Second Nationwide Tuberculosis Outbreak Caused by Bone Allografts Containing Live Cells - United States, 2023.

During July 7-11, 2023, CDC received reports of two patients in different states with a tuberculosis (TB) diagnosis following spinal surgical procedures that used bone allografts containing live cells from the same deceased donor. An outbreak associated with a similar product manufactured by the same tissue establishment (i.e., manufacturer) occurred in 2021. Because of concern that these cases represented a second outbreak, CDC and the Food and Drug Administration worked with the tissue establishment to determine that this product was obtained from a donor different from the one implicated in the 2021 outbreak and learned that the bone allograft product was distributed to 13 health care facilities in seven states. Notifications to all seven states occurred on July 12. As of December 20, 2023, five of 36 surgical bone allograft recipients received laboratory-confirmed TB disease diagnoses; two patients died of TB. Whole-genome sequencing demonstrated close genetic relatedness between positive Mycobacterium tuberculosis cultures from surgical recipients and unused product. Although the bone product had tested negative by nucleic acid amplification testing before distribution, M. tuberculosis culture of unused product was not performed until after the outbreak was recognized. The public health response prevented up to 53 additional surgical procedures using allografts from that donor; additional measures to protect patients from tissue-transmitted M. tuberculosis are urgently needed.

Trajectories of Child Cognitive and Socioemotional Development and Associations with Adolescent Health in the UK Millennium Cohort Study.

OBJECTIVE: To identify and describe distinct trajectories of cognitive and socioemotional development during childhood and to examine their relationships with adolescent health. STUDY DESIGN: We used group-based multitrajectory modeling applied to longitudinal data on 11 564 children up to age 14 years from the UK Millennium Cohort study to identify trajectories of cognitive and socioemotional development measured using validated instruments. We assessed associations between the derived trajectories and baseline socioeconomic, parental, and school factors using multinomial regression. Logistic regression was used to assess associations between trajectory groups and adolescent health at age 14 and 17 years. RESULTS: Four child development trajectories were identified: "no problems" (76.5%); "late socio-emotional problems" (10.1%); "early cognitive and socioemotional problems" (8.6%); and "persistent cognitive and socioemotional problems" (4.8%). Those in the problem trajectories were more socioeconomically disadvantaged. Compared with the "no problem" trajectory, the "late socioemotional problems" trajectory had increased odds of overweight and mental ill-health at age 14 years of 1.50 (95% CI 1.24-1.81) and 2.51 (2.03-3.10), respectively. For the "persistent problems" group, the OR for overweight was 1.41 (1.04-1.91), and for mental ill-health, 3.01 (2.10-3.30). For both groups, the associations persisted to age 17 years. CONCLUSIONS: In a representative UK cohort, groups of distinct trajectories of cognitive and socioemotional development were identified. Adverse development, if unresolved, can have a negative impact on weight and mental health in adolescence. Socioemotional development was the main driver of the impact on adolescent health and this requires emphasis in child health policy.

Probable Posttraumatic Stress Disorder and Lower Respiratory Symptoms Among Rescue/Recovery Workers and Community Members After the 9/11 World Trade Center Attacks-A Longitudinal Mediation Analysis.

OBJECTIVE: Posttraumatic stress disorder (PTSD) and lower respiratory symptoms (LRS) often coexist among survivors of the September 11, 2001 (9/11) World Trade Center (WTC) attacks. Research in police and nontraditional responders suggests that PTSD mediates the relationship between 9/11 physical exposures and LRS, but not vice versa. We replicated these findings in WTC rescue/recovery workers (R/R workers), extended them to exposed community members, and explored the interplay between both physical and psychological 9/11 exposures, probable PTSD, and LRS over a 10-year follow-up. METHODS: Participants were 12,398 R/R workers and 12,745 community members assessed in three WTC Health Registry surveys (2003-2004, 2006-2007, and 2011-2012). LRS and 9/11 exposures were self-reported. Probable PTSD was defined as a PTSD Checklist score ≥44. RESULTS: Probable PTSD predicted LRS (R/R workers: ß = 0.88-0.98, p < .001; community members: ß = 0.67-0.86, p < .001) and LRS predicted PTSD (R/R workers: ß = 0.83-0.91, p < .001; community members: ß = 0.68-0.75, p < .001) at follow-ups, adjusting for prior symptoms and covariates. In both R/R workers and community members, probable PTSD mediated the relationship between 9/11 physical exposures (dust cloud, long duration of work) and LRS (indirect effects, p = .001-.006), and LRS mediated the physical exposure-PTSD relationship (indirect effects, p = .001-.006). In R/R workers, probable PTSD mediated the psychological exposure (losing friends or loved ones, witnessing horrific events)-LRS relationship (indirect effect, p < .001), but LRS did not mediate the psychological exposure-PTSD relationship (indirect effect, p = .332). In community members, high 9/11 psychological exposure predicted both probable PTSD and LRS at follow-ups; probable PTSD mediated the psychological exposure-LRS relationship (indirect effect, p < .001), and LRS mediated the psychological exposure-PTSD relationship (indirect effect, p = .001). CONCLUSIONS: Probable PTSD and LRS each mediated the other, with subtle differences between R/R workers and community members. A diagnosis of either should trigger assessment for the other; treatment should be carefully coordinated.

Persistent mental and physical health impact of exposure to the September 11, 2001 World Trade Center terrorist attacks.

BACKGROUND: Asthma, gastroesophageal reflux disease (GERD), posttraumatic stress disorder (PTSD) and depression have each been linked to exposure to the September 11, 2001 World Trade Center (WTC) terrorist attacks (9/11). We described the prevalence and patterns of these conditions and associated health-related quality of life (HRQOL) fifteen years after the attacks. METHODS: We studied 36,897 participants in the WTC Health Registry, a cohort of exposed rescue/recovery workers and community members, who completed baseline (2003-2004) and follow-up (2015-16) questionnaires. Lower respiratory symptoms (LRS; cough, dyspnea, or wheeze), gastroesophageal reflux symptoms (GERS) and self-reported clinician-diagnosed asthma and GERD history were obtained from surveys. PTSD was defined as a score > 44 on the PTSD checklist, and depression as a score > 10 on the Patient Health Questionnaire (PHQ). Poor HRQOL was defined as reporting limited usual daily activities for > 14 days during the month preceding the survey. RESULTS: In 2015-16, 47.8% of participants had ≥1 of the conditions studied. Among participants without pre-existing asthma, 15.4% reported asthma diagnosed after 9/11; of these, 76.5% had LRS at follow up. Among those without pre-9/11 GERD, 22.3% reported being diagnosed with GERD after 9/11; 72.2% had GERS at follow-up. The prevalence of PTSD was 14.2%, and of depression was 15.3%. HRQOL declined as the number of comorbidities increased, and was particularly low among participants with mental health conditions. Over one quarter of participants with PTSD or depression reported unmet need for mental health care in the preceding year. CONCLUSIONS: Nearly half of participants reported having developed at least one of the physical or mental health conditions studied by 2015-2016; comorbidity among conditions was common. Poor HRQOL and unmet need for health were frequently reported, particularly among those with post-9/11 PTSD or depression. Comprehensive physical and mental health care are essential for survivors of complex environmental disasters, and continued efforts to connect 9/11-exposed persons to needed resources are critical.

Long-Term Supportive Housing is Associated with Decreased Risk for New HIV Diagnoses Among a Large Cohort of Homeless Persons in New York City.

It is unknown whether providing housing to persons experiencing homelessness decreases HIV risk. Housing, including access to preventive services and counseling, might provide a period of transition for persons with HIV risk factors. We assessed whether the new HIV diagnosis rate was associated with duration of supportive housing. We linked data from a cohort of 21,689 persons without a previous HIV diagnosis who applied to a supportive housing program in New York City (NYC) during 2007-2013 to the NYC HIV surveillance registry. We used time-dependent Cox modeling to compare new HIV diagnoses among recipients of supportive housing (defined a priori, for program evaluation purposes, as persons who spent > 7 days in supportive housing; n = 6447) and unplaced applicants (remainder of cohort), after balancing the groups on baseline characteristics with propensity score weights. Compared with unplaced applicants, persons who received ≥ 3 continuous years of supportive housing had decreased risk for new HIV diagnosis (HR 0.10; CI 0.01-0.99). Risk of new HIV diagnosis decreased with longer duration placement in supportive housing. Supportive housing might aid in primary HIV prevention.

Hospitalizations for asthma among adults exposed to the September 11, 2001 World Trade Center terrorist attack.

OBJECTIVE: We described the patterns of asthma hospitalization among persons exposed to the 2001 World Trade Center (WTC) attacks, and assessed whether 9/11-related exposures or comorbidities, including posttraumatic stress disorder (PTSD) and gastroesophageal reflux symptoms (GERS), were associated with an increased rate of hospitalization. METHODS: Data for adult enrollees in the WTC Health Registry, a prospective cohort study, with self-reported physician-diagnosed asthma who resided in New York State on 9/11 were linked to administrative hospitalization data to identify asthma hospitalizations during September 11, 2001-December 31, 2010. Multivariable zero-inflated Poisson regression was used to examine associations among 9/11 exposures, comorbid conditions, and asthma hospitalizations. RESULTS: Of 11 471 enrollees with asthma, 406 (3.5%) had ≥1 asthma hospitalization during the study period (721 total hospitalizations). Among enrollees diagnosed before 9/11 (n = 6319), those with PTSD or GERS had over twice the rate of hospitalization (adjusted rate ratio (ARR) = 2.5, 95% CI = 1.4-4.1; ARR = 2.1, 95% CI = 1.3-3.2, respectively) compared to those without. This association was not statistically significant in enrollees diagnosed after 9/11. Compared to higher educational attainment, completing less than college was associated with an increased hospitalization rate among participants with both pre-9/11- and post-9/11-onset asthma (ARR = 1.9, 95% CI = 1.2-2.9; ARR = 2.6, 95% CI = 1.6-4.1, respectively). Sinus symptoms, exposure to the dust cloud, and having been a WTC responder were not associated with asthma hospitalization. CONCLUSIONS: Among enrollees with pre-9/11 asthma, comorbid PTSD and GERS were associated with an increase in asthma hospitalizations. Management of these comorbidities may be an important factor in preventing hospitalization.

Mortality among rescue and recovery workers and community members exposed to the September 11, 2001 World Trade Center terrorist attacks, 2003-2014.

BACKGROUND: Multiple chronic health conditions have been associated with exposure to the September 11, 2001 World Trade Center (WTC) terrorist attacks (9/11). We assessed whether excess deaths occurred during 2003-2014 among persons directly exposed to 9/11, and examined associations of 9/11-related exposures with mortality risk. MATERIALS AND METHODS: Deaths occurring in 2003-2014 among members of the World Trade Center Health Registry, a cohort of rescue/recovery workers and lower Manhattan community members who were exposed to 9/11, were identified via linkage to the National Death Index. Participants' overall levels of 9/11-related exposure were categorized as high, intermediate, or low. We calculated standardized mortality ratios (SMR) using New York City reference rates from 2003 to 2012. Proportional hazards were used to assess associations of 9/11-related exposures with mortality, accounting for age, sex, race/ethnicity and other potential confounders. RESULTS: We identified 877 deaths among 29,280 rescue/recovery workers (3.0%) and 1694 deaths among 39,643 community members (4.3%) during 308,340 and 416,448 person-years of observation, respectively. The SMR for all causes of death was 0.69 [95% confidence interval (CI) 0.65-0.74] for rescue/recovery workers and 0.86 (95% CI 0.82-0.90) for community members. SMRs for diseases of the cardiovascular and respiratory systems were significantly lower than expected in both groups. SMRs for several other causes of death were significantly elevated, including suicide among rescue recovery workers (SMR 1.82, 95% CI 1.35-2.39), and brain malignancies (SMR 2.25, 95% CI 1.48-3.28) and non-Hodgkin's lymphoma (SMR 1.79, 95% CI 1.24-2.50) among community members. Compared to low exposure, both intermediate [adjusted hazard ratio (AHR) 1.36, 95% CI 1.10-1.67] and high (AHR 1.41, 95% CI 1.06-1.88) levels of 9/11-related exposure were significantly associated with all-cause mortality among rescue/recovery workers (p-value for trend 0.01). For community members, intermediate (AHR 1.13, 95% CI 1.01-1.27), but not high (AHR 1.14, 95% CI 0.94-1.39) exposure was significantly associated with all-cause mortality (p-value for trend 0.03). AHRs for associations of overall 9/11-related exposure with heart disease- and cancer-related mortality were similar in magnitude to those for all-cause mortality, but with 95% CIs crossing the null value. CONCLUSIONS: Overall mortality was not elevated. Among specific causes of death that were significantly elevated, suicide among rescue/recovery workers is a plausible long-term consequence of 9/11 exposure, and is potentially preventable. Elevated mortality due to other causes, including non-Hodgkin's lymphoma and brain cancer, and small but statistically significant associations of 9/11-related exposures with all-cause mortality hazard warrant additional surveillance.

Identifying inequitable healthcare in older people: systematic review of current research practice.

BACKGROUND: There is growing consensus on the importance of identifying age-related inequities in the receipt of public health and healthcare interventions, but concerns regarding conceptual and methodological rigour in this area of research. Establishing age inequity in receipt requires evidence of a difference that is not an artefact of poor measurement of need or receipt; is not warranted on the grounds of patient preference or clinical safety; and is judged to be unfair. METHOD: A systematic, thematic literature review was undertaken with the objective of characterising recent research approaches. Studies were eligible if the population was in a country within the Organisation for Economic Co-operation and Development and analyses included an explicit focus on age-related patterns of healthcare receipt including those 60 years or older. A structured extraction template was applied. Extracted material was synthesised in thematic memos. A set of categorical codes were then defined and applied to produce summary counts across key dimensions. This process was iterative to allow reconciliation of discrepancies and ensure reliability. RESULTS: Forty nine studies met the eligibility criteria. A wide variety of concepts, terms and methodologies were used across these studies. Thirty five studies employed multivariable techniques to produce adjusted receipt-need ratios, though few clearly articulated their rationale, indicating the need for great conceptual clarity. Eighteen studies made reference to patient preference as a relevant consideration, but just one incorporated any kind of adjustment for this factor. Twenty five studies discussed effectiveness among older adults, with fourteen raising the possibility of differential effectiveness, and one differential cost-effectiveness, by age. Just three studies made explicit reference to the ethical nature of healthcare resource allocation by age. While many authors presented suitably cautious conclusions, some appeared to over-stretch their findings concluding that observed differences were 'inequitable'. Limitations include possible biases in the retrieved material due to inconsistent database indexing and a focus on OECD country populations and studies with English titles. CONCLUSIONS: Caution is needed among clinicians and other evidence-users in accepting claims of healthcare 'ageism' in some published papers. Principles for improved research practice are proposed.

Risk factors for persistence of lower respiratory symptoms among community members exposed to the 2001 World Trade Center terrorist attacks.

OBJECTIVES: We studied the course of lower respiratory symptoms (LRS; cough, wheeze or dyspnoea) among community members exposed to the 9/11/2001 World Trade Center (WTC) attacks during a period of 12-13 years following the attacks, and evaluated risk factors for LRS persistence, including peripheral airway dysfunction and post-traumatic stress disorder (PTSD). METHODS: Non-smoking adult participants in a case-control study of post-9/11-onset LRS (exam 1, 2008-2010) were recruited for follow-up (exam 2, 2013-2014). Peripheral airway function was assessed with impulse oscillometry measures of R5 and R5-20. Probable PTSD was a PTSD checklist score ≥44 on a 2006-2007 questionnaire. RESULTS: Of 785 exam 1 participants, 545 (69%) completed exam 2. Most (321, 59%) were asymptomatic at all assessments. Among 192 participants with initial LRS, symptoms resolved for 110 (57%) by exam 2, 55 (29%) had persistent LRS and 27 (14%) had other patterns. The proportion with normal spirometry increased from 65% at exam 1 to 85% at exam 2 in the persistent LRS group (p<0.01) and was stable among asymptomatic participants and those with resolved LRS. By exam 2, spirometry results did not differ across symptom groups; however, R5 and R5-20 abnormalities were more common among participants with persistent LRS (56% and 46%, respectively) than among participants with resolved LRS (30%, p<0.01; 27%, p=0.03) or asymptomatic participants (20%, p<0.001; 8.2%, p<0.001). PTSD, R5 at exam 1, and R5-20 at exam 1 were each independently associated with persistent LRS. CONCLUSIONS: Peripheral airway dysfunction and PTSD may contribute to LRS persistence. Assessment of peripheral airway function detected pulmonary damage not evident on spirometry. Mental and physical healthcare for survivors of complex environmental disasters should be coordinated carefully.

Risk factors for and consequences of persistent lower respiratory symptoms among World Trade Center Health Registrants 10†years after the disaster.

OBJECTIVES: The prevalence of persistent lower respiratory symptoms (LRS) among rescue/recovery workers, local area workers, residents and passers-by in the World Trade Center Health Registry (WTCHR) was analysed to identify associated factors and to measure its effect on quality of life (QoL) 10 years after 9/11/2001. METHODS: This cross-sectional study included 18 913 adults who completed 3 WTCHR surveys (2003-2004 (Wave 1 (W1)), 2006-2007 (Wave 2 (W2)) and 2011-2012 (Wave 3 (W3)). LRS were defined as self-reported cough, wheeze, dyspnoea or inhaler use in the 30 days before survey. The prevalence of three LRS outcomes: LRS at W1; LRS at W1 and W2; and LRS at W1, W2 and W3 (persistent LRS) was compared with no LRS on WTC exposure and probable mental health conditions determined by standard screening tests. Diminished physical and mental health QoL measures were examined as potential LRS outcomes, using multivariable logistic and Poisson regression. RESULTS: Of the 4 outcomes, persistent LRS was reported by 14.7%. Adjusted ORs for disaster exposure, probable post-traumatic stress disorder (PTSD) at W2, lacking college education and obesity were incrementally higher moving from LRS at W1, LRS at W1 and W2 to persistent LRS. Half of those with persistent LRS were comorbid for probable PTSD, depression or generalised anxiety disorder. Enrollees with persistent LRS were 3 times more likely to report poor physical health and ∼ 50% more likely to report poor mental health than the no LRS group. CONCLUSIONS: LRS, accompanied by mental health conditions and decreased QoL, have persisted for at least 10 years after 9/11/2001. Affected adults require continuing surveillance and treatment.

Effect of asthma and PTSD on persistence and onset of gastroesophageal reflux symptoms among adults exposed to the September 11, 2001, terrorist attacks.

BACKGROUND: Little is known about the direction of causality among asthma, posttraumatic stress disorder (PTSD), and onset of gastroesophageal reflux symptoms (GERS) after exposure to the 9/11/2001 World Trade Center (WTC) disaster. METHODS: Using data from the WTC Health Registry, we investigated the effects of early diagnosed post-9/11 asthma and PTSD on the late onset and persistence of GERS using log-binomial regression, and examined whether PTSD mediated the asthma-GERS association using structural equation modeling. RESULTS: Of 29,406 enrollees, 23% reported GERS at follow-up in 2011-2012. Early post-9/11 asthma and PTSD were each independently associated with both the persistence of GERS that was present at baseline and the development of GERS in persons without a prior history. PTSD mediated the association between early post-9/11 asthma and late-onset GERS. CONCLUSIONS: Clinicians should assess patients with post-9/11 GERS for comorbid asthma and PTSD, and plan medical care for these conditions in an integrated fashion. Am. J. Ind. Med. 59:805-814, 2016. © 2016 Wiley Periodicals, Inc.

Factors associated with poor control of 9/11-related asthma 10-11 years after the 2001 World Trade Center terrorist attacks.

OBJECTIVE: To identify key factors associated with poor asthma control among adults in the World Trade Center (WTC) Health Registry, a longitudinal study of rescue/recovery workers and community members who were directly exposed to the 2001 WTC terrorist attacks and their aftermath. METHODS: We studied incident asthma diagnosed by a physician from 12 September 2001 through 31 December 2003 among participants aged ≥18 on 11 September 2001, as reported on an enrollment (2003-2004) or follow-up questionnaire. Based on modified National Asthma Education and Prevention Program criteria, asthma was considered controlled, poorly-controlled, or very poorly-controlled at the time of a 2011-2012 follow-up questionnaire. Probable post-traumatic stress disorder, depression, and generalized anxiety disorder were defined using validated scales. Self-reported gastroesophageal reflux symptoms (GERS) and obstructive sleep apnea (OSA) were obtained from questionnaire responses. Multinomial logistic regression was used to examine factors associated with poor or very poor asthma control. RESULTS: Among 2445 participants, 33.7% had poorly-controlled symptoms and 34.6% had very poorly-controlled symptoms in 2011-2012. Accounting for factors including age, education, body mass index, and smoking, there was a dose-response relationship between the number of mental health conditions and poorer asthma control. Participants with three mental health conditions had five times the odds of poor control and 13 times the odds of very poor control compared to participants without mental health comorbidities. GERS and OSA were significantly associated with poor or very poor control. CONCLUSIONS: Rates of poor asthma control were very high in this group with post-9/11 diagnosed asthma. Comprehensive care of 9/11-related asthma should include management of mental and physical health comorbidities.

Posttraumatic stress disorder and new-onset diabetes among adult survivors of the World Trade Center disaster.

OBJECTIVE: To explore the temporal relationship between 9/11-related posttraumatic stress disorder (PTSD) and new-onset diabetes in World Trade Center (WTC) survivors up to 11 years after the attack in 2001. METHODS: Three waves of surveys (conducted from 2003 to 2012) from the WTC Health Registry cohort collected data on physical and mental health status, sociodemographic characteristics, and 9/11-related exposures. Diabetes was defined as self-reported, physician-diagnosed diabetes reported after enrollment. After excluding prevalent cases, there were 36,899 eligible adult enrollees. Logistic regression and generalized multilevel growth models were used to assess the association between PTSD measured at enrollment and subsequent diabetes. RESULTS: We identified 2143 cases of diabetes. After adjustment, we observed a significant association between PTSD and diabetes in the logistic model [adjusted odds ratio (AOR) 1.28, 95% confidence interval (CI) 1.14-1.44]. Results from the growth model were similar (AOR 1.37, 95% CI 1.23-1.52). CONCLUSION: This exploratory study found that PTSD, a common 9/11-related health outcome, was a risk factor for self-reported diabetes. Clinicians treating survivors of both the WTC attacks and other disasters should be aware that diabetes may be a long-term consequence.

Once in Contact, Forever Contaminated! Introducing a Clinically Validated Imagery- and Video-Based Chain of Contagion Task for the Measurement of Disgust and Contamination Change in Experimental Research and Clinical Practice.

Tolin et al. (2004) developed the Chain of Contagion Task (CCT) to experimentally test the law of contagion and looming vulnerability (LV). In the CCT, contaminated pencils are brought into contact with clean pencils. The degree of contamination transferred to further new pencils refers to the level of biased contagious beliefs. Although this could be an important transdiagnostic tool, the usability of the original paradigm has been very laborious. Therefore, an imagery- and video-based CCT is introduced and validated in Study 1 in a nonclinical sample with 85 participants. In Study 2, the imagery-based CCT was validated in a clinical study with 15 participants diagnosed with contamination-related obsessive-compulsive disorder (C-OCD), 15 participants suffering from an anxiety disorder, and 15 nonclinical controls. The number of participants is consistent with those in Tolin's original sample and the statistical evaluation of Study 2 was preregistered. Both CCT could be validated and the results could be replicated. In the imagery-based CCT, the C-OCD group displayed significantly higher contamination ratings, avoidance tendencies and LV than the two control groups. We argue that this open access diagnostic instrument can be applied in research as well as in therapeutic practice (Download CCT videos and imagery: https://doi.org/10.5281/zenodo.7730459).

HIV-1 latency reversal agent boosting is not limited by opioid use.

Opioid use may impact the HIV-1 reservoir and its reversal from latency. We studied forty-seven virally suppressed people with HIV (PWH) and observed that lower concentration of HIV-1 latency reversal agents (LRA), used in combination with small molecules that did not reverse latency, synergistically increased the magnitude of HIV-1 re-activation ex vivo, regardless of opioid use. This LRA boosting, which combined a Smac mimetic or low-dose protein kinase C agonist with histone deacetylase inhibitors, generated significantly more unspliced HIV-1 transcription than phorbol 12-myristate 13-acetate (PMA) with ionomycin (PMAi), the maximal known HIV-1 reactivator. LRA boosting associated with greater histone acetylation, modulated surface activation-induced markers, and altered T cell production of TNFα, IL-2, and IFNγ. HIV-1 reservoirs in PWH contained unspliced and polyadenylated (polyA) virus mRNA, the ratios of which were greater in resting than total CD4+ T cells and correct to 1:1 with PMAi exposure. We characterized treated suppressed HIV-1 infection as a period of inefficient, not absent, virus transcription. Multiply spliced HIV-1 transcripts and virion production did not consistently increase with LRA boosting, suggesting the presence of a persistent post-transcriptional block. LRA boosting can be leveraged to probe mechanisms of an effective cellular HIV-1 latency reversal program.

Opioid use does not limit potent low-dose HIV-1 latency reversal agent boosting.

The combined effects of the HIV-1 and opioid epidemics on virus reservoir dynamics are less well characterized. To assess the impact of opioid use on HIV-1 latency reversal, we studied forty-seven suppressed participants with HIV-1 and observed that lower concentrations of combination latency reversal agents (LRA) led to synergistic virus reactivation ex vivo, regardless of opioid use. The use of a Smac mimetic or low-dose protein kinase C agonist, compounds that did not reverse latency alone, in combination with low-dose histone deacetylase inhibitors generated significantly more HIV-1 transcription than phorbol 12-myristate 13-acetate (PMA) with ionomycin, the maximal known HIV-1 reactivator. This LRA boosting did not differ by sex or race and associated with greater histone acetylation in CD4+ T cells and modulation of T cell phenotype. Virion production and the frequency of multiply spliced HIV-1 transcripts did not increase, suggesting a post-transcriptional block still limits potent HIV-1 LRA boosting.

Trace and Major Element Concentrations in Cadaveric Lung Tissues from World Trade Center Health Registry Decedents and Community Controls.

Studies of the health impacts of the 11 September 2001 terrorist attacks on New York City's (NYC's) World Trade Center (WTC) towers have been hindered by imprecise estimates of exposure. We sought to identify potential biomarkers of WTC exposure by measuring trace and major metal concentrations in lung tissues from WTC-exposed individuals and less exposed community controls. We also investigated associations of lung tissue metal concentrations with self-reported exposure and respiratory symptoms. The primary analyses contrasted post-mortem lung tissue concentrations obtained from autopsies in 2007-2011 of 76 WTC Health Registry (WTCHR) enrollees with those of 55 community controls. Community controls were frequency-matched to WTCHR decedents by age at death, calendar quarter of death, gender, race, ethnicity and education and resided at death in NYC zip codes less impacted by WTC dust and fumes. We found WTCHR decedents to have significantly higher iron (Fe) lung tissue concentrations than community controls. Secondary analyses among WTCHR decedents adjusted for sex and age showed the log(molybdenum (Mo)) concentration to be significantly associated with non-rescue/recovery exposure. Post hoc analyses suggested that individuals whose death certificates listed usual occupation or industry as the Sanitation or Police Departments had elevated lung tissue Fe concentrations. Among WTCHR decedents, exposure to the WTC dust cloud was significantly associated with elevated lung tissue concentrations of titanium (Ti), chromium (Cr) and cadmium (Cd) in non-parametric univariable analyses but not in multivariable analyses adjusted for age and smoking status. Logistic regression adjusted for age and smoking status among WTCHR decedents showed one or more respiratory symptoms to be positively associated with log (arsenic (As)), log(manganese (Mn)) and log(cobalt (Co)) concentrations, while new-onset wheezing and sinus problems were negatively associated with log(Fe) concentration. Fe concentrations among individuals with wheezing, nonetheless, exceeded those in community controls. In conclusion, these data suggest that further research may be warranted to explore the utility as biomarkers of WTC exposure of Fe in particular and, to a lesser extent, Mo, Ti, Cr and Cd in digestions of lung tissue.

Viral and Host Mediators of Non-Suppressible HIV-1 Viremia.

Non-suppressible HIV-1 viremia (NSV) can occur in persons with HIV despite adherence to combination antiretroviral therapy (ART) and in the absence of significant drug resistance. Here, we show that plasma NSV sequences are comprised primarily of large clones without evidence of viral evolution over time. We defined proviruses that contribute to plasma viremia as "producer", and those that did not as "non-producer". Compared to ART-suppressed individuals, NSV participants had a significantly larger producer reservoir. Producer proviruses were enriched in chromosome 19 and in proximity to the activating H3K36me3 epigenetic mark. CD4+ cells from NSV participants demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, NSV participants showed no elevation in HIV-specific CD8+ cell responses and producer proviruses were enriched for HLA escape mutations. We identified critical host and viral mediators of NSV that represent potential targets to disrupt HIV persistence and promote viral silencing.

Viral and host mediators of non-suppressible HIV-1 viremia.

Non-suppressible HIV-1 viremia (NSV) is defined as persistent low-level viremia on antiretroviral therapy (ART) without evidence of ART non-adherence or significant drug resistance. Unraveling the mechanisms behind NSV would broaden our understanding of HIV-1 persistence. Here we analyzed plasma virus sequences in eight ART-treated individuals with NSV (88% male) and show that they are composed of large clones without evidence of viral evolution over time in those with longitudinal samples. We defined proviruses that match plasma HIV-1 RNA sequences as 'producer proviruses', and those that did not as 'non-producer proviruses'. Non-suppressible viremia arose from expanded clones of producer proviruses that were significantly larger than the genome-intact proviral reservoir of ART-suppressed individuals. Integration sites of producer proviruses were enriched in proximity to the activating H3K36me3 epigenetic mark. CD4+ T cells from participants with NSV demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, participants with NSV showed significantly lower HIV-specific CD8+ T cell responses compared with untreated viremic controllers with similar viral loads. We identified potential critical host and viral mediators of NSV that may represent targets to disrupt HIV-1 persistence.

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 categorised 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 haematological 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. FUNDING: US Centers for Disease Control and Prevention (National Institute for Occupational Safety and Health, Agency for Toxic Substances and Disease Registry, and National Center for Environmental Health); New York City Department of Health and Mental Hygiene.