Improvements in pain, medication use and quality of life in onabotulinumtoxinA-resistant chronic migraine patients following erenumab treatment - real world outcomes.

BACKGROUND: The CGRP antagonists offer a novel therapeutic approach in migraine. Their utility in patients with severe forms of chronic migraine is a subject of particular interest. We present outcomes of 9 months of erenumab treatment in a cohort of patients with difficult-to-control chronic migraine, all of whom had prior unsatisfactory response to onabotulinumtoxinA. METHODS: We offered erenumab to 98 patients with a prior unsatisfactory response to onabotulinumtoxinA. Eighty of 98 had trialled greater occipital nerve injections (82%), 32/98 peripheral neurostimulation (33%) and 18/98 intravenous dihydroergotamine (18%). Thirty eight of 98 (39%) met the definition of triptan overuse and 43/98 (44%) analgesic overuse. All patients met the EHF criteria for 'resistant migraine'. Outcome measures (recorded monthly) included days with headache limiting activities of daily living ("red"), not limiting ("amber"), headache free ("green"), and requiring triptans or other analgesics. Quality of life scores - headache impact test 6 (HIT-6), patient health questionnaire 9 (PHQ-9) and pain disability index (PDI) - were also measured. RESULTS: Mean number of red days improved by - 6.4 days (SE 0.67, 95%CI - 7.7 to - 5.1, p=0.001) at 3 months; - 6.8 days (SE 0.96, 95%CI - 8.80 to - 4.9, p=0.001) at 6 months and - 6.5 days (SE 0.86, 95%CI - 8.3 to - 4.8, p=0.001) at 9 months. Repeated measures ANOVA confirmed improvements in the number of red (p=0.001), green (p=0.001), triptan (p=0.001) and painkiller days (p=0.001) as well as scores of the HIT-6 (p=0.001), PHQ-9 (p=0.001), and PDI (p=0.001) across the duration of study. CONCLUSION: We observed improvements in pain, medication use and quality of life in onabotulinumtoxinA-resistant chronic migraine patients following erenumab treatment.

Treatment of Ebola-related critical illness.

PURPOSE: To explore contemporary clincial case management of patients with Ebola virus disease. METHODS: A narrative review from a clinical perspective of clinical features, diagnostic tests, treatments and outcomes of patients with Ebola virus disease. RESULTS: Substantial advances have been made in the care of patients with Ebola virus disease (EVD), precipitated by the unprecedented extent of the 2014-2016 outbreak. There has been improved point-of-care diagnostics, improved characterization of the clinical course of EVD, improved patient-optimized standards of care, evaluation of effective anti-Ebola therapies, administration of effective vaccines, and development of innovative Ebola treatment units. A better understanding of the Ebola virus disease clinical syndrome has led to the appreciation of a central role for critical care clinicians-over 50% of patients have life-threatening complications, including hypotension, severe electrolyte imbalance, acute kidney injury, metabolic acidosis and respiratory failure. Accordingly, patients often require critical care interventions such as monitoring of vital signs, intravenous fluid resuscitation, intravenous vasoactive medications, frequent diagnostic laboratory testing, renal replacement therapy, oxygen and occasionally mechanical ventilation. CONCLUSION: With advanced training and adherence to infection prevention and control practices, clinical interventions, including critical care, are feasible and safe to perform in critically ill patients. With specific anti-Ebola medications, most patients can survive Ebola virus infection.

Neurological effects of glucocerebrosidase gene mutations.

The association between Gaucher disease (GD) and Parkinson disease (PD) has been described for almost two decades. In the biallelic state (homozygous or compound heterozygous) mutations in the glucocerebrosidase gene (GBA) may cause GD, in which glucosylceramide, the sphingolipid substrate of the glucocerebrosidase enzyme (GCase), accumulates in visceral organs leading to a number of clinical phenotypes. In the biallelic or heterozygous state, GBA mutations increase the risk for PD. Mutations of the GBA allele are the most significant genetic risk factor for idiopathic PD, found in 5%-20% of idiopathic PD cases depending on ethnicity. The neurological consequences of GBA mutations are reviewed and the proposition that GBA mutations result in a disparate but connected range of clinically and pathologically related neurological features is discussed. The literature relating to the clinical, biochemical and genetic basis of GBA PD, type 1 GD and neuronopathic GD is considered highlighting commonalities and distinctions between them. The evidence for a unifying disease mechanism is considered.

Mechanism of action of and mechanism of reduced susceptibility to the novel anti-Clostridium difficile compound LFF571.

LFF571 is a novel semisynthetic thiopeptide and potent inhibitor of Gram-positive bacteria. We report that the antibacterial activity of LFF571 against Clostridium difficile is due to inhibition of translation. Single-step mutants of C. difficile with reduced susceptibility to LFF571 were selected at frequencies of <4.5 × 10(-11) to 1.2 × 10(-9). Sequencing revealed a G260E substitution in the thiopeptide-binding pocket of elongation factor Tu. Importantly, this mutation did not confer cross-resistance to clinically used antimicrobials. These results support the development of LFF571 as a treatment for C. difficile infection.

In vitro and in vivo activities of novel, semisynthetic thiopeptide inhibitors of bacterial elongation factor Tu.

Recently, we identified aminothiazole derivatives of GE2270 A. These novel semisynthetic congeners, like GE2270 A, target the essential bacterial protein elongation factor Tu (EF-Tu). Medicinal chemistry optimization of lead molecules led to the identification of preclinical development candidates 1 and 2. These cycloalklycarboxylic acid derivatives show activity against difficult to treat Gram-positive pathogens and demonstrate increased aqueous solubility compared to GE2270 A. We describe here the in vitro and in vivo activities of compounds 1 and 2 compared to marketed antibiotics. Compounds 1 and 2 were potent against clinical isolates of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci (MIC(90) ≤ 0.25 µg/ml) but weaker against the streptococci (MIC(90) ≥ 4 µg/ml). Like GE2270 A, the derivatives inhibited bacterial protein synthesis and selected for spontaneous loss of susceptibility via mutations in the tuf gene, encoding EF-Tu. The mutants were not cross-resistant to other antibiotic classes. In a mouse systemic infection model, compounds 1 and 2 protected mice from lethal S. aureus infections with 50% effective doses (ED(50)) of 5.2 and 4.3 mg/kg, respectively. Similarly, compounds 1 and 2 protected mice from lethal systemic E. faecalis infections with ED(50) of 0.56 and 0.23 mg/kg, respectively. In summary, compounds 1 and 2 are active in vitro and in vivo activity against difficult-to-treat Gram-positive bacterial infections and represent a promising new class of antibacterials for use in human therapy.

High prevalence of distal sensory polyneuropathy in antiretroviral-treated and untreated people with HIV in Tanzania.

OBJECTIVES: To describe the prevalence of distal sensory polyneuropathy (DSP), a complication of both advanced HIV disease and of antiretroviral therapy (ART), amongst Tanzanians with HIV, on and off ART (including stavudine) with CD4 counts above and below 200 cells/µl. METHODS: We recruited participants attending ART clinic into four groups: >6 months ART exposure and (i) CD4 < 200 cells/µl or (ii) CD4 > 200 cells/µl (ART/CD4 < 200 and ART/CD4 > 200, respectively); ART-naïve and (iii) CD4 < 200 cells/µl or iv)CD4 > 200 cells/µl (noART/CD4 < 200 and noART/CD4 > 200, respectively). Primary outcome was DSP, as defined by presence of at least one symptom and one sign. RESULTS: Of 326 evaluable participants, 81 (32 men, median age 38 years, median CD4 142 cells/µl) were enrolled in the ART/CD4 < 200 group, 78 (17 men, median age 37 years, median CD4 345 cells/µl) in ART/CD4 > 200, 81 (30 men, median age 37 years, median CD4 128 cells/µl) in noART/CD4 < 200 and 86 (22 men, median age 33 years, median CD4 446 cells/µl) in noART/CD4 > 200. Numbness was the most commonly reported symptom. DSP prevalence ranged from 43.2% in ART/CD4 < 200 to 20.9% in noART/CD4 > 200. DSP was more common among men (adjusted odds ratio [aOR] 1.9, 95% confidence interval [CI] 1.2-3.3) and older participants (aOR 2.7, 95% CI 1.1-6.2 for age 40 + vs. <30 years). CONCLUSION: Distal sensory polyneuropathy is common amongst those attending this clinic, even those with no ART exposure and a CD4 count above 200 cells/µl. Stavudine and didanosine expose HIV-infected patients to an additional avoidable risk of DSP. Access to non-neurotoxic ART regimes as well as earlier HIV diagnosis and initiation of ART is needed.

Enhanced recovery of cryopreserved islets using SIS.

Although cryopreservation of pancreatic islets would add flexibility to transplantation, the recoveries are only 60% to 90% and function is decreased. Islets are multicellular structures approximately 50 to 250 microm in diameter organized into a network of cells and vascular channels. Due to this complexity, islets are more susceptible to damage during cryopreservation than an individual cell. This study investigated porcine small intestinal submucosa (SIS) as a matrix to support islets recovery and function post-thaw. Groups of frozen/thawed human islets (150 IE/condition; n = 4 preparations) were cultured for 5 weeks in plates containing noncoated Biopore membrane inserts alone or inserts covered with SIS. Islets were placed directly on the insert post-thaw (SIS(1)), or cultured overnight in standard plates, washed, and then transferred to the SIS (SIS(2)). Function was assessed by determining glucose-stimulated release of insulin, which was measured by radioimmunoassay. Analysis of basal insulin secretion showed time and treatment to be significantly different (P =.0043 and P =.0123, respectively) but without an interaction (P >.05). The two SIS treatments were not significantly different (P >.05); however, both SIS(1) and SIS(2) were significantly different from controls (P =.0108 and P =.0420, respectively). Similar results were obtained for stimulation indices; time and treatment were significantly different (P =.0161 and P =.0264, respectively) but not an interaction (P >.05). The two SIS treatments were not significantly different (P =.05); however, both SIS(1) and SIS(2) differed from controls (P =.0248 and P =.0407, respectively). The results indicate that SIS enables frozen-thawed islets to exhibit superior post-thaw function compared with a non-SIS-supported condition.

Epidemic West Nile encephalitis, New York, 1999: results of a household-based seroepidemiological survey.

BACKGROUND: In the summer of 1999, West Nile virus was recognised in the western hemisphere for the first time when it caused an epidemic of encephalitis and meningitis in the metropolitan area of New York City, NY, USA. Intensive hospital-based surveillance identified 59 cases, including seven deaths in the region. We did a household-based seroepidemiological survey to assess more clearly the public-health impact of the epidemic, its range of illness, and risk factors associated with infection. METHODS: We used cluster sampling to select a representative sample of households in an area of about 7.3 km(2) at the outbreak epicentre. All individuals aged 5 years or older were eligible for interviews and phlebotomy. Serum samples were tested for IgM and IgG antibodies specific for West Nile virus. FINDINGS: 677 individuals from 459 households participated. 19 were seropositive (weighted seroprevalence 2.6% [95% CI 1.2-4.1). Six (32%) of the seropositive individuals reported a recent febrile illness compared with 70 of 648 (11%) seronegative participants (difference 21% [0-47]). A febrile syndrome with fatigue, headache, myalgia, and arthralgia was highly associated with seropositivity (prevalence ratio 7.4 [1.5-36.6]). By extrapolation from the 59 diagnosed meningoencephalitis cases, we conservatively estimated that the New York outbreak consisted of 8200 (range 3500-13000) West Nile viral infections, including about 1700 febrile infections. INTERPRETATION: During the 1999 West Nile virus outbreak, thousands of symptomless and symptomatic West Nile viral infections probably occurred, with fewer than 1% resulting in severe neurological disease.

Mail-in questionnaire for monitoring nausea and vomiting in oncology outpatients.

A patient questionnaire designed to help pharmacists monitor nausea and vomiting in outpatients receiving cancer chemotherapy was studied. A 12-item questionnaire was designed by combining items from the Morrow Assessment of Nausea and Emesis (MANE) and the Functional Living Index-Emesis (FLIE). Items included number of vomiting episodes, duration of nausea, number of antiemetics, severity of nausea and vomiting, impact on quality of life, and adverse effects. The questionnaire was printed on an addressed, postage-paid card. Over an eight-week period, outpatients in a hospital's oncology clinic were asked to complete the questionnaire at home during the three days after chemotherapy. Of 48 patients asked, 42 (88%) agreed to complete the questionnaire, and 36 (86%) of these patients mailed it back to the clinic. Of the respondents, 11 reported at least one episode of vomiting, and 22 reported nausea. Thirteen respondents logged nausea ratings of 3 or higher on a 7-point scale. Twenty respondents used antiemetics. Responses given by the patients in follow-up telephone interviews did not differ significantly from the responses collected with the questionnaire. More than 90% of patients who returned the questionnaire rated it as simple to complete. Pharmacists used the self-reports of nausea or vomiting in 7 (17%) of 42 cases to recommend alternative antiemetic regimens. A mail-in questionnaire for monitoring nausea and vomiting in outpatients undergoing chemotherapy was completed and returned by a high percentage of patients and was useful to clinic pharmacists.

Differences between American Indian and non-Indian children referred for psychological services.

The physical and social characteristics of 60 American Indian children referred for psychological services were compared to those of 60 matched, non-Indian controls. Data were obtained from detailed records available in a multidisciplinary, medical school-related child study clinic. Indian children exhibited more health and social risk factors, but were superior to non-Indians on a variety of motor variables. Interpretations are offered concerning better psychological services for American Indian children based on better understanding of their possible exposure to physical health and social risks which may be related to psychological development.

Effect of hyaluronidase on mortality and morbidity in patients with early peaking of plasma creatine kinase MB and non-transmural ischaemia. Multicentre investigation for the limitation of infarct size (MILIS).

A multicentred, randomised, blind study was started in 1978 to compare propranolol or hyaluronidase with placebo in patients with acute myocardial infarction admitted within 18 hours of onset of symptoms. Patients were randomised to group A and received hyaluronidase, propranolol, or placebo, or, if propranolol was contraindicated, to group B and received hyaluronidase or placebo. Hyaluronidase (500 U/kg given every six hours for 48 hours) had no effect on mortality or infarct size in the overall population. Because spontaneous reperfusion was more common in patients with early peaking of plasma creatine kinase MB or non-transmural electrocardiographic changes or both, the results were reanalysed for two subgroups: those in whom plasma creatine kinase peaked less than 15 hours after the onset of symptoms (early peak, n = 184) and those with a peak greater than 15 h after the onset of symptoms (late peak, n = 546). The distribution of time to peak activity of creatine kinase MB was similar in the hyaluronidase and placebo groups. In the early peak patients who were given hyaluronidase (groups A and B) total mortality and cardiac-specific four year mortality were significantly lower. This was most pronounced in group B in which the total mortality was 45% and cardiovascular mortality was 47% less than in the placebo group. Similarly, mortality from cardiovascular disease in patients (groups A and B) with nontransmural ischaemia (ST-T changes) given hyaluronidase was significantly lower, with group B showing a 50% reduction. In the subsets of patients with late peaking of creatine kinase MB or those presenting with transmural electrocardiographic changes there was no difference in total mortality or deaths from cardiac disease between those given hyaluronidase and those given placebo. Hyaluronidase was associated with improved survival in patients with early peaking of plasma creatine kinase MB, suggesting the possibility of salvage of myocardium in patients who have early spontaneous reperfusion and possibly after therapeutic reperfusion.

Measuring chaplaincy productivity.

Examines idea of productivity as it relates to the practice of chaplaincy in a large health care institution. Defines three dimensions of the Productivity Model: measure of quality of service, quality of service rendered, and value of service to institution. Author then identifies seven areas of chaplaincy functioning based on departmental study of chaplaincy activities.

Sex differences in early and long-term results of coronary angioplasty in the NHLBI PTCA Registry.

To assess whether gender influenced the outcome of percutaneous transluminal coronary angioplasty (PTCA), we analyzed data from the NHLBI PTCA Registry. Early results were compared in 705 women and 2374 men. Women were older (p less than .01) and had more unstable angina (p less than .01), and class 3 or 4 angina (p less than .01). Men had more multivessel disease (p less than .01), prior bypass surgery (p less than .01), and abnormal left ventricular function (p less than .05). Women had a lower angiographic success rate (60.3 vs 66.2%; p less than .01) and had a lower clinical success rate (56.6% vs 62.2%; p less than .01). More women had complications (27.2% vs 19.4%; p less than .01), but overall frequency of major complications (death, myocardial infarction, emergency surgery) was not different (9.8% vs 9.3%). Women had a higher incidence of coronary dissection (p less than .05) and higher in-hospital mortality (1.8% vs 0.7%; p less than .01). PTCA-related mortality was nearly six times higher in women (1.7% vs 0.3%; p less than .001) and mortality with emergency surgery was more than five time higher (17.4% vs 3.2%; p less than .001). Multivariate analysis indicated that female gender was an independent predictor for lower success (p less than .05) and early mortality (p less than .05) and was the only baseline predictor for PTCA-related mortality.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of propranolol on myocardial-infarct size in a randomized blinded multicenter trial.

A multicenter randomized single-blind study was performed to evaluate the effects of propranolol administered during the evolution of myocardial infarction. Five centers enrolled a total of 269 patients, with 134 receiving propranolol and 135 placebo. Propranolol or placebo was given intravenously upon randomization (0.1 mg per kilogram of body weight) and then orally for nine days to keep the heart rate between 45 and 60 beats per minute. Less than 2 per cent of patients were treated within 4 hours after the onset of symptoms, but 50 per cent received therapy within 8 hours of onset of chest pain, and the remainder between 8 and 18 hours. The heart rates in the propranolol-treated group were significantly lower than those in the placebo group (P less than 0.001). Base-line characteristics, including the mean heart rate (79.6 vs. 81.3) and the left ventricular ejection fraction (49.0 vs. 49.5), were similar in the two groups. The primary end point evaluated--infarct size as estimated from plasma MB creatine kinase activity--was virtually identical in the two groups, averaging 13.3 and 13.6 gram-equivalents of MB creatine kinase per square meter of body-surface area. Peak plasma levels of the enzyme were also similar in the two groups. No significant difference was observed between the propranolol and placebo groups in the change in left ventricular ejection fraction, extent of area involved in pyrophosphate uptake, R-wave loss on electrocardiograms, or mortality (after three years). These results do not support the use of propranolol administered four or more hours after the onset of symptoms to limit infarct size.

In-hospital mortality rate in the National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty Registry.

Twenty-nine patients died among the first 3,079 patients enrolled in the NHLBI PTCA Registry. The overall morality rate was 0.9%; the mortality rate was 0.8% in patients with 1-vessel CAD, 1.0% in those with multivessel CAD (excluding left main CAD), and 3.8% in those with left main CAD (p less than 0.01). The in-hospital morality rate was significantly higher among women (p less than 0.01), in patients older than 60 years, in patients with previous CABG (p less than 0.01), the presence of left main CAD, (p less than 0.01), in patients who required dilatation of a vein graft stenosis (p less than 0.05), and in patients who had had angina for longer than 6 months (p less than 0.01).

Effect of investigator experience on percutaneous transluminal coronary angioplasty.

The NHLBI PTCA Registry collected clinical data on 3,101 PTCA procedures performed at 105 clinical centers between September 1977 and September 1981. To investigate the "learning curve" from introduction through the early application of this new therapy for revascularization, success rates and complication rates were examined by calendar year and according to investigator experience. Success rates improved by calendar year, from 54% in 1979 to 66% in 1981. Investigators with fewer than 50 cases had a success rate of 55%. After an investigator had performed 150 procedures, the success rate was 77%. The increase in success rate was largely the result of a dramatic increase in the ability to cross the narrowing with the catheter, and was accounted for by experience and improved equipment. Patient selection for PTCA was characterized by sex, age, previous CABG, number of diseased coronary arteries and stable Canadian Heart classification over time. Reflecting the increase in the success rate was the decrease in the need to perform elective CABG. Emergency CABG, death and MI rates were low (1% mortality, 5% nonfatal MI) and did not change significantly with time or with investigator experience.