Diet-induced metabolic and immune impairments are sex-specifically modulated by soluble TNF signaling in the 5xFAD mouse model of Alzheimer's disease.

Emerging evidence indicates that high-fat, high carbohydrate diet (HFHC) impacts central pathological features of Alzheimer's disease (AD) across both human incidences and animal models. However, the mechanisms underlying this association are poorly understood. Here, we identify compartment-specific metabolic and inflammatory dysregulations that are induced by HFHC diet in the 5xFAD mouse model of AD pathology. We observe that both male and female 5xFAD mice display exacerbated adiposity, cholesterolemia, and dysregulated insulin signaling. Independent of biological sex, HFHC diet also resulted in altered inflammatory cytokine profiles across the gastrointestinal, circulating, and central nervous systems (CNS) compartments demonstrating region-specific impacts of metabolic inflammation. Interestingly, inhibiting the inflammatory cytokine, soluble tumor necrosis factor (TNF) with the brain-permeant soluble TNF inhibitor XPro1595 was able to restore aspects of HFHC-induced metabolic inflammation, but only in male mice. Targeted transcriptomics of CNS regions revealed that inhibition of soluble TNF was sufficient to alter expression of hippocampal and cortical genes associated with beneficial immune and metabolic responses. Collectively, these results suggest that HFHC diet impairs metabolic and inflammatory pathways in an AD-relevant genotype and that soluble TNF has sex-dependent roles in modulating these pathways across anatomical compartments. Modulation of energy homeostasis and inflammation may provide new therapeutic avenues for AD.

Incomplete tissue product tracing during an investigation of a tissue-derived tuberculosis outbreak.

In the United States, there is currently no system to track donated human tissue products to individual recipients. This posed a challenge during an investigation of a nationwide tuberculosis outbreak that occurred when bone allograft contaminated with Mycobacterium tuberculosis (Lot A) was implanted into 113 patients in 18 US states, including 2 patients at 1 health care facility in Colorado. A third patient at the same facility developed spinal tuberculosis with an isolate genetically identical to the Lot A outbreak strain. However, health care records indicated this patient had received bone allograft from a different donor (Lot B). We investigated the source of this newly identified infection, including the possibilities of Lot B donor infection, product switch or contamination during manufacturing, product switch at the health care facility, person-to-person transmission, and laboratory error. The findings included gaps in tissue traceability at the health care facility, creating the possibility for a product switch at the point of care despite detailed tissue-tracking policies. Nationally, 6 (3.9%) of 155 Lot B units could not be traced to final disposition. This investigation highlights the critical need to improve tissue-tracking systems to ensure unbroken traceability, facilitating investigations of recipient adverse events and enabling timely public health responses to prevent morbidity and mortality.

Phasing segmented telescopes via deep learning methods: application to a deployable CubeSat.

Capturing high-resolution imagery of the Earth's surface often calls for a telescope of considerable size, even from low Earth orbits (LEOs). A large aperture often requires large and expensive platforms. For instance, achieving a resolution of 1 m at visible wavelengths from LEO typically requires an aperture diameter of at least 30 cm. Additionally, ensuring high revisit times often prompts the use of multiple satellites. In light of these challenges, a small, segmented, deployable CubeSat telescope was recently proposed creating the additional need of phasing the telescope's mirrors. Phasing methods on compact platforms are constrained by the limited volume and power available, excluding solutions that rely on dedicated hardware or demand substantial computational resources. Neural networks (NNs) are known for their computationally efficient inference and reduced onboard requirements. Therefore, we developed a NN-based method to measure co-phasing errors inherent to a deployable telescope. The proposed technique demonstrates its ability to detect phasing errors at the targeted performance level [typically a wavefront error (WFE) below 15 nm RMS for a visible imager operating at the diffraction limit] using a point source. The robustness of the NN method is verified in presence of high-order aberrations or noise and the results are compared against existing state-of-the-art techniques. The developed NN model ensures its feasibility and provides a realistic pathway towards achieving diffraction-limited images.

Transmission of Mycobacterium tuberculosis to Healthcare Personnel Resulting From Contaminated Bone Graft Material, United States, June 2021-August 2022.

A nationwide tuberculosis outbreak linked to a viable bone allograft product contaminated with Mycobacterium tuberculosis was identified in June 2021. Our subsequent investigation identified 73 healthcare personnel with new latent tuberculosis infection following exposure to the contaminated product, product recipients, surgical instruments, or medical waste.

Epidemiology of Covid-19 in a Long-Term Care Facility in King County, Washington.

BACKGROUND: Long-term care facilities are high-risk settings for severe outcomes from outbreaks of Covid-19, owing to both the advanced age and frequent chronic underlying health conditions of the residents and the movement of health care personnel among facilities in a region. METHODS: After identification on February 28, 2020, of a confirmed case of Covid-19 in a skilled nursing facility in King County, Washington, Public Health-Seattle and King County, aided by the Centers for Disease Control and Prevention, launched a case investigation, contact tracing, quarantine of exposed persons, isolation of confirmed and suspected cases, and on-site enhancement of infection prevention and control. RESULTS: As of March 18, a total of 167 confirmed cases of Covid-19 affecting 101 residents, 50 health care personnel, and 16 visitors were found to be epidemiologically linked to the facility. Most cases among residents included respiratory illness consistent with Covid-19; however, in 7 residents no symptoms were documented. Hospitalization rates for facility residents, visitors, and staff were 54.5%, 50.0%, and 6.0%, respectively. The case fatality rate for residents was 33.7% (34 of 101). As of March 18, a total of 30 long-term care facilities with at least one confirmed case of Covid-19 had been identified in King County. CONCLUSIONS: In the context of rapidly escalating Covid-19 outbreaks, proactive steps by long-term care facilities to identify and exclude potentially infected staff and visitors, actively monitor for potentially infected patients, and implement appropriate infection prevention and control measures are needed to prevent the introduction of Covid-19.

Household Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Alpha Variant-United States, 2021.

BACKGROUND: In Spring 2021, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.7 (Alpha) became the predominant variant in the United States. Research suggests that Alpha has increased transmissibility compared with non-Alpha lineages. We estimated household secondary infection risk (SIR), assessed characteristics associated with transmission, and compared symptoms of persons with Alpha and non-Alpha infections. METHODS: We followed households with SARS-CoV-2 infection for 2 weeks in San Diego County and metropolitan Denver, January to April 2021. We collected epidemiologic information and biospecimens for serology, reverse transcription-polymerase chain reaction (RT-PCR), and whole-genome sequencing. We stratified SIR and symptoms by lineage and identified characteristics associated with transmission using generalized estimating equations. RESULTS: We investigated 127 households with 322 household contacts; 72 households (56.7%) had member(s) with secondary infections. SIRs were not significantly higher for Alpha (61.0% [95% confidence interval, 52.4-69.0%]) than non-Alpha (55.6% [44.7-65.9%], P = .49). In households with Alpha, persons who identified as Asian or Hispanic/Latino had significantly higher SIRs than those who identified as White (P = .01 and .03, respectively). Close contact (eg, kissing, hugging) with primary cases was associated with increased transmission for all lineages. Persons with Alpha infection were more likely to report constitutional symptoms than persons with non-Alpha (86.9% vs 76.8%, P = .05). CONCLUSIONS: Household SIRs were similar for Alpha and non-Alpha. Comparable SIRs may be due to saturation of transmission risk in households due to extensive close contact, or true lack of difference in transmission rates. Avoiding close contact within households may reduce SARS-CoV-2 transmission for all lineages among household members.

Household Transmission and Symptomology of Severe Acute Respiratory Syndrome Coronavirus 2 Alpha Variant among Children-California and Colorado, 2021.

OBJECTIVE: To assess the household secondary infection risk (SIR) of B.1.1.7 (Alpha) and non-Alpha lineages of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among children. STUDY DESIGN: During January to April 2021, we prospectively followed households with a SARS-CoV-2 infection. We collected questionnaires, serial nasopharyngeal swabs for reverse transcription polymerase chain reaction testing and whole genome sequencing, and serial blood samples for serology testing. We calculated SIRs by primary case age (pediatric vs adult), household contact age, and viral lineage. We evaluated risk factors associated with transmission and described symptom profiles among children. RESULTS: Among 36 households with pediatric primary cases, 21 (58%) had secondary infections. Among 91 households with adult primary cases, 51 (56%) had secondary infections. SIRs among pediatric and adult primary cases were 45% and 54%, respectively (OR, 0.79; 95% CI, 0.41-1.54). SIRs among pediatric primary cases with Alpha and non-Alpha lineage were 55% and 46%, respectively (OR, 1.52; 95% CI, 0.51-4.53). SIRs among pediatric and adult household contacts were 55% and 49%, respectively (OR, 1.01; 95% CI, 0.68-1.50). Among pediatric contacts, no significant differences in the odds of acquiring infection by demographic or household characteristics were observed. CONCLUSIONS: Household transmission of SARS-CoV-2 from children and adult primary cases to household members was frequent. The risk of secondary infection was similar among child and adult household contacts. Among children, household transmission of SARS-CoV-2 and the risk of secondary infection was not influenced by lineage. Continued mitigation strategies (eg, masking, physical distancing, vaccination) are needed to protect at-risk groups regardless of virus lineage circulating in communities.

Identification and description of patients with multisystem inflammatory syndrome in adults associated with SARS-CoV-2 infection using the Premier Healthcare Database.

Multisystem inflammatory syndrome in adults (MIS-A) is a hyperinflammatory illness related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The characteristics of patients with this syndrome and the frequency with which it occurs among patients hospitalised after SARS-CoV-2 infection are unclear. Using the Centers for Disease Control and Prevention case definition for MIS-A, we created ICD-10-CM code and laboratory criteria to identify potential MIS-A patients in the Premier Healthcare Database Special COVID-19 Release, a database containing patient-level information on hospital discharges across the United States. Modified MIS-A criteria were applied to hospitalisations with discharge from March to December 2020. The proportion of hospitalisations meeting electronic health record criteria for MIS-A and descriptive statistics for patients in the potential MIS-A cohort were calculated. Of 34 515 SARS-CoV-2-related hospitalisations with complete clinical and laboratory data, 53 met modified criteria for MIS-A (0.15%). The median age was 62 years (IQR 52-74). Most patients met the severe cardiac illness criterion through either myocarditis (66.0%) or new-onset heart failure (35.8%). A total of 79.2% of patients required ICU admission, while 43.4% of patients in the cohort died. MIS-A appears to be a rare but severe outcome of SARS-CoV-2 infection. Additional studies are needed to investigate how this syndrome differs from severe coronavirus disease 2019 (COVID-19) in adults.

Hemoglobin Target and Transfusion Modality for Adult Patients With Sickle Cell Disease Acute Chest Syndrome.

BACKGROUND: Despite the importance of transfusion in treating sickle cell disease acute chest syndrome, the target hemoglobin and optimal modality for transfusion remain unknown. OBJECTIVES: To compare hospital length of stay (LOS) in intensive care unit (ICU) patients with acute chest syndrome transfused to hemoglobin ≥ 8 g/dL versus patients transfused to hemoglobin < 8 g/dL; and to compare hospital LOS in acute chest syndrome patients treated with and without exchange transfusion. METHODS: We performed a retrospective cohort study of all acute chest syndrome patients treated in the medical ICU at 2 tertiary care hospitals between January 2011 and August 2016 (n = 82). We compared median hospital LOS in patients transfused to hemoglobin ≥ 8 g/dL by the time of ICU transfer to the medical floor versus patients transfused to hemoglobin < 8 g/dL as well as patients who received exchange transfusion versus no exchange transfusion using Wilcoxon rank-sum tests. We modeled the association between hospital LOS and hemoglobin at ICU transfer to the medical floor using multivariable log-linear regression. RESULTS: Median hospital LOS was about half as long for patients transfused to hemoglobin ≥ 8 g/dL versus hemoglobin < 8 g/dL (8.0 versus 16.5 days, P = 0.008). There was no difference in LOS for patients treated with and without exchange transfusion. On average, a 1 g/dL increase in hemoglobin was associated with a 19.5% decrease (95% CI 10.8-28.2%) in LOS, controlling for possible confounding factors. CONCLUSIONS: Transfusion to a hemoglobin target ≥ 8 g/dL is associated with decreased hospital LOS in patients with acute chest syndrome. There was no difference in LOS between patients who received exchange transfusion and those who did not.

Low SARS-CoV-2 Transmission in Elementary Schools - Salt Lake County, Utah, December 3, 2020-January 31, 2021.

School closures affected more than 55 million students across the United States when implemented as a strategy to prevent the transmission of SARS-CoV-2, the virus that causes COVID-19 (1). Reopening schools requires balancing the risks for SARS-CoV-2 infection to students and staff members against the benefits of in-person learning (2). During December 3, 2020-January 31, 2021, CDC investigated SARS-CoV-2 transmission in 20 elementary schools (kindergarten through grade 6) that had reopened in Salt Lake County, Utah. The 7-day cumulative number of new COVID-19 cases in Salt Lake County during this time ranged from 290 to 670 cases per 100,000 persons.† Susceptible§ school contacts¶ (students and staff members exposed to SARS-CoV-2 in school) of 51 index patients** (40 students and 11 staff members) were offered SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) testing. Among 1,041 susceptible school contacts, 735 (70.6%) were tested, and five of 12 cases identified were classified as school-associated; the secondary attack rate among tested susceptible school contacts was 0.7%. Mask use among students was high (86%), and the median distance between students' seats in classrooms was 3 ft. Despite high community incidence and an inability to maintain ≥6 ft of distance between students at all times, SARS-CoV-2 transmission was low in these elementary schools. The results from this investigation add to the increasing evidence that in-person learning can be achieved with minimal SARS-CoV-2 transmission risk when multiple measures to prevent transmission are implemented (3,4).

Tuberculosis - United States, 2019.

Since 1989, the United States has pursued a goal of eliminating tuberculosis (TB) through a strategy of rapidly identifying and treating cases and evaluating exposed contacts to limit secondary cases resulting from recent TB transmission (1). This strategy has been highly effective in reducing U.S. TB incidence (2), but the pace of decline has significantly slowed in recent years (2.2% average annual decline during 2012-2017 compared with 6.7% during 2007-2012) (3). For this report, provisional 2019 data reported to CDC's National Tuberculosis Surveillance System were analyzed to determine TB incidence overall and for selected subpopulations and these results were compared with those from previous years. During 2019, a total of 8,920 new cases were provisionally reported in the United States, representing a 1.1% decrease from 2018.* TB incidence decreased to 2.7 cases per 100,000 persons, a 1.6% decrease from 2018. Non-U.S.-born persons had a TB rate 15.5 times greater than the rate among U.S.-born persons. The U.S. TB case count and rate are the lowest ever reported, but the pace of decline remains slow. In recent years, approximately 80% of U.S. TB cases have been attributed to reactivation of latent TB infection (LTBI) acquired years in the past, often outside the United States (2). An expanded TB elimination strategy for this new decade should leverage existing health care resources, including primary care providers, to identify and treat persons with LTBI, without diverting public health resources from the continued need to limit TB transmission within the United States. Partnerships with health care providers, including private providers, are essential for this strategy's success.

SARS-CoV-2 Transmission and Infection Among Attendees of an Overnight Camp - Georgia, June 2020.

Limited data are available about transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), among youths. During June 17-20, an overnight camp in Georgia (camp A) held orientation for 138 trainees and 120 staff members; staff members remained for the first camp session, scheduled during June 21-27, and were joined by 363 campers and three senior staff members on June 21. Camp A adhered to the measures in Georgia's Executive Order* that allowed overnight camps to operate beginning on May 31, including requiring all trainees, staff members, and campers to provide documentation of a negative viral SARS-CoV-2 test ≤12 days before arriving. Camp A adopted most† components of CDC's Suggestions for Youth and Summer Camps§ to minimize the risk for SARS-CoV-2 introduction and transmission. Measures not implemented were cloth masks for campers and opening windows and doors for increased ventilation in buildings. Cloth masks were required for staff members. Camp attendees were cohorted by cabin and engaged in a variety of indoor and outdoor activities, including daily vigorous singing and cheering. On June 23, a teenage staff member left camp A after developing chills the previous evening. The staff member was tested and reported a positive test result for SARS-CoV-2 the following day (June 24). Camp A officials began sending campers home on June 24 and closed the camp on June 27. On June 25, the Georgia Department of Public Health (DPH) was notified and initiated an investigation. DPH recommended that all attendees be tested and self-quarantine, and isolate if they had a positive test result.

Adolescent with COVID-19 as the Source of an Outbreak at a 3-Week Family Gathering - Four States, June-July 2020.

There is increasing evidence that children and adolescents can efficiently transmit SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19) (1-3). During July-August 2020, four state health departments and CDC investigated a COVID-19 outbreak that occurred during a 3-week family gathering of five households in which an adolescent aged 13 years was the index and suspected primary patient; 11 subsequent cases occurred.

Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection - United Kingdom and United States, March-August 2020.

During the course of the coronavirus disease 2019 (COVID-19) pandemic, reports of a new multisystem inflammatory syndrome in children (MIS-C) have been increasing in Europe and the United States (1-3). Clinical features in children have varied but predominantly include shock, cardiac dysfunction, abdominal pain, and elevated inflammatory markers, including C-reactive protein (CRP), ferritin, D-dimer, and interleukin-6 (1). Since June 2020, several case reports have described a similar syndrome in adults; this review describes in detail nine patients reported to CDC, seven from published case reports, and summarizes the findings in 11 patients described in three case series in peer-reviewed journals (4-6). These 27 patients had cardiovascular, gastrointestinal, dermatologic, and neurologic symptoms without severe respiratory illness and concurrently received positive test results for SARS-CoV-2, the virus that causes COVID-19, by polymerase chain reaction (PCR) or antibody assays indicating recent infection. Reports of these patients highlight the recognition of an illness referred to here as multisystem inflammatory syndrome in adults (MIS-A), the heterogeneity of clinical signs and symptoms, and the role for antibody testing in identifying similar cases among adults. Clinicians and health departments should consider MIS-A in adults with compatible signs and symptoms. These patients might not have positive SARS-CoV-2 PCR or antigen test results, and antibody testing might be needed to confirm previous SARS-CoV-2 infection. Because of the temporal association between MIS-A and SARS-CoV-2 infections, interventions that prevent COVID-19 might prevent MIS-A. Further research is needed to understand the pathogenesis and long-term effects of this newly described condition.

COVID-19 in a Long-Term Care Facility - King County, Washington, February 27-March 9, 2020.

On February 28, 2020, a case of coronavirus disease (COVID-19) was identified in a woman resident of a long-term care skilled nursing facility (facility A) in King County, Washington.* Epidemiologic investigation of facility A identified 129 cases of COVID-19 associated with facility A, including 81 of the residents, 34 staff members, and 14 visitors; 23 persons died. Limitations in effective infection control and prevention and staff members working in multiple facilities contributed to intra- and interfacility spread. COVID-19 can spread rapidly in long-term residential care facilities, and persons with chronic underlying medical conditions are at greater risk for COVID-19-associated severe disease and death. Long-term care facilities should take proactive steps to protect the health of residents and preserve the health care workforce by identifying and excluding potentially infected staff members and visitors, ensuring early recognition of potentially infected patients, and implementing appropriate infection control measures.

Cardiometabolic correlates of sleep disordered breathing in Andean highlanders.

Associations between sleep disordered breathing (SDB) and cardiometabolic outcomes have not been examined in highlanders.We performed nocturnal polygraphy in Peruvian highlanders (3825 m). Multivariable linear regression models examined associations between SDB metrics and haemoglobin, glucose tolerance (haemoglobin A1c (HbA1c)), fasting glucose, homeostatic model-based assessments of insulin resistance and ß-cell function (HOMA-IR and HOMA-ß, respectively), blood pressure, and lipids, while adjusting for age, sex, body mass index (BMI) and wake oxygenation.Participants (n=187; 91 men) were (median (interquartile range)) 52 (45-62) years old, and had a BMI of 27.0 (24.3-29.5) kg·m-2 and 87% (85-88%) oxyhaemoglobin (arterial oxygen) saturation during wakefulness. In fully adjusted models, worsening nocturnal hypoxaemia was associated with haemoglobin elevations in men (p=0.03), independent of wake oxygenation and apnoea-hypopnoea index (AHI), whereas worsening wake oxygenation was associated with haemoglobin elevations in older women (p=0.02). In contrast, AHI was independently associated with HbA1c elevations (p<0.05). In single-variable models, nocturnal hypoxaemia was associated with higher HbA1c, HOMA-IR and HOMA-ß (p<0.001, p=0.02 and p=0.04, respectively), whereas AHI was associated with HOMA-IR, systolic blood pressure and triglyceride elevations (p=0.02, p=0.01 and p<0.01, respectively). These associations were not significant in fully adjusted models.In highlanders, nocturnal hypoxaemia and sleep apnoea were associated with distinct cardiometabolic outcomes, conferring differential risk for excessive erythrocytosis and glucose intolerance, respectively.

Diet-induced metabolic and immune impairments are sex-specifically modulated by soluble TNF signaling in the 5xFAD mouse model of Alzheimer's disease.

Emerging evidence indicates that high-fat, high carbohydrate diet (HFHC) impacts central pathological features of Alzheimer's disease (AD) across both human incidences and animal models. However, the mechanisms underlying this association are poorly understood. Here, we identify compartment-specific metabolic and inflammatory dysregulations that are induced by HFHC diet in the 5xFAD mouse model of AD pathology. We observe that both male and female 5xFAD mice display exacerbated adiposity, cholesterolemia, and dysregulated insulin signaling. Independent of biological sex, HFHC diet also resulted in altered inflammatory cytokine profiles across the gastrointestinal, circulating, and central nervous systems (CNS) compartments demonstrating region-specific impacts of metabolic inflammation. In male mice, we note that HFHC triggered increases in amyloid beta, an observation not seen in female mice. Interestingly, inhibiting the inflammatory cytokine, soluble tumor necrosis factor (TNF) with the brain-permeant soluble TNF inhibitor XPro1595 was able to restore aspects of HFHC-induced metabolic inflammation, but only in male mice. Targeted transcriptomics of CNS regions revealed that inhibition of soluble TNF was sufficient to alter expression of hippocampal and cortical genes associated with beneficial immune and metabolic responses. Collectively, these results suggest that HFHC diet impairs metabolic and inflammatory pathways in an AD-relevant genotype and that soluble TNF has sex-dependent roles in modulating these pathways across anatomical compartments. Modulation of energy homeostasis and inflammation may provide new therapeutic avenues for AD.