Nusinersen treatment in adults with severe spinal muscular atrophy: A real-life retrospective observational cohort study.

BACKGROUND AND OBJECTIVES: Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease due to homozygous loss-of-function of the survival motor neuron gene SMN1 with absence of the functional SMN protein. Nusinersen, a costly intrathecally administered drug approved in 2017 in Europe, induces alternative splicing of the SMN2 gene, which then produces functional SMN protein, whose amount generally increases with the number of SMN2 gene copies. METHODS: We retrospectively collected data from consecutive wheelchair-bound adults with SMA managed at a single center in 2018-2020. The following were collected at each injection, on days 1, 14, 28, 63, 183, and 303: 32-item Motor Function Measurement (MFM) total score and D2 and D3 subscores; the Canadian Occupational Performance Measure (COPM) performance and satisfaction scores; and lung function tests. The patients were divided into two groups based on whether their MFM total score was

Outcome of bloodstream infections among spinal cord injury patients and impact of multidrug-resistant organisms.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: Our study aimed to describe the outcome of bloodstream infection (BSI) in spinal cord injury (SCI) patients and their associated risk factors for severity and mortality. SETTING: A French University Hospital. METHODS: We conducted a retrospective cohort study of all BSIs occurring in hospitalized SCI patients. We analyzed their outcome and risk factors especially the impact of multidrug-resistant organisms (MDROs). RESULTS: Overall, 318 BSIs occurring among 256 patients were included in the analysis. Mean age was 50.8 years and gender ratio (M/F) was 2.70, with a mean injury duration of 11.6 years.Severity and 30-day mortality of BSI episodes were, respectively, 43.4% and 7.9%. BSI severity was significantly more frequent when caused by respiratory tract infections (RTIs) (odds ratio (OR)=1.38; 95% confidence interval (CI): 1.13-1.44) and significantly lower when caused by urinary tract infections (UTIs) (OR=0.47; 95% CI: 0.28-0.76). BSI mortality was significantly higher when caused by RTIs (OR=3.08; 95% CI: 1.05-8.99), catheter-related bloodstream infections (OR=3.54; 95% CI: 1.36-9.18) or Pseudomonas aeruginosa infections (OR=3.79; 95% CI: 1.14-12.55).MDROs were responsible for 41.2% of all BSI. They have no impact on severity and mortality, whichever be the primary site of infection.In multivariate analysis, mortality was higher when BSI episodes were due to RTIs (OR=3.26; 95% CI: 1.29-8.22) and Pseudomonas aeruginosa infections (OR=3.53; 95% CI: 1.06-11.70), or when associated with immunosuppressive therapy (OR=2.57; 95% CI: 1.14-5.78) or initial severity signs (OR=1.68; 95% CI: 1.01-2.81). CONCLUSION: BSI occurring in SCI population were often severe but mortality remained low. MDROs were frequent but not associated with severity or mortality of BSI episodes. Risk factors associated with mortality were initial severe presentation, RTI, immunosuppressive therapy and BSI due to Pseudomonas aeruginosa.

Blood stream infections due to multidrug-resistant organisms among spinal cord-injured patients, epidemiology over 16 years and associated risks: a comparative study.

STUDY DESIGN: Retrospective study. OBJECTIVES: We aimed to describe the epidemiology of multidrug-resistant organisms (MDROs) during bloodstream infection (BSI) and identify associated risks of MDROs among patients with spinal cord injury (SCI). SETTING: A teaching hospital, expert center in disability, in France. METHODS: We studied a retrospective cohort of all BSIs occurring in SCI patients hospitalized over 16 years. We described the prevalence of MDRO BSI among this population and its evolution over time and compared the BSI population due to MDROs and due to non-MDROs. RESULTS: A total of 318 BSIs occurring among 256 patients were included in the analysis. The most frequent primary sites of infection were urinary tract infection (34.0%), pressure sore (25.2%) and catheter line-associated bloodstream infection (11.3%). MDROs were responsible for 41.8% of BSIs, and this prevalence was stable over 16 years. No significant associated factor for MDRO BSI could be identified concerning sociodemographic and clinical characteristics, primary site of infection and bacterial species in univariate and multivariate analyses. BSI involving MDROs was not associated with initial severity of sepsis compared with infection without MDROs (43.8 vs 43.6%, respectively) and was not associated either with 30th-day mortality (6.2 vs 9%, respectively). CONCLUSION: During BSI occurrence in an SCI population, MDROs are frequent but remain stable over years. No associated risk can be identified that would help optimize antibiotic treatment. Neither the severity of the episode nor the mortality is significantly different when an MDRO is involved.

Be careful about abdominal discomfort in adult patients with muscular dystrophy.

Muscular dystrophies are genetic muscular disease with disability. Heart failure is a classical complication mainly in Duchenne muscular dystrophy (DMD). We report 2 cases of severe acute heart failure revealed by abdominal discomfort in a patient with DMD and in a patient with gamma-sarcoglycanopathy.

A Scoping Review of Adverse Incidents Research in Aged Care Homes: Learnings, Gaps, and Challenges.

Background: Adverse incidents are well studied within acute care settings, less so within aged care homes. The aim of this scoping review was to define the types of adverse incidents studied in aged care homes and highlight strengths, gaps, and challenges of this research. Methods: An expanded definition of adverse incidents including physical, social, and environmental impacts was used in a scoping review based on the PRISMA Extension for Scoping Reviews Checklist. MEDLINE, CINAHL, and EBSCOhost were searched for English language, peer-reviewed studies conducted in aged care home settings between 2000 and 2020. Forty six articles across 12 countries were identified, charted, and analyzed using descriptive statistics and narrative summary methods. Results: Quantitative studies (n = 42, 91%) dominated adverse incidents literature. The majority of studies focused on physical injuries (n = 29, 63%), with fewer examining personal/interpersonal (15%) and environmental factors (22%). Many studies did not describe the country's aged care system (n = 26, 56%). Only five studies (11%) included residents' voices. Discussion: This review highlights a need for greater focus on resident voices, qualitative research, and interpersonal/environmental perspectives in adverse event research in aged care homes. Addressing these gaps, future research may contribute to better understanding of adverse incidents within this setting.

Home-based exercise in autoimmune myasthenia gravis: A randomized controlled trial.

The tolerance of exercise and its effects on quality of life in myasthenia gravis are not currently backed up by strong evidence. The aim of this study was to determine whether exercise as an adjunct therapy is well tolerated and can improve health-related quality of life (HRQoL) in stabilized, generalized autoimmune myasthenia gravis (gMG). We conducted a parallel-group, multi-center prospective RCT using computer-generated block randomization. Adults with stabilized, gMG, and no contra-indication to exercise, were eligible. Participants received usual care alone or usual care and exercise. The exercise intervention consisted of 3-weekly 40 min sessions of an unsupervised, moderate-intensity home rowing program over 3 months. The primary endpoint was the change in HRQoL from randomization to post-intervention. Assessor-blinded secondary endpoints were exercise tolerance and effects on clinical, psychological and immunological status. Of 138 patients screened between October 2014 and July 2017, 45 were randomly assigned to exercise (n = 23) or usual care (n = 20). Although exercise was well tolerated, the intention-to-treat analysis revealed no evidence of improved HRQoL compared to usual care (MGQOL-15-F; mean adjusted between-groups difference of -0.8 points, 95%CI -5.4 to 3.7). Two patients hospitalized for MG exacerbation were from the usual care group.

Exogenous acquisition of Pseudomonas aeruginosa in intensive care units: a prospective multi-centre study (DYNAPYO study).

BACKGROUND: Pseudomonas aeruginosa remains one of the most common nosocomial pathogens in intensive care units (ICUs). Although exogenous acquisition has been widely documented in outbreaks, its importance is unclear in non-epidemic situations. AIM: To elucidate the role of exogenous origin of P. aeruginosa in ICU patients. METHODS: A chronological analysis of the acquisition of P. aeruginosa was performed using samples collected in 2009 in the DYNAPYO cohort study, during which patients and tap water were screened weekly. Molecular relatedness of P. aeruginosa isolates was investigated by pulsed-field gel electrophoresis. Exogenous acquisition was defined as identification of a P. aeruginosa pulsotype previously isolated from another patient or tap water in the ICU. FINDINGS: The DYNAPYO cohort included 1808 patients (10,402 samples) and 233 water taps (4946 samples). Typing of 1515 isolates from 373 patients and 375 isolates from 81 tap water samples identified 296 pulsotypes. Analysis showed exogenous acquisition in 170 (45.6%) of 373 patients. The pulsotype identified had previously been isolated from another patient and from a tap water sample for 86 and 29 patients, respectively. The results differed according to the ICU. CONCLUSION: Exogenous acquisition of P. aeruginosa could be prevented in half of patients. The overall findings of this survey support the need for studies on routes of transmission and risk assessment approach to better define how to control exogenous acquisition in ICUs.

[Non specific treatment of status epilepticus]. / Prise en charge non spécifique de l'état de mal épileptique convulsif.

The systemic consequences of status epilepticus occur in two stages: the first stage is a hyperadrenergic period (high blood pressure, tachycardia, arrhythmia, hyperventilation, hypermetabolism, hyperthermia), the second stage a collapsus period, sometimes with acute circulatory failure, and hypoxemia. Symptomatic resuscitation aimed at restoring vital functions should be undertaken. Resuscitation must be started immediately before hospital transfer, by a trained emergency team. Respiratory care includes at least oxygen intake, but it can also require oral intubation (crash induction) and mechanical ventilation. The arterial blood gas objectives are SaO(2)> or =95%, and 35mmHg< or =PaCO(2)< or =40mmHg. Fluid and electrolyte care includes intravenous infusion of normal saline, with control of sodium and calcium levels as well as blood pH within normal limits. Heart rate and blood pressure must be monitored. Mean blood pressure must be kept between 70 and 90mmHg, first by means of plasma volume expansion, and then norepinephrine if necessary. Hyperthermia must be corrected to prevent further neuronal damage. Cerebromeningeal sepsis should be ruled out. Capillary glucose (most often elevated) must be corrected using a pre-established insulin infusion algorithm. Rhabdomyolysis is rare, but can result in hyperkaliemia, acidosis, and acute renal failure. In case of associated intracranial hypertension (traumatic, vascular or infectious injury), status epilepticus is considered as a secondary insult for the brain, that can worsen neuronal damage. Numerous compounds have experimental neuroprotective properties, but none have proven significant efficacy in clinical conditions. Nevertheless, convulsion cessation is considered as a neuroprotective measure.

[Management of convulsive status epilepticus: therapeutic strategies]. / Prise en charge de l'état de mal tonicoclonique généralisé : stratégies thérapeutiques.

Increasing duration of generalized tonic-clonic status epilepticus increases the risk of neuronal damage and systemic complications. It is also a recognized contributing factor to drug resistance. The most indispensable quality an anticonvulsive medication is expected to have in this situation is therefore a rapid therapeutic effect, achieved without severe depressive, neurological, cardiovascular or respiratory side effects. The anticonvulsive strategy proposed here takes into account these prerequisites, as well as previously published research findings which remain limited on a number of aspects. The duration of the convulsions before medication must be taken into account when deciding on the initial treatment. If this is less than 30 min, a single drug regimen with benzodiazepine would be appropriate and sufficient initially. If lorazepam, which is unavailable in France, cannot be used, the pharmacokinetically similar clonazepam should be preferred. Beyond 30 min, a combination of benzodiazepine and an anticonvulsive with long-lasting effects -phenobarbital or fosphenytoin- is indicated. The choice between these two latter drugs depends on their respective contraindications and the circumstances surrounding the occurrence of the status epilepticus. The persistence of seizures beyond 20 min after beginning the phenobarbital infusion or 30 min after starting fosphenytoin signals a failure of the initial treatment and requires the immediate introduction of a second line of therapy. This may be an anticonvulsive with long-lasting effects providing the convulsions have been present for less than an hour, there is no suspicion of an acute cerebral lesion and there is no associated systemic factor of cerebral aggression. If not, the employment of anesthetic medication is immediately required.

Zidovudine therapy and HIV encephalitis: a 10-year neuropathological survey.

OBJECTIVE: To assess the effect of zidovudine on productive HIV infection of the brain. DESIGN: To correlate the incidence of HIV-specific neuropathology with zidovudine therapy. PATIENTS: We examined 192 AIDS cases neuropathologically; 97 had never been treated with zidovudine, 72 had received zidovudine for over 3 months and until death, 23 had their treatment terminated more than 1 month before death. RESULTS: The incidence of HIV encephalitis/HIV leukoencephalopathy (HIVE/HIVL) and of multinucleated giant cells (MGC) was significantly lower in patients who had received zidovudine than in those who had never received zidovudine. The yearly incidence of HIVE/HIVL increased between 1982 and 1987 probably because of improved survival, and decreased between 1987 and 1990 although the percentage of patients treated with zidovudine increased. Since 1991 the incidence of HIVE/HIVL and of MGC increased slightly. The percentage of patients treated with zidovudine until death decreased and that of patients whose treatment was terminated increased concomitantly. In 1989 and 1990, most patients whose treatment was terminated had MGC and HIVE/HIVL. In 1991 and 1992 this incidence decreased markedly, coinciding with the introduction of dideoxyinosine therapy. CONCLUSION: Zidovudine treatment significantly reduces the occurrence of productive HIV infection of the brain in AIDS. Discontinuing zidovudine therapy may favour the occurrence of HIV encephalitis. Substitution therapy with dideoxyinosine also appears to protect against HIV-specific brain pathology.

Circulating tumor necrosis factor (TNF)-alpha and soluble TNF-alpha receptors in patients with Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is an inflammatory disorder that may implicate proinflammatory cytokines such as TNF-alpha in its pathogenesis. We determined serum levels of TNF-alpha and the specific antagonists sTNF-Rs p55 and p75 in 24 patients with GBS at days 1, 15 and 30 of hospitalization. Patients were in the progression phase of the disease at day 1, and in the recovery phase at day 30. They were classified as able to walk (stage A), confined to bed (B), or under assisted ventilation (C). All patients underwent plasma exchange within day 1-12. At day 1, TNF-alpha levels were elevated in 15/24 patients, and sTNF-Rs were elevated in 21/23. TNF-alpha levels had not decreased at day 15, and dropped at day 30 (p < 0.04), whereas sTNF-R p55 remained elevated at day 15 and day 30. The TNF-alpha/sTNF-Rs ratio, estimating active TNF-alpha unbound to sTNF-Rs, decreased from day 1 to day 30 (p < 0.05). A positive correlation was found between disease severity and sTNF-R serum levels (p < 0.01). In conclusion, elevated circulating sTNF-Rs assesses activation of the TNF-alpha system in almost all patients with GBS and correlates positively with disease severity. Drop of TNF-alpha contrasting with sustained elevation of sTNF-R p55 during recovery suggests that sTNF-R p55 may be important in the fading of the neural inflammatory effect of TNF-alpha in GBS.

Characterization of low molecular weight alkoxylated polymers using long column SFC/MS and an image analysis based quantitation approach.

The utility of low viscosity mobile phases and long chromatographic columns for complex polymer analysis is demonstrated. We use long column supercritical fluid chromatography/mass spectrometry (SFC/MS) with electrospray ionization (ESI) to characterize a variety of complex, low molecular weight polymers. When quantitative analysis is desired, the resulting three-dimensional (time, intensity, and mass-to-charge ratio [m/z]) data are converted to images. Custom image analysis software is used to detect and integrate peaks in arbitrarily defined regions of the time-m/z map. These integrated peak volumes can be used to quantitate distinct component classes of the polymer mixtures.

Severe tuberculosis in patients with human immunodeficiency virus infection.

Tuberculosis has now been well documented as a complication of infection with human immunodeficiency virus (HIV), but no studies concern patients requiring admission to the ICU. We report 12 cases of severe disseminated tuberculosis in patients who were seropositive for HIV. Eight patients had diffuse pulmonary involvement responsible for acute respiratory failure, 7 of whom required mechanical ventilation. Four developed septic shock, and in 3 blood cultures were positive for M. tuberculosis. Four patients had central nervous system involvement, with coma requiring mechanical ventilation 3 times. Rapid diagnosis was permitted in 10 patients by acid-fast smears of pulmonary specimens (8 patients) and/or tissue biopsies (4 patients). Seven patients died despite intensive therapy; autopsy was performed in 4 patients, showing disseminated tuberculosis. On the basis of this report, tuberculosis in HIV infection may present as an overwhelming systemic disease and thus requires an aggressive diagnostic and therapeutic approach.

Continuous positive airway pressure by face mask or mechanical ventilation in patients with human immunodeficiency virus infection and severe Pneumocystis carinii pneumonia.

We reviewed the records of 44 patients with AIDS who had 45 episodes of severe Pneumocystis carinii pneumonia (PCP). While 9 patients required intubation and mechanical ventilation (MV) on admission, continuous positive airway pressure (CPAP) by face mask was the initial measure in 36 episodes. There were 25 patients managed with CPAP alone, 23 of whom survived. Among the reasons for delayed intubation and MV (11 patients) was that treatment failure was strongly associated with non-survival, since all 6 such patients died. The in-hospital mortality for severe PCP in this study was 33% overall, and reached 65% for mechanically ventilated patients. The 1-year survival was 43% (95% confidence interval, 28%-58%). These data confirm the improved prognosis for patients with AIDS and severe PCP, and suggest that mask CPAP may be an adequate mean of ventilatory support in this setting.

Medial preoptic area delta-opioid receptors inhibit lordosis.

Endogenous opioid peptides that activate the delta-opioid receptor (DOR) are thought to facilitate female receptive behavior. This facilitation of lordosis has been demonstrated by intracerebroventricular infusions and injection of DOR-active ligands into the ventromedial hypothalamic nucleus, an area with robust DOR binding. However, DOR binding is distributed throughout the hypothalamus, and the role of DOR in other areas of the hypothalamus has not been examined. In the current study, we demonstrated DOR immunoreactivity in the medial preoptic area (MPO), in particular medial preoptic nucleus (MPN) of the preoptic area. DOR immunoreactive processes were sparsely distributed in the medial and lateral parts of the MPN. Larger DOR immunoreactive fibers were localized in the ventrolateral aspect of the lateral MPN. The MPN is involved in the modulation of female sexual receptivity and the distribution of DOR in this area suggested to us that DOR may regulate lordosis. Ovariectomized rats with unilateral cannulae aimed at the MPN were given 5microg 17beta-estradiol benzoate (EB), once every 4 days and tested for lordosis. [D-Pen(2), D-Pen(5)]-enkephalin (DPDPE), a DOR agonist, microinfused into the MPO, 52-54h after EB-priming, inhibited lordosis when compared with the aCSF (vehicle) control (P <== 0.05). The inhibitory effects of DPDPE were reversed by microinjection of naltrindole, a DOR antagonist (P <== 0.05). Interestingly, the DOR inhibition of lordosis is similar to the micro-opioid receptor inhibition of lordosis in the MPN. These results indicate that DOR in the MPO, particularly in the MPNm, plays an important role in the regulation of lordosis.

[Importance of evoked potentials in the evolutive prognosis of coma during cerebral anoxia in adults]. / Intérêt des potentiels évoqués dans le pronostic évolutif des comas par anoxie cérébrale chez l'adulte.

Ten cases of postanoxic coma have been studied. A clinical neurological examination with study of brainstem reflexes and the EEG recording were made on the first day (J1), the third day (J3) and the tenth day (J10) after the start of the coma. A recording of the visual evoked potentials, the brainstem evoked potentials and the somatosensory potentials combined was made at the same time. A clinical examination is carried out one month after the coma when the patient survives. According to the initial clinical examination, we distinguished 3 groups of subjects. The results show that in group III the visual evoked potentials such as EEG have a slightly significant prognostic value; frequently the near outcome lead to death whereas EEG activity persists and the visual evoked potentials disappear later. On the other hand, the association of brainstem evoked potentials and somatosensory potentials clearly has a higher prognostic value in this group. The disappearance of the shortest brainstem responses and the cortical somatosensory responses is clearly an unfavourable prognosis. This disappearance associated with the end EEG activity is the absolute proof of brain death. On the other hand, the persistence of these responses is of a better prognosis at least on the survival level, but their degradation during evolution is unfavourable.

[Long-term ventilation at home in adults with neurological diseases]. / Ventilation à domicile au long cours dans les maladies neurologiques de l'adulte.

Respiratory handicap due to neurological diseases is often underestimated. Given clinical signs are either mild or absent, systematic measurement of the vital capacity is the best mean to detect in practice the restrictive syndrome. The onset of home mechanical ventilatory support should be decided at steady state, apart from episodes of acute respiratory failure. Two types of indications should be distinguished. Necessary ventilation aims at supplying over day and night the respiratory insufficiency incurred by the paralysis of respiratory muscles. Although the criteria for the use of such a supply differ according to the neurological disease, a daytime hypercapnia above 45 mmHg is widely accepted in the literature. It is otherwise established to use first a non invasive technique, while tracheostomy is secondarily proposed in case of failure of these techniques. The application of this therapeutic strategy in Duchenne de Boulogne muscular dystrophy showed that, given that tracheostomy will become necessary in this evolutive disease, proposal of an early tracheostomy is not nonsensical. By contrast, preventive ventilation aims at preventing from the aggravation of the restrictive syndrome in those patients with no criterion for necessary ventilation. It has been proved ineffective in Duchenne muscular dystrophy through a controlled clinical trial.

[Adult cerebral malaria. Actual experience of the Infectious Diseases Intensive Care Department at the Claude Bernard Hospital]. / Accès pernicieux palustre de l'adulte. Expérience actuelle de la Clinique de Réanimation des maladies infectieuses de l'Hôpital Claude Bernard.

22 cases of adult cerebral malaria were observed between July 1987 and June 1989, either associated or not: parasitemia 5%, consciousness disorders, acute renal failure, thrombocytopenia. Two patients died (9%). Increased frequency of attacks is underlined. They are due to chloroquino-resistant parasite strains, even polychemoresistant, occurred in French speaking Tropical Africa since 1985. Therapeutic strategy is described. The necessity to use increased doses of quinine has been admitted, correlatively underlining importance of strict monitoring of the patients because, in first instance, the risk of hypoglycemia (eased by injecting too quickly high doses of quinine) and of acute pulmonary oedema (eased by too quick perfusions and/or transfusions).

[Corticotherapy in severe infectious states]. / Corticothérapie dans les états infectieux graves.

Septic shock is one of the leading cause of death in modern countries. Scientists have made huge improvement in the understanding of mechanisms of inflammation, and the sequence of activation of the various pro and anti-inflammatory markers is now well known. By contrary, physicians have failed to improve survival from septic shock, in spite of the development of specific targets of the various points of the cytokine cascade sought to have a key role in host survival to sepsis. Corticosteroids were among the first anti-inflammatory drugs, which have been tested in high quality randomised controlled trials. These trials clearly showed that patients with septic shock are unlikely to benefit from a short course of a large dose of an anti-inflammatory steroid. More recent findings highlighting the role of the integrity of the hypothalamic-pituitary -adrenal axis to appropriately respond to a septic insult, have led to a reappraisal of the use of steroids in septic shock. Several high quality randomised controlled trials have evaluated the efficacy and safety of a prolonged treatment with low dose hydrocortisone in severe sepsis. These trials strongly suggested that this strategy of corticotherapy reduced the morbidity of septic shock and may favourably affect survival from septic shock.

[Infectious pneumopathies in immunosuppressed patients]. / Pneumopathies infectieuses de l'immunodéprimé.

Infective pneumonia occurring in immunocompromised patients is characterized by its multiple causes which create diagnostic problems and by the need for a prompt treatment. The principal criteria pointing to a specific organism are the causes of immunodeficiency (now usually due to treatment of blood diseases or cancers, organ transplantation and AIDS) and the radiological features of the pneumonia. Confirming the diagnosis frequently requires features of the pneumonia. Confirming the diagnosis frequently requires invasive explorations which in any case are limited by the patient's fragility. Consequently, empirical therapeutic measures are initiated, at least initially, taking into account all likely assumptions. The severity and frequency of these lung infections make it desirable to develop preventive measures applying to the patient himself (antibiotic prophylaxis) or to his environment.