Decoding huge phage diversity: a taxonomic classification of Lak megaphages.

High-throughput sequencing for uncultivated viruses has accelerated the understanding of global viral diversity and uncovered viral genomes substantially larger than any that have so far been cultured. Notably, the Lak phages are an enigmatic group of viruses that present some of the largest known phage genomes identified in human and animal microbiomes, and are dissimilar to any cultivated viruses. Despite the wealth of viral diversity that exists within sequencing datasets, uncultivated viruses have rarely been used for taxonomic classification. We investigated the evolutionary relationships of 23 Lak phages and propose a taxonomy for their classification. Predicted protein analysis revealed the Lak phages formed a deeply branching monophyletic clade within the class Caudoviricetes which contained no other phage genomes. One of the interesting features of this clade is that all current members are characterised by an alternative genetic code. We propose the Lak phages belong to a new order, the 'Grandevirales'. Protein and nucleotide-based analyses support the creation of two families, three sub-families, and four genera within the order 'Grandevirales'. We anticipate that the proposed taxonomy of Lak megaphages will simplify the future classification of related viral genomes as they are uncovered. Continued efforts to classify divergent viruses are crucial to aid common analyses of viral genomes and metagenomes.

Evaluation of respondent-driven sampling in seven studies of people who use drugs from rural populations: findings from the Rural Opioid Initiative.

BACKGROUND: Accurate prevalence estimates of drug use and its harms are important to characterize burden and develop interventions to reduce negative health outcomes and disparities. Lack of a sampling frame for marginalized/stigmatized populations, including persons who use drugs (PWUD) in rural settings, makes this challenging. Respondent-driven sampling (RDS) is frequently used to recruit PWUD. However, the validity of RDS-generated population-level prevalence estimates relies on assumptions that should be evaluated. METHODS: RDS was used to recruit PWUD across seven Rural Opioid Initiative studies between 2018-2020. To evaluate RDS assumptions, we computed recruitment homophily and design effects, generated convergence and bottleneck plots, and tested for recruitment and degree differences. We compared sample proportions with three RDS-adjusted estimators (two variations of RDS-I and RDS-II) for five variables of interest (past 30-day use of heroin, fentanyl, and methamphetamine; past 6-month homelessness; and being positive for hepatitis C virus (HCV) antibody) using linear regression with robust confidence intervals. We compared regression estimates for the associations between HCV positive antibody status and (a) heroin use, (b) fentanyl use, and (c) age using RDS-1 and RDS-II probability weights and no weights using logistic and modified Poisson regression and random-effects meta-analyses. RESULTS: Among 2,842 PWUD, median age was 34 years and 43% were female. Most participants (54%) reported opioids as their drug of choice, however regional differences were present (e.g., methamphetamine range: 4-52%). Many recruitment chains were not long enough to achieve sample equilibrium. Recruitment homophily was present for some variables. Differences with respect to recruitment and degree varied across studies. Prevalence estimates varied only slightly with different RDS weighting approaches, most confidence intervals overlapped. Variations in measures of association varied little based on weighting approach. CONCLUSIONS: RDS was a useful recruitment tool for PWUD in rural settings. However, several violations of key RDS assumptions were observed which slightly impacts estimation of proportion although not associations.

Contraception and Healthcare Utilization by Reproductive-Age Women Who Use Drugs in Rural Communities: a Cross-Sectional Survey.

BACKGROUND: Women who use drugs (WWUD) have low rates of contraceptive use and high rates of unintended pregnancy. Drug use is common among women in rural U.S. communities, with limited data on how they utilize reproductive, substance use disorder (SUD), and healthcare services. OBJECTIVE: We determined contraceptive use prevalence among WWUD in rural communities then compared estimates to women from similar rural areas. We investigated characteristics of those using contraceptives, and associations between contraceptive use and SUD treatment, healthcare utilization, and substance use. DESIGN: Rural Opioids Initiative (ROI) - cross-sectional survey using respondent-driven sampling (RDS) involving eight rural U.S. regions (January 2018-March 2020); National Survey on Family Growth (NSFG) - nationally-representative U.S. household reproductive health survey (2017-2019). PARTICIPANTS: Women aged 18-49 with prior 30-day non-prescribed opioid and/or non-opioid injection drug use; fecundity determined by self-reported survey responses. MAIN MEASURES: Unweighted and RDS-weighted prevalence estimates of medical/procedural contraceptive use; chi-squared tests and multi-level linear regressions to test associations. KEY RESULTS: Of 855 women in the ROI, 36.8% (95% CI 33.7-40.1, unweighted) and 38.6% (95% CI 30.7-47.2, weighted) reported contraceptive use, compared to 66% of rural women in the NSFG sample. Among the ROI women, 27% had received prior 30-day SUD treatment via outpatient counseling or inpatient program and these women had increased odds of contraceptive use (aOR 1.50 [95% CI 1.08-2.06]). There was a positive association between contraception use and recent medications for opioid use disorder (aOR 1.34 [95% CI 0.95-1.88]) and prior 6-month primary care utilization (aOR 1.32 [95% CI 0.96-1.82]) that did not meet the threshold for statistical significance. CONCLUSION: WWUD in rural areas reported low contraceptive use; those who recently received SUD treatment had greater odds of contraceptive use. Improvements are needed in expanding reproductive and preventive health within SUD treatment and primary care services in rural communities.

Treatment Initiation, Substance Use Trajectories, and the Social Determinants of Health in Persons Living With HIV Seeking Medication for Opioid Use Disorder.

BACKGROUND: People living with HIV and opioid use disorder (OUD) are disproportionally affected by adverse socio-structural exposures negatively affecting health, which have shown inconsistent associations with uptake of medications for OUD (MOUD). This study aimed to determine whether social determinants of health (SDOH) were associated with MOUD uptake and trajectories of substance use in a clinical trial of people seeking treatment. METHODS: Data are from a 2018 to 2019 randomized trial comparing the effectiveness of different MOUD to achieve viral suppression among people living with HIV and OUD. SDOH were defined by variables mapping to Healthy People 2030 domains: education (Education Access and Quality), income (Economic Stability), homelessness (Neighborhood and Built Environment), criminal justice involvement (Social and Community Context), and recent SUD care (Health Care Access and Quality). Associations between SDOH and MOUD initiation were assessed with Cox proportional hazards models, and SDOH and substance use over time with generalized estimating equation models. RESULTS: Participants (N = 114) averaged 47 years old, 63% were male, 56% were Black, and 12% Hispanic. Participants reported an average of 2.3 out of 5 positive SDOH indicators (SD = 1.2). Stable housing was the most commonly reported SDOH (61%), followed by no recent criminal justice involvement (59%), having a high-school level education or greater (56%), income stability (45%), and recent SUD care (13%). Each additional favorable SDOH was associated with a 25% increase in the likelihood of MOUD initiation during the study period [adjusted HR = 1.25, 95% CI = (1.01, 1.55), P = .044]. Positive SDOH were also associated with a decrease in the odds of baseline opioid use and a greater reduction in opioid use during subsequent weeks of the study (P < .001 for a joint test of baseline and slope differences). CONCLUSIONS: Positive social determinants of health, in aggregate, may increase the likelihood of MOUD treatment initiation among people living with HIV and OUD.

Microcomputed tomography void analysis after cement cleanup methods.

STATEMENT OF PROBLEM: Cement at the restorative margin after implementation of the manufacturer's recommended procedure for cement cleanup has not been extensively evaluated. PURPOSE: The purpose of this in vitro study was to use microcomputed tomography (µCT) to evaluate the number, volume, and width of voids left at the margin when dental cement is cleaned during the cementation process as per 2 manufacturer-prescribed methods for cement cleanup by evaluating a self-adhesive resin cement and a resin-modified glass ionomer cement. MATERIAL AND METHODS: Twenty molar Ivorine Typodont prepared teeth were scanned, and lithium disilicate crowns were milled and cemented to the prepared teeth as per the manufacturer-recommended cementation process. Two methods of cement cleanup were performed: the excess cement was tack-polymerized with a polymerization light, or a delay of 3 minutes was used for the excess cement to reach partial polymerization, and the excess cement was removed with a sharp sickle scaler. These 2 methods of cement cleanup were performed with 2 cements: a resin-modified glass ionomer cement and a self-adhesive resin. Each specimen was then scanned with a µCT machine. The buccal margin of each specimen, from mesiobuccal line angle to distobuccal line angle, was examined, and the number, volume, and width of any voids remaining at the margin open to the environment were measured. For statistical analysis, the specimens were first grouped by method of cement cleanup and then grouped by cement type. The Wilcoxon ranked sum test was implemented because of the lack of a normal distribution and the heterogeneity of the data (α=.05). RESULTS: No statistically significant difference was found in the median number of voids, median volume of voids, or median width per void between the 2 cleanup methods, irrespective of cement type (P>.05). Significant differences were found in the median number of voids, median volume of voids, and median width per void when comparing cement types, irrespective of cement cleanup methods (P<.05). CONCLUSIONS: The choice of cement may be more important than the method of cement cleanup when considering voids left at the margin. Microcomputed tomography is an excellent nondestructive tool for volumetric measurements of voids at the margin.

The Effect of Finishing and Polishing with Proprietary Vs Interchanged Polishing Kits on the Surface Roughness of Different Ceramic Materials.

PURPOSE: To evaluate the surface roughness of glazed and polished monolithic ceramic materials and to use this as a baseline for comparison after adjustment and polishing with both the recommended kit for the specific materials as well as interchanged polishing kits. MATERIAL AND METHODS: Flat ceramic specimens (n = 150) were fabricated from IPS ZirCAD Prime, IPS E.max, and Vitabloc Mark II. The specimens were adjusted and polished using either the proprietary polishing kit for the material or interchanged kits. The surface roughness was objectively assessed using Atomic Force Microscopy (AFM) and profilometer. Subjective assessment of surface finish was performed using a scanning electron microscope (SEM). Gravimetric weight loss of each sample was measured before and after polishing using a digital microscale. The mean surface roughness and standard deviation was calculated for each ceramic- polisher pair. A factorial ANOVA was used to compare the mean surface roughness values in nanometers between multiple groups (α = 0.05). The subjective results from the SEM were reported as descriptive statistics RESULTS: The zirconia polishing system produced surfaces with the lowest surface roughness regardless of the ceramic material. The polisher-ceramic combination was found to have a statistically significant effect on both Ra and RMS values when the AFM was used (p = 0.039 and 0.010, respectively). CONCLUSION: The zirconia polishing system resulted in the lowest surface roughness values regardless of ceramic materials tested. The zirconia polishing system also did not result in significant gravimetric weight loss regardless of the ceramic material used.

Reduced Mitochondrial Respiration in Hybrid Asexual Lizards.

AbstractThe scarcity of asexual reproduction in vertebrates alludes to an inherent cost. Several groups of asexual vertebrates exhibit lower endurance capacity (a trait predominantly sourced by mitochondrial respiration) compared with congeneric sexual species. Here we measure endurance capacity in five species of Aspidoscelis lizards and examine mitochondrial respiration between sexual and asexual species using mitochondrial respirometry. Our results show reduced endurance capacity, reduced mitochondrial respiration, and reduced phenotypic variability in asexual species compared with parental sexual species, along with a positive relationship between endurance capacity and mitochondrial respiration. Results of lower endurance capacity and lower mitochondrial respiration in asexual Aspidoscelis are consistent with hypotheses involving mitonuclear incompatibility.

Using a peptide-based mass spectrometry approach to quantitate proteolysis of an intact heterogeneous procollagen substrate by BMP1 for antagonistic antibody screening.

Proteases are critical proteins involved in cleaving substrates that may impact biological pathways, cellular processes, or disease progression. In the biopharmaceutical industry, modulating the levels of protease activity is an important strategy for mitigating many types of diseases. While a variety of analytical tools exist for characterizing substrate cleavages, in vitro functional screening for antibody inhibitors of protease activity using physiologically relevant intact protein substrates remains challenging. In addition, detecting such large protein substrates with high heterogeneity using high-throughput mass spectrometry screening has rarely been reported in the literature with concerns for assay robustness and sensitivity. In this study, we established a peptide-based in vitro functional screening assay for antibody inhibitors of mouse bone morphogenic protein 1 (mBMP1) metalloprotease using a heterogeneous recombinant 66-kDa mouse Procollagen I alpha 1 chain (mProcollagen) substrate. We compared several analytical tools including capillary gel electrophoresis Western blot (CE-Western blot), as well as both intact protein and peptide-based mass spectrometry (MS) to quantitate the mBMP1 proteolytic activity and its inhibition by antibodies using this heterogeneous mProcollagen substrate. We concluded that the peptide-based mass spectrometry screening assay was the most suitable approach in terms of throughput, sensitivity, and assay robustness. We then optimized our mBMP1 proteolysis reaction after characterizing the enzyme kinetics using the peptide-based MS assay. This assay resulted in Z' values ranging from 0.6 to 0.8 from the screening campaign. Among over 1200 antibodies screened, IC50 characterization was performed on the top candidate hits, which showed partial or complete inhibitory activities against mBMP1.

911 Calls for Emergency Medical Services in Heart Failure: A Descriptive Qualitative Study.

BACKGROUND: Heart failure (HF) is a common condition leading to activation of emergency medical services (EMS). OBJECTIVE: The aim of this study was to describe reasons given by persons with HF, family members, or other caregivers for requesting EMS activation during 911 calls. METHODS: In this descriptive qualitative study, a content analysis was performed on transcribed audio files of 383 EMS requests involving 383 persons with HF in the community. RESULTS: One hundred forty-seven calls (38.4%) were placed by the family members, 75 (19.6%) were placed by the patients, 56 (14.6%) were placed by healthcare workers or personnel from living facilities, and the remaining calls (n = 105, 27.4%) were placed by others (eg, friends, neighbors, officers). Three broad categories of symptoms, signs, and events were identified as the reasons for an EMS request. Frequently reported symptoms were breathing problems (55.4%), chest pain (18.3%), and other pain (eg, head, extremities) (16.7%). Signs included decreased consciousness (15.4%), swelling (5.7%), and bleeding (5.0%). The reported events involved falls (8.1%), heart attack (6.3%), hypoxic episodes (6.0%), stroke (5.2%), and post-hospital-discharge complications (4.7%). In most calls (74.9%), multiple reasons were reported and a combination of symptoms, signs, and events were identified. Heart failure diagnosis was mentioned in fewer than 10% of the calls. CONCLUSIONS: Overall, symptoms and signs of HF exacerbation were common reasons to activate 911 calls. Falls were frequently reported. Under the duress of the emergent situations surrounding the 911 call, callers rarely mentioned the existence of HF. Interventions are needed to guide patients with HF and their family members to promote the management of HF to reduce EMS activation as well as to activate EMS quickly for acute changes in HF conditions.

Feasibility and Acceptability of a Group Counseling Intervention for Opioid Use Disorder: An Exploratory Study.

The goal of the current exploratory study was to examine the feasibility and acceptability of an evidence-based group counseling intervention for individuals with opioid use disorders (OUD) reporting mental health issues and using medications for OUD. The intervention combines motivational interviewing and cognitive-behavioral therapy. Qualitative research methodology, specifically focus group interviewing, with seven individuals was used to examine the feasibility and acceptability of the intervention. Qualitative analysis of the focus group yielded four themes: Intervention Format, Group Counseling Factors, Comorbid Mental Health Issues, and Counselor Factors. The intervention proposed was found to be acceptable and feasible for addressing OUD and co-occurring mental health conditions, specifically depression, anxiety, and stress. [Journal of Psychosocial Nursing and Mental Health Services, 60(6), 7-10.].

Extracellular BMP1 is the major proteinase for COOH-terminal proteolysis of type I procollagen in lung fibroblasts.

Proteolytic processing of procollagens is a central step during collagen fibril formation. Bone morphogenic protein 1 (BMP1) is a metalloprotease that plays an important role in the cleavage of carboxy-terminal (COOH-terminal) propeptides from procollagens. Although the removal of propeptides is required to generate mature collagen fibrils, the contribution of BMP1 to this proteolytic process and its action site remain to be fully determined. In this study, using postnatal lung fibroblasts as a model system, we showed that genetic ablation of Bmp1 in primary murine lung fibroblasts abrogated COOH-terminal cleavage from type I procollagen as measured by COOH-terminal propeptide of type I procollagen (CICP) production. We also showed that inhibition of BMP1 by siRNA-mediated knockdown or small-molecule inhibitor reduced the vast majority of CICP production and collagen deposition in primary human lung fibroblasts. Furthermore, we discovered and characterized two antibody inhibitors for BMP1. In both postnatal lung fibroblast and organoid cultures, BMP1 blockade prevented CICP production. Together, these findings reveal a nonredundant role of extracellular BMP1 to process CICP in lung fibroblasts and suggest that development of antibody inhibitors is a viable pharmacological approach to target BMP1 proteinase activity in fibrotic diseases.

Optical properties of a novel glass-ceramic restorative material.

OBJECTIVE: To examine the optical properties of a dental restorative material manufactured from lithium aluminosilicate ceramic and reinforced with lithium disilicate. Translucency and the optical effects of various supporting materials on color were the primary focus. METHODS: Five 10 × 10 mm samples were prepared in thicknesses of 0.5, 1.0, 1.5, and 2.0 mm of both high translucency (HT) and low translucency (LT) versions of the material in shade A3. A spectrophotometer was used to measure the illuminance of the samples with black and white backings in order to calculate contrast ratio (CR) and relative translucency parameter (RTP). A baseline relationship between translucency and material thickness was examined and the effects of composite, titanium, and zirconia abutments on color change were studied. RESULTS: No significant findings were identified for RTP or CR between the HT and LT material, regardless of the material thickness (p = 0.39, p = 0.14, respectively). Regardless of material thickness (HT vs. LT), translucencies (RTP and CR) were significantly different with composite, titanium, and zirconia backings compared to baseline values (p < 0.0001). Titanium had the most significant decrease in translucency compared to composite and zirconia. There was no difference in ΔE00 between the HT and LT materials (p > 0.05) regardless of the backing. Titanium had the most significant effect on color of both materials followed by composite then zirconia (p < 0.0001). CONCLUSIONS: There is not a clinically significant difference in translucency between the high translucency and low translucency materials. Only zirconia supporting structures produced changes in color that are clinically acceptable. CLINICAL SIGNIFICANCE: Understanding the optical properties of glass-ceramic restorative materials aids providers in selecting appropriate materials for optimum esthetic outcomes. The lithium-aluminosilicate reinforced with lithium disilicate material does a poor job masking supporting structures and resisting color change.

Psychometric properties of measures of substance use: a systematic review and meta-analysis of reliability, validity and diagnostic test accuracy.

BACKGROUND: Synthesis of psychometric properties of substance use measures to identify patterns of use and substance use disorders remains limited. To address this gap, we sought to systematically evaluate the psychometric properties of measures to detect substance use and misuse. METHODS: We conducted a systematic review and meta-analysis of literature on measures of substance classes associated with HIV risk (heroin, methamphetamine, cocaine, ecstasy, alcohol) that were published in English before June 2016 that reported at least one of the following psychometric outcomes of interest: internal consistency (alpha), test-retest/inter-rater reliability (kappa), sensitivity, specificity, positive predictive value, and negative predictive value. We used meta-analytic techniques to generate pooled summary estimates for these outcomes using random effects and hierarchical logistic regression models. RESULTS: Findings across 387 paper revealed that overall, 65% of pooled estimates for alpha were in the range of fair-to-excellent; 44% of estimates for kappa were in the range of fair-to-excellent. In addition, 69, 97, 37 and 96% of pooled estimates for sensitivity, specificity, positive predictive value, and negative predictive value, respectively, were in the range of moderate-to-excellent. CONCLUSION: We conclude that many substance use measures had pooled summary estimates that were at the fair/moderate-to-excellent range across different psychometric outcomes. Most scales were conducted in English, within the United States, highlighting the need to test and validate these measures in more diverse settings. Additionally, the majority of studies had high risk of bias, indicating a need for more studies with higher methodological quality.

Time-lasting ceramic stains and glaze: A toothbrush simulation study.

OBJECTIVE: To evaluate and compare color stability and gloss retention of ceramic stains and glaze under simulated toothbrushing using dentifrices with different relative dentin abrasion (RDA). MATERIALS AND METHODS: Feldspathic porcelain, lithium disilicate, 3 mol% yttria partially stabilized zirconia, and 5 mol% yttria partially stabilized zirconia were evaluated. Ceramics were externally stained, glazed and mounted in the toothbrush simulator. A toothbrush with 300 g force was applied. Regular toothpaste (72 RDA) and charcoal toothpaste (RDA <200) were used. Linear brushing motion with cycle intervals: 5 k, 10 k, 30 k, and 50 k was achieved. Change in color (CIEΔE2000) and gloss measurements were collected using a reflection spectrophotometer (Ci 7600, X-rite) at baseline and cycle intervals. Repeated measures analysis of variance within specimen factors (ceramic type, toothpaste and cycles) was performed. RESULTS: ΔE00 was significantly different at 50 k cycles and with zirconia ceramics (P < .0001). Charcoal toothpaste was significantly different in ΔE00 compared to regular toothpaste (P > .0001). Loss of gloss was observed at 5 k and 30 k (charcoal and regular toothpaste respectively) regardless type of ceramic (P > .0001). CONCLUSION: Glass-phase ceramics retain stains longer than zirconia ceramics. Charcoal toothpaste affect color and gloss stability. Ceramic glaze maybe lost within the first 6 months in patients' mouth. CLINICAL SIGNIFICANCE: Long-term color and gloss stability of externally stained and glazed ceramics maybe a clinical concern. Charcoal toothpastes enhance loss of color and gloss of ceramic restorations.

Fracture load of two thicknesses of different zirconia types after fatiguing and thermocycling.

STATEMENT OF PROBLEM: A direct relationship has been reported between yttria concentration and translucency in zirconia restorations. However, increased yttria concentration also increases the cubic phase of the zirconia, which reduces its strength. The effect of increased yttria content on the fracture resistance of zirconia as a function of material thickness after fatigue testing requires evaluation. PURPOSE: The purpose of this in vitro study was to use the biaxial flexural test to evaluate the effect of yttria concentration on the mean fracture load (N) before and after fatiguing and thermocycling as a function of zirconia thickness. MATERIAL AND METHODS: Disk-shaped specimens of 5 mol% yttria partially stabilized zirconia (5Y-PSZ, BruxZir Anterior Solid Zirconia) and 3 mol% yttria partially stabilized zirconia (3Y-PSZ, BruxZir Shaded Zirconia) were prepared to thicknesses of 1.2 and 0.7 mm. For each thickness, the biaxial flexural test was used to measure the fracture load (N) before and after fatigue testing, with 1.2 million cycles at a 110-N load and simultaneous thermocycling at 5 °C to 55 °C (n=20). The data were analyzed by repeated-measures ANOVA (α=.05). RESULTS: Yttria concentration, thickness, and exposure to fatiguing had a statistically significant effect on the mean biaxial flexural load (yttria concentration: P<.001; thickness: P<.001; fatiguing: P=.004 for the 3Y-PSZ). One of the major findings in this study was that 30% of the 1.2-mm-thick 5Y-PSZ specimens and 80% of the 0.7-mm-thick 5Y-PSZ specimens fractured during fatiguing. All specimens of the 3Y-PSZ groups survived the fatiguing protocol. The 3Y-PSZ groups had statistically significant higher flexural loads than the 5Y-PSZ groups. The 1.2-mm thickness groups had statistically significant higher flexural loads than the 0.7-mm thickness groups. CONCLUSIONS: Yttria concentration had a significant effect on the strength of zirconia. 5Y-PSZ was considerably less resistant to fracture before and after fatigue testing than 3Y-PSZ. Decreasing the thickness of zirconia reduces its fracture resistance, regardless of the zirconia type.

Movement Demands of an Elite Cricket Team During the Big Bash League in Australia.

There is a lack of research on the movement patterns within Twenty20 (T20) cricket, thus the purpose of this study was to investigate the movement demands placed on elite T20 cricket players playing in The Big Bash League, in Australia, in the 2017/2018 season. Player positional movements were determined from the time motion data obtained from a portable 10 Hz global positioning (GPS) unit. Overall, all the players covered between 1.77km and 6.54km in a time ranging between 40.4 minutes and 96.5 minutes. Fast bowlers covered a mean distance of 6.5 (±0.5) km, batsmen 1.7 (±1.2) km and fielders 5.9 (±0.9) km. This is the first study that has looked at the movement demands of players in The Big Bash League and found that bowlers have the highest movement demands followed by fielding. With that, arguably, more attention needs to be devoted to bowling and particularly fielding which is often not prioritized. However, overall demands of T20 cricketers have decreased. Cricketers and coaches need to ensure that they adapt training to ensure that their players are physically prepared for the associated demands.

Adverse Health Outcomes in Relationship to Hypogonadism After Chemotherapy: A Multicenter Study of Testicular Cancer Survivors.

BACKGROUND: This study examined the prevalence of hypogonadism, its clinical and genetic risk factors, and its relationship to adverse health outcomes (AHOs) in North American testicular cancer survivors (TCS) after modern platinum-based chemotherapy. PATIENTS AND METHODS: Eligible TCS were <55 years of age at diagnosis and treated with first-line platinum-based chemotherapy. Participants underwent physical examinations and completed questionnaires regarding 15 AHOs and health behaviors. Hypogonadism was defined as serum testosterone levels ≤3.0 ng/mL or use of testosterone replacement therapy. We investigated the role of 2 single nucleotide polymorphisms (rs6258 and rs12150660) in the sex hormone-binding globulin (SHBG) locus implicated in increased hypogonadism risk in the general population. RESULTS: Of 491 TCS (median age at assessment, 38.2 years; range, 18.7-68.4 years), 38.5% had hypogonadism. Multivariable binary logistic regression analysis identified hypogonadism risk factors, including age at clinical evaluation (odds ratio [OR], 1.42 per 10-year increase; P= .006) and body mass index of 25 to <30 kg/m2 (OR, 2.08; P= .011) or ≥30 kg/m2 (OR, 2.36; P= .005) compared with <25 kg/m2. TCS with ≥2 risk alleles for the SHBG SNPs had a marginally significant increased hypogonadism risk (OR, 1.45; P= .09). Vigorous-intensity physical activity appeared protective (OR, 0.66; P= .07). Type of cisplatin-based chemotherapy regimen and socioeconomic factors did not correlate with hypogonadism. Compared with TCS without hypogonadism, those with hypogonadism were more likely to report ≥2 AHOs (65% vs 51%; P= .003), to take medications for hypercholesterolemia (20.1% vs 6.0%; P<.001) or hypertension (18.5% vs 10.6%; P= .013), and to report erectile dysfunction (19.6% vs 11.9%; P= .018) or peripheral neuropathy (30.7% vs 22.5%; P= .041). A marginally significant trend for increased use of prescription medications for either diabetes (5.8% vs 2.6%; P= .07) or anxiety/depression (14.8% vs 9.3%; P= .06) was observed. CONCLUSIONS: At a relatively young median age, more than one-third of TCS have hypogonadism, which is significantly associated with increased cardiovascular disease risk factors, and erectile dysfunction. Providers should screen TCS for hypogonadism and treat symptomatic patients.

Bouncier Particles at Night: Biogenic Secondary Organic Aerosol Chemistry and Sulfate Drive Diel Variations in the Aerosol Phase in a Mixed Forest.

Aerosol phase state is critical for quantifying aerosol effects on climate and air quality. However, significant challenges remain in our ability to predict and quantify phase state during its evolution in the atmosphere. Herein, we demonstrate that aerosol phase (liquid, semisolid, solid) exhibits a diel cycle in a mixed forest environment, oscillating between a viscous, semisolid phase state at night and liquid phase state with phase separation during the day. The viscous nighttime particles existed despite higher relative humidity and were independently confirmed by bounce factor measurements and atomic force microscopy. High-resolution mass spectrometry shows the more viscous phase state at night is impacted by the formation of terpene-derived and higher molecular weight secondary organic aerosol (SOA) and smaller inorganic sulfate mass fractions. Larger daytime particulate sulfate mass fractions, as well as a predominance of lower molecular weight isoprene-derived SOA, lead to the liquid state of the daytime particles and phase separation after greater uptake of liquid water, despite the lower daytime relative humidity. The observed diel cycle of aerosol phase should provoke rethinking of the SOA atmospheric lifecycle, as it suggests diurnal variability in gas-particle partitioning and mixing time scales, which influence aerosol multiphase chemistry, lifetime, and climate impacts.

Pathologies of matrix metalloproteinase-2 underactivity: a perspective on a neglected condition 1.

A member of the matrix metalloproteinase family, matrix metalloproteinase-2 (MMP-2, gelatinase A), has been extensively studied for its role in both normal physiology and pathological processes. Whereas most research efforts in recent years have investigated the pathologies associated with MMP-2 overactivity, the pathological mechanisms elicited by MMP-2 underactivity are less well understood. Here, we distinguish between 2 states and describe their causes: (i) MMP-2 deficiency (complete loss of MMP-2 activity) and (ii) MMP-2 insufficiency (defined as MMP-2 activity below baseline levels). Further, we review the biology of MMP-2, summarizing the current literature on MMP-2 underactivity in both mice and humans, and describe research being conducted by our lab towards improving our understanding of the pathological mechanisms elicited by MMP-2 deficiency/insufficiency. We think that this research could stimulate the discovery of new therapeutic approaches for managing pathologies associated with MMP-2 underactivity. Moreover, similar concepts could apply to other members of the matrix metalloproteinase family.

Effects of Substance Use and Sex Practices on the Intestinal Microbiome During HIV-1 Infection.

Background: Human immunodeficiency virus type 1 (HIV-1) infection alters the human intestinal microbiome; however, behavioral factors driving these changes remain poorly defined. Here we examine the effects of substance use and sex behavior on the microbiome during HIV-1 infection. Methods: Archival rectal swab specimens, urine drug test results, and responses to substance use and sex behavior questionnaires were obtained from 37 HIV-positive participants at 2 time points, separated by 6 months, in a cohort examining the effects of substance use in men who have sex with men (MSM). Microbiome profiling was performed using 16S ribosomal RNA gene sequencing, and associations with behavioral factors were examined using 0-inflated negative binomial regression. Further analysis of selected variables of interest was performed using propensity scores to account for multiple confounders. Results: Using permutational multivariate analysis of variance, we found that receptive anal intercourse, methamphetamine use, and marijuana use were among the most important drivers of microbiome variation. Propensity score-adjusted analyses revealed that methamphetamine use and marijuana use displayed unique associations; methamphetamine use was associated with an increased abundance of Porphyromonas and Granulicatella organisms and a decreased abundance of Ruminococcus, Collinsella, and Parabacteroides organisms, whereas marijuana use was associated with an increased abundance of Ruminococcus, Clostridium cluster IV, Solobacterium, and Fusobacterium organisms and a decreased abundance of Acidaminococcus, Prevotella, Dialister, Anaerostipes, and Dorea organisms. Conclusions: Drug use and sex behavior are important factors associated with intestinal dysbiosis during chronic HIV-1 infection among young MSM.