Pathways from assaultive violence to post-traumatic stress, depression, and generalized anxiety symptoms through stressful life events: longitudinal mediation models.

BACKGROUND: Assaultive violence events are associated with increased risk for adverse psychiatric outcomes, including post-traumatic stress (PTS), depression, and generalized anxiety. Prior research has indicated that economic, legal, and social stressors that could follow assaultive events may explain the increased risk for adverse psychiatric outcomes, yet longitudinal studies have not adequately examined this pathway. In the current study, we aimed to address this limitation. METHODS: Participants (N = 1360) were part of a longitudinal population-based study of adults living in Detroit. At three waves, participants indicated their exposure to assaultive violence and economic, legal, and social stressors, and completed inventories of PTS, depression, and generalized anxiety. Longitudinal mediation models were used to test the hypothesized pathway from assaultive violence to each psychiatric outcome. RESULTS: The hypothesized models evidenced good fit with the data and, in each, the paths from Wave 1 (W1) assaultive violence to W2 stressors, and from W2 stressors to W3 symptoms were significant (range of Standardized Estimates: 0.09-0.15, all p < 0.01). Additionally, the indirect paths from W1 assaultive violence to W3 symptoms were significant (range of Standardized Estimates: 0.01-0.02, all p < 0.05). CONCLUSIONS: The findings illustrate that the economic, legal, and social stressors that could follow assaultive violence increase risk for a range of psychiatric symptoms. Although future research is needed, the results suggest that investment in interventions that prevent and mitigate assaultive violence survivors' exposure to such stressors may be an effective way to prevent mental illness in the aftermath of violent assaults.

Twin pregnancies complicated by gestational diabetes mellitus: a single centre cohort study.

AIMS: In women with a twin pregnancy, to determine the incidence of, risk factors for and outcomes of women with gestational diabetes mellitus, and assess how these have changed with a change in gestational diabetes screening. METHODS: Retrospective cohort study of women with a twin pregnancy attending an Australian tertiary hospital, 2002-2013. Information on gestational diabetes status, gestational diabetes risk factors and pregnancy outcomes was ascertained. Pregnancy outcomes included hypertensive disorders, twin birthweight centile and a composite adverse pregnancy outcome. Analysis was stratified pre/post screening protocol change (epoch 1: 2002-2009, epoch 2: 2010-2013) and by gestational diabetes status. RESULTS: Gestational diabetes was diagnosed in 86/982 (8.8%) women, increasing from 4.4% to 14.7% between epochs (P = 0.0001). The proportion of women with hypertensive disorders increased (11.7% vs. 13.4%, P = 0.009), but the proportion of infant's birthweight > 90th centile decreased (11.0% vs. 7.6%, P = 0.02) between epochs. Overall, 33.6% of women had ≥ 1 risk factors for gestational diabetes. Three-quarters (73.7%) of women overall had an adverse pregnancy outcome, with a slightly higher proportion in women with gestational diabetes compared with those with no gestational diabetes (79.7% vs. 73.1%, P = 0.06). The rate of the adverse pregnancy outcome did not change by epoch, after adjusting for maternal and pregnancy risk factors (adjusted odds ratio = 0.96, 95% confidence interval 0.73-1.26). CONCLUSIONS: Almost 1 in 10 women with a twin pregnancy were diagnosed with gestational diabetes, with the incidence of gestational diabetes increasing threefold with a new screening protocol. The pregnancy outcomes of women with a twin pregnancy did not change with increased detection and treatment for gestational diabetes.

Cutaneous pseudovasculitis, antiphospholipid syndrome and obstetric misadventure.

We present two women with severe obstetric complications from antiphospholipid (aPL) syndrome associated with a rare dermatological manifestation, cutaneous pseudovasculitis. Both of these women developed a rash on the palmar aspect of the hands during the post partum period, with histology consistent with microthrombotic disease, despite anticoagulation. Cutaneous pseudovasculitis appears to be a maternal manifestation of aPL coagulopathy, possibly reflecting the severity of the underlying pregnancy pathology.

Report on Hyperbaric Oxygen Therapy: An Overlooked Therapeutic Option in Stroke Recovery and a Potential Source of Health Sector Revenue and Health Tourism.

This is a special case report on Jamaica's first use of hyperbaric oxygen therapy (HBOT) in stroke recovery, presented at the 56th Annual Conference of the Association of Surgeons in Jamaica, Kingston, Jamaica. The literature and story behind the trial ‒ covering case history, diagnosis and discussion of outcome ‒ technical issues, costing, insurance and possibilities for income earning and health tourism are explored.

Acquired epidermodysplasia verruciformis due to multiple and unusual HPV infection among vertically-infected, HIV-positive adolescents in Zimbabwe.

BACKGROUND: We have previously described the presentation of epidermodysplasia verruciformis (EV)-like eruptions in almost a quarter of hospitalized adolescents with vertically-acquired human immunodeficiency virus (HIV) infection in Harare, Zimbabwe, a region with a high prevalence of HIV infection. METHODS: We performed a clinical case note review and skin biopsy from affected sites in 4 HIV-infected adolescents with EV-like lesions in Harare. Biopsies were processed for histology and for human papillomavirus (HPV) typing. RESULTS: All patients had long-standing skin lesions that pre-dated the diagnosis of HIV by several years. The histology of skin biopsies from all patients was consistent with EV. In each biopsy, EV-associated ß-HPV type 5 was identified (additionally, type 19 was found in 1 biopsy). Cutaneous wart-associated HPV types 1 and 2 were detected in all biopsies, together with genital lesion-associated HPV types 6, 16, and 52, (as well as ≥3 other genital lesion-associated HPV types). Despite immune reconstitution with combination antiretroviral therapy (cART), there was no improvement in EV-like lesions in any patient. CONCLUSIONS: EV is a disfiguring and potentially stigmatizing condition among this patient group and is difficult to treat; cART appears to have no impact on the progression of skin disease. Among adolescents with longstanding HIV-induced immunosuppression and with high levels of sun exposure, close dermatological surveillance for potential skin malignancy is required.

Improving the performance of power plant cooling ponds.

A study was conducted on the effectiveness of using vertical baffles to improve the thermal performance of power plant cooling ponds. A small scale physical model of a rectangular cooling pond was used. A base case was established using traditional horizontal baffles to create a serpentine flow pattern through the pond. The horizontal baffles were then replaced by a series of underflow weirs that spanned the pond. An improvement in cooling of over 30% was realized.

Report and viewpoint on the Vaccine Safety Conference, Tryall Club, Jamaica, January 3-7, 2011: cautionary tales and implications for the Caribbean.

This paper represents information obtained from a recent conference on vaccination safety and policy: Vaccine Safety: Evaluating the Science Conference, Tryall Club, Jamaica, January 3-7, 2011 and the author's viewpoint on the same. The first section represents a synopsis of recorded information and the second the author's view of Caribbean concerns related to the recorded information.

Do social support and community engagement act as mechanisms in the association between neighbourhood income inequality and the mental health of mothers in Calgary, Canada? A mediation analysis.

PURPOSE: According to the social determinants of health framework, income inequality is a potential risk factor for adverse mental health. However, few studies have explored the mechanisms suspected to mediate this relationship. The current study addresses this gap through a mediation analysis to determine if social support and community engagement act as mediators linking neighbourhood income inequality to maternal anxiety and depressive symptoms within a cohort of new mothers living in the City of Calgary, Canada. METHODS: Data collected at three years postpartum from mothers belonging to the All Our Families (AOF) cohort were used in the current study. Maternal data were collected between 2012 and 2015 and linked to neighbourhood socioeconomic data from the 2006 Canadian Census. Income inequality was measured using Gini coefficients derived from 2006 after-tax census data. Generalized structural equation models were used to quantify the associations between income inequality and mental health symptoms, and to assess the potential direct and indirect mediating effects of maternal social support and community engagement. RESULTS: Income inequality was not significantly associated with higher depressive symptoms (ß = 0.32, 95%CI = -0.067, 0.70), anxiety symptoms (ß = 0.11, 95%CI = -0.39, 0.60), or lower social support. Income inequality was not associated with community engagement. For the depression models, higher social support was significantly associated with lower depressive symptoms (ß = -0.13, 95%CI = -0.15, -0.097), while community engagement was not significantly associated with depressive symptoms (ß = 0.059, 95%CI = -0.15, 0.27). Similarly, for the anxiety models, lower anxiety symptoms were significantly associated with higher levels of social support (ß = -0.17, 95%CI = -0.20, -0.13) but not with higher levels of community engagement (ß = 0.14, 95%CI = -0.14, 0.41). CONCLUSION: The current study did not find clear evidence for social support or community engagement mediating the relationship between neighbourhood income inequality and maternal mental health. Future investigations should employ a broader longitudinal approach to capture changes in income inequality, potential mediators, and mental health symptomatology over time.

Preparedness, Hurricanes Irma and Maria, and Impact on Health in Puerto Rico.

OBJECTIVES: Only few studies evaluated whether hurricane preparedness impacts health. The PREPARE study addresses this gap. METHODS: We recruited participants who had pertinent pre-hurricane data from the San Juan Overweight Adults Longitudinal Study (SOALS: n=364) and 125 patients with diabetes from Federally Qualified Health Center (COSSMA) in Puerto Rico. Participants aged 42-75 years completed interviews 20-34 months after Hurricanes Irma and Maria. We evaluated associations between self-reported hurricane preparedness and health and other related associations using logistic regression controlling for age, location, education and interview date. RESULTS: Only 41% of participants reported high pre-hurricane preparedness; 25% reported gaps (moderate/low availability) in information and 48% reported gaps in resources for hurricane preparedness. Participants reporting lower pre-hurricane preparedness had higher reported hurricane-related detrimental health impact (OR=1.96; 95% CI: 1.31, 2.95) and higher odds (OR=2.07; 95% CI: 0.92, 4.68) of developing new non-communicable disease (NCD) compared to others. Post-hurricane drinking water disruption for ≥ 3 months versus none or less (OR=2.76; 95% CI: 1.39, 5.47) and similarly diet changes due to cooking/refrigeration access (OR=1.96; 95% CI: 1.24, 3.07), and diet changes for ≥ 20 months due to finances/access to shops (OR=2.83; 95% CI: 1.85, 4.32) were also associated with detrimental health impact. CONCLUSION: Lower preparedness was associated with higher detrimental impact of the hurricanes on overall health, and marginally significant impact on NCD. Future preparedness efforts could especially target means of coping with disruption of water services and regular diet, as these were also associated with detrimental health impact.

Genetic analysis of chemoresistance in primary murine lymphomas.

Understanding the basis of chemoresistance is a principal goal of molecular oncology. We have exploited a murine lymphoma model and retroviral gene transfer to rapidly generate a series of spontaneous tumors differing only in a gene of interest, and subsequently studied the impact of the test gene on the treatment sensitivity of tumors at their natural site. We demonstrate that the Bcl-2 oncoprotein produces multi-drug resistance when assessed in primary lymphomas in vivo. In contrast, this effect was dramatically reduced when the primary lymphomas were subjected to long-term culture, and completely missed in the standard clonogenic survival assay. This model highlights the importance of physiological test systems to address the complexity of clinical drug resistance and provides a novel strategy to evaluate compounds targeting specific genetic lesions.

Donanemab (LY3002813) Phase 1b Study in Alzheimer's Disease: Rapid and Sustained Reduction of Brain Amyloid Measured by Florbetapir F18 Imaging.

BACKGROUND: Donanemab (LY3002813) is an IgG1 antibody directed at an N­terminal pyroglutamate of amyloid beta epitope that is present only in brain amyloid plaques. OBJECTIVES: To assess effects of donanemab on brain amyloid plaque load after single and multiple intravenous doses, as well as pharmacokinetics, safety/tolerability, and immunogenicity. DESIGN: Phase 1b, investigator- and patient-blind, randomized, placebo-controlled study. SETTING: Patients recruited at clinical research sites in the United States and Japan. PARTICIPANTS: 61 amyloid plaque-positive patients with mild cognitive impairment due to Alzheimer's disease and mild-to-moderate Alzheimer's disease dementia. INTERVENTION: Six cohorts were dosed with donanemab: single dose 10-, 20- or 40- mg/kg (N = 18), multiple doses of 10-mg/kg every 2 weeks for 24 weeks (N = 10), and 10- or 20-mg/kg every 4 weeks for 72 weeks (N=18) or placebo (N = 15). MEASUREMENTS: Brain amyloid plaque load, using florbetapir positron emission tomography, was assessed up to 72 weeks. Safety was evaluated by occurrence of adverse events, magnetic resonance imaging, electrocardiogram, vital signs, laboratory testing, neurological monitoring, and immunogenicity. RESULTS: Treatment with donanemab resulted in rapid reduction of amyloid, even after a single dose. By 24 weeks, amyloid positron emission tomography mean changes from baseline for single donanemab doses in Centiloids were: -16.5 (standard error 11.22) 10-mg/kg intravenous; 40.0 (standard error 11.23) 20 mg/kg intravenous; and -49.6 (standard error 15.10) 40-mg/kg intravenous. Mean reduction of amyloid plaque in multiple dose cohorts by 24 weeks in Centiloids were: 55.8 (standard error 9.51) 10-mg/kg every 2 weeks; -50.2 (standard error 10.54) 10-mg/kg every 4 weeks; and -58.4 (standard error 9.66) 20-mg/kg every 4 weeks. Amyloid on average remained below baseline levels up to 72 weeks after a single dose of donanemab. Repeated dosing resulted in continued florbetapir positron emission tomography reductions over time compared to single dosing with 6 out of 28 patients attaining complete amyloid clearance within 24 weeks. Within these, 5 out of 10 patients in the 20 mg/kg every 4 weeks cohort attained complete amyloid clearance within 36 weeks. When dosing with donanemab was stopped after 24 weeks of repeat dosing in the 10 mg every 2 weeks cohort, florbetapir positron emission tomography reductions were sustained up to 72 weeks. For the single dose cohorts on day 1, dose proportional increases in donanemab pharmacokinetics were observed from 10 to 40 mg/kg. Dose proportional increases in pharmacokinetics were also observed at steady state with the multiple dose cohorts. Donanemab clearance was comparable across the dose levels. Mean donanemab elimination-half-life following 20 mg/kg single dose was 9.3 days with range of 5.6 to 16.2 days. Greater than 90% of patients had positive treatment-emergent antidrug antibodies with donanemab. However, overall, the treatment-emergent antidrug antibodies did not have a significant impact on pharmacokinetics. Donanemab was generally well tolerated. Amongst the 46 participants treated with donanemab, the following amyloid-related imaging abnormalities, common to the drug class, were observed: 12 vasogenic cerebral edema events (12 [19.7%] patients), 10 cerebral microhemorrhage events (6 [13.0%] patients), and 2 superficial siderosis events (2 [4.3%] patients). CONCLUSIONS: Single and multiple doses of donanemab demonstrated a rapid, robust, and sustained reduction up to 72 weeks in brain amyloid plaque despite treatment-emergent antidrug antibodies detected in most patients. Amyloid-related imaging abnormalities were the most common treatment-emergent event.

Convergent evolution of pain-inducing defensive venom components in spitting cobras.

Convergent evolution provides insights into the selective drivers underlying evolutionary change. Snake venoms, with a direct genetic basis and clearly defined functional phenotype, provide a model system for exploring the repeated evolution of adaptations. While snakes use venom primarily for predation, and venom composition often reflects diet specificity, three lineages of cobras have independently evolved the ability to spit venom at adversaries. Using gene, protein, and functional analyses, we show that the three spitting lineages possess venoms characterized by an up-regulation of phospholipase A2 (PLA2) toxins, which potentiate the action of preexisting venom cytotoxins to activate mammalian sensory neurons and cause enhanced pain. These repeated independent changes provide a fascinating example of convergent evolution across multiple phenotypic levels driven by selection for defense.

Staphylococcal enterotoxin A has two cooperative binding sites on major histocompatibility complex class II.

The superantigen staphylococcal enterotoxin A (SEA) binds to major histocompatibility complex (MHC) class II molecules at two sites on either side of the peptide groove. Two separate but cooperative interactions to the human class II molecule HLA-DR1 were detected. The first high affinity interaction to the DR1 beta chain is mediated by a zinc atom coordinated by H187, H225, and D227 in SEA and H81 in the polymorphic DR1 beta chain. The second low affinity site is to the DR1 alpha chain analogous to SEB binding and is mediated by residue F47 in SEA. Binding of one SEA to the DR1 beta chain enhances the binding of a second SEA molecule to the DR1 alpha chain. The zinc site is on the opposite side of the SEA molecule from residue F47 so that one SEA molecule can readily bind two class II molecules. Both binding sites on SEA are required for maximal activity. Thus, unlike, SEB, SEA requires two separate binding sites for optimal activity, which may allow it to stabilize SEA interaction with T cell receptors, as well as to activate the antigen-presenting cell by cross-linking MHC class II.

How effective are population health surveys for estimating prevalence of chronic conditions compared to anonymised clinical data?

INTRODUCTION: Population health surveys are used to record person-reported outcome measures for chronic health conditions and provide a useful source of data when evaluating potential disease burdens. The reliability of survey-based prevalence estimates for chronic diseases is unclear nonetheless. This study applied methodological triangulation via a data linkage method to validate prevalence of selected chronic conditions (angina, myocardial infarction, heart failure, and asthma). METHODS: Linked healthcare records were used for a combined cohort of 11,323 adults from the 2013 and 2014 sweeps of the Welsh Health Survey (WHS). The approach utilised consented survey data linked to primary and secondary care electronic health record (EHR) data back to 2002 within the Secure Anonymised Information Linkage (SAIL) Databank. RESULTS: This descriptive study demonstrates validation of survey and clinical data using data linkage for selected chronic cardiovascular conditions and asthma with varied success. The results indicate that identifying cases for separate cardiovascular conditions was limited without specific medication codes for each condition, but more straightforward for asthma, where there was an extensive list of medications available. For asthma there was better agreement between prevalence estimates based on survey and clinical data as a result. CONCLUSION: Whilst the results provide external validity for the WHS as an instrument for estimating the burden of chronic disease, they also indicate that a data linkage appproach can be used to produce comparable prevalence estimates using clinical data if a defined condition-specific set of clinical codes are available.

p53 status and the efficacy of cancer therapy in vivo.

The therapeutic responsiveness of genetically defined tumors expressing or devoid of the p53 tumor suppressor gene was compared in immunocompromised mice. Tumors expressing the p53 gene contained a high proportion of apoptotic cells and typically regressed after treatment with gamma radiation or adriamycin. In contrast, p53-deficient tumors treated with the same regimens continued to enlarge and contained few apoptotic cells. Acquired mutations in p53 were associated with both treatment resistance and relapse in p53-expressing tumors. These results establish that defects in apoptosis, here caused by the inactivation of p53, can produce treatment-resistant tumors and suggest that p53 status may be an important determinant of tumor response to therapy.

Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition.

The ability of p53 to promote apoptosis in response to mitogenic oncogenes appears to be critical for its tumor suppressor function. Caspase-9 and its cofactor Apaf-1 were found to be essential downstream components of p53 in Myc-induced apoptosis. Like p53 null cells, mouse embryo fibroblast cells deficient in Apaf-1 and caspase-9, and expressing c-Myc, were resistant to apoptotic stimuli that mimic conditions in developing tumors. Inactivation of Apaf-1 or caspase-9 substituted for p53 loss in promoting the oncogenic transformation of Myc-expressing cells. These results imply a role for Apaf-1 and caspase-9 in controlling tumor development.

Requirement of NF-kappaB activation to suppress p53-independent apoptosis induced by oncogenic Ras.

The ras proto-oncogene is frequently mutated in human tumors and functions to chronically stimulate signal transduction cascades resulting in the synthesis or activation of specific transcription factors, including Ets, c-Myc, c-Jun, and nuclear factor kappa B (NF-kappaB). These Ras-responsive transcription factors are required for transformation, but the mechanisms by which these proteins facilitate oncogenesis have not been fully established. Oncogenic Ras was shown to initiate a p53-independent apoptotic response that was suppressed through the activation of NF-kappaB. These results provide an explanation for the requirement of NF-kappaB for Ras-mediated oncogenesis and provide evidence that Ras-transformed cells are susceptible to apoptosis even if they do not express the p53 tumor-suppressor gene product.

FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis.

FADD (also known as Mort-1) is a signal transducer downstream of cell death receptor CD95 (also called Fas). CD95, tumor necrosis factor receptor type 1 (TNFR-1), and death receptor 3 (DR3) did not induce apoptosis in FADD-deficient embryonic fibroblasts, whereas DR4, oncogenes E1A and c-myc, and chemotherapeutic agent adriamycin did. Mice with a deletion in the FADD gene did not survive beyond day 11.5 of embryogenesis; these mice showed signs of cardiac failure and abdominal hemorrhage. Chimeric embryos showing a high contribution of FADD null mutant cells to the heart reproduce the phenotype of FADD-deficient mutants. Thus, not only death receptors, but also receptors that couple to developmental programs, may use FADD for signaling.

Chain of evidence in sexual assault cases.

Chain of evidence (COE) sampling is a legal concept demonstrating the journey of a sample from origin to court. Positive sexually transmitted infection (STI) results may have importance in criminal proceedings and require a demonstrated COE for them to be used as admissible evidence. A retrospective case-notes review of female sexual assault patients was carried out to review COE sampling in two clinics. Three hundred and eighteen patients underwent sexual health screening and COE sampling was indicated in 58 (18%). COE sampling was carried out in 44 (92%) of 48 indicated cases at the Haven (a dedicated sexual assault centre) and five (50%) of 10 at the Ambrose King Centre (a sexual health clinic). COE protocols should be in place in both sexual assault referral centres and sexual health clinics. In specialist clinics, with well-established guidelines and trained dedicated staff, COE sampling standards can be achieved.

[Is postoperative antibiotic treatment mandatory after abscess tonsillectomy]. / Ist eine begleitende Antibiotikatherapie nach Abszesstonsillektomie erforderlich?

BACKGROUND: Peritonsillar abscess (PTA) is a common and serious complication of acute exudative tonsillitis. We wanted to answer the following question: Are postoperative antibiotics mandatory after abscess tonsillectomy? PATIENTS AND METHODS: In an epidemiological observational study, 283 patients (98 females and 185 males, age range 2-72 years) were treated with abscess tonsillectomy for PTA. For a prospective randomized multicenter study, 105 patients were divided into two groups; one group was treated postoperatively with benzylpenicillin, and antibiotics were omitted in the control group. We evaluated postoperative pain scores, swallowing disorders, and well-being. Additionally, laboratory parameters such as C-reactive protein, leukocytes, and antistreptolysin titer were measured, and blood cultures were collected. RESULTS: Male patients in the 2nd-4th decades of life were predominantly affected, mostly in the summer. For the patients in the two groups, we assessed no significant differences in either the subjective or the laboratory parameters. The blood cultures showed no evidence of bacteremia. CONCLUSIONS: We conclude that immediately performed abscess tonsillectomy is an effective and safe treatment for PTA. No higher complication rate was found when additional antibiotic treatment was not used. Because of the small number of cases, the results can be regarded only as a tendency, not as a general recommendation.