Faculty Bibliography

OBJECTIVES/OBJECTIVE:Characterisation of firefighters' exposures to dangerous chemicals in smoke from non-wildfire incidents, directly through personal monitoring and indirectly from work-related records, is scarce. The aim of this study was to evaluate the association between smoke particle exposures (P) and pulmonary function. METHODS:). Models controlled for age, race/ethnicity, height, smoking and weight. RESULTS:(β=-26.87; 95% CI=-34.54 to -19.20). When evaluating P estimated within 3 months of a pulmonary function test (PFT), stronger associations were observed among those most highly exposed to the World Trade Center (WTC) disaster (β=-12.90; 95% CI=-22.70 to -2.89); the association of cumulative exposures was similar for both highly and less highly exposed individuals. DISCUSSION/CONCLUSIONS:Smoke particle exposures were observed to have modest short-term and long-term associations with pulmonary function, particularly in those who, previously, had high levels of WTC exposure. Future work examining the association between P and pulmonary function among non-WTC exposed firefighters will be essential for disentangling the effects of ageing, routine firefighting and WTC exposures.

Alzheimer's disease typically progresses in stages, which have been defined by the presence of disease-specific biomarkers: amyloid (A), tau (T) and neurodegeneration (N). This progression of biomarkers has been condensed into the ATN framework, in which each of the biomarkers can be either positive (+) or negative (-). Over the past decades, genome-wide association studies have implicated ∼90 different loci involved with the development of late-onset Alzheimer's disease. Here, we investigate whether genetic risk for Alzheimer's disease contributes equally to the progression in different disease stages or whether it exhibits a stage-dependent effect. Amyloid (A) and tau (T) status was defined using a combination of available PET and CSF biomarkers in the Alzheimer's Disease Neuroimaging Initiative cohort. In 312 participants with biomarker-confirmed A-T- status, we used Cox proportional hazards models to estimate the contribution of APOE and polygenic risk scores (beyond APOE) to convert to A+T- status (65 conversions). Furthermore, we repeated the analysis in 290 participants with A+T- status and investigated the genetic contribution to conversion to A+T+ (45 conversions). Both survival analyses were adjusted for age, sex and years of education. For progression from A-T- to A+T-, APOE-e4 burden showed a significant effect [hazard ratio (HR) = 2.88; 95% confidence interval (CI): 1.70-4.89; P < 0.001], whereas polygenic risk did not (HR = 1.09; 95% CI: 0.84-1.42; P = 0.53). Conversely, for the transition from A+T- to A+T+, the contribution of APOE-e4 burden was reduced (HR = 1.62; 95% CI: 1.05-2.51; P = 0.031), whereas the polygenic risk showed an increased contribution (HR = 1.73; 95% CI: 1.27-2.36; P < 0.001). The marginal APOE effect was driven by e4 homozygotes (HR = 2.58; 95% CI: 1.05-6.35; P = 0.039) as opposed to e4 heterozygotes (HR = 1.74; 95% CI: 0.87-3.49; P = 0.12). The genetic risk for late-onset Alzheimer's disease unfolds in a disease stage-dependent fashion. A better understanding of the interplay between disease stage and genetic risk can lead to a more mechanistic understanding of the transition between ATN stages and a better understanding of the molecular processes leading to Alzheimer's disease, in addition to opening therapeutic windows for targeted interventions.

BACKGROUND/UNASSIGNED:The emergency personnel who responded to the World Trade Center (WTC) attacks endured severe occupational exposures, yet the prevalence of cognitive impairment remains unknown among WTC-exposed-FDNY-responders. The present study screened for mild and severe cognitive impairment in WTC-exposed FDNY responders using objective tests, compared prevalence rates to a cohort of non-FDNY WTC-exposed responders, and descriptively to meta-analytic estimates of MCI from global, community, and clinical populations. METHODS/UNASSIGNED:= 7102) who completed the MoCA during a similar time frame. RESULT/UNASSIGNED:< .001) and meta-analytic estimates from different global, community, and clinical populations. Following NIA-AA diagnostic guidelines, 4.96% of WTC-exposed-FDNY-responders met the criteria for severe impairments (95% CI = [2.91% to 7.82%]), a prevalence that remained largely unchanged after excluding responders over the age of 65 years. DISCUSSION/UNASSIGNED:There is a high prevalence of mild and severe cognitive impairment among WTC-responders highlighting the putative role of occupational/environmental and disaster-related exposures in the etiology of accelerated cognitive decline.

OBJECTIVES:Iatrogenic cutaneous siderosis is a well-recognized dermatologic complication after parenteral iron infusion. The condition manifests as discrete, hyperpigmented patches near the site of injection. Most cases do not resolve spontaneously, leading to significant aesthetic and psychological distress to patients. A recent case of iatrogenic cutaneous siderosis at our institution prompted a systematic review of the efficacy of energy-based devices previously reported in the treatment of this condition. METHODS:PubMed and Cochrane databases were searched for all peer-reviewed articles published using the following search terms: "iron OR heme OR hemosiderosis OR siderosis" and "hyperpigmentation OR staining OR tattoo." Articles reporting on energy-based devices in the treatment of iron-induced hyperpigmentation were included. RESULTS:depending on both the device and spot size. Outcomes were measured after an average of 5.4 laser treatments and 10.4 months, with over half of all reported patients experiencing complete clearance (27/50, 54%). Our patient received treatment in three test areas with picosecond alexandrite 785 nm, nanosecond Nd:YAG 532 nm, and picosecond Nd:YAG 532 nm devices. The nanosecond Nd:YAG 532 nm treated area demonstrated the greatest improvement, and the entire arm was subsequently treated with this device. CONCLUSIONS:Despite the often intractable nature of iatrogenic cutaneous siderosis, laser surgery is a reasonable and safe treatment modality for patients seeking cosmetic improvement of this dyschromia. Dermatologists should be aware of this entity and the efficacy of the energy-based devices currently in our armamentarium. A combination approach may need to be utilized with different wavelengths and pulsed widths to target iron pigment in both dermal and subcutaneous layers.

Insulin, insulin-like growth factors (IGF) and their receptors are highly expressed in the adult hippocampus. Thus, disturbances in the insulin-IGF signalling pathway may account for the selective vulnerability of the hippocampus to nascent Alzheimer's disease (AD) pathology. In the present study, we examined the predominant IGF-binding protein in the CSF, IGFBP2. CSF was collected from 109 asymptomatic members of the parental history-positive PREVENT-AD cohort. CSF levels of IGFBP2, core AD and synaptic biomarkers were measured using proximity extension assay, ELISA and mass spectrometry. Cortical amyloid-beta (Aβ) and tau deposition were examined using 18F-NAV4694 and flortaucipir. Cognitive assessments were performed during up to 8 years of follow-up, using the Repeatable Battery for the Assessment of Neuropsychological Status. T1-weighted structural MRI scans were acquired, and neuroimaging analyses were performed on pre-specified temporal and parietal brain regions. Next, in an independent cohort, we allocated 241 dementia-free ADNI-1 participants into four stages of AD progression based on the biomarkers CSF Aβ42 and total-tau (t-tau). In this analysis, differences in CSF and plasma IGFBP2 levels were examined across the pathological stages. Finally, IGFBP2 mRNA and protein levels were examined in the frontal cortex of 55 autopsy-confirmed AD and 31 control brains from the Quebec Founder Population (QFP) cohort, a unique population isolated from Eastern Canada. CSF IGFBP2 progressively increased over 5 years in asymptomatic PREVENT-AD participants. Baseline CSF IGFBP2 was positively correlated with CSF AD biomarkers and synaptic biomarkers, and negatively correlated with longitudinal changes in delayed memory (P = 0.024) and visuospatial abilities (P = 0.019). CSF IGFBP2 was negatively correlated at a trend-level with entorhinal cortex volume (P = 0.082) and cortical thickness in the piriform (P = 0.039), inferior temporal (P = 0.008), middle temporal (P = 0.014) and precuneus (P = 0.033) regions. In ADNI-1, CSF (P = 0.009) and plasma (P = 0.001) IGFBP2 were significantly elevated in Stage 2 [CSF Aβ(+)/t-tau(+)]. In survival analyses in ADNI-1, elevated plasma IGFBP2 was associated with a greater rate of AD conversion (hazard ratio = 1.62, P = 0.021). In the QFP cohort, IGFBP2 mRNA was reduced (P = 0.049); however, IGFBP2 protein levels did not differ in the frontal cortex of autopsy-confirmed AD brains (P = 0.462). Nascent AD pathology may induce an upregulation in IGFBP2 in asymptomatic individuals. CSF and plasma IGFBP2 may be valuable markers for identifying CSF Aβ(+)/t-tau(+) individuals and those with a greater risk of AD conversion.

OBJECTIVE:As the prognosis for endometrial cancer is excellent, management of the effects of estrogen deprivation has an important influence on quality of life. We examined the trends in the use of estrogen replacement therapy (ERT) and non-hormonal medications among patients with uterine cancer following surgery. METHODS:The MarketScan Database was used to identify patients 18-49 years who underwent hysterectomy plus oophorectomy and those aged 50-75 years who underwent hysterectomy between 2008 and 2020. ERT and non-hormonal treatments of menopause were identified preoperatively and postoperatively. After propensity score balancing, difference-in-differences (DID) analyses were performed to compare the pre-and-postoperative changes in ERT and non-hormonal medication use between groups. The trends in postoperative use of ERT were assessed and tested using Cochran-Armitage trend tests. RESULTS:A total of 19,700 patients with uterine cancer and 185,150 controls were identified. Overall, postoperative ERT use decreased for both age groups and for patients with and without uterine cancer. The DID in ERT use between those with uterine cancer and those with benign pathology after hysterectomy was -37.1% (95% CI, -40.5 to -33.6%) for patients 18-49 years of age and - 10.4% (95% CI, -10.9 to -9.9%) for those 50-75 years. The DID for non-hormonal medication use between those with uterine cancer and those with benign pathology after hysterectomy was 11.2% (95% CI, 7.8 to 14.7%) for younger patients and 3.4% (95% CI, 2.9 to 4.0%) for those 50-75 years. The postoperative new ERT use has been declining over time in patients with uterine cancer in those 18-49 years of age (P = .02) and those 50-75 years of age (P < .001). CONCLUSIONS:The use of ERT is uncommon and has declined over time in patients with uterine cancer. Conversely, non-hormonal medications are more commonly used among patients with uterine cancer.

OBJECTIVE:To evaluate the association between hospital volume and the quality of gynecologic emergency care for tubal ectopic pregnancies, ovarian torsion, and pelvic inflammatory disease (PID). METHODS:In this cross-sectional analysis, we analyzed patients who presented for emergency care for tubal ectopic pregnancies, ovarian torsion, and PID using the Premier Healthcare Database from 2006 to 2020. We measured the following outcomes: methotrexate use for ectopic pregnancy, ovarian cystectomy for torsion, and guideline-based antibiotic use for PID. For each condition, we measured outlier hospitals that performed the above interventions at below the 10th percentile. Multivariable logistic regression models were used to analyze associations between outlier care and hospital factors such as annualized mean case volume, urban or rural location, teaching status, bed capacity, and geographic region, as well as hospital-level patient population factors, including age, insurance status, and race. RESULTS:A total of 602 hospitals treated patients with tubal ectopic pregnancies, of which 21.9% were outliers, with no cases managed with methotrexate. Of 512 hospitals treating patients with ovarian torsion, 17.4% were outliers, with no cases managed with cystectomy. Of 929 hospitals that treated patients with PID, 9.9% were deemed outliers with low rates of guideline-adherent antibiotic administration. Low-volume hospitals were more likely to be outliers with low rates of use of methotrexate for ectopic pregnancy (6.7% of high-volume hospitals vs 49.7% of low-volume hospitals were outliers; adjusted odds ratio [aOR] 0.13, 95% CI, 0.05-0.31 for high-volume hospitals) and cystectomy for torsion (34.9% of low-volume vs 2.4% of high-volume hospitals were outliers; aOR 0.05, 95% CI, 0.01-0.18 for high-volume hospitals). There was no association between hospital volume and lower rates of guideline-based antibiotic use for PID. CONCLUSION/CONCLUSIONS:Higher hospital volume is associated with use of conservative, fertility-preserving treatment of emergency gynecologic conditions, including ectopic pregnancy and ovarian torsion.