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Evaluating the impact of hurricanes and the COVID-19 pandemic on colorectal cancer incidence in Puerto Rico: An interrupted time-series analysis
Get PDFBackground: Major events, such as Hurricanes Irma and Maria and the coronavirus disease 2019 (COVID-19) pandemic disrupted Puerto Rico's health system. Lack of access to colorectal cancer (CRC) screening services may have impeded timely diagnosis. The authors examined the impact of these events on CRC incidence in Puerto Rico.
Methods: The Puerto Rico Central Cancer Registry database allowed the authors to obtain CRC cases from 2012 to 2021. An interrupted time-series analysis was performed to examine changes in CRC incidence immediately after and during the periods after the hurricanes and the pandemic. Analysis periods included: pre-hurricanes, post-hurricanes, and post-COVID-19 lockdown restrictions.
Results: We observed a level change of -8.3 CRC cases was observed in the month the hurricanes struck Puerto Rico, corresponding to an immediate decrease of 17.5%. After a slight upward trend, a second decline of 39.4 CRC cases was estimated after the COVID-19 lockdown restrictions, representing an immediate change of -24.2%. By the end of the study, the estimated numbers of patients with early stage CRC patients and those aged 50-75 years did not reach the expected numbers. In addition, CRC cases in patients with late-stage disease and in those aged younger than 50 years and aged 76 years and older exceeded the expected numbers.
Conclusions: Hurricanes Irma and Maria and the COVID-19 pandemic caused a decrease in CRC incidence in Puerto Rico. This analysis suggests that limited access to CRC screening services during these events likely hindered CRC diagnoses. To fully understand the long-term effects, monitoring of CRC trends will be necessary in the coming years.No embarg
Effect of Early and Delayed Treatment With Remdesivir on Mortality in Patients Hospitalized With COVID-19
No full textBackground: We applied a target trial emulation framework to estimate the association between early and delayed initiation of remdesivir (RDV) with mortality in hospitalized adults between May 1, 2020, and July 31, 2024, with varying coronavirus disease 2019 (COVID-19) clinical severity.
Methods: Using electronic health records in the National COVID Cohort Collaborative (N3C) database, we emulated a sequence of randomized target trials initiated on each of the first 7 days of hospitalization. We identified 373 226 eligible person-trial hospitalizations, of which 53 959 were initiators and 319 267 were noninitiators of RDV treatment. Patients were divided into clinical severity subgroups based on baseline oxygenation, which included no supplemental oxygen (NSO), noninvasive supplemental oxygen (NISO), or invasive ventilation (IV). In each trial, initiators were matched with replacement to noninitiators receiving the same oxygenation type. Trials beginning on days 1-3 and days 4-7 of hospitalization were pooled separately to evaluate the effects of early and delayed initiation of RDV, respectively. Cox proportional hazards regression was used to estimate the marginal hazard ratio for mortality between initiators and noninitiators within each treatment delay.
Results: Across trials, 53 449 initiators were matched to 26 600 unique noninitiators. Early, but not delayed, RDV treatment was associated with a reduction in 60-day mortality in the NSO (hazard ratio [HR], 0.89; 95% CI, 0.84-0.95) and NISO subgroups (HR, 0.91; 95% CI, 0.84-0.99), but not in those receiving IV. Results were consistent across sensitivity analyses.
Conclusions: Early treatment with RDV is associated with reduced mortality risk in hospitalized COVID-19 patients either not on supplemental oxygen or receiving noninvasive supplemental oxygen.The UMass Center for Clinical and Translational Science (UMCCTS), UL1TR001453, helped fund this study.No embarg
ARISE II Consensus on the Management of Intracranial Atherosclerotic Disease
No full textIntracranial atherosclerotic disease (ICAD) is one of the leading causes of ischemic stroke worldwide. Despite advances in its diagnosis and management, there is no clear consensus on best practices to manage ICAD. This report summarizes the ARISE II (Roundtable Discussion With Industry and Stroke Experts) consensus in treating ICAD. The consensus underscored the importance of lifestyle modification and medical management in patients with ICAD. Patients who fail medical management are candidates for endovascular treatment. Open surgery is not recommended in patients who lack demonstrated hemodynamic insufficiency. The consensus also identified gaps in knowledge about the optimal duration of antithrombotics, the effect of the CYP2C19 genotype on medical management, the need for newer devices, and the standardization of antithrombotic protocols before stenting in an acute setting. Optical coherence tomography requires additional clinical data before defining its role in the diagnosis of ICAD.No embarg
Effect of Paxlovid treatment during acute COVID-19 on Long COVID onset: An EHR-based target trial emulation from the N3C and RECOVER consortia
No full textBackground: Preventing and treating post-acute sequelae of COVID-19 infection (PASC), commonly known as Long COVID, has become a public health priority. This study tests whether Paxlovid treatment in the acute phase of COVID-19 could help prevent the onset of PASC.
Methods and findings: We used electronic health records from the National Clinical Cohort Collaborative to define a cohort of 445,738 patients who had COVID-19 since April 1, 2022, and were eligible for Paxlovid treatment due to risk for progression to severe COVID-19. We used the target trial emulation framework to estimate the effect of Paxlovid treatment on PASC incidence. We emulated a series of six sequential trials: one for each day of a 5-day treatment grace period. For each sequential trial, the treatment group was defined as patients prescribed Paxlovid on the trial start day, and the control group was defined as all patients meeting eligibility criteria who remained untreated on the trial start day. We pooled individual record-level data from the sequential trials for analysis. The follow-up period was 180 days. The primary outcome was overall PASC incidence measured using a computable phenotype. Secondary outcomes were incident cognitive, fatigue, and respiratory symptoms in the post-acute period. We controlled for a wide range of demographic and medical history covariates. Compared to the control group, Paxlovid treatment did not have a significant effect on overall PASC incidence or incident respiratory symptoms. It had a small protective effect against cognitive (relative risk [RR] 0.91; 95% CI [0.84, 0.98]; p = 0.019) and fatigue (RR 0.94; 95% CI [0.90, 0.98]; p = 0.002) symptoms. Finally, we estimated Paxlovid's effect on overall PASC incidence across strata of age, COVID-19 vaccination status, and Charlson Comorbidity Index (CCI) prior to COVID-19. We found small protective effects among patients aged 65 years or more (RR 0.92; 95% CI [0.88, 0.97]; p < 0.001; absolute risk difference [ARD] -0.43%; number needed to treat [NNT] 233) and with a CCI of 3 or 4 (RR 0.83; 95% CI [0.75, 0.92]; p < 0.001; ARD -1.30%; NNT 76). This study's main limitation is that the causal interpretation relies on the assumption that we controlled for all confounding variables.
Conclusions: Although some prior observational studies suggested that Paxlovid held promise as a PASC preventive, this study-with a large, nationally sampled cohort; a contemporary study period; and causal inference methodology-found that Paxlovid treatment during acute COVID-19 had no effect on subsequent PASC incidence. Stratified analyses suggest that Paxlovid may have a small protective effect among higher-risk patients, but the NNT is high. In conclusion, we see Paxlovid as unlikely to become a definitive solution for PASC prevention.The UMass Center for Clinical and Translational Science (UMCCTS), UL1TR001453, helped fund this study.No embarg
Association of Systemic Thromboxane Generation With Risk of Developing Heart Failure
No full textBackground: Systemic thromboxane A2 generation, which is readily assessed by quantifying thromboxane B2 metabolites (TXB2-M) in the urine, is associated with impaired cardiac performance and mortality in aspirin (ASA) users with heart failure (HF).
Objectives: This study sought to determine the association of urinary TXB2-M with the risk of developing HF in individuals without prior history of HF and with normal left ventricular function irrespective of ASA use.
Methods: Urine TXB2-M were measured by immunoassay and adjusted to urine concentration and renal function (TXB2-MGFR) in 2,611 Framingham Heart Study participants (54.9% women, mean age 65 ± 9 years, 43.8% ASA users) without prior history of HF and with left ventricular ejection fraction (LVEF) ≥55%. The association of TXB2-MGFR with HF risk over a median observation period of 14.8 years (Q1-Q3: 12.6-15.7 years) was modeled using Cox regression.
Results: HF occurred in 189 participants (7.2%), with 104 of the first events (55.0%) classified as HF with preserved LVEF, 56 (29.6%) as HF with reduced LVEF, and 29 (15.3%) were unclassifiable. TXB2-MGFR levels, above compared to below, of 16.6 and 62.1 filtered prostanoid units for ASA users and nonusers, respectively, were associated with increased risk of developing HF (HR: 1.81; 95% CI: 1.38-2.64; P < 0.0001, adjusted for age, sex, ASA use, and HF risk factors), including both HF subtypes (HF with preserved LVEF: HR: 1.81; 95% CI: 1.17-2.80; P = 0.0081, and HF with reduced LVEF: HR: 2.63; 95% CI: 1.48-4.68; P = 0.0010, adjusted for age, sex, ASA use, and cardiovascular disease). Neither ASA use nor evidence of platelet activation, as measured by plasma P-selectin, were independently associated with HF risk.
Conclusions: Systemic thromboxane A2 generation as measured by urinary TXB2-MGFR was significantly associated with HF risk and remained so after accounting for traditional risk factors. Urinary TXB2-MGFR is therefore a potentially useful novel biomarker to identify at-risk individuals who might benefit from aggressive primary prevention.No embarg
Translational Epigenetics for Trisomy Silencing in a Down Syndrome Mouse Model
No full textEmerging technologies have made significant progress for gene therapies involving monogenic disorders, but chromosomal and microduplication disorders remain outside these therapeutic realms. This work seeks to develop an epigenetic approach built on XIST transgenes as an experimental toolkit to investigate the biology of Down syndrome (DS) and test the promising concept of “chromosome therapy”. We previously demonstrated in human iPSCs that the XIST gene, responsible for X-chromosome dosage compensation, can be translated to “silence trisomy 21”, the cause of DS. The full-length of XIST RNA (14-17 kb) presents technical challenges, but our lab found a tiny XIST minigene that can itself repress a small region around the insertion site in human cells. The goals of this thesis were to translate “trisomy silencing” to a DS mouse model carrying human chr21 (TcMAC21). We tested two approaches: i) an XIST minigene targeted for repression of the chr21 “Down syndrome critical region” and ii) target full-length mouse Xist and study efficacy for chromosome-wide silencing.
First, we demonstrated a new procedure that generated several fully-transgenic mice carrying the minigene, directly from IVF zygotes. The minigene RNA, just 4% of XIST, successfully represses DYRK1A and several genes in the region. Moreover, minigene mice show mitigation of certain phenotypes, including newly discovered cerebellar defects, pre-mature aging and neurodegeneration. Additionally, we have generated chimeric mice in which full length-Xist RNA coats the human chr21 and induces heterochromatin marks in differentiated mouse cells. This research advances translational potential of XIST transgenes as an approach to investigate, and possibly treat, duplication disorders.Interdisciplinary Graduate Program2 years2027-03-2
Genome-wide analyses identify 30 loci associated with obsessive-compulsive disorder
No full textObsessive-compulsive disorder (OCD) affects ~1% of children and adults and is partly caused by genetic factors. We conducted a genome-wide association study (GWAS) meta-analysis combining 53,660 OCD cases and 2,044,417 controls and identified 30 independent genome-wide significant loci. Gene-based approaches identified 249 potential effector genes for OCD, with 25 of these classified as the most likely causal candidates, including WDR6, DALRD3 and CTNND1 and multiple genes in the major histocompatibility complex (MHC) region. We estimated that ~11,500 genetic variants explained 90% of OCD genetic heritability. OCD genetic risk was associated with excitatory neurons in the hippocampus and the cortex, along with D and D type dopamine receptor-containing medium spiny neurons. OCD genetic risk was shared with 65 of 112 additional phenotypes, including all the psychiatric disorders we examined. In particular, OCD shared genetic risk with anxiety, depression, anorexia nervosa and Tourette syndrome and was negatively associated with inflammatory bowel diseases, educational attainment and body mass index.No embarg
Chronic Stenosing Enteritis: A Variant of Chronic Non-specific Stenosing Ulceration (CNSU) that Is Distinct from Crohn's Disease
No full textObjective: Chronic non-specific stenosing ulcers (CNSU) of the small intestine is an under-recognized syndrome characterized by iron-deficiency anemia, superficial ulcerations, and stenoses of the small intestine. Despite the recent identification of a gene mutation SLCO2A1 in some Japanese patients that plays an etiological role, much remains uncertain about the etiology and pathogenesis of CNSU in the Western Hemisphere. We report a similar pattern of non-specific ulceration that is nontransmural and often associated with small intestinal stenosis and iron deficiency but not hypoalbuminemia, and that appears to be distinct from Crohn's disease, and compare the demographic, clinic, and histopathologic features.
Methods: This was a retrospective, single-center study performed at a tertiary care hospital between 2007 and 2019. Forty patients were included, of whom 20 were diagnosed with CNSU and 20 with small intestinal CD. Demographic, clinical, and histopathologic data were collected and compared.
Results: Patients with CNSU were significantly older than patients with CD (56.9-years vs. 33.6-years, p < 0.0001), and had significantly lower rates of diarrhea (10% vs 90%; p < 0.01) and weight loss (5% vs 40%; p = 0.005) and greater rates of blood transfusions (50% vs 10%, p = 0.005) and iron infusions (35% vs. 0%, p = 0.001). In addition, qualitative descriptions of endoscopic findings and histopathologic features differed between the two groups.
Conclusion: CNSU is an uncommon small intestinal disease with clinical and pathologic features that distinguish it from CD. However, the immunology of both conditions is similar, suggesting a generic immune response. Further research is needed to better define the pathogenesis and prognosis of the disease.No embarg
Association between Time and Severe Hypoperfusion with Risk of Hemorrhagic Transformation in Stroke Patients
No full textIntroduction: Perfusion imaging studies show a substantially increased risk of hemorrhagic transformation (HT) in severely hypoperfused tissue. Preclinical evidence indicates that ischemic damage is influenced not only by the degree of hypoperfusion but also by the duration of exposure to that hypoperfused state. We aim to investigate the association of time and severe hypoperfusion with parenchymal hematoma (PH) in ischemic stroke and explore whether there is a combined effect of the two variables on PH.
Methods: Data are from the ESCAPE-NA1 trial, which evaluated the effect of nerinetide in large vessel occlusion patients treated with thrombectomy. This study included patients with some degree of recanalization (expanded Thrombolysis in Cerebral Infarct [eTICI] >0) and available baseline CT perfusion. Severe hypoperfusion was defined as at least 1mL volume of relative cerebral blood flow (rCBF)<20%. We assess 24-hour imaging for the presence of PH, according to Heidelberg bleeding criteria. Univariable and multivariable logistic regression analyses, including interaction terms, were used to assess the effect of time and severe hypoperfusion on outcomes.
Results: Out of 1105 patients from ESCAPE-NA1, 396 (35.8%) were included. The median age was 70 years (IQR=59.8-79.2), 202 (51%) were females, and 50 (12.6%) experienced PH. Onset-to-imaging time (adjusted OR 1.04 [95%CI=1.01-1.06] per 15-minute increase) and the presence of severe hypoperfusion (adjusted OR 2.87 [95%CI=1.47-5.63]) were the only variables associated with PH in multivariable analysis. No significant interaction effect of time and severe hypoperfusion on PH was found. The presence of severe hypoperfusion had a negative predictive value of 98% and a positive predictive value of 39.4% for predicting PH in patients presenting within three hours and after six hours from symptom onset, respectively.
Conclusion: Both severe hypoperfusion and time affect the risk of hemorrhagic transformation. However, the interaction between these two variables was not statistically significant, indicating that their effects on hemorrhagic transformation risk are not dependent on each other. Analyzing these variables may help identify patients with a leaky, severely compromised blood-brain barrier in the ischemic core-a "leaky core."No embarg
Weight-based determination of administered activity in 99mTc-DMSA renal SPECT in infants: are minimum administered activities necessary?
No full textBackground: The North American consensus guidelines recommend a weight-based administered activity for renal cortical scintigraphy with 99mTc-dimercaptosuccinic acid (DMSA; 1.85 MBq/kg or 0.05 mCi/kg). Patients weighing less than 10 kg are recommended to receive a minimum administered activity of 18.5 MBq (0.5 mCi), irrespective of their weight. This approach is presumably to provide sufficient counts for adequate image quality, but it has not been rigorously evaluated.
Objective: To compare the adequacy of image quality of infant DMSA renal SPECT examinations obtained using the minimum administered activity recommended by the consensus guidelines with simulated data utilizing a strict weight-based dosage.
Materials and methods: Phase 1: Datasets of 55 infants (29 females, 26 males, median age 3.0 months and weight 5.6 kg) undergoing DMSA SPECT from 2016 to 2021 were identified with 7 used for training and 48 used for study analysis. Data from patients receiving the administered activity recommended by the consensus guidelines ("full dosage", group A) were processed using binomial resampling to add Poisson noise to mimic a strict weight-based scheme ("simulated reduced dosage", group A'). Three experienced nuclear medicine physicians, who were blinded to group membership and clinical information, independently evaluated adequacy of image quality for clinical interpretation on a 4-point scale. Student's paired t-test was utilized for group comparisons and inter-rater agreements were calculated using kappa statistics. Phase 2: Group A' simulated data were compared to a second cohort of 99mTc-DMSA SPECT cases where the administered activity followed a strict weight-based regime ("true reduced dosage", group B). Subjects weighing between 4-7 kg were selected (group A', 10 patients, 4 females, 6 males, median age 3.00 months and weight 5.35 kg) to compare with similar-weight group B subjects (10 patients, 5 females, 5 males, median age 2.50 months and weight 6.05 kg). The same observers and 4-point scale from phase 1 were used. The Wilcoxon rank sum test was utilized for analysis.
Results: Observers' ratings were combined for analysis resulting in n=144 case-pairs (3 observers × 48 case-pairs) in phase 1. In phase 1, the ratings of groups A and A' were identical for 73.6% (106/144) of case-pairs and never differed by more than ±1 level. No significant rating difference was found between the groups (mean (SD) of 1.17 (0.93) versus 1.22 (0.98), P=0.20). Similarly, in phase 2, no significant rating difference was found between groups A' and B (mean (SD) of 0.80 (0.81) versus 0.50 (0.68), P=0.14).
Conclusion: There was no significant difference in the adequacy of image quality of 99mTc-DMSA SPECT examinations using a strict weight-based dosage compared to using the recommended minimum dosage for infants as small as 3 kg.No embarg