Comparing forces on the fetal neck in breech delivery in lithotomy versus all-fours position: a simulation model.

PURPOSE: To measure forces applied to the fetal neck, in a simulation model for breech delivery, in both lithotomy versus all-fours position. METHODS: We used a Laerdal SimMom simulator and a Birthing Baby together with PROMPT Flex Software. The descent of the fetus was accomplished using the Automatic Delivery Module 2. The baby was always in breech position; the SimMom in either all-fours or lithotomy positions. Sensors were located inside the fetal neck region to simulate forces applied to the plexus. RESULTS: The lowest force on the fetal neck region was recorded for the delivery in all-fours position without further maneuvers (mean force 58.70 Newton, standard deviation 2.54 N). As weight was added to the baby, the force increased (i.e. + 500 g, mean force 71.8 N, SD 3.08 N, p < 0.001). Delivery in lithotomy position resulted in a mean force of 81.56 N (SD 19.55 N). The force significantly increased in case of delivery of the head without assistance from contractions (mean force 127.93 N, SD 23.10 N). In all-fours position, the delivery of the fetal head from pelvic floor level without contractions (Frank's Nudge maneuver) resulted in a mean force of 118.45 N (SD 15.48 N, p = 0.02). Maneuvers for shoulder dystocia (the inverted type that can occur during breech delivery) led to significantly higher mean forces independent from birthing positions. CONCLUSION: Breech delivery in all-fours position was associated with the lowest force acting on the fetal neck in our simulation model.

Self-Rated Health Among Patients With Severe Traumatic Brain Injury and Their Close Relatives: The Role of Posttraumatic Stress Symptoms.

OBJECTIVE: Severe traumatic brain injury (sTBI) is accompanied by significant declines in self-rated health (SRH). Although such deteriorations in SRH are related to various consequences of sTBI, the effect of posttraumatic reactions (i.e., posttraumatic stress [PTS] symptoms) has been tested insufficiently to date, especially among civilians. The present investigation is based on Trajectories of Recovery After Severe Traumatic brain injury-Matters In families (TRAST-MI), a unique study among civilians with sTBI and their families. Previous research revealed that civilian sTBI has effects beyond the injured patient, influencing their close relatives as well. The aim of this study was to assess the association between PTS symptoms and SRH among patients with civilian sTBI and their close relatives. METHODS: Patients with sTBI (assessed by an Abbreviated Injury Scale of the head region score >3) and their close relatives participated in TRAST-MI. One hundred twenty-six patient-relative dyads were assessed at 3, 6, and 12 months after the injury. RESULTS: Multilevel modeling revealed that patients' PTS symptoms were associated with consequent SRH (slope = 0.42; p < .001), and relatives' PTS symptoms were associated with their respective SRH (slope = 0.2; p = .012). CONCLUSIONS: The findings of this study reveal that SRH of both patients with sTBI and their relatives are negatively affected by their own PTS symptoms. These findings underline the understanding that sTBI is not merely a medical trauma but rather a comprehensive psychosocial trauma, which has consequences for the whole family system.

The effect of mindful attention training for pain modulation capacity: Exploring the mindfulness-pain link.

OBJECTIVE: Mindfulness has been shown to be beneficial for chronic pain. The underlying mechanisms of the mindfulness-pain link, however, are yet to be established. Particularly, the effects of mindfulness on pain modulation, which is shown to be dysfunctional among chronic pain patients, barely has been tested. This study investigated whether a short mindful attention training based on Langerian mindfulness mitigates reductions in pain modulation. METHOD: Systemic quantitative-somatosensory testing of conditioned pain modulation (CPM) was conducted in 60 undergraduates, who were randomly assigned to one of three groups: (1) Pain-specific mindful attention training; (2) nonspecific mindful attention training; and (3) no mindful attention training. CPM was tested before and after the intervention. RESULTS: As hypothesized, a reduction in CPM magnitude was observed only in the control group, whereas this reduction was abolished in the two mindfulness groups. CONCLUSIONS: Langerian mindfulness may mitigate pain modulation reduction as observed in chronic pain, thus shedding light on its potential advantages.

Cell-Wall-Targeting Antibiotics Cause Lag-Phase Bacteria to Form Surface-Mediated Filaments Promoting the Formation of Biofilms and Aggregates.

Antibiotics are known to promote bacterial formation of enhanced biofilms, the mechanism of which is not well understood. Here, using biolayer interferometry, we have shown that bacterial cultures containing antibiotics that target cell walls cause biomass deposition on surfaces over time with a linear profile rather than the Langmuir-like profiles exhibited by bacterial adherence in the absence of antibiotics. We observed about three times the initial rate and 12 times the final biomass deposition on surfaces for cultures containing carbenicillin than without. Unexpectedly, in the presence of antibiotics, the rate of biomass deposition inversely correlated with bacterial densities from different stages of a culture. Detailed studies revealed that carbenicillin caused faster growth of filaments that were seeded on surfaces from young bacteria (from lag phase) than those from high-density fast-growing bacteria, with rates of filament elongation of about 0.58 and 0.13 µm min-1 , respectively. With surfaces that do not support bacterial adherence, few filaments were observed even in solution. These filaments aggregated in solution and formed increased amounts of biofilms on surfaces. These results reveal the lifestyle of antibiotic-induced filamentous bacteria, as well as one way in which the antibiotics promote biofilm formation.

Identification of Substance-Exposed Newborns and Neonatal Abstinence Syndrome Using ICD-10-CM - 15 Hospitals, Massachusetts, 2017.

Opioid use disorder and neonatal abstinence syndrome (NAS) increased in Massachusetts from 1999 to 2013 (1,2). In response, in 2016, the state passed a law requiring birth hospitals to report the number of newborns who were exposed to controlled substances to the Massachusetts Department of Public Health (MDPH)* by mandating monthly reporting of International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnostic codes related to maternal dependence on opioids (F11.20) or benzodiazepines (F13.20) and to newborns affected by maternal use of drugs of addiction (P04.49) or experiencing withdrawal symptoms from maternal drugs of addiction (P96.1) separately.† MDPH uses these same codes for monthly, real-time crude estimates of NAS and uses P96.1 alone for official NAS state reporting.§ MDPH requested CDC's assistance in evaluating the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of either maternal or newborn codes to identify substance-exposed newborns, and of newborn exposure codes (both exposure [P04.49] or withdrawal [P96.1]) and the newborn code for withdrawal alone (P96.1) to identify infants with NAS cases related to three exposure scenarios: 1) opioids, 2) opioids or benzodiazepines, and 3) any controlled substance. Confirmed diagnoses of substance exposure and NAS abstracted from linked clinical records for 1,123 infants born in 2017 and their birth mothers were considered the diagnostic standard and were compared against hospital-reported ICD-10-CM codes. For identifying substance-exposed newborns across the three exposure scenarios, the newborn exposure codes had higher sensitivity (range = 31%-61%) than did maternal drug dependence codes (range = 16%-41%), but both sets of codes had high PPV (≥74%). For identifying NAS, for all exposure scenarios, the sensitivity for either newborn code (P04.49 or P96.1) was ≥92% and the PPV was ≥64%; for P96.1 alone the sensitivity was ≥79% and the PPV was ≥92% for all scenarios. Whereas ICD-10-CM codes are effective for NAS surveillance in Massachusetts, they should be applied cautiously for substance-exposed newborn surveillance. Surveillance for substance-exposed newborns using ICD-10-CM codes might be improved by increasing the use of validated substance-use screening tools and standardized facility protocols and improving communication between patients and maternal health and infant health care providers.

Gender Non-affirmation from Cisgender Male Partners: Development and Validation of a Brief Stigma Scale for HIV Research with Transgender Men Who Have Sex with Men (Trans MSM).

Some transgender men who have sex with men (trans MSM) are vulnerable to HIV infection and face stigma from sexual partners. We evaluated a brief 4-item measure of gender non-affirmation from cisgender male partners. A non-probability sample of American trans MSM (n = 843) reporting past 6-month sexual contact with a cisgender male completed a cross-sectional survey. Psychometric analyses assessed the scale and modeled HIV risk associations. Overall, 78% experienced past 6-month gender non-affirmation from cisgender male partners. The scale demonstrated good reliability (α = 0.78). Convergent validity was supported in associations with psychological distress and anxiety (p < 0.05). Lower frequency of cisgender male partner stigma was associated with increased odds of past 6-month HIV testing and decreased odds of past 6-month condomless receptive sex (all p < 0.01). The gender non-affirmation from cisgender male sexual partners scale found negative associations with protective health behaviors and can be used to better understand the context of trans MSM risk behavior.

Patients' recovery after severe TBI is associated with their close relatives' interpersonal functioning: a 12-months prospective cohort study.

OBJECTIVE: The aim of this study was to investigate the association between relatives' interpersonal functioning and patients' recovery after severe traumatic brain injury (TBI) across one year in Switzerland. Design: This prospective, multi-center cohort study is comprised of 188 adult patients with severe TBI (Abbreviated Head Injury Score > 3) and their relatives. Patients and relatives were assessed 3, 6, and 12 months post-injury. Main outcome measures: Interpersonal functioning (Patient Competency Rating Scale for Neurorehabilitation, PCRS-NR), Physical and Mental Health related Quality of Life (HRQoL, SF-12), and overall functioning (Glasgow Outcome Comma Scale Extended, GOSE). Results: Multilevel analyses showed that relatives' interpersonal functioning was positively associated with a) patients' mental HRQoL (p =.002; slope = 2.95; ß =.24) independently of age, b) a moderation time*patients' physical HRQoL among patients > 50 years of age (p <.045; slope = 2.63; ß =.2) and c) patients' GOSE among younger individuals (p <.001; slope =.60; ß =.23). Conclusion: These findings show that health and overall functioning are linked with interpersonal dimensions. Thus, the interplay between relatives and patients with TBI needs to be further investigated.

Physical and Mental Health and Functioning Among Traumatic Brain Injury Close Relatives: The Role of Posttraumatic Stress Symptoms.

Severe Traumatic brain injury (sTBI) often instigates widespread long-lasting disability and is accompanied by extensive rehabilitation. Unsurprisingly, sTBI also holds malignant consequences for patients' close relatives. The burden caused by the injury and its severity explains some of the ramifications for the relatives. Additionally, some findings demonstrate that patients with sTBI and their relatives develop posttraumatic stress (PTS) symptoms. However, although the link between PTS symptoms and physical and mental health is well-documented in literature, the effect of PTS symptoms on relatives of patients with sTBI has barely been examined. This study examines the influence of PTS symptoms of patients with sTBI and their relatives on the physical and mental health and functioning of the relatives. Patients who sustained a severe sTBI (Abbreviated Injury Scale of the head region > 3) and close relatives were included in a multi-center, prospective cohort study (TRAST-MI). One-hundred patients and their relatives were assessed at 2, 6, and 12 months post injury. Outcome variables included health-related quality of life (SF-12) as well as emotional, cognitive, interpersonal, and total functioning (PCRS). Relatives' physical health was predicted by relatives' PTS symptoms (Slope=-1.76; p = .043), and mental health was predicted by both patients' (Slope=-2.77; p = .034) and relatives' (Slope=-6.59; p < .001) PTS symptoms. Functioning level was only predicted by patients' PTS symptoms (Slope=-.25; p< .001). The findings emphasize that TBI should be considered a comprehensive traumatic experience reaching further than mere physical damage to the brain and its direct consequences, affecting the injured individual and close relatives.

El traumatismo craneoencefálico grave (TCEG) generalmente provoca una discapacidad duradera generalizada y está acompañado por una larga rehabilitación. Como es de esperarse, el TCEG también tiene consecuencias nocivas para los familiares cercanos de los pacientes. El agobio causado por la lesión y su gravedad explica algunas de las repercuciones en los familiares. Además, algunos resultados demuestran que los pacientes con TCEG y sus familiares desarrollan síntomas de estrés postraumático (EPT). Sin embargo, aunque la asociación entre los síntomas de EPT y la salud física y mental está bien documentada en la bibliografía, el efecto de los síntomas de EPT en los familiares de los pacientes con TCEG casi no se ha analizado. Este estudio analiza la influencia de los síntomas de EPT de los pacientes con TCEG y sus familiares en la salud física y mental y en el funcionamiento de los familiares. Se incluyó a pacientes que sufrieron un TCEG (escala abreviada de lesiones de la región craneana > 3) y a familiares cercanos en un estudio de cohorte prospectivo realizado en varios centros (TRAST-MI). Se evaluó a cien pacientes y a sus familiares a los dos, a los seis y a los doce meses después de la lesión. Entre los criterios de valoración se encontraron la calidad de vida relacionada con la salud (SF-12) así como el funcionamiento emocional, cognitivo, interpersonal y total (PCRS). La salud física de los familiares se predijo mediante los síntomas de EPT de los familiares (Pendiente = -1.76; p = .043), y la salud mental se predijo mediante los síntomas de EPT de los pacientes (Pendiente = -2.77; p = .034) y los familiares (Pendiente = -6.59; p < .001). El nivel de funcionamiento solo se predijo mediante los síntomas de EPT de los pacientes (Pendiente = -.25; p < .001). Los resultados enfatizan que el TCE debe considerarse una experiencia traumática amplia que va más allá del mero daño físico al cerebro y sus consecuencias directas, y que afecta a la persona lesionada y a sus familiares cercanos.

Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients.

In this retrospective study, we conducted a clinico-genetic analysis of patients with autosomal recessive limb-girdle muscular dystrophy (LGMD) and Miyoshi muscular dystrophy (MMD). Patients were identified at the tertiary referral centre for DNA diagnosis in the Netherlands and included if they carried two mutations in CAPN3, DYSF, SGCG, SGCA, SGCB, SGCD, TRIM32, FKRP or ANO5 gene. DNA was screened by direct sequencing and multiplex ligand-dependent probe amplification (MLPA) analysis. A total of 244 patients was identified; 68 LGMDR1/LGMD2A patients with CAPN3 mutations (28%), 67 sarcoglycanopathy patients (LGMDR3-5/LGMD2C-E) (27%), 64 LGMDR12/LGMD2L and MMD3 patients with ANO5 mutations (26%), 25 LGMDR2/LGMD2B and MMD1 with DYSF mutations (10%), 21 LGMDR9/LGMD2I with FKRP mutations (9%) and one LGMDR8/LGMD2H patient with TRIM32 mutations (<1%). The estimated minimum prevalence of AR-LGMD and MMD in the Netherlands amounted to 14.4 × 10-6 . Thirty-three novel mutations were identified. A wide range in age of onset (0-72 years) and loss of ambulation (5-74 years) was found. Fifteen patients (6%) initially presented with asymptomatic hyperCKemia. Cardiac abnormalities were found in 35 patients (17%). Non-invasive ventilation was started in 34 patients (14%). Both cardiac and respiratory involvement occurs across all subtypes, stressing the need for screening in all included subtypes.

Prognostic and predictive role of neutrophil/lymphocytes ratio in metastatic colorectal cancer: a retrospective analysis of the TRIBE study by GONO.

Background: Neutrophil/lymphocyte ratio (NLR), defined as absolute neutrophils count divided by absolute lymphocytes count, has been reported as poor prognostic factor in several neoplastic diseases but only a few data are available about unresectable metastatic colorectal cancer (mCRC) patients (pts). The aim of our study was to evaluate the prognostic and predictive role of NLR in the TRIBE trial. Patients and methods: Pts enrolled in TRIBE trial were included. TRIBE is a multicentre phase III trial randomizing unresectable and previously untreated mCRC pts to receive FOLFOXIRI or FOLFIRI plus bevacizumab. A cut-off value of 3 was adopted to discriminate pts with low (NLR < 3) versus high (NLR ≥ 3) NLR, as primary analysis. As secondary analysis, NLR was treated as an ordinal variable with three levels based on terciles distribution. Results: NLR at baseline was available for 413 patients. After multiple imputation at univariate analysis, patients with high NLR had significantly shorter progression-free survival (PFS) [hazard ratio (HR) 1.27 (95% CI 1.05-1.55), P = 0.017] and overall survival (OS) [HR 1.56 (95% CI 1.25-1.95), P < 0.001] than patients with low NLR. In the multivariable model, NLR retained a significant association with OS [HR 1.44 (95% CI 1.14-1.82), P = 0.014] but not with PFS [HR 1.18 (95% CI 0.95-1.46), P = 0.375]. No interaction effect between treatment arm and NLR was evident in terms of PFS (P for interaction = 0.536) or OS (P for interaction = 0.831). Patients with low [HR 0.84 (95% CI 0.64-1.08)] and high [HR 0.73 (95% CI 0.54-0.97)] NLR achieved similar PFS benefit from the triplet and consistent results were obtained in terms of OS [HR 0.83 (95% CI 0.62-1.12) for low NLR; HR 0.82 (95% CI 0.59-1.12) for high NLR]. Conclusion: This study confirmed the prognostic role of NLR in mCRC pts treated with bevacizumab plus chemotherapy in the first line, showing the worse prognosis of pts with high NLR. The advantage of the triplet is independent of NLR at baseline.

Association of Posttraumatic Stress Symptom Severity With Health-Related Quality of Life and Self-Reported Functioning Across 12 Months After Severe Traumatic Brain Injury.

OBJECTIVE: To investigate the relation between posttraumatic stress (PTS) symptom severity and health-related quality of life (HRQoL) after severe traumatic brain injury (TBI). DESIGN: Longitudinal prospective multicenter, cohort study on severe TBI in Switzerland (2007-2011). SETTING: Hospital, rehabilitation unit, and/or patient's living facility. PARTICIPANTS: Patients with severe TBI (N=109) were included in the analyses. Injury severity was determined using the Abbreviated Injury Score of the head region after clinical assessment and initial computed tomography scan. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: HRQoL (Medical Outcomes Study 12-Item Short-Form Health Survey Physical and Mental Component Summaries) and self-reported emotional, cognitive, and interpersonal functioning (Patient Competency Rating Scale for Neurorehabilitation). RESULTS: Multilevel models for patients >50 and ≤50 years of age revealed significant negative associations between PTS symptom severity and interpersonal functioning (P<.001 and P=.002), respectively. Among patients ≤50 years of age, PTS symptom severity was significantly associated with total functioning (P=.001) and emotional functioning (P<.001). Among all patients, PTS symptom severity was significantly associated with cognitive functioning (P<.001) and mental HRQoL (P=.01). CONCLUSIONS: Findings indicate that PTS symptoms after severe TBI are negatively associated with HRQoL and emotional, cognitive, and interpersonal functioning.

Longitudinal functional brain imaging study in early course schizophrenia before and after cognitive enhancement therapy.

OBJECTIVE: Schizophrenia is characterized by impaired -social and non social cognition both of which lead to functional deficits. These deficits may benefit from cognitive remediation, but the neural underpinnings of such improvements have not been clearly delineated. METHODS: We conducted a functional magnetic resonance (fMRI) study in early course schizophrenia patients randomly assigned to cognitive enhancement therapy (CET) or enriched supportive therapy (EST) and treated for two years. Imaging data over three time points including fMRI blood oxygen level dependent (BOLD) data were acquired during performance of a cognitive control paradigm, the Preparing to Overcome Prepotency (POP) task, and functional connectivity data, were analyzed. RESULTS: During the two years of treatment, CET patients showed a continual increase in BOLD activity in the right dorsolateral prefrontal cortex (DLPFC), whereas EST patients tended to show no change in prefrontal brain function throughout treatment. Increases in right DLPFC activity were modestly associated with improved neurocognition (ß = .14, p = .041), but not social cognition. Functional connectivity analyses showed reduced connectivity between the DLPFC and the anterior cingulate cortex (ACC) in CET compared to EST over the two years of treatment, which was associated with neurocognitive improvement. CONCLUSIONS: These findings suggest that CET leads to enhanced neural activity in brain regions mediating cognitive control and increased efficiency in prefrontal circuits; such changes may be related to the observed therapeutic effects of CET on neurocognitive function.

Mindful creativity matters: trajectories of reported functioning after severe traumatic brain injury as a function of mindful creativity in patients' relatives: a multilevel analysis.

OBJECTIVE: The objective of the present investigation was to examine the association of mindful creativity with the trajectory of recovery (emotional, interpersonal, cognitive, and total functioning) of patients with severe TBI. METHODS: This was drawn from a subsample of an adult prospective cohort study on severe TBI in Switzerland; patients and their relatives were assessed at 3, 6, and 12 months (patients N = 176, relatives N = 176). Predictor measures were assessed using Mindful Creativity Scale-short form and time (trajectory of functioning of the patient over time). Outcome measures were assessed using Patient Competency Rating Scale for Neuro-rehabilitation (PCRS-NR; measuring emotional, interpersonal, cognitive, and total functioning post-injury). All measures were assessed at each time point. Mixed linear models were run separately for ages >50 and ≤50 (i.e., bimodal distribution). RESULTS: Patients' mindful creativity showed no significant association with patients' functioning across time in any of the models. In all age groups, interpersonal functioning decreased across time (slope>50 = -4.66, p = .037; slope≤50 = -7.19, p = .007). Interestingly, in age group ≤50, interpersonal functioning increased when looking at relative mindful creativity by time (slope = 1.69, p = .005). Additionally, relatives mindful creativity was significantly associated with patients' functioning in age group ≤50: (a) patients' total functioning (slope = 0.18, p = .03) and (b) cognitive functioning (slope = 0.72, p = .020). CONCLUSIONS: Relatives' mindful creativity was significantly associated with patients' functioning after severe TBI. Implications for treatment and future research are discussed.

The Relatives' Big Five Personality Influences the Trajectories of Recovery of Patients After Severe TBI: A Multilevel Analysis.

This study examines the influence of the personality of relatives on the trajectories of recovery of patients with severe traumatic brain injury (TBI). The present subsample (N = 376) of a larger population-based, prospective, 12-month multicenter cohort study in Switzerland (2007-2011) consists of patients with severe TBI (age ≥ 16) and their relatives. The predictors are the NEO Five-Factor Inventory and time (trajectory of functioning of the patient over time). The outcomes are the patients' (a) neurological functioning; (b) reported emotional, interpersonal, cognitive, and total functioning post-injury; and (c) health-related quality of life (HRQoL). The covariates included Abbreviated Injury Scale score of the head region and age. Results for patients > 50 are (a) relatives' Extraversion influenced patients' total, interpersonal, and cognitive functioning; (b) relatives' Agreeableness influenced patients' interpersonal functioning; and (c) relatives' Conscientiousness influenced patients' physical HRQoL (ps < .05). Results for patients ≤ 50 are (a) relatives' Neuroticism influenced patients' neurological and emotional functioning, and (b) relatives' Extraversion influenced patients' emotional functioning and psychological HRQoL (ps < .05). The personality traits of the relative covary with the functioning of the patient, and psychological adaptation to the loss of function may progress at a later stage after physical health improvements have been achieved. Thus, a biopsychosocial perspective on the rehabilitation process is needed.

Twelve-month prospective cohort study of patients with severe traumatic brain injury and their relatives: Coping, satisfaction with life and neurological functioning.

BACKGROUND: To examine the associations between the functioning of patients with severe traumatic brain injury (TBI), and their relatives' coping style and quality of life across 12 months post-injury. METHODS: Prospective, population-based cohort study assessing 188 patients with severe TBI (Abbreviated Injury Scale of the head region [HAIS] score >3), and their relatives, 3, 6 and 12 months post-injury. Data were drawn from a larger national study run in Switzerland (2007-2011). Patient assessment: Glasgow Coma Outcome Scale Extended (GOSE), Patient Competency Rating Scale for Neurorehabilitation (PCRS-NR). Relative assessment: Health-Related Quality of Life (HRQoL; 12-item short form health survey [SF-12]), Coping Inventory for Stressful Situations (CISS). Mixed linear models were run separately for ages >50 and ≤50 (i.e. bimodal distribution). RESULTS: Patients' GOSE score was associated with relatives' reported mental SF-12 scores across age (ps < 0.01). Relatives' CISS was associated with patients' PCRS score (age > 50 years): Total and cognitive functioning decreased as emotion-oriented coping increased (ps = 0.01), while interpersonal functioning increased as task-oriented coping increased (p = 0.01) and decreased as avoidance-oriented coping increased (p = 0.02). CONCLUSION: Patients' functioning and relatives' mental HRQoL and coping strategies are associated with each other.

Trajectory of disability and quality-of-life in non-geriatric and geriatric survivors after severe traumatic brain injury.

OBJECTIVE: The objective was to investigate disability and health-related quality-of-life (HRQoL) 3, 6 and 12 months after traumatic brain injury (TBI) in non-geriatric (≤ 65 years) and geriatric patients (> 65 years). METHODS: Patients ≥ 16 years who sustained a severe TBI (Abbreviated Injury Scale of the head region > 3) were included in this prospective, multi-centre study. Outcome measures were Glasgow Outcome Scale Extended (GOSE; disability), SF-12 (HRQoL). Mixed linear model analyses were performed. RESULTS: Three hundred and fifty-one patients (median age = 50 years; interquartile range (IQR) = 27-67) were included; 73.2% were male and 27.6% were geriatric patients. Median GOSE at 3, 6 and 12 months was 5 (IQR = 3-7), 6 (IQR = 4-8) and 7 (IQR = 5-8); this increase (slopetime = 0.22, p < 0.0001) was age dependent (slopeage*time = -0.06, p = 0.003). Median SF-12 physical component scale score at 3, 6 and 12 months was 42.1 (IQR = 33.6-50.7), 46.6 (IQR = 37.4-53.9) and 50.4 (IQR = 39.2-55.1); this increase (slopetime = 1.52, p < 0.0001) was not age dependent (slopeage*time = -0.30, p = 0.083). SF-12 mental component scale scores were unchanged. CONCLUSIONS: Disability decreased and HRQoL improved after TBI between 3-12 months. In geriatric patients this improvement was relevant for HRQoL only.

Efficacy of idebenone on respiratory function in patients with Duchenne muscular dystrophy not using glucocorticoids (DELOS): a double-blind randomised placebo-controlled phase 3 trial.

BACKGROUND: Cardiorespiratory failure is the leading cause of death in Duchenne muscular dystrophy. Based on preclinical and phase 2 evidence, we assessed the efficacy and safety of idebenone in young patients with Duchenne muscular dystrophy who were not taking concomitant glucocorticoids. METHODS: In a multicentre phase 3 trial in Belgium, Germany, the Netherlands, Switzerland, France, Sweden, Austria, Italy, Spain, and the USA, patients (age 10-18 years old) with Duchenne muscular dystrophy were randomly assigned in a one-to-one ratio with a central interactive web response system with a permuted block design with four patients per block to receive idebenone (300 mg three times a day) or matching placebo orally for 52 weeks. Study personnel and patients were masked to treatment assignment. The primary endpoint was change in peak expiratory flow (PEF) as percentage predicted (PEF%p) from baseline to week 52, measured with spirometry. Analysis was by intention to treat (ITT) and a modified ITT (mITT), which was prospectively defined to exclude patients with at least 20% difference in the yearly change in PEF%p, measured with hospital-based and weekly home-based spirometry. This study is registered with ClinicalTrials.gov, number NCT01027884. FINDINGS: 31 patients in the idebenone group and 33 in the placebo group comprised the ITT population, and 30 and 27 comprised the mITT population. Idebenone significantly attenuated the fall in PEF%p from baseline to week 52 in the mITT (-3·05%p [95% CI -7·08 to 0·97], p=0·134, vs placebo -9·01%p [-13·18 to -4·84], p=0·0001; difference 5·96%p [0·16 to 11·76], p=0·044) and ITT populations (-2·57%p [-6·68 to 1·54], p=0·215, vs -8·84%p [-12·73 to -4·95], p<0·0001; difference 6·27%p [0·61 to 11·93], p=0·031). Idebenone also had a significant effect on PEF (L/min), weekly home-based PEF, FVC, and FEV1. The effect of idebenone on respiratory function outcomes was similar between patients with previous corticosteroid use and steroid-naive patients. Treatment with idebenone was safe and well tolerated with adverse event rates were similar in both groups. Nasopharyngitis and headache were the most common adverse events (idebenone, eight [25%] and six [19%] of 32 patients; placebo, nine [26%] and seven [21%] of 34 patients). Transient and mild diarrhoea was more common in the idebenone group than in the placebo group (eight [25%] vs four [12%] patients). INTERPRETATION: Idebenone reduced the loss of respiratory function and represents a new treatment option for patients with Duchenne muscular dystrophy. FUNDING: Santhera Pharmaceuticals.

FOLFOXIRI or FOLFOXIRI plus bevacizumab as first-line treatment of metastatic colorectal cancer: a propensity score-adjusted analysis from two randomized clinical trials.

BACKGROUND: FOLFOXIRI plus bevacizumab is a valid option as upfront treatment for metastatic colorectal cancer (mCRC) patients. While several trials investigated the effect of combining bevacizumab with different chemotherapy regimens, including fluoropyrimidines monotherapy and oxaliplatin- or irinotecan-containing doublets, no randomized comparison assessing the impact of the addition of bevacizumab to FOLFOXIRI is available. PATIENTS AND METHODS: A total of 122 mCRC patients received first-line FOLFOXIRI in the phase III trial by the GONO (FOLFOXIRI group) and 252 patients received first-line FOLFOXIRI plus bevacizumab in the TRIBE trial (FOLFOXIRI plus bevacizumab group). A propensity score-adjusted method was adopted to provide an estimation of the benefit from the addition of bevacizumab to FOLFOXIRI in terms of survival and activity parameters. RESULTS: Patients in the FOLFOXIRI group had more frequently Eastern Cooperative Oncology Group performance status of one or two, high Köhne score, metachronous and liver-limited disease, had previously received adjuvant treatments and had their primary tumors resected. The median progression-free survival (PFS) was 12.3 months in the FOLFOXIRI plus bevacizumab group compared with 10.0 months in the FOLFOXIRI group {propensity score-adjusted hazard ratio (HR) 0.74 [95% confidence interval (CI) 0.59-0.94], P = 0.013}. This association was significant also in the multivariable model (P = 0.024). The median OS was 29.8 months in the FOLFOXIRI plus bevacizumab group compared with 23.6 months in the FOLFOXIRI group [propensity score-adjusted HR: 0.72 (95% CI 0.56-0.93), P = 0.014]. At the multivariable model, the addition of bevacizumab was still associated with significantly longer OS (P = 0.030). No significant differences in RECIST response rate (RR) [65.1% versus 55.7%; propensity score-adjusted odds ratio (OR): 1.29 (95% CI 0.81-2.05), P = 0.280], early RR [62.7% versus 57.8%; OR: 1.14 (95% CI 0.68-1.93), P = 0.619] and median depth of response (42.2% versus 53.8%, P = 0.259) were reported. CONCLUSIONS: Though in the absence of a randomized comparison, the addition of bevacizumab to FOLFOXIRI provides significant benefit in PFS and OS, thus supporting the use of FOLFOXIRI plus bevacizumab as upfront treatment for mCRC patients. TRIALS' NUMBERS: NCT01219920 and NCT00719797.

Diagnosis of becker muscular dystrophy: Results of Re-analysis of DNA samples.

INTRODUCTION: The phenotype of Becker muscular dystrophy (BMD) is highly variable, and the disease may be underdiagnosed. We searched for new mutations in the DMD gene in a cohort of previously undiagnosed patients who had been referred in the period 1985-1995. METHODS: All requests for DNA analysis of the DMD gene in probands with suspected BMD were re-evaluated. If the phenotype was compatible with BMD, and no deletions or duplications were detected, DNA samples were screened for small mutations. RESULTS: In 79 of 185 referrals, no mutation was found. Analysis could be performed on 31 DNA samples. Seven different mutations, including 3 novel ones, were found. Long-term clinical follow-up is described. CONCLUSIONS: Refining DNA analysis in previously undiagnosed cases can identify mutations in the DMD gene and provide genetic diagnosis of BMD. A delayed diagnosis can still be valuable for the proband or the relatives of BMD patients.

Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial.

BACKGROUND: The combination of bevacizumab with fluorouracil-based chemotherapy is a standard first-line treatment option in metastatic colorectal cancer (mCRC). We studied the efficacy of continuing or reintroducing bevacizumab in combination with second-line chemotherapy after progression to bevacizumab-based first-line therapy. PATIENTS AND METHODS: In this phase III study, patients with mCRC treated with fluoropyrimidine-based first-line chemotherapy plus bevacizumab were randomized to receive in second-line mFOLFOX-6 or FOLFIRI (depending on first-line regimen) with or without bevacizumab. The primary end point was progression-free survival. To detect a hazard ratio (HR) for progression of 0.70 with an α and ß error of 0.05 and 0.20, respectively, 262 patients were required. RESULTS: In consideration of the results of the ML18147 trial, the study was prematurely stopped. Between April 2008 and May 2012, a total of 185 patients were randomized. Bevacizumab-free interval was longer than 3 months in 43% of patients in chemotherapy alone arm and in 50% of patients in the bevacizumab arm. At a median follow-up of 45.3 months, the median progression-free survival was 5.0 months in the chemotherapy group and 6.8 months in the bevacizumab group [adjusted HR = 0.70; 95% confidence interval (CI) 0.52-0.95; stratified log-rank P = 0.010]. Subgroup analyses showed a consistent benefit in all subgroups analyzed and in particular in patients who had continued or reintroduced bevacizumab. An improved overall survival was also observed in the bevacizumab arm (adjusted HR = 0.77; 95% CI 0.56-1.06; stratified log-rank P = 0.043). Responses (RECIST 1.0) were similar in the chemotherapy and bevacizumab groups (17% and 21%; P = 0.573). Toxicity profile was consistent with previously reported data. CONCLUSIONS: This study demonstrates that the continuation or the reintroduction of bevacizumab with second-line chemotherapy beyond first progression improves the outcome and supports the use of this strategy in the treatment of mCRC. ClinicalTrials.gov number: NCT00720512.