Short-term and medium-term health effects of 9/11

The New York City terrorist attacks on Sept 11, 2001 (9/11), killed nearly 2800 people and thousands more had subsequent health problems. In this Review of health effects in the short and medium terms, strong evidence is provided for associations between experiencing or witnessing events related to 9/11 and post-traumatic stress disorder and respiratory illness, with a correlation between prolonged, intense exposure and increased overall illness and disability. Rescue and recovery workers, especially those who arrived early at the World Trade Center site or worked for longer periods, were more likely to develop respiratory illness than were other exposed groups. Risk factors for post-traumatic stress disorder included proximity to the site on 9/11, living or working in lower Manhattan, rescue or recovery work at the World Trade Center site, event-related loss of spouse, and low social support. Investigators note associations between 9/11 exposures and additional disorders, such as depression and substance use; however, for some health problems association with exposures related to 9/11 is unclear

Primary Care Physicians’ Views on Medical Error and Disclosure in Cancer Care

Introduction: Effective physician-patient communication is critical in cancer care. Breakdowns in communication may follow an actual or suspected medical error because of various professional or medicolegal concerns about those events. We examined views of primary care physicians (PCPs) regarding two hypothetical medical errors, their perceptions of responsibility and intent to communicate these events to patients. Objectives: To describe PCPs views on medical errors, perceived responsibility and communication after errors during cancer care. Methods: We surveyed 630 PCPs at 3 healthcare organizations participating in the Cancer Research Network. Questionnaires included two vignettes describing possible medical errors: a delayed diagnosis of breast cancer and; preventable complications of colon cancer treatment. Questions assessed perceived responsibility and intent to communicate with the patient after the event. Results: A total of 333 PCPs responded (response rate =53%). Eighty-one percent felt that the delayed diagnosis vignette described a serious error; (60%) believed that the preventable complications of colon cancer treatment vignette represented a serious medical error. Few would offer no apology at all for the delayed diagnosis (4%) or the colon cancer complications complications (7%). The most common expression of regret was “I am sorry about what happened to you” without elaboration (48% delayed diagnosis; 56% complications). Just over half (51%) would not volunteer the cause of the delayed diagnosis; compared to 25% in the complications vignette. Perception of the error as serious, and of greater personal responsibility were both predictive of being more forthcoming when communicating to patient after the event; perceived self-efficacy in communication and the belief that one’s organization values good communication were not. Conclusion: PCPs vary in their attitudes towards medical errors, and their perceptions of responsibility. These attitudes and perceptions are predictive of how physicians intend to communicate with patients after such events, at least in response to two hypothetical cases

Left atrial function in heart failure with preserved ejection fraction:a systematic review and meta-analysis

Aims Left atrial (LA) mechanical function may play a significant role in the development and progression of heart failure with preserved ejection fraction (HFpEF). We performed a systematic review and meta-analysis to evaluate association of impaired LA function with outcomes in HFpEF. Methods and results Multiple databases were searched for original studies measuring different phases of LA function in HFpEF patients. Comparative LA function between HFpEF patients and healthy controls was assessed by pooling weighted mean differences (WMD). Adjusted hazard ratios (HRs) with 95% confidence intervals were pooled to evaluate the prognostic utility of LA function. Twenty-two studies (2 trials, 20 observational) comprising 1974 HFpEF patients and 751 healthy controls were included. HFpEF patients had decreased LA reservoir [WMD = -12.21% (-15.47, -8.95); P <0.001], LA conduit [WMD = -5.68% (-8.56, -2.79); P <0.001], and pump [WMD = -11.07% (-14.81, -7.34); P <0.001] emptying fractions compared with controls. LA reservoir [WMD = -13.38% (-16.07, -10.68); P <0.001], conduit [WMD = -4.09% (-6.77, -1.42); P = 0.003], and pump [WMD = -3.53% (-4.47, -2.59); P <0.001] strains were also significantly lower in HFpEF patients. Decreased LA reservoir strain [HR 1.24 (1.02, 1.50); P = 0.03] was significantly associated with risk of composite all-cause mortality or heart failure hospitalization. Conclusions Impaired LA function appears to have diagnostic and prognostic value in HFpEF, but whether indices of LA function truly refine discrimination for diagnosis or prognosis remains to be fully determined. Larger studies are needed to better evaluate associations between LA function and clinical outcomes and the role of LA function as a target for novel HFpEF therapies

Comparison of front-loaded recombinant tissue-type plasminogen activator, anistreplase and combination thrombolytic therapy for acute myocardial infarction: Results of the thrombolysis in myocardial infarction (TIMI) 4 trial

AbstractObjectives. The aim of our study was to determine a superior tbrombolytic regimen from three: anistreplase (APSAC), frontloaded recombinant tissue-type plasminogen activator (rt-PA) or combination thrombolytic therapy.Background. Although thrombolytic therapy has been shown to reduce mortality and morbidity after acute myocardial infarction, it has not been clear whether more aggressive thrombolyticantithrombotic regimens could improve the outcome achieved with standard regimens.Methods. To address this issue, 382 patients with acute myocardial infection were randomized to receive in a double-blind fashion (along with intravenous heparin and aspirin) APSAC, front-loaded rt-PA or a combination of both agents. The primary end point “unsatisfactory outcome” was a composite clinical end point assessed through hospital discharge.Results. Patency of the infarct-related artery (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3 flow) at 60 min after the start of thrombolysis was significantly higher in rt-PA-treated patients (77.8% vs. 59.5% for APSAC-treated patients and 59.3% for combination-treated patients [rt-PA vs. APSAC, p = 0.02; rt-PA vs. combination, p = 0.03]). At 90 min, the incidence of both infarct-related artery patency and TIMI grade 3 flow was significantly higher in rt-PA-treated patients (60.2% had TIMI grade 3 flow vs. 42.9% and 44.8% of APSAC- and combination-treated patients, respectively [rt-PA vs. APSAC, p < 0.01; rt-PA vs. combination, p = 0.02]). The incidence of unsatisfactory outcome was 41.3% for rt-PA compared with 49% for APSAC and 53.6% for the combination (rt-PA vs. APSAC, p = 0.19; rt-PA vs. combination, p = 0.06). The mortality rate at 6 weeks was lowest in the rt-PA-treated patients (2.2% vs. 8.8% for APSAC and 7.2% for combination thrombolytic therapy [rt-PA vs. APSAC, p = 0.02; rt-PA vs. combination, p = 0.06]).Conclusions. Front-loaded rt-PA achieved significantly higher rates of early reperfusion and was associated with trends toward better overall clinical benefit and survival than those achieved with a standard thrombolytic agent or combination thrombolytic therapy. These findings support the concept that more rapid reperfusion of the infarct-related artery is associated with improved clinical outcome

Invasive Group A Streptococcal Infection in Older Adults in Long-term Care Facilities and the Community, United States, 1998–20031

Invasive infection develops almost 6 times as frequently in the elderly in long-term care facilities

Association Between World Trade Center Exposure and Excess Cancer Risk

Context: The terrorist attacks of September 11, 2001, resulted in the release of known and suspected carcinogens into the environment. There is public concern that exposures may have resulted in increased cancers. Objective: To evaluate cancer incidence among persons enrolled in the World Trade Center Health Registry. Design, Setting, and Participants: Observational study of 55 778 New York State residents enrolled in the World Trade Center Health Registry in 2003-2004, including rescue/recovery workers (n = 21 850) and those not involved in rescue/recovery (n = 33 928), who were followed up from enrollment through December 31, 2008. Within-cohort comparisons using Cox proportional hazards models assessed the relationship between intensity of World Trade Center exposure and selected cancers. Main Outcome Measures: Cases were identified through linkage with 11 state cancer registries. Standardized incidence ratios (SIRs) adjusted for age, race/ethnicity, and sex were computed with 2003-2008 New York State rates as the reference, focusing on cancers diagnosed in 2007-2008 as being most likely to be related to exposure during September 11 and its aftermath. The total and site-specific incidence rate differences (RDs) per 100 000 person-years between the study population and the New York State population in 2007-2008 also were calculated. Results: There were 1187 incident cancers diagnosed, with an accumulated 253 269 person-years (439 cancers among rescue/recovery workers and 748 among those not involved in rescue/recovery). The SIR for all cancer sites combined in 2007-2008 was not significantly elevated (SIR, 1.14 [95% CI, 0.99 to 1.30]; RD, 67 [95% CI, −6 to 126] per 100 000 person-years among rescue/recovery workers vs SIR, 0.92 [95% CI, 0.83 to 1.03]; RD, −45 [95% CI, −106 to 15] per 100 000 person-years among those not involved in rescue/recovery). Among rescue/recovery workers, the SIRs had significantly increased by 2007-2008 for 3 cancer sites and were 1.43 (95% CI, 1.11 to 1.82) for prostate cancer (n = 67; RD, 61 [95% CI, 20 to 91] per 100 000 person-years), 2.02 (95% CI, 1.07 to 3.45) for thyroid cancer (n = 13; RD, 16 [95% CI, 2 to 23] per 100 000 person-years), and 2.85 (95% CI, 1.15 to 5.88) for multiple myeloma (n = 7; RD, 11 [95% CI, 2 to 14] per 100 000 person-years). No increased incidence was observed in 2007-2008 among those not involved in rescue/recovery. Using within-cohort comparisons, the intensity of World Trade Center exposure was not significantly associated with cancer of the lung, prostate, thyroid, non-Hodgkin lymphoma, or hematological cancer in either group. Conclusions: Among persons enrolled in the World Trade Center Health Registry, there was an excess risk for prostate cancer, thyroid cancer, and myeloma in 2007-2008 compared with that for New York State residents; however, these findings were based on a small number of events and multiple comparisons. No significant associations were observed with intensity of World Trade Center exposures. Longer follow-up for typically long-latency cancers and attention to specific cancer sites are needed

Identification of broadly neutralizing antibody epitopes in the HIV-1 envelope glycoprotein using evolutionary models

Background: Identification of the epitopes targeted by antibodies that can neutralize diverse HIV-1 strains can provide important clues for the design of a preventative vaccine. Methods: We have developed a computational approach that can identify key amino acids within the HIV-1 envelope glycoprotein that influence sensitivity to broadly cross-neutralizing antibodies. Given a sequence alignment and neutralization titers for a panel of viruses, the method works by fitting a phylogenetic model that allows the amino acid frequencies at each site to depend on neutralization sensitivities. Sites at which viral evolution influences neutralization sensitivity were identified using Bayes factors (BFs) to compare the fit of this model to that of a null model in which sequences evolved independently of antibody sensitivity. Conformational epitopes were identified with a Metropolis algorithm that searched for a cluster of sites with large Bayes factors on the tertiary structure of the viral envelope. Results: We applied our method to ID50 neutralization data generated from seven HIV-1 subtype C serum samples with neutralization breadth that had been tested against a multi-clade panel of 225 pseudoviruses for which envelope sequences were also available. For each sample, between two and four sites were identified that were strongly associated with neutralization sensitivity (2ln(BF) > 6), a subset of which were experimentally confirmed using site-directed mutagenesis. Conclusions: Our results provide strong support for the use of evolutionary models applied to cross-sectional viral neutralization data to identify the epitopes of serum antibodies that confer neutralization breadth

Mortality among survivors of the Sept 11, 2001, World Trade Center disaster: results from the World Trade Center Health Registry cohort

Background The Sept 11, 2001 (9/11) World Trade Center (WTC) disaster has been associated with several subacute and chronic health effects, but whether excess mortality after 9/11 has occurred is unknown. We tested whether excess mortality has occurred in people exposed to the WTC disaster. Methods In this observational cohort study, deaths occurring in 2003–09 in WTC Health Registry participants residing in New York City were identified through linkage to New York City vital records and the National Death Index. Eligible participants were rescue and recovery workers and volunteers; lower Manhattan area residents, workers, school staff and students; and commuters and passers-by on 9/11. Study participants were categorized as rescue and recovery workers (including volunteers), or non-rescue and non-recovery participants. Standardised mortality ratios (SMR) were calculated with New York City rates from 2000–09 as the reference. Within the cohort, proportional hazards were used to examine the relation between a three-tiered WTC-related exposure level (high, intermediate, or low) and total mortality. Findings We identified 156 deaths in 13 337 rescue and recovery workers and 634 deaths in 28 593 non-rescue and non-recovery participants. All-cause SMRs were significantly lower than that expected for rescue and recovery participants (SMR 0·45, 95% CI 0·38–0·53) and non-rescue and non-recovery participants (0·61, 0·56–0·66). No significantly increased SMRs for diseases of the respiratory system or heart, or for hematological malignancies were found. In non-rescue and non-recovery participants, both intermediate and high levels of WTC-related exposure were significantly associated with mortality when compared with low exposure (adjusted hazard ratio 1·22, 95% CI 1·01–1·48, for intermediate exposure and 1·56, 1·15–2·12, for high exposure). High levels of exposure in non-rescue and non-recovery individuals, when compared with low exposed non-rescue and non-recovery individuals, were associated with heart disease- related mortality (adjusted hazard ratio 2·06, 1·10–3·86). In rescue and recovery participants, level of WTC-related exposure was not significantly associated with all-cause mortality (adjusted hazard ratio 1·25, 95% CI 0·56–2·78, for high exposure and 1·03, 0·52–2·06, for intermediate exposure when compared with low exposure). Interpretation This exploratory study of mortality in a well defined cohort of 9/11 survivors provides a baseline for continued surveillance. Additional follow-up is needed to establish whether these associations persist and whether a similar association over time will occur in rescue and recovery participants

A dominant gain-of-function mutation in universal tyrosine kinase <i>SRC </i>causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies

The Src family kinase (SFK)member SRC is amajor target in drug development because it is activated in many human cancers, yet deleterious SRC germline mutations have not been reported. We used genome sequencing and Human Phenotype Ontology patient coding to identify a gain-of-function mutation in SRC causing thrombocytopenia, myelofibrosis, bleeding, and bone pathologies in nine cases. Modeling of the E527K substitution predicts loss of SRC's self-inhibitory capacity, whichwe confirmedwith in vitro studies showing increased SRC kinase activity and enhanced Tyr419 phosphorylation in COS-7 cells overexpressing E527K SRC. The active form of SRC predominates in patients' platelets, resulting in enhanced overall tyrosine phosphorylation. Patientswith myelofibrosis have hypercellular bone marrow with trilineage dysplasia, and their stem cells grown in vitro form more myeloid and megakaryocyte (MK) colonies than control cells. These MKs generate platelets that are dysmorphic, low in number, highly variable in size, and have a paucity of a-granules. Overactive SRC in patient-derived MKs causes a reduction in proplatelet formation, which can be rescued by SRC kinase inhibition. Stem cells transduced with lentiviral E527K SRC formMKs with a similar defect and enhanced tyrosine phosphorylation levels. Patient-derived and E527K-transduced MKs show Y419 SRC- positive stained podosomes that induce altered actin organization. Expression of mutated src in zebrafish recapitulates patients' blood and bone phenotypes. Similar studies of platelets andMKs may reveal the mechanism underlying the severe bleeding frequently observed in cancer patients treated with next-generation SFK inhibitors. © 2016 by the American Association for the Advancement of Science; all rights reserved