Matrix metalloproteinase inhibition lowers mortality and brain injury in experimental pneumococcal meningitis

Pneumococcal meningitis (PM) results in high mortality rates and long-lasting neurological deficits. Hippocampal apoptosis and cortical necrosis are histopathological correlates of neurofunctional sequelae in rodent models and are frequently observed in autopsy studies of patients who die of PM. In experimental PM, inhibition of matrix metalloproteinases (MMPs) and/or tumor necrosis factor (TNF)-converting enzyme (TACE) has been shown to reduce brain injury and the associated impairment of neurocognitive function. However, none of the compounds evaluated in these studies entered clinical development. Here, we evaluated two second-generation MMP and TACE inhibitors with higher selectivity and improved oral availability. Ro 32-3555 (Trocade, cipemastat) preferentially inhibits collagenases (MMP-1, -8, and -13) and gelatinase B (MMP-9), while Ro 32-7315 is an efficient inhibitor of TACE. PM was induced in infant rats by the intracisternal injection of live Streptococcus pneumoniae. Ro 32-3555 and Ro 32-7315 were injected intraperitoneally, starting at 3 h postinfection. Antibiotic (ceftriaxone) therapy was initiated at 18 h postinfection, and clinical parameters (weight, clinical score, mortality rate) were recorded. Myeloperoxidase activities, concentrations of cytokines and chemokines, concentrations of MMP-2 and MMP-9, and collagen concentrations were measured in the cerebrospinal fluid. Animals were sacrificed at 42 h postinfection, and their brains were assessed by histomorphometry for hippocampal apoptosis and cortical necrosis. Both compounds, while exhibiting disparate MMP and TACE inhibitory profiles, decreased hippocampal apoptosis and cortical injury. Ro 32-3555 reduced mortality rates and cerebrospinal fluid TNF, interleukin-1β (IL-1β) and collagen levels, while Ro 32-7315 reduced weight loss and cerebrospinal fluid TNF and IL-6 levels.

Electrolyte disorders and in-hospital mortality during prolonged heat periods: a cross-sectional analysis

BACKGROUND Heat periods during recent years were associated with excess hospitalization and mortality rates, especially in the elderly. We intended to study whether prolonged warmth/heat periods are associated with an increased prevalence of disorders of serum sodium and potassium and an increased hospital mortality. METHODS In this cross-sectional analysis all patients admitted to the Department of Emergency Medicine of a large tertiary care facility between January 2009 and December 2010 with measurements of serum sodium were included. Demographic data along with detailed data on diuretic medication, length of hospital stay and hospital mortality were obtained for all patients. Data on daily temperatures (maximum, mean, minimum) and humidity were retrieved by Meteo Swiss. RESULTS A total of 22.239 patients were included in the study. 5 periods with a temperature exceeding 25 °C for 3 to 5 days were noticed and 2 periods with temperatures exceeding 25 °C for more than 5 days were noted. Additionally, 2 periods with 3 to 5 days with daily temperatures exceeding 30 °C were noted during the study period. We found a significantly increased prevalence of hyponatremia during heat periods. However, in the Cox regression analysis, prolonged heat was not associated with the prevalence of disorders of serum sodium or potassium. Admission during a heat period was an independent predictor for hospital mortality. CONCLUSIONS Although we found an increased prevalence of hyponatremia during heat periods, no convincing connection could be found for hypernatremia or disorders of serum potassium.

Mortality in patients with HIV-1 infection starting antiretroviral therapy in South Africa, Europe, or North America: a collaborative analysis of prospective studies.

BACKGROUND High early mortality in patients with HIV-1 starting antiretroviral therapy (ART) in sub-Saharan Africa, compared to Europe and North America, is well documented. Longer-term comparisons between settings have been limited by poor ascertainment of mortality in high burden African settings. This study aimed to compare mortality up to four years on ART between South Africa, Europe, and North America. METHODS AND FINDINGS Data from four South African cohorts in which patients lost to follow-up (LTF) could be linked to the national population register to determine vital status were combined with data from Europe and North America. Cumulative mortality, crude and adjusted (for characteristics at ART initiation) mortality rate ratios (relative to South Africa), and predicted mortality rates were described by region at 0-3, 3-6, 6-12, 12-24, and 24-48 months on ART for the period 2001-2010. Of the adults included (30,467 [South Africa], 29,727 [Europe], and 7,160 [North America]), 20,306 (67%), 9,961 (34%), and 824 (12%) were women. Patients began treatment with markedly more advanced disease in South Africa (median CD4 count 102, 213, and 172 cells/µl in South Africa, Europe, and North America, respectively). High early mortality after starting ART in South Africa occurred mainly in patients starting ART with CD4 count <50 cells/µl. Cumulative mortality at 4 years was 16.6%, 4.7%, and 15.3% in South Africa, Europe, and North America, respectively. Mortality was initially much lower in Europe and North America than South Africa, but the differences were reduced or reversed (North America) at longer durations on ART (adjusted rate ratios 0.46, 95% CI 0.37-0.58, and 1.62, 95% CI 1.27-2.05 between 24 and 48 months on ART comparing Europe and North America to South Africa). While bias due to under-ascertainment of mortality was minimised through death registry linkage, residual bias could still be present due to differing approaches to and frequency of linkage. CONCLUSIONS After accounting for under-ascertainment of mortality, with increasing duration on ART, the mortality rate on HIV treatment in South Africa declines to levels comparable to or below those described in participating North American cohorts, while substantially narrowing the differential with the European cohorts. Please see later in the article for the Editors' Summary.

High Hepatic and Extrahepatic Mortality and Low Treatment Uptake in HCV-coinfected Persons in the Swiss HIV Cohort Study between 2001 and 2013

BACKGROUND & AIMS The landscape of HCV treatments is changing dramatically. At the beginning of this new era, we highlight the challenges for HCV-therapy by assessing the long-term epidemiological trends in treatment uptake, efficacy and mortality among HIV/HCV-coinfected people since the availability of HCV therapy. METHODS We included all SHCS participants with detectable HCV RNA between 2001 and 2013. To identify predictors for treatment uptake uni- and multivariable Poisson regression models were applied. We further used survival analyses with Kaplan-Meier curves and Cox regression with drop-out as competing risk. RESULTS Of 12,401 participants 2107 (17%) were HCV RNA positive. Of those, 636 (30%) started treatment with an incidence of 5.8/100 person years (PY) (95% CI 5.3-6.2). Sustained virological response (SVR) with pegylated interferon/ribavirin was achieved in 50% of treated patients, representing 15% of all participants with replicating HCV infection. 344 of 2107 (16%) HCV RNA positive persons died, 59% from extrahepatic causes. Mortality/100 PY was 2.9 (95% CI 2.6-3.2) in untreated patients, 1.3 (1.0-1.8) in those treated with failure, and 0.6 (0.4-1.0) in patients with SVR. In 2013, 869/2107 (41%) participants remained HCV RNA positive. CONCLUSIONS Over the last 13 years HCV treatment uptake was low and by the end of 2013, a large number of persons remain to be treated. Mortality was high, particularly in untreated patients, and mainly due to non-liver related causes. Accordingly, in HIV/HCV-coinfected patients, integrative care including the diagnosis and therapy of somatic and psychiatric disorders is important to achieve mortality rates similar to HIV-monoinfected patients.

Time trends in avoidable cancer mortality in Switzerland and neighbouring European countries 1996-2010.

QUESTION UNDER STUDY What are the trends in avoidable cancer mortality in Switzerland and neighbouring countries? METHODS Mortality data and population estimates 1996-2010 were obtained from the Swiss Federal Statistical Office for Switzerland and the World Health Organization Mortality Database (http://www.who.int/healthinfo/mortality_data/en/) for Austria, Germany, France and Italy. Age standardised mortality rates (ASMRs, European standard) per 100 000 person-years were calculated for the population <75 years old by sex for the following groups of cancer deaths: (1) avoidable through primary prevention; (2) avoidable through early detection and treatment; (3) avoidable through improved treatment and medical care; and (4) remaining cancer deaths. To assess time trends in ASMRs, estimated annual percentage changes (EAPCs) with 95% confidence intervals (95% CIs) were calculated. RESULTS In Switzerland and neighbouring countries cancer mortality in persons <75 years old continuously decreased 1996-2010. Avoidable cancer mortality decreased in all groups of avoidable cancer deaths in both sexes, with one exception. ASMRs for causes avoidable through primary prevention increased in females in all countries (in Switzerland from 16.2 to 20.3 per 100 000 person years, EAPC 2.0 [95% CI 1.4 to 2.6]). Compared with its neighbouring countries, Switzerland showed the lowest rates for all groups of avoidable cancer mortality in males 2008-2010. CONCLUSION Overall avoidable cancer mortality decreased, indicating achievements in cancer care and related health policies. However, increasing trends in avoidable cancer mortality through primary prevention for females suggest there is a need in Switzerland and its European neighbouring countries to improve primary prevention.

Causes of late mortality with dual antiplatelet therapy after coronary stents.

AIMS In the dual antiplatelet therapy (DAPT) study, continued thienopyridine beyond 12 months after drug-eluting stent placement was associated with increased mortality compared with placebo. We sought to evaluate factors related to mortality in randomized patients receiving either drug-eluting or bare metal stents in the DAPT study. METHODS AND RESULTS Patients were enrolled after coronary stenting, given thienopyridine and aspirin for 12 months, randomly assigned to continued thienopyridine or placebo for an additional 18 months (while taking aspirin), and subsequently treated with aspirin alone for another 3 months. A blinded independent adjudication committee evaluated deaths. Among 11 648 randomized patients, rates of all-cause mortality rates were 1.9 vs. 1.5% (continued thienopyridine vs. placebo, P = 0.07), cardiovascular mortality, 1.0 vs. 1.0% (P = 0.97), and non-cardiovascular mortality, 0.9 vs. 0.5% (P = 0.01) over the randomized period (Months 12-30). Rates of fatal bleeding were 0.2 vs. 0.1% (P = 0.81), and deaths related to any prior bleeding were 0.3 vs. 0.2% (P = 0.36), Months 12-33). Cancer incidence did not differ (2.0 vs. 1.6%, P = 0.12). Cancer-related deaths occurred in 0.6 vs. 0.3% (P = 0.02) and were rarely related to bleeding (0.1 vs. 0, P = 0.25). After excluding those occurring in patients with cancer diagnosed before enrolment, rates were 0.4 vs. 0.3% (P = 0.16). CONCLUSION Bleeding accounted for a minority of deaths among patients treated with continued thienopyridine. Cancer-related death in association with thienopyridine therapy was mainly not related to bleeding and may be a chance finding. Caution is warranted when considering extended thienopyridine in patients with advanced cancer. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00977938.

Firearm legislation and firearm mortality in the USA: a cross-sectional, state-level study.

BACKGROUND In an effort to reduce firearm mortality rates in the USA, US states have enacted a range of firearm laws to either strengthen or deregulate the existing main federal gun control law, the Brady Law. We set out to determine the independent association of different firearm laws with overall firearm mortality, homicide firearm mortality, and suicide firearm mortality across all US states. We also projected the potential reduction of firearm mortality if the three most strongly associated firearm laws were enacted at the federal level. METHODS We constructed a cross-sectional, state-level dataset from Nov 1, 2014, to May 15, 2015, using counts of firearm-related deaths in each US state for the years 2008-10 (stratified by intent [homicide and suicide]) from the US Centers for Disease Control and Prevention's Web-based Injury Statistics Query and Reporting System, data about 25 firearm state laws implemented in 2009, and state-specific characteristics such as firearm ownership for 2013, firearm export rates, and non-firearm homicide rates for 2009, and unemployment rates for 2010. Our primary outcome measure was overall firearm-related mortality per 100 000 people in the USA in 2010. We used Poisson regression with robust variances to derive incidence rate ratios (IRRs) and 95% CIs. FINDINGS 31 672 firearm-related deaths occurred in 2010 in the USA (10·1 per 100 000 people; mean state-specific count 631·5 [SD 629·1]). Of 25 firearm laws, nine were associated with reduced firearm mortality, nine were associated with increased firearm mortality, and seven had an inconclusive association. After adjustment for relevant covariates, the three state laws most strongly associated with reduced overall firearm mortality were universal background checks for firearm purchase (multivariable IRR 0·39 [95% CI 0·23-0·67]; p=0·001), ammunition background checks (0·18 [0·09-0·36]; p<0·0001), and identification requirement for firearms (0·16 [0·09-0·29]; p<0·0001). Projected federal-level implementation of universal background checks for firearm purchase could reduce national firearm mortality from 10·35 to 4·46 deaths per 100 000 people, background checks for ammunition purchase could reduce it to 1·99 per 100 000, and firearm identification to 1·81 per 100 000. INTERPRETATION Very few of the existing state-specific firearm laws are associated with reduced firearm mortality, and this evidence underscores the importance of focusing on relevant and effective firearms legislation. Implementation of universal background checks for the purchase of firearms or ammunition, and firearm identification nationally could substantially reduce firearm mortality in the USA. FUNDING None.

Hematopoietic stem cell transplantation in Switzerland: a comprehensive quality control report on centre effect

QUESTIONS UNDER STUDY / PRINCIPLES: Interest groups advocate centre-specific outcome data as a useful tool for patients in choosing a hospital for their treatment and for decision-making by politicians and the insurance industry. Haematopoietic stem cell transplantation (HSCT) requires significant infrastructure and represents a cost-intensive procedure. It therefore qualifies as a prime target for such a policy. METHODS: We made use of the comprehensive database of the Swiss Blood Stem Cells Transplant Group (SBST) to evaluate potential use of mortality rates. Nine institutions reported a total of 4717 HSCT - 1427 allogeneic (30.3%), 3290 autologous (69.7%) - in 3808 patients between the years 1997 and 2008. Data were analysed for survival- and transplantation-related mortality (TRM) at day 100 and at 5 years. RESULTS: The data showed marked and significant differences between centres in unadjusted analyses. These differences were absent or marginal when the results were adjusted for disease, year of transplant and the EBMT risk score (a score incorporating patient age, disease stage, time interval between diagnosis and transplantation, and, for allogeneic transplants, donor type and donor-recipient gender combination) in a multivariable analysis. CONCLUSIONS: These data indicate comparable quality among centres in Switzerland. They show that comparison of crude centre-specific outcome data without adjustment for the patient mix may be misleading. Mandatory data collection and systematic review of all cases within a comprehensive quality management system might, in contrast, serve as a model to ascertain the quality of other cost-intensive therapies in Switzerland.

Age at hip or knee joint replacement surgery predicts likelihood of revision surgery

We compared revision and mortality rates of 4668 patients undergoing primary total hip and knee replacement between 1989 and 2007 at a University Hospital in New Zealand. The mean age at the time of surgery was 69 years (16 to 100). A total of 1175 patients (25%) had died at follow-up at a mean of ten years post-operatively. The mean age of those who died within ten years of surgery was 74.4 years (29 to 97) at time of surgery. No change in comorbidity score or age of the patients receiving joint replacement was noted during the study period. No association of revision or death could be proven with higher comorbidity scoring, grade of surgeon, or patient gender. We found that patients younger than 50 years at the time of surgery have a greater chance of requiring a revision than of dying, those around 58 years of age have a 50:50 chance of needing a revision, and in those older than 62 years the prosthesis will normally outlast the patient. Patients over 77 years old have a greater than 90% chance of dying than requiring a revision whereas those around 47 years are on average twice as likely to require a revision than die. This information can be used to rationalise the need for long-term surveillance and during the informed consent process.

Antenatal corticosteroids for fetal lung maturation in threatened preterm delivery: indications and administration

Antenatal maternal administration of corticosteroids has been shown to reduce morbidity and mortality rates in preterm delivery. Threatened spontaneous or medically indicated preterm delivery for maternal or fetal indications between 24 and 34 weeks of gestation with unknown fetal lung maturity status are indications for antenatal corticosteroid administration. Recent studies have challenged current practice of antenatal glucocorticoid use. The goal of this expert letter is to provide recommendations based for the clinical use of antenatal glucocorticoids based on the current evidence from published studies.

Meta-analysis of selective serotonin reuptake inhibitors in patients with depression and coronary heart disease

The occurrence of depression in patients with coronary heart disease (CHD) substantially increases the likelihood of a poorer cardiovascular prognosis. Although antidepressants are generally effective in decreasing depression, their use in patients with CHD is controversial. We carried out a meta-analysis to evaluate the health effects of selective serotonin reuptake inhibitors (SSRIs) versus placebo or no antidepressants in patients with CHD and depression. Observational studies and randomized controlled trials (RCTs) were searched in MEDLINE, EMBASE, PsycINFO, Cochrane Controlled Clinical Trial Register and other trial registries, and references of relevant articles. Primary outcomes were readmission for CHD (including myocardial infarction, unstable angina, and stroke) and all-cause mortality; the secondary outcome was severity of depression symptoms. Seven articles on 6 RCTs involving 2,461 participants were included. One study incorrectly randomized participants, and another was a reanalysis of RCT data. These were considered observational and analyzed separately. When only properly randomized trials were considered (n = 734 patients), patients on SSRIs showed no significant differences in mortality (risk ratio 0.39, 95% confidence interval 0.08 to 2.01) or CHD readmission rates (0.74, 0.44 to 1.23) compared to controls. Conversely, when all studies were included, SSRI use was associated with a significant decrease in CHD readmission (0.63, 0.46 to 0.86) and mortality rates (0.56, 0.35 to 0.88). A significantly greater improvement in depression symptoms was always apparent in patients on SSRIs with all selected indicators. In conclusion, in patients with CHD and depression, SSRI medication decreases depression symptoms and may improve CHD prognosis.

Treatment algorithm for moderate to severe ulcerative colitis

The care for a patient with ulcerative colitis (UC) remains challenging despite the fact that morbidity and mortality rates have been considerably reduced during the last 30 years. The traditional management with intravenous corticosteroids was modified by the introduction of ciclosporin and infliximab. In this review, we focus on the treatment of patients with moderate to severe UC. Four typical clinical scenarios are defined and discussed in detail. The treatment recommendations are based on current literature, published guidelines and reviews, and were discussed at a consensus meeting of Swiss experts in the field. Comprehensive treatment algorithms were developed, aimed for daily clinical practice.

[Oesophageal and fundic variceal bleeding]

Oesophageal and fundic varices belong to the most frequent complications of cirrhosis and portal hypertension. Due to their significant morbidity and mortality, bleedings from oesophageal or fundic varices represent a challenge for the emergency medical team as well as for the gastroenterologist. The patient with a variceal bleeding should be accurately monitored and his/her hemodynamic parameters should be maintained stable with the administration of plasma expanders and blood units when indicated. An antibiotic prophylaxis in this setting--norfloxacin or ceftriaxon--has been demonstrated to significantly reduce morbidity and mortality. Additionally, the early administration of vasoactive compounds, such as terlipressin, somatostatin or octreotide, is associated with beneficial effects in reducing the bleeding. An upper gastrointestinal endoscopy should be generally performed within the first twelve hours from the beginning of the bleeding in order to obtain an accurate diagnosis and to provide an adequate treatment. Endoscopic procedures to control the bleeding include the rubber band ligation, the treatment of the varix with a sclerosing agent or the injection of tissue glue into the varix. In case of recurrent bleeding, beyond the above methods, different techniques, such as the transjugular porto-caval shunt, surgical shunt procedures, as well as embolisation of splanchnic blood vessels, represent additional therapeutic options. However, they are associated with very high mortality rates and their indication has to be discussed case by case by an interdisciplinary team of experts. Future therapies include the optimisation and the improvement of the current medical and endoscopic armamentarium, as well as the application of treatments to novel targets, such as the coagulation cascade.

Leukaemia, brain tumours and exposure to extremely low frequency magnetic fields: cohort study of Swiss railway employees

AIMS: To investigate the relationship between extremely low frequency magnetic field (ELF-MF) exposure and mortality from leukaemia and brain tumour in a cohort of Swiss railway workers. METHODS: 20,141 Swiss railway employees with 464,129 person-years of follow-up between 1972 and 2002 were studied. Mortality rates for leukaemia and brain tumour of highly exposed train drivers (21 muT average annual exposure) were compared with medium and low exposed occupational groups (i.e. station masters with an average exposure of 1 muT). In addition, individual cumulative exposure was calculated from on-site measurements and modelling of past exposures. RESULTS: The hazard ratio (HR) for leukaemia mortality of train drivers was 1.43 (95% CI 0.74 to 2.77) compared with station masters. For myeloid leukaemia the HR of train drivers was 4.74 (95% CI 1.04 to 21.60) and for Hodgkin's disease 3.29 (95% CI 0.69 to 15.63). Lymphoid leukaemia, non-Hodgkin's disease and brain tumour mortality were not associated with magnetic field exposure. Concordant results were obtained from analyses based on individual cumulative exposure. CONCLUSIONS: Some evidence of an exposure-response association was found for myeloid leukaemia and Hodgkin's disease, but not for other haematopoietic and lymphatic malignancies and brain tumours.

Matched-pair analysis of endovascular versus open surgical repair of abdominal aortic aneurysms in young patients at low risk

PURPOSE: To compare clinical outcomes of endovascular and open aortic repair of abdominal aortic aneurysms (AAAs) in young patients at low risk. It was hypothesized that endovascular aneurysm repair (EVAR) compares favorably with open aneurysm repair (OAR) in these patients. MATERIALS AND METHODS: Twenty-five patients aged 65 years or younger with a low perioperative surgical risk profile underwent EVAR at a single institution between April 1994 and May 2007 (23 men; mean age, 62 years+/-2.8). A sex- and risk-matched control group of 25 consecutive patients aged 65 years or younger who underwent OAR was used as a control group (23 men; mean age, 59 years+/-3.9). Patient outcomes and complications were classified according to Society of Vascular Surgery/International Society for Cardiovascular Surgery reporting standards. RESULTS: Mean follow-up times were 7.1 years+/-3.2 after EVAR and 5.9 years+/-1.8 after OAR (P=.1020). Total complication rates were 20% after EVAR and 52% after OAR (P=.0378), and all complications were mild or moderate. Mean intensive care unit times were 0.2 days+/-0.4 after EVAR and 1.1 days+/-0.4 after OAR (P<.0001) and mean lengths of hospital stay were 2.3 days+/-1.0 after EVAR and 5.0 days+/-2.1 after OAR (P<.0001). Cumulative rates of long-term patient survival did not differ between EVAR and OAR (P=.144). No AAA-related deaths or aortoiliac ruptures occurred during follow-up for EVAR and OAR. In addition, no surgical conversions were necessary in EVAR recipients. Cumulative rates of freedom from secondary procedures were not significantly different between the EVAR and OAR groups (P=.418). Within a multivariable Cox proportional-hazards analysis adjusted for patient age, maximum AAA diameter, and cardiac risk score, all-cause mortality rates (odds ratio [OR], 0.125; 95% CI, 0.010-1.493; P=.100) and need for secondary procedures (OR, 5.014; 95% CI, 0.325-77.410; P=.537) were not different between EVAR and OAR. CONCLUSIONS: Results from this observational study indicate that EVAR offers a favorable alternative to OAR in young patients at low risk.