Large-scale HEV genotype 3 outbreak on New Caledonia Island.

BACKGROUND AND AIMS: Several symptomatic cases of HEV infections were reported to the New Caledonia Island Public Health Service between August and December 2023. This prompted epidemiological and virological investigations to identify the source of infection. APPROACH AND RESULTS: HEV RNA was assessed in symptomatic patients, various food items, and pig farms on the Island. HEV strains were characterized by sequencing. A seroprevalence study was also conducted on asymptomatic blood donors before and after the outbreak. One hundred twenty-seven symptomatic cases were reported. Hospitalization was required for 29/127 patients (22.8%). Hospitalized patients presented more frequently with comorbidities, including liver and cardiovascular diseases (80.7% vs. 27%, p < 0.01), and 3 persons died (2.3%). Among the 100 HEV RNA-positive samples received at the French National Reference Centre for HEV, viral sequencing was possible for 76 samples. All strains were identified as HEV genotype 3, and 74/76 strains were grouped together (nucleotide identity: 98%-100%). Full-length sequencing indicated a new HEV-3 subtype within HEV-3 subclade abk. Only genotype 3f strains were detected on the Island's pig farms. No food items tested positive for HEV RNA. The seroprevalence of HEV IgG and IgM in blood donors was 9.2% (9/98) and 0%, respectively, in 2020, rising to 17.3% (17/98) and 2% (2/98) in 2024. CONCLUSIONS: Although all previous large-scale epidemics in Asia and Africa were associated with HEV-1 or 2, the New Caledonia outbreak was linked to HEV-3. A high number of symptomatic cases were admitted to the hospital, with a case-fatality rate of 2.3%.

GRID1/GluD1 homozygous variants linked to intellectual disability and spastic paraplegia impair mGlu1/5 receptor signaling and excitatory synapses.

The ionotropic glutamate delta receptor GluD1, encoded by the GRID1 gene, is involved in synapse formation, function, and plasticity. GluD1 does not bind glutamate, but instead cerebellin and D-serine, which allow the formation of trans-synaptic bridges, and trigger transmembrane signaling. Despite wide expression in the nervous system, pathogenic GRID1 variants have not been characterized in humans so far. We report homozygous missense GRID1 variants in five individuals from two unrelated consanguineous families presenting with intellectual disability and spastic paraplegia, without (p.Thr752Met) or with (p.Arg161His) diagnosis of glaucoma, a threefold phenotypic association whose genetic bases had not been elucidated previously. Molecular modeling and electrophysiological recordings indicated that Arg161His and Thr752Met mutations alter the hinge between GluD1 cerebellin and D-serine binding domains and the function of this latter domain, respectively. Expression, trafficking, physical interaction with metabotropic glutamate receptor mGlu1, and cerebellin binding of GluD1 mutants were not conspicuously altered. Conversely, upon expression in neurons of dissociated or organotypic slice cultures, we found that both GluD1 mutants hampered metabotropic glutamate receptor mGlu1/5 signaling via Ca2+ and the ERK pathway and impaired dendrite morphology and excitatory synapse density. These results show that the clinical phenotypes are distinct entities segregating in the families as an autosomal recessive trait, and caused by pathophysiological effects of GluD1 mutants involving metabotropic glutamate receptor signaling and neuronal connectivity. Our findings unravel the importance of GluD1 receptor signaling in sensory, cognitive and motor functions of the human nervous system.

The skin autofluorescence may help to select patients with Type 2 diabetes candidates for screening to revascularization procedures.

Chen et al. recently related the skin autofluorescence (SAF) of Advanced Glycation End-products to subclinical cardiovascular disease in the 3001 participants from the general population (Rotterdam study), with a particularly close relationship for the 413 subjects with diabetes. Because conventional vascular risk factors do not capture the risk in diabetes very well, this relationship may help to select high-risk individuals for the screening of silent myocardial ischemia, which has yet to prove its benefit in randomized controlled trials. Among 477 patients with uncontrolled and/or complicated Type 2 Diabetes, we measured the SAF ten years ago, and we registered new revascularizations during a 54-months follow-up. The patients with SAF > 2.6 Arbitrary units (AUs), the median population value, experienced more revascularizations of the coronary (17/24) and lower-limb arteries (13/17) than patients with a lower SAF, adjusted for age, sex, diabetes duration, vascular complications, and smoking habits: HR 2.17 (95% CI: 1.05-4.48), p = 0.035. The SAF has already been reported to predict cardiovascular events in three cohorts of people with diabetes. We suggest that its measurement may help to improve the performance of the screening before vascular explorations and revascularizations.

Negative affect related to door-in-the-face strategy.

A full 46 years after the first study of the door-in-the-face strategy (DITF), there is still a debate about the processes behind its effect. One relatively unexplored interpretation is the presence of negative affect related to large request refusal. We explored negative affect after large request refusal both explicitly (Experiment 1) and implicitly (Experiments 1 and 2). Participants were in a negative state after large request refusal (Experiment 1), and target request acceptance was a function of their emotional state (Experiment 2). Negative affect appears to play a role in acceptance of the target request in the door-in-the-face strategy. However, this pattern of results was only observed when affect was measured implicitly. The findings shed new light on the DIFT, by taking into account the complexity of the interaction with emotion. The reasons why negative affect occurs after large request refusal are discussed.

A systematic review and meta-analysis of the effect of obesity on patients undergoing lower extremity revascularization.

OBJECTIVE: In the present review, we assessed the effect of obesity on clinical outcomes for patients with peripheral arterial disease who had undergone endovascular or open lower extremity revascularization surgery. METHODS: A systematic search strategy of MEDLINE, EMBASE, CINAHL, Web of Science, and Cochrane Library was conducted. The included studies had compared obese and nonobese cohorts with peripheral arterial disease who had undergone endovascular or open lower extremity revascularization. The outcomes included mortality, major adverse cardiovascular events, major adverse limb events, surgical site infections, endovascular access site complications, and perioperative complications. RESULTS: Eight studies were included with 171,648 patients. The obese patients (body mass index ≥30 kg/m2) were more likely to be women, to have diabetes, and to have more cardiovascular comorbidities despite being younger. No association was found between obesity and peripheral arterial disease severity. Obesity was associated with an overall 22% decreased mortality risk after lower extremity revascularization (risk ratio [RR], 0.78; 95% confidence interval [CI], 0.71-0.85; P < .001; I2 = 0%; GRADE (grading of recommendations assessment, development, evaluation), very low quality). A subgroup analysis by intervention type showed similar findings (endovascular: RR, 0.79; 95% CI, 0.71-0.87; P < .001; I2 = 0%; open: RR, 0.70; 95% CI, 0.51-0.95; P = .024; I2 = 43%). Obesity was associated with a 14% decreased risk of major adverse cardiovascular events for open surgery only (RR, 0.86; 95% CI, 0.76-0.98; P = .021; I2 = 0%; GRADE, very low quality). Obesity was associated with an increased risk of surgical site infections pooled across intervention types (RR, 1.69; 95% CI, 1.34-2.14; P < .001; I2 = 78%; GRADE, very low quality). No association was found between obesity and major adverse limb events (RR, 1.02; 95% CI, 0.93-1.11; P = .73; I2 = 15%; GRADE, very low quality) or endovascular access site complications (RR, 1.11; 95% CI, 0.76-1.63; P = .58; I2 = 86%; GRADE, very low quality). Pooled perioperative complications did not differ between the obese and nonobese cohorts (RR, 1.04; 95% CI, 0.84-1.28; P = .73; I2 = 92%; GRADE, very low quality). CONCLUSIONS: Obesity was associated with reduced mortality risk with both endovascular and open surgery, although a reduction in major adverse cardiovascular events was only observed with open surgery. In addition, obese patients had an increased risk of surgical site infections. Obesity was not associated with major adverse limb events, endovascular access site complications, or perioperative complications. The GRADE quality of evidence was very low. The findings from the present review suggest a survival advantage for obese patients with peripheral arterial disease. Future studies could focus on prospectively investigating the effect of obesity on peripheral arterial disease outcomes. A nuanced evaluation of body mass index as a preoperative risk factor is warranted.

Diabetic retinopathy relates to the incidence of foot ulcers and amputations in type 2 diabetes.

AIMS: We investigated whether Diabetic Retinopathy (DR) is related to Diabetic Foot Ulcer (DFU) development, adjusted for the stratification of the International Work Group on Diabetic Foot (IWGDF) guidance. MATERIALS AND METHODS: DR and IWGDF stratification was registered retrospectively in patients hospitalised from 2009 to 2017 for uncontrolled and/or complicated type 2 diabetes. New DFUs were registered until 2020. Survival analyses categorised the subjects for DR, and multivariate Cox regression adjusted for confounders. RESULTS: The 522 patients (57.9% male) were 62 ± 9 years old with a diabetes duration of 14 ± 10 years, HbA1c of 8.7 ± 1.8%, 33.9% macroangiopathies and 44.8% diabetic kidney diseases. Their grades of DFU risk were 0 for 43.3%, 1 for 23.9%, 2 for 7.1%, and 3 for 25.6%. During the 52 months follow-up (Inter Quartile Range: 32-71), 58 new DFUs and 18 lower-limb amputations occurred, mostly in patients with DR present in 140 (26.8%) patients. Adjusted for age, sex and conventional risk factors (duration and control of diabetes, arterial hypertension, and dyslipidemia), and other complications (macroangiopathy and diabetic kidney disease), DR was associated with a greater incidence of DFUs. Adjusted for the IWGDF classification, DR was related to new DFUs (HR: 2.51, 95%Confidence Interval [CI]: 1.48-4.26) and amputations (HR: 3.56, 95%CI: 1.26-10.07). This relationship persisted in ascending IWGDF grades with incidences of DFUs from 2/1000 (grade 0, no DR) to 121/1000 patient-years (grade 3 and DR) and amputations from 0 (grade 0, no DR) to 38/1000 patient-years (grade 3 and DR). CONCLUSIONS: Diabetic retinopathy independently relates to the incidence of foot ulcers and amputations in patients hospitalised for type 2 diabetes.

Impact of follow-up by peer support workers on mental health service users' global functioning and self-stigmatisation.

OBJECTIVES: The introduction of the first French professional peer support workers training program. (« Médiateurs de santé pairs en santé mentale ¼) led to a series of evaluations. After a number of qualitative studies demonstrating benefits of peer support for all stakeholders, our objective was to evaluate its direct effects for users by focusing on repeated quantitative measures: global functioning and self-stigma scores. The hypothesis was that peer support would improve the former and decrease the latter. METHOD: The procedure was based on a one-year follow-up of two groups of mental health service users. Both groups received usual care, either with or without additional peer support. All of them were asked to respond to three questionnaires at the beginning of the study and 6 and 12 months later: a sociodemographic and clinical questionnaire, a global functioning scale and a self-stigmatization scale. Samples included 85/64/35 participants at the three stages for the PHM group, and 205/157/105 for the control group. RESULTS: Peer support improved global functioning. Nevertheless, it had no impact on self-stigmatization scores which remained rather low throughout the observational period. CONCLUSIONS: Despite difficulties concerning follow-up of service users during the course of the study and the reluctance to integrate a new profession based on experiential knowledge, it appears that the hope of recovery can improve global functioning of people with mental disorders. The reasons for low self-stigmatization and its stability over time remain to be explored.

Predicting Factors of Protracted Intestinal Failure in Children with Gastroschisis.

OBJECTIVE: To identify prenatal and neonatal predictors of short bowel syndrome-related intestinal failure (SBS-IF) in gastroschisis. STUDY DESIGN: This retrospective study included all patients with gastroschisis born between 2000 and 2017 who were enrolled in our home parenteral nutrition program, and all patients with gastroschisis born in our institution who survived 2 weeks, during the same time period. Prenatal ultrasound features, neonatal status, anatomic features, oral feeding, and parenteral nutrition dependency were analyzed. RESULTS: Among 180 patients, 35 required long-term parenteral nutrition (SBS-IF group) and 145 acquired full oral feeding within 6 months (oral feeding group). The mean follow-up was 7.9 years (IQR, 1.6-17.5 years) and 5.0 years (IQR, 0.1-18.2 years), respectively. Both bowel matting (OR, 14.23; 1.07-16.7; P = .039) and secondarily diagnosed atresia or stenosis (OR, 17.78; 3.13-100.98; P = .001) were independent postnatal predictors of SBS-IF. Eighteen children (51% of the SBS-IF group) were still dependent on artificial nutrition at the last follow-up. patients with SBS-IF who achieved full oral feeding had a median residual small-bowel length of 74 cm (IQR, 51-160 cm) vs 44 cm (IQR, 10-105 cm) for those still dependent on artificial nutrition (P = .02). An initial residual small bowel length of more than 50 cm was the best predictive cut-off for nutritional autonomy, with a sensitivity of 67% and a specificity of 100%. CONCLUSIONS: Bowel matting, complex gastroschisis, and secondary intestinal obstruction were associated with SBS-IF in gastroschisis. For patients with SBS-IF, a small bowel length of more than 50 cm was predictive of secondary nutritional autonomy.

Comorbid Depression is Associated with Increased Major Adverse Limb Events in Peripheral Arterial Disease: A Systematic Review and Meta-analysis.

OBJECTIVE: Depression is a significant risk factor for death in coronary artery disease. Conversely, the research surrounding depression and peripheral arterial disease is limited. This review aimed to systematically evaluate the available literature on the impact of comorbid depression on adverse outcomes in peripheral arterial disease. DATA SOURCES: A systematic review and meta-analysis were performed using the following databases MEDLINE, EMBASE, CINAHL, PsycINFO, and Cochrane Library from inception until July 2021. REVIEW METHODS: Included studies compared depressed and non-depressed patients with peripheral arterial disease. The outcomes included death, major adverse cardiovascular events, and major adverse limb events. RESULTS: A total of 9 297 articles were searched. Of these, seven studies were identified. Depressed patients were more likely to be women, diabetic, have a history of smoking, and have chronic limb threatening ischaemia, despite being younger than non-depressed patients. There was a 20% increase in major adverse limb events in depressed patients (RR 1.20, 95% CI 1.11 - 1.31, z = 3.9, p < .001, GRADE strength: very low) but no increased risk of death (RR 1.03, 95% CI 0.72 - 1.40, z = 0.06, p = .95, GRADE strength: very low) or major adverse cardiovascular events (RR 1.16, 95% CI 0.67 - 2.01, z = 0.54, p = .59, GRADE strength: very low). A follow up meta-regression of various comorbidities and demographic variables did not demonstrate a significant contribution to the observed risk ratio for major adverse limb events. CONCLUSION: Depression was reported in 13% of patients with peripheral arterial disease, associated with more medical comorbidity, and a 20% increased risk of major adverse limb events. Although the strength of this evidence is very low, the current state of the literature remains limited. Future studies should prospectively assess the impact of depression and its relationship to medical comorbidities and high risk health behaviours.

Retrospective and integrative analyses of molecular characteristics and their specific imaging parameters in pediatric grade 1 gliomas.

BACKGROUND: Pediatric low-grade gliomas (PLGG) are the most common brain tumors diagnosed during childhood and represent a heterogeneous group associating variable molecular abnormalities. To go further and develop specific statistical patterns between tumor molecular background, imaging features, and patient outcome, a retrospective study was performed in a group of non-neurofibromatosis type 1 (non-NF1) grade 1 PLGGs. PATIENTS AND METHODS: Seventy-eight children, followed from 2004 to 2017, were retrospectively reported. In this population, we analyzed radiological and molecular parameters. Their therapeutic management comprised surgery or surgery plus chemotherapies. RESULTS: Considering all 78 patients, 59 had only a surgical removal and 19 patients were treated with postoperative chemotherapy. Twelve progressions were reported in the partially resected and chemotherapeutic groups, whereas four deaths occurred only in the highly treated patients. As expected, in the global cohort, PLGG with BRAF p.V600E and/or CDKN2A loss exhibited poor outcomes and we evidenced significant associations between those molecular characteristics and their imaging presentation. In the chemo-treated patients, when associating initial and 6-month magnetic resonance imaging (MRI) parameters to the molecular features, the good risk situations were significantly linked to the presence of a large tumor cyst at diagnosis and the appearance during treatment of a higher cystic proportion that we called cystic conversion. CONCLUSION: So, additionally to the presence of BRAF p.V600E or CDKN2A deletion in grade 1 PLGGs, the absence on diagnostic MRI of cystic parts and/or cystic conversion at 6-month chemotherapy were significantly linked to a worst prognosis and response to treatment. These imaging features should be considered as prognostic markers in future PLGG studies.

Dynapenia in digestive cancer outpatients: association with markers of functional and nutritional status (the FIGHTDIGO study).

BACKGROUND: The FIGHTDIGO study determined the feasibility and acceptability of handgrip strength (HGS) measurement in digestive cancer outpatients. PURPOSE: To assess the relationship between muscle strength and markers of functional and nutritional status in this population. DESIGN: In this prospective study, a total of 201 patients were followed during 6 months and were asked to perform HGS measurement at each hospitalization. Anthropometric measurements, laboratory tests, and performance status (PS) evaluation were collected. The modified Glasgow Prognostic Score (mGPS) was calculated using CRP and albumin levels. Severe malnutrition was defined as body mass index (BMI) < 18 kg/m2 in patients > 70 years old, and BMI < 16 kg/m2 in those < 70 years old. Dynapenia was defined as HGS < 30 kg (men) and < 20 kg (women). Mixed logistic regressions and mixed linear regressions were performed to study factors associated with dynapenia and HGS value, respectively. RESULTS: A total of 879 HGS measurements were analyzed. Dynapenia occurred in 177 measurements (20.1%). BMI and HGS were significantly associated in univariate analysis (p = 0.001). In multivariate analysis, mGPS score (ß = - 0.54 ± 0.31; p = 0.06) and severe malnutrition (ß = - 2.8 ± 1.4; p = 0.08) tended to be associated with HGS. Dynapenia was only associated with functional status impairment in univariate analysis (n = 140/803, 17.4% in ECOG 0 and 1 versus n = 37/76, 58.7% in ECOG 2 and 3; p = 0.002). CONCLUSIONS: Identification of dynapenia using HGS measurement may be useful to predict nutritional vulnerability in digestive cancer outpatients undergoing chemotherapy. Patients could then benefit from nutritional support, adapted physical activity programs, and early therapeutic adjustments. Trial registration ClinicalTrials.gov, NCT02797197.

Practices and attitudes about delayed umbilical cord clamping for term infants: a descriptive survey among midwives.

The aim of this study was to assess variations in midwives' practices of cord clamping (early versus delayed) and to identify factors potentially associated with delayed clamping. This was a descriptive cross-sectional survey by self-administered online questionnaire among French midwives working in delivery rooms from March to July 2018. We obtained complete responses from 350 midwives. Only 120 (34.3%) reported always or sometimes performing delayed cord clamping at one minute or more after birth. Delayed cord clamping was significantly associated with midwives' experience (adjusted OR 3.99; 95% confidence interval [CI] 2.10, 7.83 for experience >10 years), maternity unit written protocol (adjusted OR (aOR) 5.17; 95% CI 1.88, 16.00), knowledge of guidelines (aOR 3.33; 95% CI 1.98, 5.71) and neonatal care level 1 (aOR 2.95; 95% CI 1.53, 5.78).Impact StatementWhat is already know on this subject? Despite benefits and the safety of delayed cord clamping, many newborns likely had their umbilical cords clamped immediately after delivery as part of routine care or because providers were not convinced of the benefits of delayed clamping.What do the results of this study add? Most of the midwives surveyed did not systematically delay cord clamping. Individual and organisational factors were associated with adherence to guidelines regarding delayed cord clamping.What are the implications of these findings for clinical and/or further research? A protocol should be implemented in every maternity unit with information about the benefits and risks of delayed cord clamping to reduce variations in practice and improve the safety of care.

Flying Fox Hemolytic Fever, Description of a New Zoonosis Caused by Candidatus Mycoplasma haemohominis.

BACKGROUND: Hemotropic mycoplasmas, previously classified in the genus Eperythrozoon, have been reported as causing human infections in Brazil, China, Japan, and Spain. METHODS: In 2017, we detected DNA from Candidatus Mycoplasma haemohominis in the blood of a Melanesian patient from New Caledonia presenting with febrile splenomegaly, weight loss, life-threatening autoimmune hemolytic anemia, and hemophagocytosis. The full genome of the bacterium was sequenced from a blood isolate. Subsequently, we retrospectively (2011-2017) and prospectively (2018-2019) tested patients who had been hospitalized with a similar clinico-biological picture. In addition, as these patients had been in contact with frugivorous bats (authorized under conditions for hunting and eating in New Caledonia), we investigated the role of these animals and their biting flies by testing them for hemotropic mycoplasmas. RESULTS: There were 15 patients found to be infected by this hemotropic mycoplasma. Among them, 4 (27%) died following splenectomy performed either for spontaneous spleen rupture or to cure refractory autoimmune hemolytic anemia. The bacterium was cultivated from the patient's blood. The full genome of the Neocaledonian Candidatus M. haemohominis strain differed from that of a recently identified Japanese strain. Of 40 tested Pteropus bats, 40% were positive; 100% of collected bat flies Cyclopodia horsfieldi (Nycteribiidae, Diptera) were positive. Human, bat, and dipteran strains were highly similar. CONCLUSIONS: The bacterium being widely distributed in bats, Candidatus M. haemohominis, should be regarded as a potential cause of severe infections in humans.

Association of Continuous Opioids and/or Midazolam During Early Mechanical Ventilation with Survival and Sensorimotor Outcomes at Age 2 Years in Premature Infants: Results from the French Prospective National EPIPAGE 2 Cohort.

OBJECTIVE: To evaluate the association of early continuous infusions of opioids and/or midazolam with survival and sensorimotor outcomes at age 2 years in very premature infants who were ventilated. STUDY DESIGN: This national observational study included premature infants born before 32 weeks of gestation intubated within 1 hour after birth and still intubated at 24 hours from the French EPIPAGE 2 cohort. Infants only treated with bolus were excluded. Treated infants received continuous opioid and/or midazolam infusion started before 7 days of life and before the first extubation. Naive infants did not receive these treatments before the first extubation, or received them after the first week of life, or never received them. This study compared treated (n = 450) vs naive (n = 472) infants by using inverse probability of treatment weighting after multiple imputation in chained equations. The primary outcomes were survival and survival without moderate or severe neuromotor or sensory impairment at age 2 years. RESULTS: Survival at age 2 years was significantly higher in the treated group (92.5% vs 87.9%, risk difference, 4.7%; 95% CI, 0.3-9.1; P = .037), but treated and naive infants did not significantly differ for survival without moderate or severe neuromotor or sensory impairment (86.6% vs 81.3%; risk difference, 5.3%; 95% CI -0.3 to 11.0; P = .063). These results were confirmed by sensitivity analyses using 5 alternative models. CONCLUSIONS: Continuous opioid and/or midazolam infusions in very premature infants during initial mechanical ventilation that continued past 24 hours of life were associated with improved survival without any difference in moderate or severe sensorimotor impairments at age 2 years.

Per- and Polyfluoroalkyl Substance (PFAS) Transport from Groundwater to Streams near a PFAS Manufacturing Facility in North Carolina, USA.

We quantified per- and polyfluoroalkyl substance (PFAS) transport from groundwater to five tributaries of the Cape Fear River near a PFAS manufacturing facility in North Carolina (USA). Hydrologic and PFAS data were coupled to quantify PFAS fluxes from groundwater to the tributaries. Up to 29 PFAS were analyzed, including perfluoroalkyl acids and recently identified fluoroethers. Total quantified PFAS (ΣPFAS) in groundwater was 20-4773 ng/L (mean = 1863 ng/L); the range for stream water was 426-3617 ng/L (mean = 1717 ng/L). Eight PFAS constituted 98% of ΣPFAS; perfluoro-2-(perfluoromethoxy)propanoic acid (PMPA) and hexafluoropropylene oxide dimer acid (GenX) accounted for 61%. For PFAS discharge from groundwater to one tributary, values estimated from stream water measurements (18 ± 4 kg/yr) were similar to those from groundwater measurements in streambeds (22-25 ± 5 kg/yr). At baseflow, 32 ± 7 kg/yr of PFAS discharged from groundwater to the five tributaries, eventually reaching the Cape Fear River. Given the PFAS emission timeline at the site, groundwater data suggest the abundant fluoroethers moved through the subsurface to streams in ≪50 yr. Discharge of contaminated groundwater may lead to long-term contamination of surface water and impacts on downstream drinking water supplies. This work addresses a gap in the PFAS literature: quantifying PFAS mass transfer between groundwater and surface water using field data.

Prenatal exome sequencing in 65 fetuses with abnormality of the corpus callosum: contribution to further diagnostic delineation.

PURPOSE: Abnormality of the corpus callosum (AbnCC) is etiologically a heterogeneous condition and the prognosis in prenatally diagnosed cases is difficult to predict. The purpose of our research was to establish the diagnostic yield using chromosomal microarray (CMA) and exome sequencing (ES) in cases with prenatally diagnosed isolated (iAbnCC) and nonisolated AbnCC (niAbnCC). METHODS: CMA and prenatal trio ES (pES) were done on 65 fetuses with iAbnCC and niAbnCC. Only pathogenic gene variants known to be associated with AbnCC and/or intellectual disability were considered. RESULTS: pES results were available within a median of 21.5 days (9-53 days). A pathogenic single-nucleotide variant (SNV) was identified in 12 cases (18%) and a pathogenic CNV was identified in 3 cases (4.5%). Thus, the genetic etiology was determined in 23% of cases. In all diagnosed cases, the results provided sufficient information regarding the neurodevelopmental prognosis and helped the parents to make an informed decision regarding the outcome of the pregnancy. CONCLUSION: Our results show the significant diagnostic and prognostic contribution of CMA and pES in cases with prenatally diagnosed AbnCC. Further prospective cohort studies with long-term follow-up of the born children will be needed to provide accurate prenatal counseling after a negative pES result.

Cytokine changes in sickle-cell disease patients as markers predictive of the onset of delayed hemolytic transfusion reactions.

BACKGROUND: Changes in cytokine production are known to contribute to the pathogenesis of sickle-cell disease (SCD), particularly in painful acute complications (crises) and episodes of post-transfusion hemolysis. Little is known about cytokine profiles in patients with these complications. STUDY DESIGN AND METHODS: We investigated possible associations between cytokine profile and the onset of delayed hemolytic transfusion reactions (DHTRs), particularly during acute-phase episodes, to improve characterization of the biological parameters predictive of such events. We included SCD patients with severe acute symptoms (n = 36) or steady-state disease (n = 31), both possibly leading to a DHTR (n = 18) event. Luminex® technology was used to determine the plasma concentrations of 23 cytokines. RESULTS: Regardless of clinical context, the concentrations of interleukin (IL)-6, IL-10, inducible protein-10, and macrophage inflammatory protein-1ß were higher in plasma samples from SCD patients than in those from healthy controls. IL-6 and IL-10 concentrations were even higher in acute-phase plasma samples from SCD patients. In addition, IL-27 and TNFα levels were higher, and IL-6 and RANTES levels were lower in acute-phase SCD patients just before the onset of DHTR than in patients experiencing painful occlusive episodes. CONCLUSION: In addition to reporting the plasma cytokine profiles of SCD patients in various clinical phases of the disease, we provide the first evidence of a significant association between low plasma TNFα concentration, high plasma IP-10 concentration and the onset of DHTR in SCD patients.

SFCE METRO-01 four-drug metronomic regimen phase II trial for pediatric extracranial tumor.

OBJECTIVE: To investigate the antitumor activity of a four-drug metronomic chemotherapy (MC) regimen in relapsed/progressing pediatric extracranial solid tumors (EST). The primary objective was clinical benefit (complete response /partial response/stable disease [SD]) after two cycles of therapy (four months). METHODS: Patients aged ≥4 to 25 years with progressing EST and adequate organ function were eligible. Treatment consisted of an eight-week cycle of oral celecoxib b.i.d., weekly vinblastine, and oral cyclophosphamide for three weeks alternating with oral methotrexate for three weeks, with a two-week rest. The Kepner-Chang two-stage model was used with 10 patients in the first stage. If primary objective was reached in two or more patients, eight additional patients were included according to four groups: neuroblastoma (NBL), soft-tissue sarcoma (STS), bone sarcoma (BS), and miscellaneous (Misc.). RESULTS: Forty-four patients were evaluable. The NBL cohort could be expanded to 18 patients: 4 of 18 patients stabilized with MC treatment for 6 (n = 1) and 12 (n = 3) months. In STS, two of seven patients (metastatic hemangioendothelioma and angiosarcoma) had SD for > 2 cycles. One of nine Misc. (metastatic myoepithelial carcinoma) had SD for one year. All patients with BS had progressive disease. One-year progression-free survival of the whole cohort was 6.8% and one-year overall survival was 55.3%. Grade 3 toxicity occurred in 18 patients and grade 4 in 15 patients. The most frequent toxicity was hematologic, predominantly neutropenia. CONCLUSIONS: This MC has no activity in BS and limited though interesting activity in NBL with some patients being stable for > 1 year. It is not possible to conclude activity in STS and Misc.

Measles seroprevalence after reactive vaccination campaigns during the 2015 measles outbreak in four health zones of the former Katanga Province, Democratic Republic of Congo.

BACKGROUND: Measles continues to circulate in the Democratic Republic of Congo, and the country suffered from several important outbreaks over the last 5 years. Despite a large outbreak starting in the former province of Katanga in 2010 and the resulting immunization activities, another outbreak occurred in 2015 in this same region. We conducted measles seroprevalence surveys in four health zones (HZ) in the former Katanga Province in order to assess the immunity against measles in children 6 months to 14 years after the 2015 outbreak. METHODS: We conducted multi-stage cluster surveys stratified by age group in four HZs, Kayamba, Malemba-Nkulu, Fungurume, and Manono. The age groups were 6-11 months, 12-59 months, and 5-14 years in Kayamba and Malemba-Nkulu, 6-59 months and 5-14 years in Manono and Fungurume. The serological status was measured on dried capillary blood spots collected systematically along with vaccination status (including routine Extended Program of Immunization (EPI), and supplementary immunization activities (SIAs)) and previous self-reported history of suspected measles. RESULTS: Overall seroprevalence against measles was 82.7% in Kayamba, 97.6% in Malemba-Nkulu, 83.2% in Manono, and 74.4% in Fungurume, and it increased with age in all HZs. It was 70.7 and 93.8% in children 12-59 months in Kayamba and Malemba-Nkulu, and 49.8 and 64.7% in children 6-59 months in Fungurume and Manono. The EPI coverage was low but varied across HZ. The accumulation of any type of vaccination against measles resulted in an overall vaccine coverage (VC) of at least 85% in children 12-59 months in Kayamba and Malemba-Nkulu, 86.1 and 74.8% in children 6-59 months in Fungurume and Manono. Previous measles infection in 2015-early 2016 was more frequently reported in children aged 12-59 months or 6-59 months (depending on the HZ). CONCLUSION: The measured seroprevalence was consistent with the events that occurred in these HZs over the past few years. Measles seroprevalence might prove a valuable source of information to help adjust the timing of future SIAs and prioritizing support to the EPI in this region as long as the VC does not reach a level high enough to efficiently prevent epidemic flare-ups.