Mid-life sleep is associated with cognitive performance later in life in aging American Indians: data from the Strong Heart Study.

Background: Sleep-related disorders have been associated with cognitive decline and neurodegeneration. American Indians are at increased risk for dementia. Here, we aim to characterize, for the first time, the associations between sleep characteristics and subsequent cognitive performance in a sample of aging American Indians. Methods: We performed analyses on data collected in two ancillary studies from the Strong Heart Study, which occurred approximately 10 years apart with an overlapping sample of 160 American Indians (mean age at follow-up 73.1, standard deviation 5.6; 69.3% female and 80% with high school completion). Sleep measures were derived by polysomnography and self-reported questionnaires, including sleep timing and duration, sleep latency, sleep stages, indices of sleep-disordered breathing, and self-report assessments of poor sleep and daytime sleepiness. Cognitive assessment included measures of general cognition, processing speed, episodic verbal learning, short and long-delay recall, recognition, and phonemic fluency. We performed correlation analyses between sleep and cognitive measures. For correlated variables, we conducted separate linear regressions. We analyzed the degree to which cognitive impairment, defined as more than 1.5 standard deviations below the average Modified Mini Mental State Test score, is predicted by sleep characteristics. All regression analyses were adjusted for age, sex, years of education, body mass index, study site, depressive symptoms score, difference in age from baseline to follow-up, alcohol use, and presence of APOE e4 allele. Results: We found that objective sleep characteristics measured by polysomnography, but not subjective sleep characteristics, were associated with cognitive performance approximately 10 years later. Longer sleep latency was associated with worse phonemic fluency (ß = -0.069, p = 0.019) and increased likelihood of being classified in the cognitive impairment group later in life (odds ratio 1.037, p = 0.004). Longer duration with oxygen saturation < 90% was associated with better immediate verbal memory, and higher oxygen saturation with worse total learning, short and long-delay recall, and processing speed. Conclusion: In a sample of American Indians, sleep characteristics in midlife were correlated with cognitive performance a decade later. Sleep disorders may be modifiable risk factors for cognitive impairment and dementia later in life, and suitable candidates for interventions aimed at preventing neurodegenerative disease development and progression.

Implementation and Performance of a Point-of-Care COVID-19 Test Program in 4,000 California Schools.

OBJECTIVE: To evaluate the feasibility and accuracy of an unprecedented COVID-19 antigen testing program in schools, which required a healthcare provider order, laboratory director, a Clinical Laboratory Improvement Amendments (CLIA) certificate of waiver, as well as training of school personnel. STUDY DESIGN: Descriptive report of a point-of-care, school-based antigen testing program in California from 8/1/2021 through 5/30/2022, in which participants grades K-12 self-swabbed and school personnel performed testing. Participants included 944,009 students, personnel, and community members from 4,022 California K-12 schools. Outcomes measured include sensitivity and specificity (with polymerase chain reaction [PCR] as comparator), of the Abbott BinaxNOW™ antigen test, number of tests performed, and active infections identified. RESULTS: Of 102,022 paired PCR/antigen tests, the overall sensitivity and specificity for the antigen test was 81.2% (95%CI:80.5%-81.8%) and 99.6% (95%CI:99.5%-99.6%), respectively using cycle threshold (Ct) values <30. During January through March 2022, the highest prevalence period, the positive predictive value (PPV) of antigen testing was 94.7% and the negative predictive value was 94.2%. Overall, 4,022 school sites were enrolled and 3,987,840 million antigen tests were performed on 944,009 individuals. A total of 162,927 positive antigen tests were reported in 135,163 individuals (14.3% of persons tested). CONCLUSIONS: Rapidly implementing a school-based testing program in thousands of schools is feasible. Self-swabbing and testing by school personnel can yield accurate results. On-site COVID-19 testing is no longer necessary in schools, but this model provides a framework for future infectious disease threats.

Antibiotic Treatment and Health Care Use in Children and Adolescents With Conjunctivitis.

This cohort study examines ambulatory care revisits and same-day topical antibiotic prescription in insured patients with acute infectious conjunctivitis.

Nilgai antelope display no signs of infection upon experimental challenge with a virulent Babesia bovis strain.

BACKGROUND: Bovine babesiosis is caused by infection with the protozoal parasite Babesia bovis, which is transmitted by Rhipicephalus (Boophilus) spp. It can cause mortality rates up to 90% in immunologically naive Bos taurus cattle. In south Texas, R. (B.) microplus is known to infest nilgai antelope (Boselaphus tragocamelus); however, their susceptibility to infection with B. bovis and their role in the transmission of the parasite remain unknown. In this study, we challenged nilgai antelope with B. bovis and evaluated their susceptibility to infection. METHODS: Nilgai were needle inoculated with ≈108 B. bovis-parasitized erythrocytes (merozoites) or a homogenate of B. bovis-infected larval ticks (sporozoite) delivered intravenously. Bos taurus beef calves were inoculated in parallel, as this strain of B. bovis is lethal to cattle. Temperature and hematocrit were monitored daily over the course of each study, and whole blood was collected for molecular [polymerase chain reaction (PCR)] and serological [indirect enzyme-linked immunosorbent assay (ELISA)] diagnostic evaluation. Histological sections of nilgai cerebral tissue were examined for evidence of infection. Recipient bovine calves were sub-inoculated with blood from nilgai challenged with either stage of the parasite, and they were monitored for clinical signs of infection and evaluated by a PCR diagnostic assay. Red blood cells (RBCs) from prechallenged nilgai and B. taurus beef cattle were cultured with an in vitro B. bovis merozoite culture to examine colonization of the RBCs by the parasite. RESULTS: Nilgai did not display clinical signs of infection upon inoculation with either the merozoite or sporozoite stage of B. bovis. All nilgai were PCR-negative for the parasite, and they did not develop antibodies to B. bovis. No evidence of infection was detected in histological sections of nilgai tissues, and in vitro culture analysis indicated that the nilgai RBCs were not colonized by B. bovis merozoites. Cattle subinoculated with blood from challenged nilgai did not display clinical signs of infection, and they were PCR-negative up to 45 days after transfer. CONCLUSIONS: Nilgai do not appear to be susceptible to infection with a strain of B. bovis that is lethal to cattle. Tick control on these alternative hosts remains a critical priority, especially given their potential to disseminate ticks over long distances.

Toxoplasma replication is inhibited by MMV676477 without development of resistance.

Protozoan parasites cause life-threatening infections in both humans and animals, including agriculturally significant livestock. Available treatments are typically narrow spectrum and are complicated by drug toxicity and the development of resistant parasites. Protozoan tubulin is an attractive target for the development of broad-spectrum antimitotic agents. The Medicines for Malaria Pathogen Box compound MMV676477 was previously shown to inhibit replication of kinetoplastid parasites, such as Leishmania amazonensis and Trypanosoma brucei, and the apicomplexan parasite Plasmodium falciparum by selectively stabilizing protozoan microtubules. In this report, we show that MMV676477 inhibits intracellular growth of the human apicomplexan pathogen Toxoplasma gondii with an EC50 value of ~50 nM. MMV676477 does not stabilize vertebrate microtubules or cause other toxic effects in human fibroblasts. The availability of tools for genetic studies makes Toxoplasma a useful model for studies of the cytoskeleton. We conducted a forward genetics screen for MMV676477 resistance, anticipating that missense mutations would delineate the binding site on protozoan tubulin. Unfortunately, we were unable to use genetics to dissect target interactions because no resistant parasites emerged. This outcome suggests that future drugs based on the MMV676477 scaffold would be less likely to be undermined by the emergence of drug resistance.

Metformin for endometrial hyperplasia.

BACKGROUND: Endometrial cancer is one of the most common gynaecological cancers in the world. Rates of endometrial cancer are rising, in part because of rising obesity rates. Endometrial hyperplasia is a precancerous condition in women that can lead to endometrial cancer if left untreated. Endometrial hyperplasia occurs more commonly than endometrial cancer. Progesterone tablets that are currently used to treat women with endometrial hyperplasia are associated with adverse effects in up to 84% of women. A levonorgestrel intrauterine device may improve compliance, but it is invasive, is not acceptable to all women, and is associated with irregular vaginal bleeding in 82% of cases. Therefore, an alternative treatment for women with endometrial hyperplasia is needed. Metformin, a drug that is often used to treat people with diabetes, has been shown, in some human studies, to reverse endometrial hyperplasia. However, the effectiveness and safety of metformin for treatment of endometrial hyperplasia remain uncertain. This is an update of a review first published in 2017. OBJECTIVES: To determine the effectiveness and safety of metformin in treating women with endometrial hyperplasia. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Specialised Register, CENTRAL, MEDLINE, PubMed, Embase, Google Scholar, OpenGrey, LILACS, and two trials registers from inception to 5 September 2022. We searched the bibliographies of all relevant studies, and contacted experts in the field for any additional trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cross-over trials comparing metformin (used alone or in combination with other medical therapies) versus placebo, no treatment, any conventional medical treatment, or any other active intervention for women with histologically confirmed endometrial hyperplasia of any type. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility, extracted data from included studies, assessed the risk of bias in the included studies, and assessed the certainty of the evidence for each outcome. We resolved disagreements by discussion or by deferring to a third review author. When study details were missing, review authors contacted the study authors. The primary outcome of this review was regression of endometrial hyperplasia histology (with or without atypia) towards normal histology. MAIN RESULTS: We included seven RCTs, in which a total of 387 women took part. In the comparison, Metformin plus megestrol versus megestrol alone, we rated the certainty of the evidence as low for the outcome, regression of endometrial hyperplasia. We rated the quality of the evidence as very low for the rest of the outcomes, in all three comparisons. Although there was a low risk of selection bias, there was a high risk of bias in the blinding of personnel and outcome assessment (performance bias and detection bias) in many studies. This update identified four new RCTs and six ongoing RCTs. Metformin versus megestrol We are uncertain whether metformin increases the regression of endometrial hyperplasia towards normal histology over megestrol (odds ratio (OR) 4.89, 95% confidence interval (CI) 1.56 to 15.32; P = 0.006; 2 RCTs, 83 participants; I² = 7%; very low-certainty evidence). This evidence suggests that if the rate of regression with megestrol is 61%, the rate of regression with metformin would be between 71% and 96%. It is unresolved whether metformin results in different rates of abnormal uterine bleeding or hysterectomy compared to megestrol. No study in this comparison reported progression of hyperplasia to endometrial cancer, recurrence of endometrial hyperplasia, health-related quality of life, or adverse effects during treatment. Metformin plus megestrol versus megestrol monotherapy The combination of metformin and megestrol may enhance the regression of endometrial hyperplasia towards normal histology more than megestrol alone (OR 3.27, 95% CI 1.65 to 6.51; P = 0.0007; 4 RCTs, 258 participants; I² = 0%, low-certainty evidence). This suggests that if the rate of regression with megestrol monotherapy is 54%, the rate of regression with the addition of metformin would be between 66% and 84%. In one study, 3/8 (37.5%) of participants who took metformin had nausea that settled without further treatment. It is unresolved whether the combination of metformin and megestrol results in different rates of recurrence of endometrial hyperplasia, progression of endometrial hyperplasia to endometrial cancer, or hysterectomy compared to megestrol monotherapy. No study in this comparison reported abnormal uterine bleeding, or health-related quality of life. Metformin plus levonorgestrel (intrauterine system) versus levonorgestrel (intrauterine system) monotherapy We are uncertain whether there is a difference between groups in the regression of endometrial hyperplasia towards normal histology (OR 0.29, 95% CI 0.01 to 7.56; 1 RCT, 46 participants; very low-certainty evidence). This evidence suggests that if the rate of regression with levonorgestrel monotherapy is 96%, the rate of regression with the addition of metformin would be between 73% and 100%. It is unresolved whether the combination of metformin and levonorgestrel results in different rates of abnormal uterine bleeding, hysterectomy, or the development of adverse effects during treatment compared to levonorgestrel monotherapy. No study in this comparison reported recurrence of endometrial hyperplasia, progression of hyperplasia to endometrial cancer, or health-related quality of life. AUTHORS' CONCLUSIONS: Review authors found insufficient evidence to either support or refute the use of metformin, specifically megestrol acetate, given alone or in combination with standard therapy, for the treatment of women with endometrial hyperplasia. Robustly designed and adequately powered randomised controlled trials, yielding long-term outcome data are still needed to address this clinical question.

What do patients and families observe about pediatric safety?: A thematic analysis of real-time narratives.

OBJECTIVES: Data on inpatient safety are documented by hospital staff through incident reporting (IR) systems. Safety observations from families or patients are rarely captured. The Family Input for Quality and Safety (FIQS) study created a mobile health tool for pediatric patients and their families to anonymously report safety observations in real time during hospitalization. The study objectives were to describe these observations and identify domains salient to safety. METHODS: In this observational study, we analyzed pediatric patient safety reports from June 2017 to April 2018. Participants were: English-speaking family members and hospitalized patients ≥13 years old. The analysis had two stages: 1) assessment of whether narratives met established safety event criteria and whether there were companion IRs; 2) thematic analysis to identify domains. RESULTS: Of 248 enrolled participants, 58 submitted 120 narrative reports. Of the narratives, 68 (57%) met safety event criteria, while only one (0.8%) corresponded to a staff-reported IR. 25% of narratives shared positive feedback about patient safety efforts; 75% shared constructive feedback. We identified domains particularly salient to safety: 1) patients and families as safety actors; 2) emotional safety; 3) system-centered care; and 4) shared safety domains, including medication, communication, and environment of care. Some domains capture data that is otherwise difficult to obtain (#1-3), while others fit within standard healthcare safety domains (#4). CONCLUSIONS: Patients and families observe and report salient safety events that can fill gaps in IR data. Healthcare leaders should consider incorporating patient and family observations-collected with an option for anonymity and eliciting both positive and constructive comments.

Risk factors associated with cognitive performance and cognitive impairment in older adults with type 1 diabetes: Data from the Wireless Innovation for Seniors with Diabetes Mellitus (WISDM) study.

BACKGROUND: Adults with type 1 diabetes (T1D) are considered at increased risk for cognitive impairment and accelerated brain aging. However, longitudinal data on cognitive impairment and dementia in this population are scarce. OBJECTIVE: To identify risk factors associated with cognitive performance and cognitive impairment in a longitudinal sample of older adults with T1D. METHODS: We analyzed data collected as part of the Wireless Innovation for Seniors with Diabetes Mellitus (WISDM) Study, in which 22 endocrinology practices participated. Randomized participants with T1D ≥60 years of age who completed at least one cognitive assessment were included in this study (n = 203). Cognitive impairment was classified using published recommendations. RESULTS: Older age, male sex, non-private health insurance, worse daily functioning, diagnosis of neuropathy, and longer duration of diabetes were associated with worse cognitive performance, but not cognitive impairment. 49 % and 39 % of the sample met criteria for cognitive impairment at baseline and 52 weeks respectively. Of the participants that had data at both time points, 10 % were normal at baseline and impaired at 52 weeks and 22 % of participants (44 % of those classified with cognitive impairment at baseline) reverted to normal over 52 weeks. CONCLUSION: This study indicated that several demographic and clinical characteristics are associated with worse cognitive performance in older adults with T1D, but there were no associations between these characteristics and cognitive impairment defined by NIH Toolbox cognitive impairment criteria. Caution is warranted when assessing cognition in older adults with T1D, as a large percentage of those identified as having cognitive impairment at baseline reverted to normal after 52 weeks. There is need for future studies on the interrelationship of cognition and aging to better understand the effects of T1D on cognitive health, to improve clinical monitoring and help mitigate the risk of dementia in this population.

Use of Electronic Health Record-Based Measures to Assess Quality of Care for Pediatric Agitation.

OBJECTIVES: Acute agitation during pediatric mental health emergency department (ED) visits presents safety risks to patients and staff. We previously convened multidisciplinary stakeholders who prioritized 20 proposed quality measures for pediatric acute agitation management. Our objectives were to assess feasibility of evaluating performance on these quality measures using electronic health record (EHR) data and to examine performance variation across 3 EDs. METHODS: At a children's hospital and 2 nonchildren's hospitals, we assessed feasibility of evaluating quality measures for pediatric acute agitation management using structured EHR data elements. We retrospectively evaluated measure performance during ED visits by children 5 to 17 years old who presented for a mental health condition, received medication for agitation, or received physical restraints from July 2020 to June 2021. Bivariate and multivariable regression were used to examine measure performance by patient characteristics and hospital. RESULTS: We identified 2785 mental health ED visits, 275 visits with medication given for agitation, and 35 visits with physical restraints. Performance was feasible to measure using EHR data for 10 measures. Nine measures varied by patient characteristics, including 4.87 times higher adjusted odds (95% confidence interval 1.28-18.54) of physical restraint use among children with versus without autism spectrum disorder. Four measures varied by hospital, with physical restraint use varying from 0.5% to 3.3% of mental health ED visits across hospitals. CONCLUSIONS: Quality of care for pediatric acute agitation management was feasible to evaluate using EHR-derived quality measures. Variation in performance across patient characteristics and hospitals highlights opportunities to improve care quality.

Clinical physicists' perceptions of weekly chart checks and the potential role for automated image review assessed by structured interviews.

BACKGROUND: This study utilizes interviews of clinical medical physicists to investigate self-reported shortcomings of the current weekly chart check workflow and opportunities for improvement. METHODS: Nineteen medical physicists were recruited for a 30-minute semi-structured interview, with a particular focus placed on image review and the use of automated tools for image review in weekly checks. Survey-type questions were used to gather quantitative information about chart check practices and importance placed on reducing chart check workloads versus increasing chart check effectiveness. Open-ended questions were used to probe respondents about their current weekly chart check workflow, opinions of the value of weekly chart checks and perceived shortcomings, and barriers and facilitators to the implementation of automated chart check tools. Thematic analysis was used to develop common themes across the interviews. RESULTS: Physicists ranked highly the value of reducing the time spent on weekly chart checks (average 6.3 on a scale from 1 to 10), but placed more value on increasing the effectiveness of checks with an average of 9.2 on a 1-10 scale. Four major themes were identified: (1) weekly chart checks need to adapt to an electronic record-and-verify chart environment, (2) physicists could add value to patient care by analyzing images without duplicating the work done by physicians, (3) greater support for trending analysis is needed in weekly checks, and (4) automation has the potential to increase the value of physics checks. CONCLUSION: This study identified several key shortcomings of the current weekly chart check process from the perspective of the clinical medical physicist. Our results show strong support for automating components of the weekly check workflow in order to allow for more effective checks that emphasize follow-up, trending, failure modes and effects analysis, and allow time to be spent on other higher value tasks that improve patient safety.

The Vaginal Microbiota, Human Papillomavirus Infection, and Cervical Carcinogenesis: A Systematic Review in the Latina Population.

BACKGROUND: Latina women experience disproportionately higher rates of HPV infection, persistence, and progression to cervical dysplasia and cancer compared to other racial-ethnic groups. This systematic review explores the relationship between the cervicovaginal microbiome and human papillomavirus infection, cervical dysplasia, and cervical cancer in Latinas. METHODS: The review abides by the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. PubMed, EMBASE, and Scopus databases were searched from January 2000 through November 11, 2022. The review included observational studies reporting on the cervicovaginal microbiota in premenopausal Latina women with human papillomavirus infection, cervical dysplasia, and cervical cancer. RESULTS: Twenty-five articles were eligible for final inclusion (N = 131,183). Forty-two unique bacteria were reported in the cervicovaginal microbiome of Latinas. Seven bacteria: Lactobacillus crispatus, Lactobacillus iners, Chlamydia trachomatis, Prevotella spp., Prevotella amnii, Fusobacterium spp. and Sneathia spp. were enriched across multiple stages of cervical carcinogenesis in Latinas. Therefore, the total number of reported bacteria includes four bacteria associated with the healthy state, 16 bacteria enriched in human papillomavirus outcomes, 24 unique bacteria associated with abnormal cytology/dysplasia, and five bacteria associated with cervical cancer. Furthermore, three studies reported significantly higher alpha and beta diversity in Latinas with cervical dysplasia and cancer compared to controls. Lactobacillus depletion and an increased abundance of L. iners in Latinas compared to non-Latinas, regardless of human papillomavirus status or lesions, were observed. CONCLUSIONS: The identification of 42 unique bacteria and their enrichment in cervical carcinogenesis can guide future cervicovaginal microbiome research to better inform cervical cancer prevention strategies in Latinas.

A combination of conserved and diverged responses underlies Theobroma cacao's defense response to Phytophthora palmivora.

BACKGROUND: Plants have complex and dynamic immune systems that have evolved to resist pathogens. Humans have worked to enhance these defenses in crops through breeding. However, many crops harbor only a fraction of the genetic diversity present in wild relatives. Increased utilization of diverse germplasm to search for desirable traits, such as disease resistance, is therefore a valuable step towards breeding crops that are adapted to both current and emerging threats. Here, we examine diversity of defense responses across four populations of the long-generation tree crop Theobroma cacao L., as well as four non-cacao Theobroma species, with the goal of identifying genetic elements essential for protection against the oomycete pathogen Phytophthora palmivora. RESULTS: We began by creating a new, highly contiguous genome assembly for the P. palmivora-resistant genotype SCA 6 (Additional file 1: Tables S1-S5), deposited in GenBank under accessions CP139290-CP139299. We then used this high-quality assembly to combine RNA and whole-genome sequencing data to discover several genes and pathways associated with resistance. Many of these are unique, i.e., differentially regulated in only one of the four populations (diverged 40 k-900 k generations). Among the pathways shared across all populations is phenylpropanoid biosynthesis, a metabolic pathway with well-documented roles in plant defense. One gene in this pathway, caffeoyl shikimate esterase (CSE), was upregulated across all four populations following pathogen treatment, indicating its broad importance for cacao's defense response. Further experimental evidence suggests this gene hydrolyzes caffeoyl shikimate to create caffeic acid, an antimicrobial compound and known inhibitor of Phytophthora spp. CONCLUSIONS: Our results indicate most expression variation associated with resistance is unique to populations. Moreover, our findings demonstrate the value of using a broad sample of evolutionarily diverged populations for revealing the genetic bases of cacao resistance to P. palmivora. This approach has promise for further revealing and harnessing valuable genetic resources in this and other long-generation plants.

Expression of sex-specific molecular markers by Babesia bovis gametes.

BACKGROUND: Bovine babesiosis caused by Babesia bovis is one of the most important tick-borne diseases of cattle in tropical and subtropical regions. Babesia bovis parasites have a complex lifecycle, including development within the mammalian host and tick vector. In the tick midgut, extracellular Babesia parasites transform into gametes that fuse to form zygotes. To date, little is known about genes and proteins expressed by male gametes. METHODS AND RESULTS: We developed a method to separate male gametes from in vitro induced B. bovis culture. Separation enabled the validation of sex-specific markers. Collected male gametocytes were observed by Giemsa-stained smear and live-cell fluorescence microscopy. Babesia male gametes were used to confirm sex-specific markers by quantitative real-time PCR. Some genes were found to be male gamete specific genes including pka, hap2, α-tubulin II and znfp2. However, α-tubulin I and ABC transporter, trap2-4 and ccp1-3 genes were found to be upregulated in culture depleted of male gametes (female-enriched). Live immunofluorescence analysis using polyclonal antibodies confirmed surface expression of HAP2 by male and TRAP2-4 by female gametes. These results revealed strong markers to distinguish between B. bovis male and female gametes. CONCLUSIONS: Herein, we describe the identification of sex-specific molecular markers essential for B. bovis sexual reproduction. These tools will enhance our understanding of the biology of sexual stages and, consequently, the development of additional strategies to control bovine babesiosis.

In Situ X-ray Scattering Reveals Coarsening Rates of Superlattices Self-Assembled from Electrostatically Stabilized Metal Nanocrystals Depend Nonmonotonically on Driving Force.

Self-assembly of colloidal nanocrystals (NCs) into superlattices (SLs) is an appealing strategy to design hierarchically organized materials with promising functionalities. Mechanistic studies are still needed to uncover the design principles for SL self-assembly, but such studies have been difficult to perform due to the fast time and short length scales of NC systems. To address this challenge, we developed an apparatus to directly measure the evolving phases in situ and in real time of an electrostatically stabilized Au NC solution before, during, and after it is quenched to form SLs using small-angle X-ray scattering. By developing a quantitative model, we fit the time-dependent scattering patterns to obtain the phase diagram of the system and the kinetics of the colloidal and SL phases as a function of varying quench conditions. The extracted phase diagram is consistent with particles whose interactions are short in range relative to their diameter. We find the degree of SL order is primarily determined by fast (subsecond) initial nucleation and growth kinetics, while coarsening at later times depends nonmonotonically on the driving force for self-assembly. We validate these results by direct comparison with simulations and use them to suggest dynamic design principles to optimize the crystallinity within a finite time window. The combination of this measurement methodology, quantitative analysis, and simulation should be generalizable to elucidate and better control the microscopic self-assembly pathways of a wide range of bottom-up assembled systems and architectures.

A model-based approach to estimating the prevalence of disease combinations in South Africa.

BACKGROUND: The development of strategies to better detect and manage patients with multiple long-term conditions requires estimates of the most prevalent condition combinations. However, standard meta-analysis tools are not well suited to synthesising heterogeneous multimorbidity data. METHODS: We developed a statistical model to synthesise data on associations between diseases and nationally representative prevalence estimates and applied the model to South Africa. Published and unpublished data were reviewed, and meta-regression analysis was conducted to assess pairwise associations between 10 conditions: arthritis, asthma, chronic obstructive pulmonary disease (COPD), depression, diabetes, HIV, hypertension, ischaemic heart disease (IHD), stroke and tuberculosis. The national prevalence of each condition in individuals aged 15 and older was then independently estimated, and these estimates were integrated with the ORs from the meta-regressions in a statistical model, to estimate the national prevalence of each condition combination. RESULTS: The strongest disease associations in South Africa are between COPD and asthma (OR 14.6, 95% CI 10.3 to 19.9), COPD and IHD (OR 9.2, 95% CI 8.3 to 10.2) and IHD and stroke (OR 7.2, 95% CI 5.9 to 8.4). The most prevalent condition combinations in individuals aged 15+ are hypertension and arthritis (7.6%, 95% CI 5.8% to 9.5%), hypertension and diabetes (7.5%, 95% CI 6.4% to 8.6%) and hypertension and HIV (4.8%, 95% CI 3.3% to 6.6%). The average numbers of comorbidities are greatest in the case of COPD (2.3, 95% CI 2.1 to 2.6), stroke (2.1, 95% CI 1.8 to 2.4) and IHD (1.9, 95% CI 1.6 to 2.2). CONCLUSION: South Africa has high levels of HIV, hypertension, diabetes and arthritis, by international standards, and these are reflected in the most prevalent condition combinations. However, less prevalent conditions such as COPD, stroke and IHD contribute disproportionately to the multimorbidity burden, with high rates of comorbidity. This modelling approach can be used in other settings to characterise the most important disease combinations and levels of comorbidity.

MRI Detection of Lymph Node Metastasis through Molecular Targeting of C-C Chemokine Receptor Type 2 and Monocyte Hitchhiking.

Biopsy is the clinical standard for diagnosing lymph node (LN) metastasis, but it is invasive and poses significant risk to patient health. Magnetic resonance imaging (MRI) has been utilized as a noninvasive alternative but is limited by low sensitivity, with only ∼35% of LN metastases detected, as clinical contrast agents cannot discriminate between healthy and metastatic LNs due to nonspecific accumulation. Nanoparticles targeted to the C-C chemokine receptor 2 (CCR2), a biomarker highly expressed in metastatic LNs, have the potential to guide the delivery of contrast agents, improving the sensitivity of MRI. Additionally, cancer cells in metastatic LNs produce monocyte chemotactic protein 1 (MCP1), which binds to CCR2+ inflammatory monocytes and stimulates their migration. Thus, the molecular targeting of CCR2 may enable nanoparticle hitchhiking onto monocytes, providing an additional mechanism for metastatic LN targeting and early detection. Hence, we developed micelles incorporating gadolinium (Gd) and peptides derived from the CCR2-binding motif of MCP1 (MCP1-Gd) and evaluated the potential of MCP1-Gd to detect LN metastasis. When incubated with migrating monocytes in vitro, MCP1-Gd transport across lymphatic endothelium increased 2-fold relative to nontargeting controls. After administration into mouse models with initial LN metastasis and recurrent LN metastasis, MCP1-Gd detected metastatic LNs by increasing MRI signal by 30-50% relative to healthy LNs. Furthermore, LN targeting was dependent on monocyte hitchhiking, as monocyte depletion decreased accumulation by >70%. Herein, we present a nanoparticle contrast agent for MRI detection of LN metastasis mediated by CCR2-targeting and demonstrate the potential of monocyte hitchhiking for enhanced nanoparticle delivery.

Phenotype and predictors of insulin independence in adults presenting with diabetic ketoacidosis: a prospective cohort study.

AIMS/HYPOTHESIS: The aim of this work was to describe the phenotype of adults presenting with a first episode of diabetic ketoacidosis (DKA) in Cape Town, South Africa, and identify predictors of insulin independence at 12 and 60 months after presentation. METHODS: A prospective, descriptive cohort study of all individuals, 18 years or older, presenting for the first time with DKA to four public-sector hospitals of the Groote Schuur Academic Health Complex was performed. Clinical, biochemical and laboratory data including GAD antibody and C-peptide status were collected at baseline. Insulin was systematically weaned and stopped in individuals who achieved normoglycaemia within the months after DKA. Individuals were followed for 12 months and then annually until 5 years after initial presentation with ketoacidosis. RESULTS: Eighty-eight individuals newly diagnosed with diabetes when presenting with DKA were included and followed for 5 years. The mean ± SD age was 35±10 years and the median (IQR) BMI at diagnosis was 28.5 (23.3-33.4) kg/m2. Overall, 46% were insulin independent 12 months after diagnosis and 26% remained insulin independent 5 years after presentation. Forty-one participants (47%) tested negative for anti-GAD and anti-IA-2 antibodies and had C-peptide levels >0.3 nmol/l; in this group, 68% were insulin independent at 12 months and 37% at 5 years after diagnosis. The presence of acanthosis nigricans was strongly associated with insulin independence (OR 27.1 [95% CI 7.2, 102.2]; p<0.001); a positive antibody status was associated with a lower likelihood of insulin independence at 12 months (OR 0.10 [95% CI 0.03, 0.36]; p<0.001). On multivariable analysis only acanthosis (OR 11.5 [95% CI 2.5, 53.2]; p=0.004) was predictive of insulin independence 5 years after diagnosis. CONCLUSIONS/INTERPRETATION: The predominant phenotype of adults presenting with a first episode of DKA in Cape Town, South Africa, was that of ketosis-prone type 2 diabetes. These individuals presented with obesity, acanthosis nigricans, negative antibodies and normal C-peptide and could potentially be weaned off insulin at follow-up. Classic type 1 diabetes (lower weight, antibody positivity, low or unrecordable C-peptide levels and long-term insulin dependence) was less common. The simple clinical sign of acanthosis nigricans is a strong predictor of insulin independence at 12 months and 5 years after initial presentation.

Perceptions of Health, Body Size, and Nutritional Risk Factors for Obesity in People with HIV in South Africa.

Metabolic disease is increasing in people with HIV (PWH) in South Africa, but little is known about self-perceptions of body size, health, and nutritional behavior in this population. We performed a cross-sectional analysis of individual-level data from the 2016 South Africa Demographic and Health Survey. This survey measured HIV serostatus and body mass index (BMI). We categorized participants into six BMI groups: 18.5-22 kg/m2, 22-25 kg/m2, 25-27.5 kg/m2, 27.5-30 kg/m2, 30-35 kg/m2, and ≥ 35 kg/m2 and stratified them by HIV serostatus. Our outcomes were self-reported (1) body size and (2) health status among all participants, and intake of (3) chips and (4) sugar-sweetened beverages (SSB) in PWH. We described these metrics and used multivariable regression to evaluate the relationship between the nutritional behaviors and BMI ≥ 25 kg/m2 in PWH only, adjusting for age, sex, educational attainment, and household wealth quintile. Of 6138 participants, 1163 (19.7%) were PWH. Among PWH, < 10% with a BMI 25-30 kg/m2, < 20% with a BMI 30-35 kg/m2 and < 50% with a BMI ≥ 35 kg/m2 self-reported as overweight or obese. PWH reported being in poor health at higher rates than those without HIV at each BMI category except ≥ 35 kg/m2. In adjusted models, SSB consumption was associated with BMI ≥ 25 kg/m2 (1.13 [1.01-1.25], t-statistic = 2.14, p = 0.033) in PWH. Perceptions of body size may challenge efforts to prevent weight gain in PWH in South Africa. SSB intake reduction should be further explored as a modifiable risk factor for obesity.

Veteran Beliefs About the Causes of Gulf War Illness and Expectations for Improvement.

BACKGROUND: Individuals' beliefs about the etiology of persistent physical symptoms (PPS) are linked to differences in coping style. However, it is unclear which attributions are related to greater expectations for improvement. METHOD AND RESULTS: A cross-sectional regression analysis (N = 262) indicated that Veterans with Gulf War Illness (GWI) who attributed their GWI to behavior, (e.g., diet and exercise), had greater expectations for improvement (p = .001) than those who attributed their GWI to deployment, physical, or psychological causes (p values > .05). CONCLUSIONS: Findings support the possible clinical utility of exploring perceived contributing factors of PPS, which may increase perceptions that improvement of PPS is possible. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02161133.