to reflect IARC's essential elements of an organized screening program. We performed a qualitative analysis of Canada's CRC screening programs and compared programs within Canada and internationally. Results: CRC screening programs exist in 10 provinces and 2 territories. None of the programs in Canada met all the essential criteria of an organized screening program outlined by IARC. Three programs do not send invitations to participate in screening. Among those that do, 4 programs do not include a stool test kit in the invitations. While all provinces met the essential elements for leadership, governance, finance, and access to essential services, there was more heterogeneity in the domains of service delivery as well as information systems and quality assurance. Conclusions: There is considerable heterogeneity in the design of CRC screening programs in Canada and worldwide. Programs should strive to meet all the essential IARC criteria for organized screening if local resources allow, such as issuing invitations and implementing systems to track and compare outcomes to maximize screening program quality, effectiveness, and impact.

Cost-Effectiveness of Baloxavir Marboxil Versus Oseltamivir or no Treatment for the Management of Influenza in the United States.

INTRODUCTION: This study sought to evaluate the cost-effectiveness of baloxavir marboxil compared with oseltamivir or no antiviral treatment from a US payer perspective using data from a real-world US administrative claims study. Given baloxavir's ability to rapidly stop viral shedding, the potential health economic implications of a baloxavir-induced population-level reduction in viral transmission was also explored. METHODS: A decision tree cost-effectiveness model was developed for seasonal influenza (2018-2020) using a lifetime time horizon with 3.0% discounting for costs and quality-adjusted life-years (QALYs). Patients aged ≥ 12 years could receive baloxavir, oseltamivir or no antiviral treatment. Patient characteristics, complications, and costs were derived from the Merative™ MarketScan® Research Databases including US commercial claims and Medicare and Medicaid Supplemental databases. A scenario analysis explored the impact of reduced viral transmission with baloxavir. RESULTS: In the base case analysis, baloxavir was cost-effective within a willingness-to-pay threshold of US$100,000/QALY compared with oseltamivir [incremental cost-effectiveness ratio (ICER), $6813/QALY gained] or no antiviral treatment (ICER, $669/QALY gained). The net monetary benefit (NMB) of baloxavir was $1180 and $6208 compared with oseltamivir and no treatment, respectively. The NMB of baloxavir increased linearly with reductions in viral transmission, where a 5% transmission reduction yielded an NMB of $2592 versus oseltamivir and $7621 versus no treatment. Baloxavir became dominant (more effective and less costly, with ICERs < 0) starting with a 12.0% reduction in viral transmission versus oseltamivir and 6.0% versus no antiviral treatment. CONCLUSION: Baloxavir was cost-effective compared with oseltamivir or no antiviral treatment. The potential of baloxavir to reduce viral transmission offers a substantial economic benefit from a US payer perspective.

Baloxavir is a prescription medicine that reduces the duration of flu symptoms and reduces the likelihood of complications from the flu, including serious complications that may require hospitalization. Baloxavir may reduce the spread of the flu to healthy people by reducing the amount and duration of virus shedding from infected people. We designed a model to estimate the cost benefits of using baloxavir versus another flu treatment, known as oseltamivir, or no flu treatment at all. Using baloxavir led to more cost savings than oseltamivir or no treatment for people in the US who have commercial health insurance. Baloxavir was even more cost-effective in the scenario where it reduced the number of flu cases (transmission benefit). This could ultimately have a meaningful benefit across a large health insurance population.

ADAPTIVE OPTICS AND MULTIMODAL IMAGING FOR INFLAMMATORY VITREORETINAL INTERFACE ABNORMALITIES.

PURPOSE: To investigate changes to the vitreoretinal interface in uveitis with multimodal imaging including adaptive optics. METHODS: Four eyes (four patients) affected by fovea-attached (subtype 1A) or fovea-sparing epiretinal membranes (ERMs) on spectral-domain optical coherence tomography or visible internal limiting membrane (ILM) on infrared scanning laser ophthalmoscope (SLO) fundus imaging were recruited in this pilot study. The microstructure of the vitreoretinal interface was imaged using flood-illumination adaptive optics (FIAO), and the images were compared with the cross-sectional spectral-domain optical coherence tomography data. RESULTS: Adaptive optics images revealed multiple abnormalities of the vitreoretinal interface, such as deep linear striae in ERM, and hyperreflective microstructures at the location of ERMs and ILMs. The cone mosaic was imaged by FIAO and was found altered in the four eyes with ERMs or visible ILM. The same four eyes presented alteration of photopic 30 Hz flicker that was reduced in amplitude indicating cone inner retinal layer dysfunction. CONCLUSION: FIAO imaging can identify specific patterns associated with ERMs and ILMs. Correlating FIAO imaging of the vitreomacular interface with the structural alterations seen in FIAO at the level of the outer retinal structures can help understand the cause of significant macular dysfunction associated with ERM.

Effect modification by sex of genetic associations of vitamin C related metabolites in the Canadian Longitudinal study on aging.

Introduction: Vitamin C is an essential nutrient. Sex differences in serum vitamin C concentrations have been observed but are not fully known. Investigation of levels of metabolites may help shed light on how dietary and other environmental exposures interact with molecular processes. O-methylascorbate and ascorbic acid 2-sulfate are two metabolites in the vitamin C metabolic pathway. Past research has found genetic factors that influence the levels of these two metabolites. Therefore, we investigated possible effect modification by sex of genetic variant-metabolite associations and characterized the biological function of these interactions. Methods: We included individuals of European descent from the Canadian Longitudinal Study on Aging with available genetic and metabolic data (n = 9004). We used linear mixed models to tests for genome-wide associations with O-methylascorbate and ascorbic acid 2-sulfate, with and without a sex interaction. We also investigated the biological function of the important genetic variant-sex interactions found for each metabolite. Results: Two genome-wide statistically significant (p value < 5 × 10-8) interaction effects and several suggestive (p value < 10-5) interaction effects were found. These suggestive interaction effects were mapped to several genes including HSD11B2, associated with sex hormones, and AGRP, associated with hunger drive. The genes mapped to O-methylascorbate were differently expressed in the testis tissues, and the genes mapped to ascorbic acid 2-sulfate were differently expressed in stomach tissues. Discussion: By understanding the genetic factors that impact metabolites associated with vitamin C, we can better understand its function in disease risk and the mechanisms behind sex differences in vitamin C concentrations.

Sulfur starvation-induced autophagy in Saccharomyces cerevisiae involves SAM-dependent signaling and transcription activator Met4.

Autophagy is a key lysosomal degradative mechanism allowing a prosurvival response to stresses, especially nutrient starvation. Here we investigate the mechanism of autophagy induction in response to sulfur starvation in Saccharomyces cerevisiae. We found that sulfur deprivation leads to rapid and widespread transcriptional induction of autophagy-related (ATG) genes in ways not seen under nitrogen starvation. This distinctive response depends mainly on the transcription activator of sulfur metabolism Met4. Consistently, Met4 is essential for autophagy under sulfur starvation. Depletion of either cysteine, methionine or SAM induces autophagy flux. However, only SAM depletion can trigger strong transcriptional induction of ATG genes and a fully functional autophagic response. Furthermore, combined inactivation of Met4 and Atg1 causes a dramatic decrease in cell survival under sulfur starvation, highlighting the interplay between sulfur metabolism and autophagy to maintain cell viability. Thus, we describe a pathway of sulfur starvation-induced autophagy depending on Met4 and involving SAM as signaling sulfur metabolite.

Predictive Value of C-Reactive Protein for Infectious Complications After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: A Single-Center Prospective Study.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) can be associated with significant morbidity and prolonged hospital stay. Postoperative infections account for a high burden of these complications. This study aimed to assess the predictive value of postoperative C-reactive protein (CRP) levels for overall infectious complications and anastomotic leaks. METHODS: This was a single-center prospective study of patients undergoing CRS and HIPEC for peritoneal metastases between 2018 and 2020 at Maisonneuve-Rosemont Hospital in Montreal, QC, Canada. CRP levels were measured daily for 10 days following surgery. A comparison was made between patients with infectious complications and those without. RESULTS: Ninety-nine patients were included. Thirty patients had infectious complications (30.3%) and four patients presented an anastomotic leak (4%). CRP levels were significantly higher in patients with infectious complications from postoperative days (PODs) 2-10. Daily cut-off values most accurately predicted infectious complications on day 8 (94.3 mg/L; area under the curve [AUC] 0.85, sensitivity [SE] 76.2%, specificity [SP] 94.7%, positive predictive value [PPV] 88.9%, negative predictive value [NPV] 87.8%; p < 0.0001) and day 9 (72.7 mg/L; AUC 0.89, SE 95.2%, SP 81.8%, PPV 76.9%, NPV 96.4%; p < 0.0001). Patients with infectious complications had longer operative time, higher peritoneal cancer index, and a higher number of intestinal anastomoses, while their baseline characteristics were comparable. CONCLUSION: Measurement of CRP helps predict infectious complications following CRS and HIPEC, particularly on PODs 8 and 9. Cut-off values are more accurate after the first postoperative week, especially in ruling out infectious complications.

Caffeine consumption outcomes on amyotrophic lateral sclerosis disease progression and cognition.

Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy.

Criteria and non-criteria antiphospholipid autoantibodies screening in patients with late pregnancy morbidity: A cross-sectional study.

INTRODUCTION: Antiphospholipid syndrome (APS) is a cause of pregnancy morbidity. We aim to determine the frequency of criteria and non-criteria anti-phospholipid (aPL) autoantibodies in patients admitted for unexplained fetal death (UFD), pre-eclampsia (PE) and/or fetal growth restriction (FGR). METHODS: All consecutive patients with UFD, PE and/or FGR followed in the department of Obstetrics, Bichat Hospital, University of Paris, Paris, between January 2019 and December 2021 were screened. Patients with available serum stored from the index pregnancy were included. Patients with previously known APS or twin pregnancy were excluded. Testing for aPL autoantibodies included anti-cardiolipin (aCL), anti-ß2GPI (aß2GPI), anti-phosphatidylethanolamine (aPE), anti-phosphatidylserine/prothrombin (aPS/PT) IgG/IgM and anti-annexin V IgG. When available, placenta specimens were analyzed by a pathologist blinded to the aPL status. All clinical characteristics, pregnancy features, and comorbidities were extracted from electronic medical records. RESULTS: Overall 167 (32 (28.8-35.7) years) patients with UFD (n = 28; 16.8 %), PE (n = 60; 35.9 %) and/or FGR (n = 105; 62.9 %) were screened for aPL autoantibodies. Moderate titers of aPL autoantibodies were detected in 33 (n = 33/167, 19.8 %) patients. aPL autoantibodies were non-criteria aPE IgG/IgM in most cases (n = 28/33, 84.8 %). aPS/PT IgG/IgM were found in 11 (n = 11/33, 33.3 %) cases and aCL or aß2GP1 IgG/IgM in 4 (n = 4/33, 12.1 %). Multivariable logistic regression showed that aPL autoantibodies were mostly associated with UFD (OR 4.37 [1.72-11.20], p = 0.002), PE ≤ 34th week of gestation (3.22 [0.86-11.90], p = 0.070) and chronic deciduitis (8.03 [0.89-67.2], p = 0.060) DISCUSSION: The frequency of aPL autoantibodies, mostly aPE, is high in patients with late pregnancy morbidity and may qualify obstetrical APS.

When is a handaxe a planned-axe? exploring morphological variability in the Acheulean.

The handaxe is an iconic stone tool form used to define and symbolise both the Acheulean and the wider Palaeolithic. There has long been debate around the extent of its morphological variability between sites, and the role that extrinsic factors (especially raw material, blank type, and the extent of resharpening) have played in driving this variability, but there has been a lack of high-resolution examinations of these factors in the same study. In this paper, we present a 2D geometric morphometric analysis of 1097 handaxes from across Africa, the Levant, and western Europe to examine the patterning of this variability and what it can tell us about hominin behaviour. We replicate the findings of previous studies, that handaxe shape varies significantly between sites and entire continental regions, but we find no evidence for raw material, blank type, or resharpening in determining this pattern. What we do find, however, is that markers of reduction trajectory vary substantially between sites, suggesting that handaxes were deployed differently according to hominin need at a given site. We argue this is reflective of a continuum of reduction strategies, from those focused on the maintenance of a sharp cutting edge (i.e. direct use in cutting activities), to those focused on maintaining tip shapes, and perhaps a corresponding production of flakes. Implications for hominin behavioural flexibility are discussed.

Survey on Parkinson's Disease Diagnosis Impact: Patients, Caregivers and Health Care Professionals' Perspectives.

Background: The announcement of Parkinson's disease (PD) diagnosis may provoke negative feelings that impact the ability to cope with the disease and all life changes related to this new condition. There are scarce data on how to improve communication about PD diagnosis and which factors may influence this outcome. Methods: We performed a national French survey, investigating the diagnosis announcement impact on a large population of people living with PD (PwPD), who recently received the diagnosis (≤1 year since PD diagnosis), and on related caregivers and health care professionals (HCPs), from tertiary and community-based hospitals. Results: A total of 397 PwPD (45% female and 82% > 50 years old), 192 caregivers and 120 HCPs (69% neurologists) completed the questionnaire. The diagnosis was not expected by about 60% of PwPD and induced negative feelings in the majority (82%) of them. Negative feelings that PwPD experience in the moment of the diagnosis announcement were related with male gender [OR = 2.034, CI 95% 1.09-3.78; p = 0.025] and older age [OR = 1.05, CI 95% 1.01-1.08; p = 0.004], while tremor as the first symptom had a threshold significance [OR = 1.78, CI 95% 0.994-3.187; p = 0.052]. Half of the PwPD and caregivers considered that they did not receive enough information and one third had a short-term appointment to rediscuss the diagnosis. A total of 82% of PwPD expressed the willingness to have a multidisciplinary follow-up (PD nurse, psychologists). Only 24% of the HCPs had been trained for PD announcement. Conclusions: The way a PD diagnosis is delivered represents a pivotal moment in the journey of PwPD and caregivers. This process requires improvement in addressing the gaps expressed by PwPD, caregivers, and HCPs through a participatory approach.

Treatment continuity of amyotrophic lateral sclerosis with available riluzole formulations: state of the art and current challenges in a 'real-world' setting.

Amyotrophic lateral sclerosis (ALS) is a rare multisystem neurodegenerative disease leading to death due to respiratory failure. Riluzole was the first disease modifying treatment approved in ALS. Randomized clinical trials showed a significant benefit of riluzole on survival in the months following randomization, with a good safety profile. 'Real-world' studies suggested that the survival benefit of riluzole is substantially greater, with an extended survival ranging between 6 and 19 months. The main limiting associated adverse effects of riluzole are non-severe gastrointestinal complications and an elevation of liver enzymes, observed in 10% of patients. While different classes of drugs have been approved in some countries, riluzole remains the gold standard of therapy. Dysphagia induced by ALS is a major challenge for food intake and riluzole administration. Tablet crushing is associated with a loss of drug intake and a risk of powder aspiration, which jeopardizes the benefits of riluzole. Riluzole oral suspension (ROS) and oral film (ROF) allow riluzole intake in patients with dysphagia. Both formulations are bioequivalent to riluzole tablets with a good safety profile albeit transient oral hypoaesthesia. In case of severe dysphagia, ROS can be used with percutaneous endoscopic gastrostomy. ROF, the last approved formulation, requires low swallowing capacities and may contribute to maintain the efficacy of riluzole when tablets are inadequate according to patient's status and/or preferences. To optimize treatment continuity in newly diagnosed patients, the expected psychological impact of formulation switching that may be perceived as the sign of disease progression should be anticipated.

Earliest evidence of human occupations and technological complexity above the 45th North parallel in Western Europe. The site of Lunery-Rosieres la-Terre-des-Sablons (France, 1.1 Ma).

The site of LuneryRosieres la-Terre-des-Sablons (Lunery, Cher, France) comprises early evidence of human occupation in mid-latitudes in Western Europe. It demonstrates hominin presence in the Loire River Basin during the Early Pleistocene at the transition between an interglacial stage and the beginning of the following glacial stage. Three archaeological levels sandwiched and associated with two diamicton levels deposited on the downcutting river floor indicate repeated temporary occupations. Lithic material yields evidence of simple and more complex core technologies on local Jurassic siliceous rocks and Oligocene millstone. Hominins availed of natural stone morphologies to produce flakes with limited preparation. Some cores show centripetal management and a partially prepared striking platform. The mean ESR age of 1175 ka ± 98 ka obtained on fluvial sediments overlying the archaeological levels could correspond to the transition between marine isotopic stages (MIS) 37 and 36, during the normal Cobb Mountain subchron, and in particular at the beginning of MIS 36. The Lunery site shows that hominins were capable of adapting to early glacial environmental conditions and adopting appropriate strategies for settling in mid-latitude zones. These areas cannot be considered as inhospitable at that time as Lunery lies at some distance from the forming ice cap.

AI-based differential diagnosis of dementia etiologies on multimodal data.

Differential diagnosis of dementia remains a challenge in neurology due to symptom overlap across etiologies, yet it is crucial for formulating early, personalized management strategies. Here, we present an artificial intelligence (AI) model that harnesses a broad array of data, including demographics, individual and family medical history, medication use, neuropsychological assessments, functional evaluations and multimodal neuroimaging, to identify the etiologies contributing to dementia in individuals. The study, drawing on 51,269 participants across 9 independent, geographically diverse datasets, facilitated the identification of 10 distinct dementia etiologies. It aligns diagnoses with similar management strategies, ensuring robust predictions even with incomplete data. Our model achieved a microaveraged area under the receiver operating characteristic curve (AUROC) of 0.94 in classifying individuals with normal cognition, mild cognitive impairment and dementia. Also, the microaveraged AUROC was 0.96 in differentiating the dementia etiologies. Our model demonstrated proficiency in addressing mixed dementia cases, with a mean AUROC of 0.78 for two co-occurring pathologies. In a randomly selected subset of 100 cases, the AUROC of neurologist assessments augmented by our AI model exceeded neurologist-only evaluations by 26.25%. Furthermore, our model predictions aligned with biomarker evidence and its associations with different proteinopathies were substantiated through postmortem findings. Our framework has the potential to be integrated as a screening tool for dementia in clinical settings and drug trials. Further prospective studies are needed to confirm its ability to improve patient care.

Barriers, Solutions, and Opportunities for Adapting Critical Care Clinical Trials in the COVID-19 Pandemic.

Importance: The COVID-19 pandemic created unprecedented challenges for clinical trials worldwide, threatening premature closure and trial integrity. Every phase of research operations was affected, often requiring modifications to protocol design and implementation. Objectives: To identify the barriers, solutions, and opportunities associated with continuing critical care trials that were interrupted during the pandemic, and to generate suggestions for future trials. Design, Setting, and Participants: This mixed-methods study performed an explanatory sequential analysis involving a self-administered electronic survey and focus groups of principal investigators (PIs) and project coordinators (PCs) conducting adult and pediatric individual-patient randomized trials of the Canadian Critical Care Trials Group during the COVID-19 pandemic. Eligible trials were actively enrolling patients on March 11, 2020. Data were analyzed between September 2023 and January 2024. Main Outcomes and Measures: Importance ratings of barriers to trial conduct and completion, solutions employed, opportunities arising, and suggested strategies for future trials. Quantitative data examining barriers were analyzed using descriptive statistics. Data addressing solutions, opportunities, and suggestions were analyzed by qualitative content analysis. Integration involved triangulation of data sources and perspectives about 13 trials, synthesized by an interprofessional team incorporating reflexivity and member-checking. Results: A total of 13 trials run by 29 PIs and PCs (100% participation rate) were included. The highest-rated barriers (on a 5-point scale) to ongoing conduct during the pandemic were decisions to pause all clinical research (mean [SD] score, 4.7 [0.8]), focus on COVID-19 studies (mean [SD] score, 4.6 [0.8]), and restricted family presence in hospitals (mean [SD] score, 4.1 [0.8]). Suggestions to enable trial progress and completion included providing scientific leadership, implementing technology for communication and data management, facilitating the informed consent process, adapting the protocol as necessary, fostering site engagement, initiating new sites, streamlining ethics and contract review, and designing nested studies. The pandemic necessitated new funding opportunities to sustain trial enrollment. It increased public awareness of critical illness and the importance of randomized trial evidence. Conclusions and Relevance: While underscoring the vital role of research in society and drawing the scientific community together with a common purpose, the pandemic signaled the need for innovation to ensure the rigor and completion of ongoing trials. Lessons learned to optimize research procedures will help to ensure a vibrant clinical trials enterprise in the future.