Exploring the neurological features of individuals with germline PTEN variants: A multicenter study.

OBJECTIVE: PTEN, a known tumor suppressor gene, is a mediator of neurodevelopment. Individuals with germline pathogenic variants in the PTEN gene, molecularly defined as PTEN hamartoma tumor syndrome (PHTS), experience a variety of neurological and neuropsychiatric challenges during childhood, including autism spectrum disorder (ASD). However, the frequency and nature of seizures and the utilization of allied health services have not been described. METHODS: Young patients with PHTS and sibling controls were recruited across five centers in the United States and followed every 6-12 months for a mean of 2.1 years. In addition to the history obtained from caregivers, neurodevelopmental evaluations and structured dysmorphology examinations were conducted, and brain MRI findings, received therapies, and epilepsy characteristics were reported. RESULTS: One hundred and seven patients with PHTS (median age 8.7 years; range 3-21 years) and 38 controls were enrolled. ASD and epilepsy were frequent among patients with PHTS (51% and 15%, respectively), with generalized epilepsy strongly associated with ASD. Patients with epilepsy often required two antiseizure medications. Neuroimaging revealed prominent perivascular spaces and decreased peritrigonal myelination in individuals with PHTS-ASD. Allied therapy use was frequent and involved physical, occupational, speech, and social skills therapies, with 89% of all patients with PHTS, regardless of ASD diagnosis, utilizing at least one service. INTERPRETATION: This prospective, longitudinal study highlights the wide neurological spectrum seen in young individuals with PHTS. ASD is common in PHTS, comorbid with epilepsy, and allied health services are used universally. Our findings inform care discussions with families about neurological outcomes in PHTS.

Anisometropia and Amblyopia Outcomes in Early Versus Late Resolution of Congenital Nasolacrimal Duct Obstruction in Older Infants.

PURPOSE: Congenital nasolacrimal duct obstruction is a known risk factor for amblyopia and anisometropia. The purpose of this study was to investigate whether the rate of anisometropia and amblyopia development differed based on the age at CNLDO resolution in older infants. METHODS: This retrospective chart review at a single tertiary children's hospital from 2007 to 2017 compared early versus late spontaneous resolution (cutoff 12 months) and intervention (cutoff 15 months) groups presenting at ≥9 months of age, comparing visual outcomes, including anisometropia (≥1 D of sphere or cylinder) and amblyopia (≥2 levels difference in Teller acuity or optotype testing). Parents/guardians were contacted by phone for missing data on spontaneous resolution or intervention status. RESULTS: A total of 462 patients were included (152 early; 310 late group). The early group presented at a median age of 12.0 (interquartile range: 10.0, 13.0) months, while the late group presented at 21.0 (interquartile range: 15.0, 32.0) months. Unilateral disease occurred in 62% and 59%, respectively. Anisometropia was seen in (12/102) 12% of early versus (25/243) 10% of late patients (p = 0.686, 95% CI: -0.059, 0.088), and amblyopia in (4/131) 3% of early versus (14/286) 5% of late patients (p = 0.322, 95% CI: -0.061, 0.018). In patients presenting <24 months without undergoing surgery, spontaneous resolution occurred in 76% between 12 and 24 months (n = 41). CONCLUSIONS: Anisometropia and amblyopia rates did not significantly differ between early and delayed intervention for congenital nasolacrimal duct obstruction in this retrospective cohort presenting beyond 9 months of age to a children's hospital. This study found frequent late spontaneous resolution.

Cell-free DNA fragmentomics and second malignant neoplasm risk in patients with PTEN hamartoma tumor syndrome.

Individuals with PTEN hamartoma tumor syndrome (PHTS) harbor pathogenic germline PTEN variants that confer a significantly increased lifetime risk of various organ-specific cancers including second primary malignant neoplasms (SMNs). Currently, there are no reliable biomarkers that can predict individual-level cancer risk. Despite the highly promising value of cell-free DNA (cfDNA) as a biomarker for underlying sporadic cancers, the utility of cfDNA in individuals with known cancer-associated germline variants and subclinical cancers remains poorly understood. We perform ultra-low-pass whole-genome sequencing (ULP-WGS) of cfDNA from plasma samples from patients with PHTS and cancer as well as those without cancer. Analysis of cfDNA reveals that patients with PHTS and SMNs have distinct cfDNA size distribution, aberrant genome-wide fragmentation, and differential fragment end motif frequencies. Our work provides evidence that cfDNA profiles may be used as a marker for SMN risk in patients with PHTS.

Post-Acute and Long-Term Care Leaders' Perspectives on Leading During COVID-19.

Post-acute and long-term care (PALTC) delivery is complex, and the COVID-19 pandemic created additional complexities. This qualitative study investigates how PALTC administrators responded to the pandemic, factors that impacted their leadership role and decision-making. Participants from North Carolina (N = 15) and Pennsylvania (N = 6) were interviewed using an interview guide containing open-ended questions. The results revealed three themes: (1) critical knowledge and competencies; (2) resources, supports and essential actions taken; and (3) psychosocial impact. The findings suggest communication and relationship building were the most useful competencies. Lack of staff was a primary stress point during and after the pandemic.

The occurrence of bone and joint cancers and their association with rural living and radon exposure in Iowa.

Primary bone and joint cancers are rare and understudied, yet these neoplasms are difficult to treat and impact all age groups. To explore the long-term changes in the occurrence of bone and joint cancers, patients diagnosed with these neoplasms between 1975 and 2016 were identified in the Surveillance Epidemiology and End Results of the National Cancer Institute of the USA. The age-adjusted incidence (AAIR) and mortality (AAMR) rates were calculated for three decades and compared to AAIR and AAMR in years 1975-1984. By using the population-based cancer registries of the USA, Iowa was identified as a state with increased cases of bone and joint malignancies. The bone and joint cancer cases in Iowa were correlated with the percentage of rural population, the average farmland size, or the residential radon levels. Results demonstrated that the mean AAIR of bone and joint cancers for US female and male patients (< 50 years of age) increased from 0.57 (95% C.I. 0.55-0.63) and 0.76 (95% C.I. 0.69-0.82) for years 1975-1984 to 0.71 (95% C.I. 0.66-0.76) and 0.94 (95% C.I. 0.87-1.07) for years 2005-2014, respectively. The increase in bone and joint cancer cases in Iowa positively correlated with the percentage rural population (R = 0.222, P < 0.02), and the average farmland size (R = 0.236, P < 0.02) but not the radon levels (R = - 0.038, P < 0.7). The findings revealed that patients younger than 50 years of age and those who resided in rural areas and engaged in farming were more likely to be diagnosed with primary bone and joint cancers.

Non-canonical role of wild-type SEC23B in the cellular stress response pathway.

While germline recessive loss-of-function mutations in SEC23B in humans cause a rare form of anaemia, heterozygous change-of-function mutations result in increased predisposition to cancer. SEC23B encodes SEC23 homologue B, a component of coat protein complex II (COPII), which canonically transports proteins from the endoplasmic reticulum (ER) to the Golgi. Despite the association of SEC23B with anaemia and cancer, the precise pathophysiology of these phenotypic outcomes remains unknown. Recently, we reported that mutant SEC23B has non-canonical COPII-independent function, particularly within the ER stress and ribosome biogenesis pathways, and that may contribute to the pathobiology of cancer predisposition. In this study, we hypothesized that wild-type SEC23B has a baseline function within such cellular stress response pathways, with the mutant protein reflecting exaggerated effects. Here, we show that the wild-type SEC23B protein localizes to the nucleus in addition to classical distribution at the ER/Golgi interface and identify multiple putative nuclear localization and export signals regulating nuclear-cytoplasmic transport. Unexpectedly, we show that, independently of COPII, wild-type SEC23B can also localize to cell nucleoli under proteasome inhibition conditions, with distinct distribution patterns compared to mutant cells. Unbiased proteomic analyses through mass spectrometry further revealed that wild-type SEC23B interacts with a subset of nuclear proteins, in addition to central proteins in the ER stress, protein ubiquitination, and EIF2 signalling pathways. We validate the genotype-specific differential SEC23B-UBA52 (ribosomal protein RPL40) interaction. Finally, utilizing patient-derived lymphoblastoid cell lines harbouring either wild-type or mutant SEC23B, we show that SEC23B levels increase in response to ER stress, further corroborating its role as a cellular stress response sensor and/or effector. Overall, these observations suggest that SEC23B, irrespective of mutation status, has unexplored roles in the cellular stress response pathway, with implications relevant to cancer and beyond that, CDAII and normal cell biology.

Interventions to Reduce Healthcare Disparities in Cancer Screening Among Minority Adults: a Systematic Review.

BACKGROUND: Racial minority populations face an increased burden relative to cancer interventions. Compared with Caucasians, the cancer screening rate is substantially lower among African American, Asian American, Latinx American, and American Indian/Alaska Native populations. Barriers such as low health literacy, lack of health insurance, and miscommunication between patients and providers have been identified as important factors that result in low screening rates among minority adults. This study was designed to identify interventions targeting racial minority adults 40 years of age or older that were effective in increasing cancer screening uptake rates. METHODS: A systematic review of articles published in and after January 2009 was conducted using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Twenty-six published studies of cancer screening intervention tested with minority adults were identified through the searches of CINAHL, Global Health, PsycINFO, PubMed, and Scopus databases. RESULTS: Thirteen (50%) of the studies utilized lay community health workers to increase cancer awareness and knowledge and to encourage screening. These methods took place over the telephone, at community education sessions, or within the context of personalized patient navigation support. The intervention programs utilized culturally relevant materials as well as spoken and written information in the targeted population's native language. Various intervention designs resulted in statistically significant increases in cancer screening adherence. However, we found no intervention that consistently elevated cancer screening rates across all racial/ethnic minority adults. CONCLUSIONS: The finding suggests that highly segmented interventions are needed in order to improve cancer screening among various racial/ethnic minority adults.

Associations Between Perceived Environmental Pollution and Mental Health in Middle-Aged and Older Adults in East Asia.

Given the widely used objective measures of environmental pollution in previous research, this study investigated subjective measures in relation to mental health among middle-aged and older adults in three East Asian countries-China, Japan, and South Korea. The samples from the 2010 East Asian Social Survey included 2502 Chinese, 1794 Japanese, and 871 South Korean adults aged 40 and older. Linear regression models were used to examine the associations between mental health measure (SF-12) and 4 perceived environmental pollution indicators (ie, air, water, noise, and pollution index). Greater perceived pollution indicators, as well as the perceived pollution index, were associated with poorer mental health, even after adjusting for covariates in all three countries. Although results need to be further verified in future research, national-level efforts to improve perceptions of environmental pollution may be useful to enhance the mental health of East Asian middle-aged and older adults.

High-throughput SARS-CoV-2 and host genome sequencing from single nasopharyngeal swabs.

During COVID19 and other viral pandemics, rapid generation of host and pathogen genomic data is critical to tracking infection and informing therapies. There is an urgent need for efficient approaches to this data generation at scale. We have developed a scalable, high throughput approach to generate high fidelity low pass whole genome and HLA sequencing, viral genomes, and representation of human transcriptome from single nasopharyngeal swabs of COVID19 patients.

The Use of Online Health-Management Tools and Health Care Utilization Among Older Americans.

BACKGROUND AND OBJECTIVES: The digital divide, or differences in access to technology, can have far-reaching consequences. This study identified disparities in access to online health-related technology. It then investigated associations between online health-related technology use and health care utilization among older adults in the United States. RESEARCH DESIGN AND METHODS: The study used a cross-sectional data set of 1,497 adults aged 51 and older from the 2014 Health and Retirement Study (HRS)'s supplemental module (Health Behaviors) and the RAND version of the HRS fat file. RESULTS: Older age, being a racial/ethnic minority, married, uninsured, and having lower educational attainment, lower income, and reporting poorer health were each associated with lower levels of use of online health-management tools. The use of online health-management tools was associated with a 34% greater mean number of doctor visits (incidence rate ratio = 1.34, SE = 0.10, p < .05) than nonuse. However, such use was not associated with the number or type of hospitalizations. Indeed, only health care needs as measured by self-rated health status (odds ratio [OR] = 0.58, SE = 0.18, p < .05) and the number of chronic conditions were associated with hospitalizations (OR = 1.68, SE = 0.07, p < .05). DISCUSSION AND IMPLICATIONS: While more research is needed to clarify the purposes (e.g., prevention vs. treatment) and outcomes of health care service utilization as a function of technology use, it may be wise to proactively tackle the digital divide as one upstream strategy for improving various health and health care outcomes among older adults.

Literacy, Numeracy, and Health Information Seeking Among Middle-Aged and Older Adults in the United States.

Objectives: Health literacy is often viewed as an essential skill set for successfully seeking health information to make health-related decisions. However, this general understanding has yet to be established with the use of nationally representative data. The objective of this study was to provide the first nationally representative empirical evidence that links health information seeking behaviors with health literacy among middle-age to older adults in the United States. Methods: Data were obtained from the 2012/2014 Program for the International Assessment of Adult Literacy (PIAAC). Our analytic sample is representative of adults age 45 to 74 years (N = 2,989). Results: Distinct components of health literacy (i.e., literacy and numeracy) were uniquely associated with the use of different health information sources (e.g., health professionals, the Internet, television). Discussion: Findings should be useful for government agencies and health care providers interested in targeting health communications, as well as researchers who focus on health disparities.

Numeracy and Preventive Health Care Service Utilization among Middle-Aged and Older Adults in the U.S.

Objectives: Determine whether a specific numeracy skill cut-point(s) reflects an empirical threshold in the context of preventive health service utilization, and identify associations between numeracy and preventive health services utilization among middle-aged and older adults in the United States.Methods: A nationally representative sample (n = 2,989) of adults 45 years and older from the International Assessment of Adult Competencies (PIAAC) was analyzed. Binary logistic regression was used to examine the utilization of dental checkup, vision screening, influenza vaccination, and osteoporosis screening, using multiple numeracy level classifications.Results: A dichotomous classification of numeracy skill levels (low vs. moderate to high proficiency) was associated with dental checkup utilization, but vision screening, influenza vaccination, and osteoporosis screening.Conclusions: Middle-aged and older adults with sufficient numeracy skills are more likely to have had a dental check up in the past 12 months. Findings suggest that numeracy may be more relevant for long-term vs. short-term risk assessment in determining preventive health care service utilization.Clinical Implications: Two-level numeracy categories are recommended in preventive health contexts. Numeracy proficiency-sensitive risk communication by health care providers and education programs may enhance awareness of preventive health care and promote the utilization of specific preventive health service utilization among older adults.

The Roles of Education, Literacy, and Numeracy in Need for Health Information during the Second Half of Adulthood: A Moderated Mediation Analysis.

We examine complex pathways that link health information seeking behavior with education and health literacy (decomposed into general literacy and numeracy), and how these pathways differ by perceived health status (need) among a nationally representative sample of Americans age 50 and older (n = 2,750). Data come from the Program for International Assessment of Adult Competencies (PIAAC). Multi-group structural equation models were used to examine the use of eight health information sources (newspapers, magazines, internet, radio, TV, books, friends/family, and health professionals). Findings partially support the long-standing notion that health seeking behaviors are directly linked to educational attainment, and provide some of the first nationally representative evidence for how education functions through distinct health literacy components to shape health information seeking behaviors by health status. Findings from this moderated mediation analysis point to the importance of examining, and addressing, health literacy disparities in access to and use of health information.

Interspecies Chemical Signaling in a Methane-Oxidizing Bacterial Community.

Multiple species of bacteria oxidize methane in the environment after it is produced by anaerobic ecosystems. These organisms provide reduced carbon substrates for species that cannot oxidize methane themselves, thereby serving a key role in these niches while also sequestering this potent greenhouse gas before it enters the atmosphere. Deciphering the molecular details of how methane-oxidizing bacteria interact in the environment enables us to understand an important aspect that shapes the structures and functions of these communities. Here we show that many members of the Methylomonas genus possess a LuxR-type acyl-homoserine lactone (acyl-HSL) receptor/transcription factor that is highly homologous to MbaR from the quorum-sensing (QS) system of Methylobacter tundripaludum, another methane oxidizer that has been isolated from the same environment. We reconstitute this detection system in Escherichia coli and use mutant and transcriptomic analysis to show that the receptor/transcription factor from Methylomonas sp. strain LW13 is active and alters LW13 gene expression in response to the acyl-HSL produced by M. tundripaludum These findings provide a molecular mechanism for how two species of bacteria that may compete for resources in the environment can interact in a specific manner through a chemical signal.IMPORTANCE Methanotrophs are bacteria that sequester methane, a significant greenhouse gas, and thereby perform an important ecosystem function. Understanding the mechanisms by which these organisms interact in the environment may ultimately allow us to manipulate and to optimize this activity. Here we show that members of a genus of methane-oxidizing bacteria can be influenced by a chemical signal produced by a possibly competing species. This provides insight into how gene expression can be controlled in these bacterial communities via an exogenous chemical signal.

Experienced Subjective Well-Being During Physically Active and Passive Leisure Time Activities Among Adults Aged 65 Years and Older.

BACKGROUND AND OBJECTIVES: The encore years, or later life stages when adults enjoy health and free time, are the prime opportunity for leisure to maximize the overall quality of life. Physically active leisure is widely known to be linked to overall subjective well-being (SWB). However, experienced SWB or momentary emotion during active leisure as well as passive leisure has yet to be examined. RESEARCH DESIGN AND METHODS: Data were derived from the 2012/2013 American Time Use Survey Well-being modules. Propensity score matching (PSM) was used to identify comparable matched samples of older adults. RESULTS: The PSM identified 211 older adults who reported a series of emotions (i.e., happy, meaningful, tired, sad, stressed, pain) during active leisure, and the comparable counterpart (n = 211) during passive leisure. Results from the Wilcoxon Rank Sum tests showed that active leisure was associated with greater levels of experienced happiness and meaningfulness, as well as with lower levels of sadness (p < .05). DISCUSSION AND IMPLICATIONS: Physically active leisure is linked to greater levels of experienced SWB among older adults. Although more detailed roles of active and passive leisure for experienced SWB are yet to be verified, choices that older adults make in their free time may significantly impact their experienced SWB and, in turn, their overall quality of life. Aging and public health policies should enhance accessibility to active leisure to promote older adults' SWB.

Tundrenone: An Atypical Secondary Metabolite from Bacteria with Highly Restricted Primary Metabolism.

Methane-oxidizing bacteria, aerobes that utilize methane as their sole carbon and energy source, are being increasingly studied for their environmentally significant ability to remove methane from the atmosphere. Their genomes indicate that they also have a robust and unusual secondary metabolism. Bioinformatic analysis of the Methylobacter tundripaludum genome identified biosynthetic gene clusters for several intriguing metabolites, and this report discloses the structural and genetic characterization of tundrenone, one of these metabolites. Tundrenone is a highly oxidized metabolite that incorporates both a modified bicyclic chorismate-derived fragment and a modified lipid tail bearing a ß,γ-unsaturated α-hydroxy ketone. Tundrenone has been genetically linked to its biosynthetic gene cluster, and quorum sensing activates its production. M. tundripaludum's genome and tundrenone's discovery support the idea that additional studies of methane-oxidizing bacteria will reveal new naturally occurring molecular scaffolds and the biosynthetic pathways that produce them.

Identifying Consumers Who Search for Long-Term Care on the Web: Latent Class Analysis.

BACKGROUND: Because the internet has become a primary means of communication in the long-term care (LTC) and health care industry, an elevated understanding of market segmentation among LTC consumers is an indispensable step to responding to the informational needs of consumers. OBJECTIVE: This exploratory study was designed to identify underlying market segments of the LTC consumers who seek Web-based information. METHODS: Data on US adult internet users (n=2018) were derived from 2010 Pew Internet and America Life Project. Latent class analysis was employed to identify underlying market segments of LTC Web-based information seekers. RESULTS: Web-based LTC information seekers were classified into the following 2 subgroups: heavy and light Web-based information seekers. Overall, 1 in 4 heavy Web-based information seekers used the internet for LTC information, whereas only 2% of the light information seekers did so. The heavy information seekers were also significantly more likely than light users to search the internet for all other health information, such as a specific disease and treatment and medical facilities. The heavy Web-based information seekers were more likely to be younger, female, highly educated, chronic disease patients, caregivers, and frequent internet users in general than the light Web-based information seekers. CONCLUSIONS: To effectively communicate with their consumers, providers who target Web-based LTC information seekers can more carefully align their informational offerings with the specific needs of each subsegment of LTC markets.

Importance of an alternative approach to measuring quality in a volume-to-value world: a case study of diabetes care.

BACKGROUND: To develop a statistical tool that allows practitioners and/or their practice managers to easily select the relevant range in which volume and value are maximised. METHODS: Data for the study were based on 55 primary care practices that participated in the Colorado Improving Performance in Practice programme in 2014. We used two composite variables including the volume of processes of care variables listed in Diabetes Practice Guidelines and value (quality) as measured by changes in the intermediate outcomes. We assessed volume/value trade-offs using a multilevel model with a time-varying covariate partitioned into a between-practice and within-practice effect. RESULTS: The study revealed a strong linear relationship between volume and value (P<0.0001). Specifically, practices with an above-average volume of care as measured by their process of care scores also had above-average quality outcomes (expected value 57; average volume 49.48) as quantified by their intermediate outcome scores. Additionally, in those months when practices provided a volume of care that exceeded their average process of care score, further improvements occurred in quality as measured by intermediate outcome scores (P<0.0001). CONCLUSION: Such findings suggest an inherent linkage between volume of care and quality. This statistical approach, if provided as an app containing an easy-to-use statistical calculator, will allow practice managers and clinicians to systematically identify volume/quality trade-offs, thereby reducing undertreatment and/or overtreatment among patients with chronicities.

Direct Release of Test Results to Patients Increases Patient Engagement and Utilization of Care.

An important focus for meaningful use criteria is to engage patients in their care by allowing them online access to their health information, including test results. There has been little evaluation of such initiatives. Using a mixed methods analysis of electronic health record data, surveys, and qualitative interviews, we examined the impact of allowing patients to view their test results via patient portal in one large health system. Quantitative data were collected for new users and all users of the patient portal. Qualitative interviews occurred with patients who had received an HbA1c or abnormal Pap result. Survey participants were active patient portal users. Our main measures were patient portal usage, factors associated with viewing test results and utilizing care, and patient and provider experiences with patient portal and direct release. Usage data show 80% of all patient portal users viewed test results during the year. Of survey respondents, 82.7% noted test results to be a very useful feature and 70% agreed that patient portal has made their provider more accessible to them. Interviewed patients reported feeling they should have direct access to test results and identified the ability to monitor results over time and prepare prior to communicating with a provider as benefits. In interviews, both patients and physicians reported instances of test results leading to unnecessary patient anxiety. Both groups noted the benefits of results released with provider interpretation. Quantitative data showed patient utilization to increase with viewing test results online, but this effect is mitigated when results are manually released by physicians. Our findings demonstrate that patient portal access to test results was highly valued by patients and appeared to increase patient engagement. However, it may lead to patient anxiety and increase rates of patient visits. We discuss how such unintended consequences can be addressed and larger implications for meaningful use criteria.