Traumatic brain injury disrupts state-dependent functional cortical connectivity in a mouse model.

Traumatic brain injury (TBI) is the leading cause of death in young people and can cause cognitive and motor dysfunction and disruptions in functional connectivity between brain regions. In human TBI patients and rodent models of TBI, functional connectivity is decreased after injury. Recovery of connectivity after TBI is associated with improved cognition and memory, suggesting an important link between connectivity and functional outcome. We examined widespread alterations in functional connectivity following TBI using simultaneous widefield mesoscale GCaMP7c calcium imaging and electrocorticography (ECoG) in mice injured using the controlled cortical impact (CCI) model of TBI. Combining CCI with widefield cortical imaging provides us with unprecedented access to characterize network connectivity changes throughout the entire injured cortex over time. Our data demonstrate that CCI profoundly disrupts functional connectivity immediately after injury, followed by partial recovery over 3 weeks. Examining discrete periods of locomotion and stillness reveals that CCI alters functional connectivity and reduces theta power only during periods of behavioral stillness. Together, these findings demonstrate that TBI causes dynamic, behavioral state-dependent changes in functional connectivity and ECoG activity across the cortex.

Cortical Parvalbumin-Positive Interneuron Development and Function Are Altered in the APC Conditional Knockout Mouse Model of Infantile and Epileptic Spasms Syndrome.

Infantile and epileptic spasms syndrome (IESS) is a childhood epilepsy syndrome characterized by infantile or late-onset spasms, abnormal neonatal EEG, and epilepsy. Few treatments exist for IESS, clinical outcomes are poor, and the molecular and circuit-level etiologies of IESS are not well understood. Multiple human IESS risk genes are linked to Wnt/ß-catenin signaling, a pathway that controls developmental transcriptional programs and promotes glutamatergic excitation via ß-catenin's role as a synaptic scaffold. We previously showed that deleting adenomatous polyposis coli (APC), a component of the ß-catenin destruction complex, in excitatory neurons (APC cKO mice, APCfl/fl x CaMKIIαCre) increased ß-catenin levels in developing glutamatergic neurons and led to infantile behavioral spasms, abnormal neonatal EEG, and adult epilepsy. Here, we tested the hypothesis that the development of GABAergic interneurons (INs) is disrupted in APC cKO male and female mice. IN dysfunction is implicated in human IESS, is a feature of other rodent models of IESS, and may contribute to the manifestation of spasms and seizures. We found that parvalbumin-positive INs (PV+ INs), an important source of cortical inhibition, were decreased in number, underwent disproportionate developmental apoptosis, and had altered dendrite morphology at P9, the peak of behavioral spasms. PV+ INs received excessive excitatory input, and their intrinsic ability to fire action potentials was reduced at all time points examined (P9, P14, P60). Subsequently, GABAergic transmission onto pyramidal neurons was uniquely altered in the somatosensory cortex of APC cKO mice at all ages, with both decreased IPSC input at P14 and enhanced IPSC input at P9 and P60. These results indicate that inhibitory circuit dysfunction occurs in APC cKOs and, along with known changes in excitation, may contribute to IESS-related phenotypes.SIGNIFICANCE STATEMENT Infantile and epileptic spasms syndrome (IESS) is a devastating epilepsy with limited treatment options and poor clinical outcomes. The molecular, cellular, and circuit disruptions that cause infantile spasms and seizures are largely unknown, but inhibitory GABAergic interneuron dysfunction has been implicated in rodent models of IESS and may contribute to human IESS. Here, we use a rodent model of IESS, the APC cKO mouse, in which ß-catenin signaling is increased in excitatory neurons. This results in altered parvalbumin-positive GABAergic interneuron development and GABAergic synaptic dysfunction throughout life, showing that pathology arising in excitatory neurons can initiate long-term interneuron dysfunction. Our findings further implicate GABAergic dysfunction in IESS, even when pathology is initiated in other neuronal types.

Tonic Activation of GluN2C/GluN2D-Containing NMDA Receptors by Ambient Glutamate Facilitates Cortical Interneuron Maturation.

Developing cortical GABAergic interneurons rely on genetic programs, neuronal activity, and environmental cues to construct inhibitory circuits during early postnatal development. Disruption of these events can cause long-term changes in cortical inhibition and may be involved in neurological disorders associated with inhibitory circuit dysfunction. We hypothesized that tonic glutamate signaling in the neonatal cortex contributes to, and is necessary for, the maturation of cortical interneurons. To test this hypothesis, we used mice of both sexes to quantify extracellular glutamate concentrations in the cortex during development, measure ambient glutamate-mediated activation of developing cortical interneurons, and manipulate tonic glutamate signaling using subtype-specific NMDA receptor antagonists in vitro and in vivo We report that ambient glutamate levels are high (≈100 nm) in the neonatal cortex and decrease (to ≈50 nm) during the first weeks of life, coincident with increases in astrocytic glutamate uptake. Consistent with elevated ambient glutamate, putative parvalbumin-positive interneurons in the cortex (identified using G42:GAD1-eGFP reporter mice) exhibit a transient, tonic NMDA current at the end of the first postnatal week. GluN2C/GluN2D-containing NMDA receptors mediate the majority of this current and contribute to the resting membrane potential and intrinsic properties of developing putative parvalbumin interneurons. Pharmacological blockade of GluN2C/GluN2D-containing NMDA receptors in vivo during the period of tonic interneuron activation, but not later, leads to lasting decreases in interneuron morphological complexity and causes deficits in cortical inhibition later in life. These results demonstrate that dynamic ambient glutamate signaling contributes to cortical interneuron maturation via tonic activation of GluN2C/GluN2D-containing NMDA receptors.SIGNIFICANCE STATEMENT Inhibitory GABAergic interneurons make up 20% of cortical neurons and are critical to controlling cortical network activity. Dysfunction of cortical inhibition is associated with multiple neurological disorders, including epilepsy. Establishing inhibitory cortical networks requires in utero proliferation, differentiation, and migration of immature GABAergic interneurons, and subsequent postnatal morphological maturation and circuit integration. Here, we demonstrate that ambient glutamate provides tonic activation of immature, putative parvalbumin-positive GABAergic interneurons in the neonatal cortex via high-affinity NMDA receptors. When this activation is blocked, GABAergic interneuron maturation is disrupted, and cortical networks exhibit lasting abnormal hyperexcitability. We conclude that temporally precise activation of developing cortical interneurons by ambient glutamate is critically important for establishing normal cortical inhibition.

Cost-effectiveness of colorectal cancer screening in Ukraine.

BACKGROUND: Colorectal cancer is one of the most common cancers worldwide and is associated with high mortality when detected at a later stage. There is a paucity of studies from low and middle income countries to support the cost-effectiveness of colorectal cancer screening. We aim to analyze the cost-effectiveness of colorectal cancer screening compared to no screening in Ukraine, a lower-middle income country. METHODS: We developed a deterministic Markov cohort model to assess the cost-effectiveness of three colorectal cancer screening strategies [fecal occult blood test (FOBT) every year, flexible sigmoidoscopy with FOBT every 5 years, and colonoscopy every 10 years] compared to no screening. We modeled outcomes in terms of cost per quality-adjusted life-years (QALYs) over a lifetime time horizon. We performed sensitivity analyses on treatment adherence, test characteristics and costs. Analyses were conducted from the perspective of the Ministry of Health of Ukraine. RESULTS: The base-case lifetime cost-effectiveness analysis showed that all three screening strategies were cost saving compared to no screening, and among the three strategies, colonoscopy every 10 years was the dominant strategy compared to no screening with standard adherence to treatment. When decreased adherence to treatment was modeled, colonoscopy every 10 years was the most cost-effective strategy with an incremental cost-effectiveness ratio of $843 per QALY compared with no screening. CONCLUSION: Our findings indicate that colorectal cancer screening can save money and improve health compared to no screening in Ukraine. Colonoscopy every 10 years is superior to the other screening modalities evaluated in this study. This knowledge can be used to concentrate efforts on developing a national screening program in Ukraine.

Cost-effectiveness of HIV treatment as prevention in serodiscordant couples.

BACKGROUND: The cost-effectiveness of early antiretroviral therapy (ART) in persons infected with human immunodeficiency virus (HIV) in serodiscordant couples is not known. Using a computer simulation of the progression of HIV infection and data from the HIV Prevention Trials Network 052 study, we projected the cost-effectiveness of early ART for such persons. METHODS: For HIV-infected partners in serodiscordant couples in South Africa and India, we compared the early initiation of ART with delayed ART. Five-year and lifetime outcomes included cumulative HIV transmissions, life-years, costs, and cost-effectiveness. We classified early ART as very cost-effective if its incremental cost-effectiveness ratio was less than the annual per capita gross domestic product (GDP; $8,100 in South Africa and $1,500 in India), as cost-effective if the ratio was less than three times the GDP, and as cost-saving if it resulted in a decrease in total costs and an increase in life-years, as compared with delayed ART. RESULTS: In South Africa, early ART prevented opportunistic diseases and was cost-saving over a 5-year period; over a lifetime, it was very cost-effective ($590 per life-year saved). In India, early ART was cost-effective ($1,800 per life-year saved) over a 5-year period and very cost-effective ($530 per life-year saved) over a lifetime. In both countries, early ART prevented HIV transmission over short periods, but longer survival attenuated this effect; the main driver of life-years saved was a clinical benefit for treated patients. Early ART remained very cost-effective over a lifetime under most modeled assumptions in the two countries. CONCLUSIONS: In South Africa, early ART was cost-saving over a 5-year period. In both South Africa and India, early ART was projected to be very cost-effective over a lifetime. With individual, public health, and economic benefits, there is a compelling case for early ART for serodiscordant couples in resource-limited settings. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Low-Osmolar Diet and Adjusted Water Intake for Vasopressin Reduction in Autosomal Dominant Polycystic Kidney Disease: A Pilot Randomized Controlled Trial.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) affects millions of people worldwide. Vasopressin promotes disease progression. STUDY DESIGN: A randomized controlled trial with equal (1:1) allocation. SETTING & PARTICIPANTS: This trial examined the effect of combining a low-osmolar (low-sodium [1,500mg/d], low-protein [0.8g per kilogram of body weight]) diet and adjusted water intake on vasopressin secretion in 34 patients with ADPKD. INTERVENTION: Participants were randomly assigned to receive a low-osmolar diet followed by adjusted water intake to achieve urine osmolality ≤ 280mOsm/kg water versus no intervention for 2 weeks. OUTCOME: The primary outcome of the study was change (delta) in copeptin levels and urine osmolality between the intervention and control groups from baseline to 2 weeks. MEASUREMENTS: Fasting plasma copeptin level, 24-hour urine osmolality, and total solute intake. RESULTS: Baseline characteristics of the 2 groups were similar. Mean plasma copeptin levels and urine osmolality declined from 6.2±3.05 (SD) to 5.3±2.5pmol/L (P=0.02) and from 426±193 to 258±117mOsm/kg water (P=0.01), respectively, in the intervention group compared to a nonsignificant change in the control group (from 4.7±3.6 to 5.07±4pmol/L [P=0.2] and 329±159 to 349±139mOsm/kg water [P=0.3], respectively). The change in copeptin levels (primary outcome) and urine osmolality was statistically significant between the intervention and control groups (delta copeptin, -0.86±1.3 vs +0.39±1.2pmol/L [P=0.009]; delta urine osmolality, -167±264 vs +20±80mOsm/kg water [P=0.007], respectively). Total urinary solute decreased in only the intervention group and significantly differed between groups at week 1 (P=0.03), reducing mean water prescription from 3.2 to 2.6L/d. LIMITATIONS: Small sample size and short follow-up. CONCLUSIONS: We developed a stepwise dietary intervention that led to a significant reduction in vasopressin secretion in patients with ADPKD. Furthermore, this intervention led to a reduction in water required for vasopressin reduction.

Midlife Blood Pressure and Late-Life GFR and Albuminuria: An Elderly General Population Cohort.

BACKGROUND: Chronic kidney disease (CKD) is common in the elderly, but the cause is often not identifiable. Some posit that age-related reductions in glomerular filtration rate (GFR) and increases in albuminuria are normal, whereas others suggest that they are a consequence of vascular disease. STUDY DESIGN: Cross-sectional analysis of a substudy of a prospective cohort. SETTING & PARTICIPANTS: AGES (Age, Gene/Environment Susceptibility)-Reykjavik Study. PREDICTOR: Exposure to higher blood pressure in midlife. OUTCOMES & MEASUREMENTS: Measured GFR using plasma clearance of iohexol and urine albumin-creatinine ratio. RESULTS: GFR was measured in 805 participants with mean age in midlife and late life of 51.0±5.8 and 80.8±4.0 (SD) years, respectively. Mean measured GFR was 62.4±16.5 mL/min/1.73 m(2) and median albuminuria was 8.0 (IQR, 5.4-16.5) mg/g. Higher midlife systolic and diastolic blood pressures were associated with lower later-life GFRs. Associations persisted after adjustment. Higher midlife systolic and diastolic blood pressures were also associated with higher albumin-creatinine ratios, and associations remained significant even after adjustment. LIMITATIONS: This is a study of survivors, and people who agreed to participate in this study were healthier than those who refused. Blood pressure may encompass effects of the other risk factors. Results may not be generalizable to populations of other races. We were not able to adjust for measured GFR or albuminuria at the midlife visit. CONCLUSIONS: Factors other than advanced age may account for the high prevalence of CKD in the elderly. Midlife factors are potential contributing factors to late-life kidney disease. Further studies are needed to identify and treat midlife modifiable factors to prevent the development of CKD.

Aortic stiffness and kidney disease in an elderly population.

BACKGROUND/AIMS: The causes of chronic kidney disease (CKD) in older people are not well understood. Aortic stiffness increases with age and results in the transmission of increased pulsatility into the kidney microvasculature, potentially contributing to CKD in older populations. METHODS: We utilized data from the Age, Gene/Environment, Susceptibility-Reykjavik Study, a community-based prospective cohort study of cardiovascular disease (CVD) in Iceland. The relationship of carotid pulse pressure (CPP) and carotid-femoral pulse wave velocity (CFPWV) with estimated glomerular filtration rate (eGFR) based on creatinine and cystatin C and urine albumin-creatinine ratio (ACR) was assessed using linear regression, adjusting for demographics and CVD risk factors. RESULTS: 940 participants (mean (SD) age 75.8 (4.7) years, mean (SD) CFPWV 12.9 (4.2) m/s, mean (SD) CPP 69 (21) mm Hg, mean (SD) eGFR 68 (16) ml/min/1.73 m(2), and median (IQR) ACR 3 (2-6) mg/g) were included in this study. At CPP greater than 85 mm Hg, a higher CPP was associated with a lower eGFR in unadjusted analyses but not after adjustment. CPP was significantly associated with a higher ACR in fully adjusted models (ß (95% CI) = 0.14 (0.03, 0.24) ln mg/g per SD). Higher CFPWV was associated with lower eGFR and higher ACR in unadjusted analyses but not after adjustment. CONCLUSION: Greater aortic stiffness may be associated with modestly higher levels of albuminuria in the elderly. The association between aortic stiffness and lower eGFR may be confounded by age and CVD risk factors.

Concordance of PCR and culture from nasal swabs for detection of methicillin-resistant Staphylococcus aureus in a setting of concurrent antistaphylococcal antibiotics.

The effect of concurrent administration of antibiotics on the detection of methicillin-resistant Staphylococcus aureus (MRSA) remains unresolved. Here, we assessed the concordance of paired nasal swabs processed using commercial PCR and culture and found high concordance in both the absence and presence of antibiotics with activity against MRSA (93.7% [95% confidence interval [CI], 88.1%, 96.8%] and 90.9% [95% CI, 84.8%, 94.7%], respectively), although PCR was more likely to be positive in the presence of antibiotics. (This study has been registered at ClinicalTrials.gov under registration no. NCT01234831.).

Horizontal infection control strategy decreases methicillin-resistant Staphylococcus aureus infection and eliminates bacteremia in a surgical ICU without active surveillance.

OBJECTIVE: Methicillin-resistant Staphylococcus aureus infection is a significant contributor to morbidity and mortality in hospitalized patients worldwide. Numerous healthcare bodies in Europe and the United States have championed active surveillance per the "search and destroy" model. However, this strategy is associated with significant economic, logistical, and patient costs without any impact on other hospital-acquired pathogens. We evaluated whether horizontal infection control strategies could decrease the prevalence of methicillin-resistant S. aureus infection in the ICU, without the need for active surveillance. DESIGN AND SETTING: Retrospective, observational study in the surgical ICU of a tertiary care medical center in Boston, MA, from 2005 to 2012. PATIENTS: A total of 6,697 patients in the surgical ICU. INTERVENTIONS: Evidence-based infection prevention strategies were implemented in an iterative fashion, including 1) hand hygiene program with refresher education campaign, 2) chlorhexidine oral hygiene program, 3) chlorhexidine bathing, 4) catheter-associated bloodstream infection program, and 5) daily goals sheets. MEASUREMENTS AND MAIN RESULTS: The prevalence of methicillin-resistant S. aureus infection fell from 2.66 to 0.69 per 1,000 patient days from 2005 to 2012, an average decrease of 21% per year. The biggest decline in rate of infection was detected in 2008, which may suggest that the catheter-associated bloodstream infection prevention program was particularly effective. Among 4,478 surgical ICU admissions over the last 5 years, not a single case of methicillin-resistant S. aureus bacteremia was observed. CONCLUSIONS: Aggressive multifaceted horizontal infection control is an effective strategy for reducing the prevalence of methicillin-resistant S. aureus infection and eliminating methicillin-resistant S. aureus bacteremia in the ICU without the need for active surveillance and decontamination.

GFR decline as an alternative end point to kidney failure in clinical trials: a meta-analysis of treatment effects from 37 randomized trials.

BACKGROUND: There is increased interest in using alternative end points for trials of kidney disease progression. The currently established end points of end-stage renal disease and doubling of serum creatinine level, equivalent to a 57% decline in estimated glomerular filtration rate (eGFR), are late events in chronic kidney disease (CKD), requiring large clinical trials with long follow-up. As part of a comprehensive evaluation of lesser declines in eGFR as alternative end points, we describe the consistency of treatment effects of intervention on the alternative and established end points in past trials. STUDY DESIGN: Diagnostic test study. SETTING & POPULATION: 9,488 participants from 37 randomized controlled trials of CKD progression across 5 intervention types. INDEX TEST: Alternative end points including percentage change in eGFR from baseline (20%, 30%, 40%, and 57%) throughout study duration and to 12, 18, and 24 months. eGFR change confirmed versus nonconfirmed at the next visit. REFERENCE TEST: The historically established end point of time to composite of treated kidney failure (end-stage renal disease), untreated kidney failure (GFR<15mL/min/1.73m(2)), or doubling of serum creatinine level throughout study duration. RESULTS: Over a median of 3.62 years' follow-up, there were 3,070 established end points. Compared to the established end point, the number of alternative end points was greater for smaller versus larger declines in eGFR and longer versus shorter follow-up intervals. There was a general trend toward attenuation of the treatment effect with end points defined by a lesser eGFR decline, with greater attenuation with nonconfirmed end points, except for the low-protein-diet intervention, for which a stronger treatment effect was observed. The ratio (95% credible interval) of the HR for the alternative to established end point for the 5 intervention types ranged from 0.91 (0.64-1.43) to 1.12 (0.89-1.40) for 40% decline and from 0.88 (0.63-1.39) to 1.15 (0.88-1.54) for 30% decline for the overall study duration, indicating consistency of treatment effects. LIMITATIONS: Limited variety of interventions tested and low statistical power for many CKD clinical trials. CONCLUSIONS: These results provide some support for the use of lesser eGFR declines as a surrogate end point, with stronger support for the 40% than 30% decline.

Emergence and evolution of social self-management of Parkinson's disease: study protocol for a 3-year prospective cohort study.

BACKGROUND: Parkinson's disease affects facial, vocal and trunk muscles. As symptoms progress, facial expression becomes masked, limiting the person's ability to communicate emotions and intentions to others. As people with the disease live and reside in their homes longer, the burden of caregiving is unmitigated by social and emotional rewards provided by an expressive individual. Little is known about how adults living with Parkinson's disease manage their social lives and how an inability to be emotionally expressive can affect social connections and health. Because social networks have been shown to be crucial to the overall well-being of people living with chronic diseases, research is needed on how expressive capacity affects life trajectories and health. METHODS/DESIGN: The overall objective is to understand the emergence and evolution of the trajectories of the self-management of the social lives of people living with Parkinson's disease. The central hypothesis is that expressive capacity predicts systematic change in the pattern of social self-management and quality of life outcomes. The specific aims of this 3-year longitudinal study of 120 people with the disease and a maximum of 120 care partners are: 1) characterize social self-management trajectories over a 3-year period; 2) estimate the degree to which expressive nonverbal capacity predicts the trajectory; and 3) determine the moderating effect of gender on the association between expressive capacity and change in social self-management. Each participant will be assessed 14 times to detect rapid and non-linear changes in social participation and management of social activities; social network; and social comfort, general health and well-being. DISCUSSION: This project will provide evidence to guide the development of interventions for supporting social integration of those living with Parkinson's disease, thus leading to improved overall health. It focuses on the novel construct of social self-management and known factors-expressive capacity and gender-that contribute to stigmatization. The repeated measures design detects triggers of rapid changes in social and health outcomes.

Natural history of colonization with methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE): a systematic review.

BACKGROUND: No published systematic reviews have assessed the natural history of colonization with methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus (VRE). Time to clearance of colonization has important implications for patient care and infection control policy. METHODS: We performed parallel searches in OVID Medline for studies that reported the time to documented clearance of MRSA and VRE colonization in the absence of treatment, published between January 1990 and July 2012. RESULTS: For MRSA, we screened 982 articles, identified 16 eligible studies (13 observational studies and 3 randomized controlled trials), for a total of 1,804 non-duplicated subjects. For VRE, we screened 284 articles, identified 13 eligible studies (12 observational studies and 1 randomized controlled trial), for a total of 1,936 non-duplicated subjects. Studies reported varying definitions of clearance of colonization; no study reported time of initial colonization. Studies varied in the frequency of sampling, assays used for sampling, and follow-up period. The median duration of total follow-up was 38 weeks for MRSA and 25 weeks for VRE. Based on pooled analyses, the model-estimated median time to clearance was 88 weeks after documented colonization for MRSA-colonized patients and 26 weeks for VRE-colonized patients. In a secondary analysis, clearance rates for MRSA and VRE were compared by restricting the duration of follow-up for the MRSA studies to the maximum observed time point for VRE studies (43 weeks). With this restriction, the model-fitted median time to documented clearance for MRSA would occur at 41 weeks after documented colonization, demonstrating the sensitivity of the pooled estimate to length of study follow-up. CONCLUSIONS: Few available studies report the natural history of MRSA and VRE colonization. Lack of a consistent definition of clearance, uncertainty regarding the time of initial colonization, variation in frequency of sampling for persistent colonization, assays employed and variation in duration of follow-up are limitations of the existing published literature. The heterogeneity of study characteristics limits interpretation of pooled estimates of time to clearance, however, studies included in this review suggest an increase in documented clearance over time, a result which is sensitive to duration of follow-up.

Triage of HPV positivity in a high HIV prevalence setting: A prospective cohort study comparing visual triage methods and HPV genotype restriction in Botswana.

OBJECTIVE: Guidelines for effective triage following positive primary high-risk human papillomavirus (HPV) screening in low- and middle-income countries with high human immunodeficiency virus (HIV)-prevalence have not previously been established. In the present study, we evaluated the performance of three triage methods for positive HPV results in women living with HIV (WLHIV) and without HIV in Botswana. METHODS: We conducted baseline enrollment of a prospective cohort study from February 2021 to August 2022 in South-East District, Botswana. Non-pregnant women aged 25 or older with an intact cervix and no prior diagnosis of cervical cancer were systematically consented for enrollment, with enrichment of the cohort for WLHIV. Those who consented completed a questionnaire and then collected vaginal self-samples for HPV testing. Primary HPV testing for 15 individual genotypes was conducted using Atila AmpFire® HPV assay. Those with positive HPV results returned for a triage visit where all underwent visual inspection with acetic acid (VIA), colposcopy, and biopsy. Triage strategies with VIA, colposcopy and 8-type HPV genotype restriction (16/18/31/33/35/45/52/58), separately and in combination, were compared using histopathology as the gold standard in diagnosing cervical intraepithelial neoplasia (CIN) 2 or worse (CIN2+). RESULTS: Among 2969 women enrolled, 1480 (50%) tested HPV positive. The cohort included 1478 (50%) WLHIV; 99% were virologically suppressed after a mean of 8 years on antiretroviral therapy. In total, 1269 (86%) women had histopathology data for analysis. Among WLHIV who tested positive for HPV, 131 (19%) of 688 had CIN2+ compared with 71 (12%) of 581 in women without HIV. Screening by 8-type HPV genotype restriction was more sensitive as triage to detect CIN2+ in WLHIV 87.79% (95% CI: 80.92-92.85) and women without HIV 85.92% (95% CI: 75.62-93.03) when compared with VIA (WLHIV 62.31% [95% CI: 53.39-70.65], women without HIV 44.29% [95% CI: 32.41-56.66]) and colposcopy (WLHIV 70.77% [95% CI: 62.15-78.41], women without HIV 45.71% [95% CI: 33.74-58.06]). However, 8-type HPV genotype restriction had low specificity in WLHIV of 30.88% (95% CI: 27.06-34.90) and women without HIV 37.06% (95% CI: 32.85-41.41). These results were similar when CIN3+ was used as the outcome. When combining 8-type HPV genotype restriction with VIA as the triage strategy, there was improved specificity to detect CIN2+ in WLHIV of 81.65% (95% CI: 78.18-84.79) but dramatically reduced sensitivity of 56.15% (95% CI: 47.18-64.84). CONCLUSIONS: Eight-type HPV genotype restriction is a promising component of effective triage for HPV positivity. However, novel triage strategies in LMICs with high HIV prevalence may be needed to avoid the trade-off between sensitivity and specificity with currently available options. CLINICAL TRIALS REGISTRATION: This study is registered on Clinicaltrials.gov no. NCT04242823, https://clinicaltrials.gov/ct2/show/NCT04242823.

Virological, serological and clinical outcomes in chronic hepatitis B virus infection: development and validation of the HEPA-B simulation model.

OBJECTIVES: Detailed simulation models are needed to assess strategies for prevention and treatment of hepatitis B virus (HBV) infection, the world's leading cause of liver disease. We sought to develop and validate a simulation model of chronic HBV that incorporates virological, serological and clinical outcomes. METHODS: We developed a novel Monte Carlo simulation model (the HEPA-B Model) detailing the natural history of chronic HBV. We parameterised the model with epidemiological data from the Western Pacific and sub-Saharan Africa. We simulated the evolution of HBV DNA, 'e' antigen (HBeAg) and surface antigen (HBsAg). We projected incidence of HBeAg loss, HBsAg loss, cirrhosis, hepatocellular carcinoma (HCC) and death over 10-year and lifetime horizons. We stratified outcomes by five HBV DNA categories at the time of HBeAg loss, ranging from HBV DNA<300 copies/mL to >106 copies/mL. We tested goodness of fit using intraclass coefficients (ICC). RESULTS: Model-projected incidence of HBeAg loss was 5.18% per year over lifetime (ICC, 0.969 (95% CI: 0.728 to 0.990)). For people in HBeAg-negative phases of infection, model-projected HBsAg loss ranged from 0.78% to 3.34% per year depending on HBV DNA level (ICC, 0.889 (95% CI: 0.542 to 0.959)). Model-projected incidence of cirrhosis was 0.29-2.09% per year (ICC, 0.965 (95% CI: 0.942 to 0.979)) and HCC incidence was 0.06-1.65% per year (ICC, 0.977 (95% CI: 0.962 to 0.986)). Over a lifetime simulation of HBV disease, mortality rates were higher for people with older age, higher HBV DNA level and liver-related complications, consistent with observational studies. CONCLUSIONS: We simulated HBV DNA-stratified clinical outcomes with the novel HEPA-B Model and validated them to observational data. This model can be used to examine strategies of HBV prevention and management.

Longitudinal transitions in initiation, cessation, and relapse of cigarette smoking and e-cigarette use among US youth and adults: Validation of a microsimulation model.

INTRODUCTION: Estimates of initiation, cessation, and relapse rates of tobacco cigarette smoking and e-cigarette use can facilitate projections of longer-term impact of their use. We aimed to derive transition rates and apply them to validate a microsimulation model of tobacco that newly incorporated e-cigarettes. METHODS: We fit a Markov multi-state model (MMSM) for participants in Waves 1-4.5 of the Population Assessment of Tobacco and Health (PATH) longitudinal study. The MMSM had nine cigarette smoking and e-cigarette use states (current/former/never use of each), 27 transitions, two sex categories, and four age categories (youth: 12-17y; adults: 18-24y/25-44y/≥45y). We estimated transition hazard rates, including initiation, cessation, and relapse. We then validated the Simulation of Tobacco and Nicotine Outcomes and Policy (STOP) microsimulation model, by: (a) using transition hazard rates derived from PATH Waves 1-4.5 as inputs, and (b) comparing STOP-projected prevalence of smoking and e-cigarette use at 12 and 24 months to empirical data from PATH Waves 3 and 4. We compared the goodness-of-fit of validations with "static relapse" and "time-variant relapse," wherein relapse rates did not or did depend on abstinence duration. RESULTS: Per the MMSM, youth smoking and e-cigarette use was generally more volatile (lower probability of maintaining the same e-cigarette use status over time) than that of adults. Root-mean-squared error (RMSE) for STOP-projected versus empirical prevalence of smoking and e-cigarette use was <0.7% for both static and time-variant relapse simulations, with similar goodness-of-fit (static relapse: RMSE 0.69%, CI 0.38-0.99%; time-variant relapse: RMSE 0.65%, CI 0.42-0.87%). PATH empirical estimates of prevalence of smoking and e-cigarette use were mostly within the margins of error estimated by both simulations. DISCUSSION: A microsimulation model incorporating smoking and e-cigarette use transition rates from a MMSM accurately projected downstream prevalence of product use. The microsimulation model structure and parameters provide a foundation for estimating the behavioral and clinical impact of tobacco and e-cigarette policies.

Comparison of the AmpFire Multiplex HPV Assay to the Xpert HPV Assay for detection of human papillomavirus and cervical disease in women with human immunodeficiency virus: A pragmatic performance evaluation.

Background: Low- and middle-income countries (LMICs) account for nearly 85% of the global cervical cancer burden, yet have the least access to high-performance screening. International guidelines recommend human papillomavirus testing (HPV) as primary screening, yet implementation is inhibited by the cost of HPV testing.Atila AmpFire HPV Assay (AmpFire) is both affordable and easy to use, and offers individual genotyping. The objective of this study was to compare the performance of the AmpFire HPV assay to the Xpert HPV assay in detection of both HPV and clinically significant cervical disease. Methods: We utilized stored cervical specimens from a prospective cohortstudy of women living with human immunodeficiency virus (HIV) in Botswana conducted from May to July 2018. Positive and negative percent agreement was calculated for the AmpFire and Xpert assays, as was detection of high-grade cervical dysplasia. Results : 63 stored cervical specimens haddetectable DNA after thawing and were included in the analysis. The positive percent agreement was 91.2% (95%CI: 76.3-98.1) and negative percent agreement was 79.3% (95% CI: 60.3-92.0). Six cases positive by AmpFire but negative by Xpert were HPV genotypes 35, 52 (n=2), 58, 68, and co-infection with HPV 45 and 68. Both Xpert and AmpFire assays detected HPV in all 10 samples of women who had high-grade cervical dysplasia. Conclusions : The AmpFire HPV assay demonstrated excellent analytic performance in both detection of HPV and clinically significant cervical disease. AmpFire HPV is a promising option to increase access to affordable, type-specific HPV screening for cervical cancer in LMICs.

Comparison of the AmpFire® Multiplex HPV Assay to the Xpert® HPV Assay for detection of human papillomavirus and cervical disease in women with human immunodeficiency virus: a pragmatic performance evaluation.

BACKGROUND: Low- and middle-income countries (LMICs) account for nearly 85% of the global cervical cancer burden, yet have the least access to high-performance screening. International guidelines recommend human papillomavirus testing (HPV) as primary screening, yet implementation is inhibited by the cost of HPV testing. Atila AmpFire® HPV Assay (AmpFire) is both affordable and easy to use, and offers individual genotyping. The objective of this study was to compare the performance of the AmpFire HPV assay to the Xpert® HPV assay in detection of both HPV and clinically significant cervical disease. METHODS: We utilized stored cervical specimens from a prospective cohort study of women living with human immunodeficiency virus (HIV) in Botswana conducted from May to July 2018. Positive and negative percent agreement was calculated for the AmpFire and Xpert assays, as was detection of high-grade cervical dysplasia. RESULTS: 63 stored cervical specimens had detectable DNA after thawing and were included in the analysis. The positive percent agreement was 91.2% (95%CI 76.3-98.1) and negative percent agreement was 79.3% (95% CI 60.3-92.0). Six cases positive by AmpFire but negative by Xpert were HPV genotypes 35, 52 (n = 2), 58, 68, and co-infection with HPV 45 and 68. Both Xpert and AmpFire assays detected HPV in all 10 samples of women who had high-grade cervical dysplasia. CONCLUSIONS: The AmpFire HPV assay demonstrated excellent analytic performance in both detection of HPV and clinically significant cervical disease. AmpFire HPV is a promising option to increase access to affordable, type-specific HPV screening for cervical cancer in LMICs.

Risk of progression to active tuberculosis following reinfection with Mycobacterium tuberculosis.

BACKGROUND: The risk of progression to active tuberculosis is greatest in the several years following initial infection. The extent to which latent tuberculosis infection reduces the risk of progressive disease following reexposure and reinfection is not known. Indirect estimates from population models have been highly variable. METHODS: We reviewed prospective cohort studies of persons exposed to individuals with infectious tuberculosis that were published prior to the widespread treatment of latent tuberculosis to estimate the incidence of tuberculosis among individuals with latent tuberculosis infection (LTBI group) and without latent tuberculosis (uninfected; UI group). We calculated the incidence rate ratio (IRR) of tuberculosis disease following infection between these 2 groups. We then adjusted incidence for expected reactivation, proportion of each group that was infected, and median time of observation following infection during the study. RESULTS: We identified 18 publications reporting tuberculosis incidence among 23 paired cohorts of individuals with and without latent infection (total N = 19 886). The weighted mean adjusted incidence rate of tuberculosis in the LTBI and UI groups attributable to reinfection was 13.5 per 1000 person-years (95% confidence interval [CI]: 5.0-26.2 per 1000 person-years) and that attributable to primary infection was 60.1 per 1000 person-years (95% CI: 38.6-87.4 per 1000 person-years). The adjusted IRR for tuberculosis in the LTBI group compared with the UI group was 0.21 (95% CI: .14-.30). CONCLUSIONS: Individuals with latent tuberculosis had 79% lower risk of progressive tuberculosis after reinfection than uninfected individuals. The risk reduction estimated in this study is greater than most previous estimates made through population models.