Seroprevalence as an Indicator of Undercounting of COVID-19 Cases in a Large Well-Described Cohort.

Introduction: Reported confirmed cases represent a small portion of overall true cases for many infectious diseases. The undercounting of true cases can be considerable when a significant portion of infected individuals are asymptomatic or minimally symptomatic, as is the case with COVID-19. Seroprevalence studies are an efficient way to assess the extent to which true cases are undercounted during a large-scale outbreak and can inform efforts to improve case identification and reporting. Methods: A longitudinal seroprevalence study of active duty U.S. military members was conducted from May 2020 through June 2021. A random selection of service member serum samples submitted to the Department of Defense Serum Repository was analyzed for the presence of antibodies reactive to SARS-CoV-2. The monthly seroprevalence rates were compared with those of cumulative confirmed cases reported during the study period. Results: Seroprevalence was 2.3% in May 2020 and increased to 74.0% by June 2021. The estimated true case count based on seroprevalence was 9.3 times greater than monthly reported cases at the beginning of the study period and fell to 1.7 by the end of the study. Conclusions: In our sample, confirmed case counts significantly underestimated true cases of COVID-19. The increased availability of testing over the study period and enhanced efforts to detect asymptomatic and minimally symptomatic cases likely contributed to the fall in the seroprevalence to reported case ratio.

Post -acute sequalae of COVID-19 and cardiac outcomes in U. S. military members.

Post -acute sequalae of COVID-19 (PASC) among U.S. military members remains unexplored. A cohort study of U. S. military members who had a COVID-19 test result, with the specimen collected between March 1, 2020 and November 30, 2021 was conducted. Demographic, inpatient and outpatient data including cardiac event diagnoses were extracted from electronic medical records and compared COVID-19 test-positive and COVID-19 test-negative service members. We used univariate and multivariable logistic regression methods to determine the effect PASC on select cardiac events. Among 997,785 service members, 15,779 (1.6%) were diagnosed with a cardiac event. In fully adjusted models, PASC was significantly associated with increased odds of any cardiac event [OR =1.64 (95% CI: 1.57, 1.71]. PASC was associated with increased odds of myocarditis [OR = 5.86 (95% CI: 4.22, 8.15)], pericarditis [OR =3.08 (95% CI: 2.31, 4.11)], syncope [OR =1.52 (95% CI: 1.41, 1.63)], tachycardia [OR =1.72 (95% CI: 1.56, 1.89)], heart failure [OR =2.15 (95% CI: 1.76, 2.63)], bradycardia [OR =1.71 (95% CI: 1.50, 1.96)], and atrial fibrillation [OR =1.33(95% CI: 1.02, 1.74)] in fully adjusted models. In a sensitivity analysis of military members with no history of cardiac events, PASC was still significantly associated with increased odds of any cardiac event [OR =1.75 (95% CI: 1.67, 1.84)]. In conclusion, we observed a significant association between PASC and cardiac outcomes including; myocarditis, pericarditis, and heart failure. These associations were observed in a relatively young and healthy population and among those without pre-existing cardiac diagnoses.

Incidence and Management of Chronic Insomnia, Active Component, U.S. Armed Forces, 2012 to 2021.

The Department of Veterans Affairs and Department of Defense Clinical Practice Guideline (VA/DOD CPG) provides evidence-based management pathways to mitigate the negative consequences of common sleep disorders among service members (SMs). This retrospective cohort study estimated the incidence of chronic insomnia in active component military members from 2012 through 2021 and the percentage of SMs receiving VA/DOD CPG-recommended insomnia treatments. During this period, 148,441 incident cases of chronic insomnia occurred, with an overall rate of 116.1 per 10,000 person-years (p-yrs). A sub-analysis of SMs with chronic insomnia diagnosed during 2019-2020 found that 53.9% received behavioral therapy and 72.7% received pharmacotherapy. As case ages increased, the proportion who received therapy decreased. Co-existing mental health conditions increased the likelihood of receiving therapy for insomnia cases. Clinician education about the VA/DOD CPG may improve utilization of these evidence-based management pathways for SMs with chronic insomnia.

Surveillance of mental and behavioral health care utilization and use of telehealth, active component, U.S. Armed Forces, 1 January 2019-30 September 2020.

This analysis of population-level health care utilization data evaluates changes in monthly counts and rates of medical encounters for mental and behavioral health (MH/BH) conditions and the proportion of care delivered via telehealth among active component military members of the U.S. Armed Forces during the first 6 months (March-September 2020) of the COVID-19 pandemic. Comparisons are also made to the same time period in the previous year (2019). Telehealth usage increased during the early pandemic and was on average 25% higher during March-September 2020 as compared to the previous year. In contrast, MH/BH outpatient visit rates declined modestly between March and May 2020 before rebounding in June and remaining stable through September 2020. The number of bed days attributable to MH/BH conditions also declined during March and April 2020 and was on average 30% lower during March-September 2020 as compared to the same period in the prior year. Continued surveillance is warranted to track MH/BH health care utilization during the later months of the pandemic to ensure that sufficient resources continue to be directed towards MH/BH care to support the health and readiness of active component service members.

Surveillance for Vector-borne Diseases Among Active and Reserve Component Service Members, U.S. Armed Forces, 2016-2020.

This report summarizes data from electronic reports of reportable medical events (RMEs) to examine the incidence of vector-borne infectious diseases among members of the U.S. Armed Forces during a recent 5-year period. Case reports of such diseases were characterized as confirmed, probable, or suspected by the senders of the RME reports. Records of inpatient and outpatient care were not searched to find additional cases. Lyme disease and malaria were the most common diagnoses among confirmed cases. The next most common diagnoses were Zika virus infection, Rocky Mountain spotted fever, and dengue. Those 5 diseases were responsible for 94% of all confirmed vectorborne diseases reported as RMEs. Among the 1,068 RMEs for vector-borne diseases (confirmed, probable, and suspected), there were only 105 such cases that could be linked to a record of hospitalization for the same diagnosis.

Myelin water imaging depends on white matter fiber orientation in the human brain.

PURPOSE: The multi-exponential T2 decay of the MRI signal from cerebral white matter can be separated into short T2 components related to myelin water and long T2 components related to intracellular and extracellular water. In this study, we investigated to what degree the apparent myelin water fraction (MWF) depends on the angle between white matter fibers and the main magnetic field. METHODS: Maps of the apparent MWF were acquired using multi-echo Carr-Purcell-Meiboom-Gill and gradient-echo spin-echo sequences. The Carr-Purcell-Meiboom-Gill sequence was acquired with a TR of 1073 ms, 1500 ms, and 2000 ms. The fiber orientation was mapped with DTI. By angle-wise pooling the voxels across the brain's white matter, orientation-dependent apparent MWF curves were generated. RESULTS: We found that the apparent MWF varied between 25% and 35% across different fiber orientations. Furthermore, the selection of the TR influences the apparent MWF. CONCLUSION: White matter fiber orientation induces a strong systematic bias on the estimation of the apparent MWF. This finding has implications for future research and the interpretation of MWI results in previously published studies.

Incidence of inguinal hernia and repair procedures and rate of subsequent pain diagnoses, active component service members, U.S. Armed Forces, 2010-2019.

An inguinal hernia occurs when an internal organ protrudes through a tear or weak spot in the abdominal muscles. Among U.S. military service members, inguinal hernia is the fourth most prevalent digestive condition in terms of individuals affected and number of medical encounters. This study found that the overall incidence of inguinal hernia diagnoses between 2010 and 2019 among U.S. active component service members was 34.3 per 10,000 person-years. Older service members, males, non-Hispanic whites, and those in combat-specific occupations had comparatively higher incidence rates. Among the 44,898 incident inguinal hernia diagnoses during the surveillance period, 22,349 were followed by an open or laparoscopic inguinal hernia repair procedure. Of these, 12,210 (54.6%) were open and 10,139 (45.4%) were laparoscopic. Among the 22,349 inguinal hernia repair procedures, 6,276 (28.1%) were followed by pain diagnoses within 1 year after the repair procedures. Although the incidence of inguinal hernia diagnoses among active component service members decreased modestly during the surveillance period, the rate of hernia repair peaked in 2013, and the frequency of diagnoses of pain following hernia repair increased between 2010 and 2019.

Measles, mumps, rubella, and varicella among service members and other beneficiaries of the Military Health System, 1 January 2016-30 June 2019.

Measles, mumps, rubella, and varicella (MMR/V) are highly communicable infectious diseases whose causative agents are spread through contact with contaminated surfaces or airborne droplets. Individuals at highest risk for MMR/V infections include infants; unvaccinated or inadequately vaccinated persons; individuals living in communities with low vaccination rates or in crowded, unsanitary conditions; and persons with compromised immune systems. Between 1 January 2016 and 30 June 2019, there were 5 confirmed measles cases and 64 confirmed mumps cases among all Military Health System (MHS) beneficiaries. During this period, no cases of measles were reported among U.S. service members. There were 29 confirmed mumps cases among service members during the surveillance period; 2 cases occurred in 2016, 17 in 2017, 5 in 2018, and 5 in the first 6 months of 2019. There were 6 confirmed rubella cases among all MHS beneficiaries. Among service members, there were 39 confirmed cases of varicella during the surveillance period; 9 cases occurred in 2016, 11 in 2017, 11 in 2018, and 8 in the first 6 months of 2019. Recent trends in MMR/V in both military and civilian populations in the U.S. highlight the importance of primary and booster vaccinations.

Female infertility, active component service women, U.S. Armed Forces, 2013-2018.

This report presents the incidence and prevalence of diagnosed female infertility among active component service women. During 2013-2018, 8,744 active component women of childbearing potential were diagnosed with infertility for the first time, resulting in an overall incidence of 79.3 cases per 10,000 person-years (p-yrs). Compared to their respective counterparts, women in their 30s, non-Hispanic blacks, those in healthcare and pilot/air crew occupations, Army personnel, and those who were married had the highest incidence rates. The incidence of diagnosed female infertility decreased from 85.1 per 10,000 p-yrs in 2013 to 63.6 per 10,000 p-yrs in 2018 despite a concurrent increase in the rate of fertility testing. During the surveillance period, the average annual prevalence of diagnosed female infertility was 1.6%. Of the service women who were diagnosed with infertility for the first time during the surveillance period, 1,808 (20.7%) delivered a live birth within 2 years after the incident infertility diagnosis. Current findings indicate that the prevalence of diagnosed female infertility among active component service women is lower than estimates of self-reported infertility from surveys of U.S. civilians and service women.

Peri-implant marginal bone loss rate pre- and post-loading: An exploratory analysis of associated factors.

OBJECTIVES: To perform an exploratory analysis of factors influencing annual rates of peri-implant marginal bone loss (RBL) calculated over different time frames, at implants unaffected by peri-implantitis. MATERIAL AND METHODS: A total of 154 implants from 86 patients were reviewed at 1.6-6.8 years after placement. Marginal bone levels (MBL) were assessed on intraoral radiographs at three time-points: immediately post-placement, time of loading, and least 1-year post-loading. RBLs (mm/year) were computed using these three time frames and corresponding MBL changes as: RBL placement-loading, RBL loading-review, RBL placement-review. Exploratory ordination of three RBLs, corresponding time durations, and 17 background factors were used for visualization. Hierarchical linear mixed-effects models (MEM) with predictor selection were applied to RBL outcomes. The correlation of actual MBL with MBLs predicted by RBL placement-loading and RBL loading-review was tested. RESULTS: Median RBL placement-loading was 0.9 mm/year (IQR = 2.02), loading-review was 0.06 mm/year (IQR = 0.16), and overall RBL placement-review was 0.21 mm/year (IQR = 0.33). Among-patient variance was highest for RBL placement-loading (SD = 0.66). Longer time predicted lower RBL in all time frames. Shorter time of loading significantly predicted lower RBL placement-review. Augmentation predicted lower RBL placement-loading, while anterior location and older age predicted lower RBLs placement-loading placement-review. Only MBL projected using RBL placement-loading significantly correlated with actual MBL. CONCLUSIONS: Exploratory analysis indicated RBL varied with the time duration used for calculation in pre- and post-loading, and overall periods. In each period, RBL declined with increasing time. Earlier loading predicted lower overall RBL. Higher pre-loading RBL predicted worse actual bone level.

Surveillance for vector-borne diseases among active and reserve component service members, U.S. Armed Forces, 2010-2016.

This report summarizes available health record information about the occurrence of vector-borne infectious diseases among members of the U.S. Armed Forces during a recent 7-year surveillance period. Information about confirmed, possible, and suspected cases was obtained from electronic reports of reportable medical events (RMEs) and records of diagnoses documented during hospitalizations and outpatient healthcare encounters. Lyme disease and malaria were the most common diagnoses among confirmed and possible cases. Diagnoses of chikungunya and Zika were elevated in the years following their respective entries into the Western Hemisphere. Large numbers of diagnoses of arboviral diseases were recorded in the category of suspected cases, but the overwhelming majority were associated with coding errors and tentative diagnoses not subsequently confirmed. For many confirmed cases, documentation could not be found in healthcare databases for positive laboratory tests that would be the basis for confirmation. Discussion covers the limitations of the available data and the importance to surveillance of RMEs, confirmatory laboratory tests, and accurate recording of diagnoses and their codes.

Measles, mumps, rubella, and varicella among service members and other beneficiaries of the Military Health System, 2010-2016.

Measles, mumps, rubella, and varicella (MMR/V) are highly communicable infectious diseases whose causative agents are spread through contact with contaminated surfaces or airborne droplets. Individuals at highest risk for MMR/V infections include infants, unvaccinated or inadequately vaccinated persons, individuals living in communities with low vaccination rates or in crowded and unsanitary conditions, and persons with compromised immune systems. During 2010-2016, there were 11 confirmed measles cases and 76 confirmed mumps cases among all Military Health System (MHS) beneficiaries. Only one of the confirmed cases of measles was in a service member. There were seven confirmed rubella cases among all MHS beneficiaries. Among service members, there were 62 confirmed cases of varicella during the surveillance period. The number of confirmed cases of varicella among service members dropped from 28 cases in 2010 and 27 cases in 2011 to seven confirmed cases in 2012. There were no confirmed cases of varicella among active and reserve component service members during 2013-2016. Recent trends in MMR/V in both military and civilian populations in the U.S. highlight the importance of primary and booster vaccinations.

Inhibition of Foxp3 in cancer cells induces apoptosis of thyroid cancer cells.

Foxp3+ regulatory T cells (Tregs) in lymphocytes facilitate the thyroid tumor growth and invasion. Very limited information is available on Foxp3 expression in thyroid cancer cells and its function is totally unknown. This study demonstrated that Foxp3 expression was increased in thyroid cancer cells. Inhibition of Foxp3 decreased cell proliferation and migration, but increased apoptosis, suggesting a positive role of Foxp3 in cancer growth. Interestingly, Foxp3 inhibition enhanced PPARγ expression and activity. In addition, Foxp3 inhibition downregulated NF-κB subunit p65 and cyclin D1 but upregulated caspase-3 levels. These molecular changes are in line with Foxp3 shRNA-mediated alteration of cell functions. Collectively, our study demonstrates that thyroid cancer cells express a high level of functional Foxp3 and that the inhibition of the Foxp3 suppresses the proliferation and migration but promotes apoptosis, suggesting that targeting Foxp3 in thyroid cancer cells may offer a novel therapeutic option for thyroid cancer.

The cross-talk between estrogen receptor and peroxisome proliferator-activated receptor gamma in thyroid cancer.

BACKGROUND: Estrogen receptor (ER) and peroxisome proliferator-activated receptor gamma (PPARγ) are associated with thyroid tumorigenesis and treatment. However, the interaction between them has not been studied. METHODS: The impact of ER over-expression or down-expression by DNA/small interfering RNA (siRNA) transfection, ERα agonists, and the ERß agonist diarylpropiolnitrile (DPN) on PPARγ expression/activity was examined in papillary thyroid carcinoma (PTC) and anaplastic thyroid carcinoma (ATC) cells. The effects of PPARγ modulation by rosiglitazone (RTZ), a PPARγ ligand, and of PPARγ siRNA on ER expression were determined. Cellular functions reflected by cell proliferation and migration were assayed. Apoptosis was analyzed by terminal deoxynucleotidyl transferase dUTP nick-end labeling, and apoptotic-related proteins were evaluated by Western blot analysis. RESULTS: PPARγ protein and activity were reduced by the over-expression of either ERα or ERß, whereas repression of ERα or ERß increased PPARγ expression. The administration of RTZ counteracted the effects of ER and also reduced their expression, particularly in PTC cells. Moreover, knockdown of PPARγ increased ER expression and activity. Functionally, ERα activation offset the inhibitory effect of PPARγ on cellular functions, but ERß activation aggregated it and induced apoptosis, particularly in PTC cells. Finally, the interaction between ERß and PPARγ enhanced the expression of proapoptotic molecules, such as caspase-3 and apoptosis-inducing factor. CONCLUSIONS: This study provides evidence supporting a cross-talk between ER and PPARγ. The reciprocal interaction between PPARγ and ERß significantly inhibits the proliferation and migration of thyroid cancer cells, providing a new therapeutic strategy against thyroid cancer.

Aldo-keto reductase family 1 member C3 (AKR1C3) is expressed in adenocarcinoma and squamous cell carcinoma but not small cell carcinoma.

Human aldo-keto reductase family 1 member C3 (AKR1C3) was initially identified as a critical enzyme in reducing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α,17ß-diol (3α-diol) and oxidizing 3α-diol to androsterone. Based on these enzymatic activities, AKR1C3 was originally named type 2 3α-hydroxysteroid dehydrogenase (HSD)/type 5 17ß-HSD. Additionally, AKR1C3 was demonstrated to be capable of metabolizing other steroids including estrogen and progesterone. Subsequently, AKR1C3 was shown to possess 11-ketoprostaglandin reductase activity in metabolizing prostaglandins and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. Tissue distribution of AKR1C3 has been detected in both sex hormone-dependent organs such as the testis, breast, endometrium, and prostate as well as sex hormone-independent organs including the kidney and urothelium. Although prominent expression of AKR1C isozymes has been reported in human non-small cell lung carcinoma (NSCLC), the expression of AKR1C3 in small cell carcinoma of the lung has not been described. Also, the expression of AKR1C3 in normal lung has not been described. In this study, we demonstrated strong AKR1C3 immunoreactivity in bronchial epithelium but not in bronchial glands or alveolar pneumocytes. Strong AKR1C3 immunoreactivity was also demonstrated in columnar epithelium but only weak immunoreactivity in squamous epithelium of the gastrointestinal junction. Although AKR1C3 immunoreactivity was absent in small cell carcinoma of the lung, positive AKR1C3 immunoreactivity was extensively present in both adenocarcinoma and squamous cell carcinoma arising from the lung and the gastroesophageal junction. AKR1C3 may serve as an adjunct marker for differentiating small cell carcinoma from NSCLC. However, roles of AKR1C3 in adenocarcinoma, squamous cell carcinoma, and small cell carcinoma pathogenesis require further studies.

Differential expression of type 2 3α/type 5 17ß-hydroxysteroid dehydrogenase (AKR1C3) in tumors of the central nervous system.

Human aldo-keto reductase (AKR) 1C3, type 2 3α-hydroxysteroid dehydrogenase (HSC)/ type 5 17ß-HSD, is known to be involved in steroids, prostaglandins, and lipid aldehydes metabolism. The expression of AKR1C3 has been demonstrated in hormone-dependent normal tissues such as breast, endometrium, prostate, and testis; and de -regulated AKR1C3 expression has been shown in breast carcinoma, endometrial hyperplasia, endometrial carcinoma, and prostate carcinoma. AKR1C3 expression has also been demonstrated in hormone-independent normal tissues (renal tubules and urothelium) and neoplastic tissues (renal cell carcinoma, Wilm's tumor, and urothelial cell carcinoma). Extensive expression of AKR1C3 in normal and neoplastic as well as hormone-dependent and hormone-independent tissues indicates that AKR1C3 may have functions beyond steroid hormone metabolism. In this report, we describe a widespread expression of AKR1C3 in glial neoplasms and meningiomas, with limited expression in medulloblastoma and no expression in Schwannoma. These tumors, except meningioma, are not classically considered to be sex hormone-dependent or related brain tumors. The current results corroborate our earlier observations that AKR1C3 is expressed in both sex hormone-dependent and hormone-independent malignancies. Similar to AKR1C3 distribution in Wilm's tumor, we also demonstrate that expression of AKR1C3 is reduced in tumors with embryonic phenotypes.

Randomized trial of a pain control infusion pump following inguinal hernia repair.

BACKGROUND: Continuous ambulatory analgesia following various surgical procedures is gaining popularity. The purpose of the present paper is to evaluate this form of analgesia following open anterior inguinal hernia repair by way of a pain control infusion pump (PCIP). METHODS: Forty-eight consecutive patients scheduled for inguinal hernia repair were enrolled in a double-blind, randomized, placebo-controlled trial. Following the repair, a catheter was placed in the wound connected to an external PCIP, delivering either ropivacaine or normal saline at a fixed rate of 4 mL/ h. Regular 4-hourly postoperative pain observations according to a Visual Analogue Score (VAS) and any rescue opioid requirements were recorded, at different levels of mobility. RESULTS: Data analysis included 23 (ropivacaine) and 24 (saline) patients in each group, with one exclusion. There were no adverse effects of the PCIP in either group. Patients in the ropivacaine group ('active pump') had lower mean pain scores and less rescue analgesia compared to the saline group ('placebo pump'). This clinical effect was found to be more striking at increased levels of mobility. Importantly, no patients in the ropivacaine group required any rescue analgesia after the first 4-h block postoperatively. CONCLUSION: The PCIP provided safe and adequate analgesia following inguinal hernia repair. It provided effective analgesia especially when patients were mobilizing. This has implications for earlier discharge from hospital and associated cost-savings.