Auricular Acupuncture for Preoperative Anxiety in Parturient Women with Scheduled Cesarean Section: A Randomized Placebo-Controlled Blind Study.

Introduction: Preoperative anxiety before cesarean section is a major issue. Nonpharmacologic anxiety control is believed to be more suitable in pregnant women. Auricular acupuncture (AA) is an inexpensive, easy-to-use, and validated intervention to reduce anxiety in different surgical settings. We evaluated the effect of AA on preoperative cesarean section anxiety. Methods: In a prospective, blind, controlled trial, pregnant women with a scheduled cesarean section under spinal anesthesia were randomized to receive AA with needle, AA without needle (sham), or usual care (no intervention). Anxiety level was assessed by using a visual analogue scale for anxiety (VAS-A; 0-minimal anxiety, 100-maximal anxiety) at three time points: inclusion (pre-induction room-T0), when entering the operating room (T1), and before incision (T2). The primary outcome was the VAS-A variation (percentage changes) between T0 and T1 in the AAe group compared with that in the sham AA group. The secondary outcomes were the VAS-A variation between T0 and T1 in the AA group compared with that in the control group, and the variation between T0 and T2 compared between the three groups, the effect of AA on parasympathetic tone, and the incidence of adverse effects. Results: In women immediately before anesthesia for cesarean section, the AA produced a 19% decrease of anxiety, compared with a 21% anxiety increase in sham AA, which is significantly different. The effect of AA was more present in women with low initial anxiety. The proportion of patients reaching clinically significant anxiety reduction (>33% from the initial level) was 2.5 times higher in the AA group (p = 0.02) compared with the sham group. No differences in anxiety variations were found compared with the no-intervention group. No effect of AA was noted on parasympathetic tone. Conclusion: Compared with sham, AA decreased maternal anxiety level when arriving in the operation room and just before the beginning of the cesarean section, with a trend toward improvement compared with usual care.

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

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

Beyond the Traditional Clinical Trials for Amyotrophic Lateral Sclerosis and The Future Impact of Gene Therapy.

Amyotrophic lateral sclerosis (ALS) is a devastating and incurable motor neuron (MN) disorder affecting both upper and lower MNs. Despite impressive advances in the understanding of the disease's pathological mechanism, classical pharmacological clinical trials failed to provide an efficient cure for ALS over the past twenty years. Two different gene therapy approaches were recently approved for the monogenic disease Spinal muscular atrophy, characterized by degeneration of lower MNs. This milestone suggests that gene therapy-based therapeutic solutions could be effective for the treatment of ALS. This review summarizes the possible reasons for the failure of traditional clinical trials for ALS. It provides then a focus on the advent of gene therapy approaches for hereditary forms of ALS. Specifically, it describes clinical use of antisense oligonucleotides in three familial forms of ALS, caused by mutations in SOD1, C9orf72 and FUS genes, respectively.. Clinical and pre-clinical studies based on AAV-mediated gene therapy approaches for both familial and sporadic ALS cases are presented as well. Overall, this overview highlights the potential of gene therapy as a transforming technology that will have a huge impact on treatment perspective for ALS patients and on the design of future clinical trials.

Closed-Loop Control of the Centre of Pressure in Post-Stroke Patients With Balance Impairments.

When a lightly touched surface is moved according to a closed-loop control law, it has been shown in young adults that the centre of pressure (CoP) can be displaced in a controllable way without the conscious cooperation of participants. In this closed-loop paradigm, the surface velocity was continuously adjusted according to the CoP position. Since the closed-loop control of the CoP does not require the participant's voluntary cooperation, it could be of interest for the development of innovative biofeedback devices in balance rehabilitation. Before anticipating the implementation of this closed-loop control paradigm with patients, it is necessary to establish its effects on people suffering from balance impairments. The aim of this paper was to assess the effects of this CoP closed-loop control in post-stroke (PS) patients and aged-matched healthy controls. Efficacy of the closed-loop control for driving the patients' CoP was assessed using the saturation time and two scores computing the error between the predefined and the current CoP trajectories. 68% and 83% of the trials were considered as successful in patients and controls, respectively. The global tracking error of the closed-loop score was similar between the two groups. However, when examining the real CoP displacement from the starting position to the desired one, PS patients responded to the closed-loop control to a lesser extent than controls. These results, obtained in the same conditions for healthy and PS individuals could be improved by tuning the closed-loop parameters according to individual characteristics. This paper paves the road towards the development of involuntary/automatic biofeedback techniques in more ecological conditions.

MRI of the cervical spinal cord predicts respiratory dysfunction in ALS.

For patients with amyotrophic lateral sclerosis (ALS), the primary therapeutic goal is to minimize morbidity. Non-invasive ventilation improves survival. We aim to assess whether Magnetic Resonance Imaging (MRI) of the cervical spinal cord predicts the progression of respiratory disorders in ALS. Brain and spinal MRI was repeatedly performed in the SOD1G86R mouse model, in 40 patients and in healthy controls. Atrophy, iron overload, white matter diffusivity and neuronal loss were assessed. In Superoxide Dismutase-1 (SOD1) mice, iron accumulation appeared in the cervical spinal cord at symptom onset but disappeared with disease progression (after the onset of atrophy). In ALS patients, the volumes of the motor cortex and the medulla oblongata were already abnormally low at the time of diagnosis. Baseline diffusivity in the internal capsule was predictive of functional handicap. The decrease in cervical spinal cord volume from diagnosis to 3 months was predictive of the change in slow vital capacity at 12 months. MRI revealed marked abnormalities at the time of ALS diagnosis. Early atrophy of the cervical spinal cord may predict the progression of respiratory disorders, and so may be of value in patient care and as a primary endpoint in pilot neuroprotection studies.

Early diaphragm pacing in patients with amyotrophic lateral sclerosis (RespiStimALS): a randomised controlled triple-blind trial.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder associated with respiratory muscle weakness and respiratory failure. Non-invasive ventilation alleviates respiratory symptoms and prolongs life, but is a palliative intervention. Slowing the deterioration of diaphragm function before respiratory failure would be desirable. We aimed to assess whether early diaphragm pacing could slow down diaphragm deterioration and would therefore delay the need for non-invasive ventilation. METHODS: We did a multicentre, randomised, controlled, triple-blind trial in patients with probable or definite ALS in 12 ALS centres in France. The main inclusion criterion was moderate respiratory involvement (forced vital capacity 60-80% predicted). Other key eligibility criteria were age older than 18 years and bilateral responses of the diaphragm to diagnostic phrenic stimulation. All patients were operated laparoscopically and received phrenic stimulators. Clinicians randomly assigned patients (1:1) to receive either active or sham stimulation with a central web-based randomisation system (computer-generated list). Investigators, patients, and an external outcome allocation committee were masked to treatment. The primary outcome was non-invasive ventilation-free survival, analysed in the intention-to-treat population. Safety outcomes were also assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01583088. FINDINGS: Between Sept 27, 2012, and July 8, 2015, 74 participants were randomly assigned to receive either active (n=37) or sham (n=37) stimulation. On July 16, 2015, an unplanned masked analysis was done after another trial showed excess mortality with diaphragm pacing in patients with hypoventilation (DiPALS, ISRCTN 53817913). In view of this finding, we analysed mortality in our study and found excess mortality (death from any cause) in our active stimulation group. We therefore terminated the study on July, 16, 2015. Median non-invasive ventilation-free survival was 6·0 months (95% CI 3·6-8·7) in the active stimulation group versus 8·8 months (4·2-not reached) in the control (sham stimulation) group (hazard ratio 1·96 [95% CI 1·08-3·56], p=0·02). Serious adverse events (mainly capnothorax or pneumothorax, acute respiratory failure, venous thromboembolism, and gastrostomy) were frequent (24 [65%] patients in the active stimulation group vs 22 [59%] patients in the control group). No treatment-related death was reported. INTERPRETATION: Early diaphragm pacing in patients with ALS and incipient respiratory involvement did not delay non-invasive ventilation and was associated with decreased survival. Diaphragm pacing is not indicated at the early stage of the ALS-related respiratory involvement. FUNDING: Hospital Program for Clinical Research, French Ministry of Health; French Patients' Association for ALS Research (Association pour la Recherche sur la Sclérose Latérale Amyotrophique); and Thierry de Latran Foundation.

Gait Performance and Use of Mental Imagery as a Measure of Disease Progression in Amyotrophic Lateral Sclerosis.

OBJECTIVE: Gait and balance are key determinants of disease status in amyotrophic lateral sclerosis (ALS). This study aims at testing the relationship between the imagery of gait and disability in patients with ALS. METHODS: Twenty-five consecutive patients (63.8 ± 2.4 years; 52% female) performed the timed up and go (TUG) test and a validated imagined version of the TUG between March 2011 and May 2012. The revised ALS functional rating score (ALSFRS-R) was assessed simultaneously. RESULTS: The mean duration of TUG (16.7 ± 2.2 s) was significantly longer than imagined TUG (iTUG; 10.5 ± 1.4 s, p < 0.001). The TUG (R2 = 0.40, p = 0.001) and the iTUG (R2 = 0.30, p = 0.007) were significantly associated with results of the ALSFRS-R score (37.0 ± 7.3) as well as with muscle strength in arms (TUG R2 = 0.42, p < 0.001, iTUG R2 = 0.38, p = 0.001) and legs (TUG R2 = 0.47, p < 0.001, iTUG R2 = 0.46, p < 0.001). TUG and iTUG increased with age (TUG R2 = 0.18, p = 0.04, iTUG R2 = 0.12, p = 0.05). CONCLUSION: ALS patients performed the imagined gait faster than the real gait. Both TUG and iTUG correlated with disability measured by the ALSFRS-R score and by muscle strength. These inexpensive and easy clinical tests represent promising tools in clinical practice to study gait in ALS.

Marked 25-hydroxyvitamin D deficiency is associated with poor prognosis in patients with alcoholic liver disease.

BACKGROUND & AIMS: Vitamin D deficiency has been frequently reported in advanced liver disease. However, its influence on alcoholic liver disease (ALD) has been poorly elucidated. We investigated the association of vitamin D with clinical, biological, and histological parameters and survival in ALD patients. Furthermore, we explored the effect of vitamin D treatment on ALD patient peripheral blood mononuclear cells (PBMCs), and in a murine experimental model of ALD. METHODS: Serum levels of 25-hydroxyvitamin D [25(OH)D] were determined in 324 Caucasian ALD patients and 201 healthy controls. In vitro experiments on vitamin D pre-treated PBMCs evaluated TNFα production by ELISA in culture supernatants. Mice were submitted to an ethanol-fed diet and some of them were orally supplemented three times per week with 1,25(OH)2D. RESULTS: Severe deficiency in 25(OH)D (<10 ng/ml) was significantly associated with higher aspartate aminotransferase levels (p=1.00 × 10(-3)), increased hepatic venous pressure gradient (p=5.80 × 10(-6)), MELD (p=2.50 × 10(-4)), and Child-Pugh scores (p=8.50 × 10(-7)). Furthermore, in multivariable analysis, a low 25(OH)D concentration was associated with cirrhosis (OR=2.13, 95% CI=1.18-3.84, p=0.013) and mortality (HR=4.33, 95% CI=1.47-12.78, p=7.94 × 10(-3)) at one year. In addition, in vitro, 1,25(OH)2D pretreatment decreased TNFα production by stimulated PBMCs of ALD patients (p=3.00 × 10(-3)), while in vivo, it decreased hepatic TNFα expression in ethanol-fed mice (p=0.04). CONCLUSIONS: Low 25(OH)D levels are associated with increased liver damage and mortality in ALD. Our results suggest that vitamin D might be both a biomarker of severity and a potential therapeutic target in ALD.

Guidelines for preclinical animal research in ALS/MND: A consensus meeting.

The development of therapeutics for ALS/MND is largely based on work in experimental animals carrying human SOD mutations. However, translation of apparent therapeutic successes from in vivo to the human disease has proven difficult and a considerable amount of financial resources has been apparently wasted. Standard operating procedures (SOPs) for preclinical animal research in ALS/MND are urgently required. Such SOPs will help to establish SOPs for translational research for other neurological diseases within the next few years. To identify the challenges and to improve the research methodology, the European ALS/MND group held a meeting in 2006 and published guidelines in 2007 (1). A second international conference to improve the guidelines was held in 2009. These second and improved guidelines are dedicated to the memory of Sean F. Scott.