Characterization of a de novo SCN8A mutation in a patient with epileptic encephalopathy

Objective Recently, de novo SCN8A missense mutations have been identified as a rare dominant cause of epileptic encephalopathies. Functional studies on the first described case demonstrated gain-of-function effects of the mutation. We describe a novel de novo mutation of SCN8A in a patient with epileptic encephalopathy, and functional characterization of the mutant protein. Design Whole exome sequencing was used to discover the variant. We generated a mutant cDNA, transfected HEK293 cells, and performed Western blotting to assess protein stability. To study channel functional properties, patch-clamp experiments were carried out in transfected neuronal ND7/23 cells. Results The proband exhibited seizure onset at 6 months of age, diffuse brain atrophy, and more profound developmental impairment than the original case. The mutation p.Arg233Gly in the voltage sensing transmembrane segment D1S4 was present in the proband and absent in both parents. This mutation results in a temperature-sensitive reduction in protein expression as well as reduced sodium current amplitude and density and a relative increased response to a slow ramp stimulus, though this did not result in an absolute increased current at physiological temperatures. Conclusion The new de novo SCN8A mutation is clearly deleterious, resulting in an unstable protein with reduced channel activity. This differs from the gain-of-function attributes of the first SCN8A mutation in epileptic encephalopathy, pointing to heterogeneity of mechanisms. Since Nav1.6 is expressed in both excitatory and inhibitory neurons, a differential effect of a loss-of-function of Nav1.6 Arg223Gly on inhibitory interneurons may underlie the epilepsy phenotype in this patient

Identifying the severely injured benefitting from a specific level of trauma care in an inclusive network:A multicentre retrospective study

Introduction: Defining major trauma (MT) with an Injury Severity Score (ISS) &gt; 15 has limitations. This threshold is used for concentrating MT care in networks with multiple levels of trauma care. Objective: This study aims to identify subgroups of severely injured patients benefiting on in-hospital mortality and non-fatal clinical outcome measures in an optimal level of trauma care. Methods: A multicentre retrospective cohort study on data of the Dutch National Trauma Registry, region South West, from January 1, 2015 until December 31, 2019 was conducted. Patients ≥ 16 years admitted within 48 h after trauma transported with (H)EMS to a level I trauma centre (TC) or a non-level I trauma facility with a Maximum Abbreviated Injury Scale (MAIS) ≥ 3 were included. Patients with burns or patients of ≥ 65 years with an isolated hip fracture were excluded. Logistic regression models were used for comparing level I with non-level I. Subgroup analysis were done for MT patients (ISS &gt; 15) and non-MT patients (ISS 9–14). Results: A total of 7,493 records were included. In-hospital mortality of patients admitted to a non-level I trauma facility did not differ significantly from patients admitted to the level I TC (adjusted Odds Ratio (OR): 0.94; 95% confidence interval (CI) 0.68–1.30). This was also applicable for MT patients (OR: 1.06; 95% CI 0.73–1.53) and non-MT patients (OR: 1.30; 95% CI (0.56–3.03). Hospital and ICU LOS were significantly shorter for patients admitted to a non-level I trauma facilities, and patients admitted to a non-level I trauma facility were more likely to be discharged home. Findings were confirmed for MT and non-MT patients, per injured body region. Conclusion: All levels of trauma care performed equally on in-hospital mortality among severely injured patients (MAIS ≥ 3), although patients admitted to the level I TC were more severely injured. Subgroups of patients by body region or ISS, with a survival benefit or more favorable clinical outcome measures were not identified. Subgroups analysis on clinical outcome measures across different levels of trauma care in an inclusive trauma network is too simplistic if subgroups are based on injuries in specific body region or ISS only.</p

Prognosis and institutionalization of frail community-dwelling older patients following a proximal femoral fracture:a multicenter retrospective cohort study

SUMMARY: Hip fractures are a serious public health issue with major consequences, especially for frail community dwellers. This study found a poor prognosis at 6 months post-trauma with regard to life expectancy and rehabilitation to pre-fracture independency levels. It should be realized that recovery to pre-trauma functioning is not a certainty for frail community-dwelling patients. INTRODUCTION: Proximal femoral fractures are a serious public health issue in the older patient. Although a significant rise in frail community-dwelling elderly is expected because of progressive aging, a clear overview of the outcomes in these patients sustaining a proximal femoral fracture is lacking. This study assessed the prognosis of frail community-dwelling patients who sustained a proximal femoral fracture. METHODS: A multicenter retrospective cohort study was performed on frail community-dwelling patients with a proximal femoral fracture who aged over 70 years. Patients were considered frail if they were classified as American Society of Anesthesiologists score ≥ 4 and/or a BMI < 18.5 kg/m(2) and/or Functional Ambulation Category ≤ 2 pre-trauma. The primary outcome was 6-month mortality. Secondary outcomes were adverse events, health care consumption, rate of institutionalization, and functional recovery. RESULTS: A total of 140 out of 2045 patients matched the inclusion criteria with a median age of 85 (P(25)–P(75) 80–89) years. The 6-month mortality was 58 out of 140 patients (41%). A total of 102 (73%) patients experienced adverse events. At 6 months post-trauma, 29 out of 120 (24%) were readmitted to the hospital. Out of the 82 surviving patients after 6 months, 41 (50%) were unable the return to their home, and only 32 (39%) were able to achieve outdoor ambulation. CONCLUSION: Frail community-dwelling older patients with a proximal femoral fracture have a high risk of death, adverse events, and institutionalization and often do not reobtain their pre-trauma level of independence. Foremost, the results can be used for realistic expectation management

An analysis of the relationship between being deaf and sexual offending

Female Genital Schistosomiasis (FGS) is a neglected disease affecting millions, however challenging to diagnose. This explorative descriptive study compares Schistosoma real-time PCR analysis of cervico-vaginal lavages (CVL) with corresponding urine and stool samples of 933 women from five different previously described study populations. Sampling included 310 women from an S. mansoni endemic region in Mwanza, Tanzania and 112 women from a nearby S. haematobium endemic region. Findings were compared with samples collected from S. haematobium endemic regions in South Africa from 394 women and from 117 women from Madagascar of which 79 were urine pre-selected microscopy positive cases from highly-endemic communities and 38 were urine microscopy negatives from a low-endemic community. As anticipated, urine and stool microscopy and gynecological investigations varied substantially between study populations; however, the same Schistosoma real-time PCR was performed in one reference laboratory. Schistosoma DNA was detected in 13% (120/933) of the CVL, ranging from 3% in the S. mansoni Tanzanian endemic region to 61% in the pre-selected Malagasy urine microscopy positive cases. Detectable Schistosoma DNA in CVL was associated with Schistosoma DNA in urine but not with microscopic detection of eggs in urine or by cytological examination. This study confirmed real-time PCR for the detection of Schistosoma DNA in gynecological samples to be a valuable diagnostic tool to study the distribution of FGS within schistosomiasis endemic areas.Host-parasite interactio

Cost-effectiveness of immediate total-body CT in patients with severe trauma (REACT-2 trial)

Background: The effect of immediate total-body CT (iTBCT) on health economic aspects in patients with severe trauma is an underreported issue. This study determined the cost-effectiveness of iTBCT compared with conventional radiological imaging with selective CT (standard work-up (STWU)) during the initial trauma evaluation. Methods: In this multicentre RCT, adult patients with a high suspicion of severe injury were randomized in-hospital to iTBCT or STWU. Hospital healthcare costs were determined for the first 6 months after the injury. The probability of iTBCT being cost-effective was calculated for various levels of willingness-to-pay per extra patient alive. Results: A total of 928 Dutch patients with complete clinical follow-up were included. Mean costs of hospital care were (sic)25 809 (95 per cent bias-corrected and accelerated (bca) c.i. (sic)22 617 to (sic)29 137) for the iTBCT group and (sic)26 155 ((sic)23 050 to (sic)29 344) for the STWU group, a difference per patient in favour of iTBCT of (sic)346 ((sic)4987 to (sic)4328) (P = 0.876). Proportions of patients alive at 6 months were not different. The proportion of patients alive without serious morbidity was 61.6 per cent in the iTBCT group versus 66.7 per cent in the STWU group (difference -5.1 per cent; P = 0.104). The probability of iTBCT being cost-effective in keeping patients alive remained below 0.56 for the whole group, but was higher in patients with multiple trauma (0.8-0.9) and in those with traumatic brain injury (more than 0.9). Conclusion: Economically, from a hospital healthcare provider perspective, iTBCT should be the diagnostic strategy of first choice in patients with multiple trauma or traumatic brain injury