The role of high-risk HPV-DNA testing in the male sexual partners of women with HPV-induced lesions

OBJECTIVES: The objectives were to assess the prevalence of high-risk HPV in the male sexual partners of women with HPV-induced lesions, and correlate it with biopsies guided by peniscopy. STUDY DESIGN: Fifty-four asymptomatic male sexual partners of women with low-grade squamous intra-epithelial lesions (LSIL) associated with high-risk HPV were examined between April 2003 and June 2005. The DNA-HPV was tested using a second-generation hybrid capture technique in scraped penile samples. Peniscopy identified acetowhite lesions leading to biopsy. RESULTS: High-risk HPV was present in 25.9% (14 out of 54) of the cases. Peniscopy led to 13 biopsies (24.07%), which resulted in two cases of condyloma, two cases of intra-epithelial neoplasia (PIN) I, one case of PIN II, and eight cases of normal tissue. The high-risk HPV test demonstrated 80% sensitivity, 100% specificity, 100% positive predictive value, and 88.9% negative predictive value for the identification of penile lesions. There was a greater chance of finding HPV lesions in the biopsy in the positive cases of high-risk HPV with abnormal peniscopy (p=0.007); OR=51 (CI 1.7-1527.1). CONCLUSION: Among asymptomatic male sexual partners of women with low-grade intra-epithelial squamous lesions, those infected by high-risk HPV have a higher chance of having abnormal penile tissue compared with male partners without that infection.     

Availability of Safe Childbirth Supplies in 284 Facilities in Uttar Pradesh,India

Maternal and Child Health Journal - Objectives Vital to implementation of the World Health Organization (WHO) Safe Childbirth Checklist (SCC), designed to improve delivery of 28 essential birth...     

Reduced H+ channel activity disrupts pH homeostasis and calcification in coccolithophores at low ocean pH

Coccolithophores are major producers of ocean biogenic calcite, but this process is predicted to be negatively affected by future ocean acidification scenarios. Since coccolithophores calcify intracellularly, the mechanisms through which changes in seawater carbonate chemistry affect calcification remain unclear. Here we show that voltage-gated H⁺ channels in the plasma membrane of Coccolithus braarudii serve to regulate pH and maintain calcification under normal conditions but have greatly reduced activity in cells acclimated to low pH. This disrupts intracellular pH homeostasis and impairs the ability of C. braarudii to remove H⁺ generated by the calcification process, leading to specific coccolith malformations. These coccolith malformations can be reproduced by pharmacological inhibition of H⁺ channels. Heavily calcified coccolithophore species such as C. braarudii, which make the major contribution to carbonate export to the deep ocean, have a large intracellular H⁺ load and are likely to be most vulnerable to future decreases in ocean pH.

Anthropogenic CO₂ emissions and the subsequent dissolution of CO₂ in seawater have resulted in substantial changes in ocean carbonate chemistry (1). The resultant decrease in seawater pH, termed ocean acidification, is predicted to be particularly detrimental for calcifying organisms (2). Mean global surface ocean pH is currently around 8.2 but is predicted to fall as low as 7.7 by 2100 (3) and is likely to continue to fall further in the following centuries. Present-day marine organisms can experience significant fluctuations in seawater pH, particularly in coastal and upwelling regions (4, 5). Ocean acidification is therefore predicted to have an important influence not only on mean surface ocean pH but also on the extremes of pH experienced by marine organisms (6, 7).Coccolithophores (Haptophyta) are a group of globally distributed unicellular phytoplankton that are characterized by their covering of intricately formed calcite scales (coccoliths). Coccolithophores account for a significant proportion of ocean productivity and are the main producers of biogenic calcite, making major contributions to global biogeochemical cycles, including the long-term export of both inorganic and organic carbon from the ocean photic zone to deep waters (8, 9). Unlike the vast majority of calcifying organisms, coccolithophore calcification occurs in an intracellular compartment, the Golgi-derived coccolith vesicle (CV), effectively isolating the calcification process from direct changes in seawater carbonate chemistry. Nevertheless, extensive laboratory observations indicate that ocean acidification may negatively impact coccolithophore calcification, albeit with significant variability of responses between species and strains (10–14). The negative impact on calcification rates occurs at calcite saturation states (Ω_calcite) >1, indicating that it results primarily from impaired cellular production rather than dissolution (10, 15). However, prediction of how natural coccolithophore populations may respond to future changes in ocean pH are hampered by lack of mechanistic understanding of pH impacts at the cellular level (10).As calcification occurs intracellularly using external HCO₃⁻ as the primary dissolved inorganic carbon (DIC) source (16–18), coccolith formation is not directly dependent on external CO₃²⁻ concentrations. However, the uptake of HCO₃⁻ as a substrate for calcification results in the equimolar production of CaCO₃ and H⁺ in the CV (18). In order to maintain saturation conditions for calcite formation, H⁺ produced by the calcification process must be rapidly removed from the CV, placing extraordinary demands for cellular pH regulation to prevent cellular acidosis (18).Lower calcification rates under ocean acidification conditions appear to be primarily due to decreased pH rather than other aspects of carbonate chemistry (10, 19, 20). Coccolithophores exhibit highly unusual membrane physiology, including the presence of voltage-gated H⁺ channels in the plasma membrane (21) and a high sensitivity of cytosolic pH (pH_cyt) to changes in external pH (pH_o) (21, 22). Voltage-gated H⁺ channels are associated with rapid H⁺ efflux in a number of specialized animal cell types (23) and contribute to effective pH regulation in coccolithophores (21). As H⁺ channel function is dependent on the electrochemical gradient of H⁺ across the plasma membrane, this mechanism could be impaired under lower seawater pH. However, it remains unknown whether H⁺ channels play a direct role in removal of calcification-derived H⁺ or contribute to the sensitivity of coccolithophores to ocean acidification.Coccolithophores exhibit significant diversity in their extent of calcification (SI Appendix, Fig. S1). The ratio of particulate inorganic carbon to particulate organic carbon (PIC/POC) of a coccolithophore culture is a measure of the relative rates of inorganic carbon fixation by calcification and organic carbon fixation by photosynthesis, respectively, and is commonly used as a simple metric to define the degree of calcification. The abundant bloom-forming species Emiliania huxleyi is moderately calcified (PIC/POC of around 1) and has been the focus of the vast majority of the studies into the effects of environmental change in coccolithophores (13). Coastal species belonging to the Pleurochrysidaceae and Hymenomonadaceae are lightly calcified, commonly exhibiting a PIC/POC of less than 0.5 (24–27). Species such as Coccolithus braarudii, Calcidiscus leptoporus, and Helicosphaera carteri exhibit much higher PIC/POC ratios and contribute the majority of carbonate export to the deep ocean in many areas (28–30). The physiological response of heavily calcified coccolithophores to ocean acidification is therefore of considerable biogeochemical significance. Growth and calcification rates in C. leptoporus and C. braarudii are sensitive to pH values predicted to prevail on a future decadal timescale (10, 15, 31, 32). However, a mechanistic understanding of the different sensitivity of coccolithophore species to changing ocean carbonate chemistry is lacking.The net H⁺ load in a cell is determined by the combination of metabolic processes that consume or produce H⁺. H⁺ fluxes in coccolithophores will be primarily determined by the balance of H⁺ consumed by photosynthesis and H⁺ generated by calcification, with uptake of different carbon sources a particularly important consideration (Fig. 1A). CO₂ uptake for photosynthesis results in no net production or consumption of H⁺, whereas uptake of HCO₃⁻ requires the equimolar consumption of H⁺ in order to generate CO₂. Growth at elevated CO₂ causes a switch from HCO₃⁻ uptake to predominately CO₂ uptake in E. huxleyi (33, 34). The associated net decrease in H⁺ consumption will therefore increase the H⁺ load in coccolithophores grown at elevated CO₂, which may exacerbate the potential for cytosolic acidosis caused by lower seawater pH.Open in a separate windowFig. 1.Physiology and H⁺ fluxes of C. braarudii cells grown at different seawater pH. (A) Schematic indicating H⁺ fluxes associated with photosynthesis and calcification in a coccolithophore cell. While many metabolic processes may contribute to the cellular H⁺ budget, these two processes are likely to be the major contributors. In a cell taking up HCO₃⁻, the overall H⁺ budget is determined by the relative rates of H⁺ consumed during photosynthesis and H⁺ generated during calcification. In a cell taking up CO₂, the H⁺ budget is determined primarily by calcification, as 2 H⁺ are produced for each molecule of CaCO₃ produced and H⁺ are no longer consumed during photosynthesis. In both scenarios, excess H⁺ may be removed from the cell by H⁺ transporters in the plasma membrane, such as voltage-gated H⁺ channels (H_v). Coccolithophores take up both HCO₃⁻ and CO₂ across the plasma membrane, with increasing proportions of DIC taken up as CO₂ as seawater CO₂ increases (34). (B) Growth rate of C. braarudii cells acclimated to different seawater pH. n = 3 replicates per treatment; line represents polynomial fit to mean. (C) Cellular production of POC through photosynthesis and PIC through calcification. The optima for both processes are close to the control conditions (pH 8.15). (D) As a consequence of the unequal changes in cellular POC and PIC production across the applied pH values, cellular PIC/POC ratios are minimal at pH 7.55 (∼1.0) and maximal at pH 8.45 (∼1.8). (E) Calculated net H⁺ budgets under the different pH regimes, based on rates of photosynthesis and calcification shown in C (see Materials and Methods). The concentration of CO₂ in seawater is also shown (dashed line). Estimates are shown for cells using taking up only HCO₃⁻ or only CO₂. As C. braarudii cells will likely take up a mixture of both DIC species, with a shift toward greater CO₂ usage at elevated CO₂, the shaded area represents the potential range of H⁺ production. Regardless of DIC species used C. braarudii produces excess H⁺ at all applied pH values, but H⁺ production is much lower at pH 7.55 due to the decrease in calcification.In this study we set out to better understand the cellular mechanisms underlying the sensitivity of coccolithophore calcification to lower pH. We subjected the heavily calcified species C. braarudii, which is commonly found in temperate upwelling regions (35, 36), to conditions that reflect the range of pH values it may experience in current and future oceans. We show that acclimation to low pH leads to loss of H⁺ channel function and disruption of cellular pH regulation in C. braarudii. These effects are coincident with very specific defects in coccolith morphology that can be reproduced by direct inhibition of H⁺ channels. We conclude that H⁺ efflux through H⁺ channels is essential for maintaining both calcification rate and coccolith morphology. By providing a mechanistic insight into pH regulation during the calcification process, our results indicate that disruption of coccolithophore calcification in a future acidified ocean is likely to be most severe in heavily calcified species.     

The seasonal relationships between household dietary diversity and child growth in a rural Timor‐Leste community

Both child growth and dietary diversity are poor in rural Timor‐Leste. The rainy season is associated with food scarcity, yet the association between seasonal scarcity, food diversity, and child growth is underdocumented. This study assesses the relationship between household dietary diversity and children''s standardized growth across the 2018 food‐scarce (April–May; post‐rainy period) and post‐harvest (October) seasons in the agricultural community of Natarbora, on the south‐coastal plains of Timor‐Leste. We conducted household interviews and collected anthropometric data across 98 and 93 households in the post‐rainy and post‐harvest periods, respectively. Consumed household foods were obtained via 24‐h diet recalls and were subsequently categorized into a nine‐food‐group dietary diversity score (DDS; number of different food groups consumed). The DDS was related to children''s standardized short‐term growth (z‐weight, z‐body mass index [BMI] and percent change in weight over the harvest season) via linear mixed models. Across seasons, DDS increased from 3.9 (standard deviation [SD] = 1.0) to 4.3 (SD = 1.4; p < 0.05). In the post‐rainy season, children in high DDS households had higher z‐weight than those in low DDS households and higher z‐BMI than children in medium and low DDS households. In the post‐harvest period, household DDS did not predict children''s z‐weight but predicted z‐BMI. Consumption of protein‐rich foods, particularly animal‐source foods and legumes, in low‐ and medium‐DDS households may be associated with improved child growth. While consuming more animal‐source foods in the post‐rainy season would be ideal, promoting the consumption of locally grown legumes, such as beans and pulses, may facilitate better nutritional outcomes for more children in rural Timor‐Leste.     

Evaluation of a Wastewater-Based Epidemiological Approach to Estimate the Prevalence of SARS-CoV-2 Infections and the Detection of Viral Variants in Disparate Oregon Communities at City and Neighborhood Scales

Background: Positive correlations have been reported between wastewater SARS-CoV-2 concentrations and a community’s burden of infection, disease or both. However, previous studies mostly compared wastewater to clinical case counts or nonrepresentative convenience samples, limiting their quantitative potential.Objectives: This study examined whether wastewater SARS-CoV-2 concentrations could provide better estimations for SARS-CoV-2 community prevalence than reported cases of COVID-19. In addition, this study tested whether wastewater-based epidemiology methods could identify neighborhood-level COVID-19 hotspots and SARS-CoV-2 variants.Methods: Community SARS-CoV-2 prevalence was estimated from eight randomized door-to-door nasal swab sampling events in six Oregon communities of disparate size, location, and demography over a 10-month period. Simultaneously, wastewater SARS-CoV-2 concentrations were quantified at each community’s wastewater treatment plant and from 22 Newport, Oregon, neighborhoods. SARS-CoV-2 RNA was sequenced from all positive wastewater and nasal swab samples. Clinically reported case counts were obtained from the Oregon Health Authority.Results: Estimated community SARS-CoV-2 prevalence ranged from 8 to 1,687/10,000 persons. Community wastewater SARS-CoV-2 concentrations ranged from 2.9 to 5.1log10 gene copies per liter. Wastewater SARS-CoV-2 concentrations were more highly correlated (Pearson’s r=0.96; R2=0.91) with community prevalence than were clinically reported cases of COVID-19 (Pearson’s r=0.85; R2=0.73). Monte Carlo simulations indicated that wastewater SARS-CoV-2 concentrations were significantly better than clinically reported cases at estimating prevalence (p<0.05). In addition, wastewater analyses determined neighborhood-level COVID-19 hot spots and identified SARS-CoV-2 variants (B.1 and B.1.399) at the neighborhood and city scales.Discussion: The greater reliability of wastewater SARS-CoV-2 concentrations over clinically reported case counts was likely due to systematic biases that affect reported case counts, including variations in access to testing and underreporting of asymptomatic cases. With these advantages, combined with scalability and low costs, wastewater-based epidemiology can be a key component in public health surveillance of COVID-19 and other communicable infections. https://doi.org/10.1289/{"type":"entrez-protein","attrs":{"text":"EHP10289","term_id":"372009674","term_text":"EHP10289"}}EHP10289     

Aerobic exercise elicits clinical adaptations in myotonic dystrophy type 1 patients independently of pathophysiological changes

BackgroundMyotonic dystrophy type 1 (DM1) is a complex life-limiting neuromuscular disorder characterized by severe skeletal muscle atrophy, weakness, and cardiorespiratory defects. Exercised DM1 mice exhibit numerous physiological benefits that are underpinned by reduced CUG foci and improved alternative splicing. However, the efficacy of physical activity in patients is unknown.MethodsEleven genetically diagnosed DM1 patients were recruited to examine the extent to which 12 weeks of cycling can recuperate clinical and physiological metrics. Furthermore, we studied the underlying molecular mechanisms through which exercise elicits benefits in skeletal muscle of DM1 patients.RESULTSDM1 was associated with impaired muscle function, fitness, and lung capacity. Cycling evoked several clinical, physical, and metabolic advantages in DM1 patients. We highlight that exercise-induced molecular and cellular alterations in patients do not conform with previously published data in murine models and propose a significant role of mitochondrial function in DM1 pathology. Finally, we discovered a subset of small nucleolar RNAs (snoRNAs) that correlated to indicators of disease severity.ConclusionWith no available cures, our data support the efficacy of exercise as a primary intervention to partially mitigate the clinical progression of DM1. Additionally, we provide evidence for the involvement of snoRNAs and other noncoding RNAs in DM1 pathophysiology.Trial registrationThis trial was approved by the HiREB committee (no. 7901) and registered under ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT04187482","term_id":"NCT04187482"}}NCT04187482).FundingNeil and Leanne Petroff. Canadian Institutes of Health Research Foundation (no. 143325).     

Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial

Context  Standard therapy for hot flashes has been hormone replacement with estradiol or progestational agents, but recent data suggest that antidepressants inhibiting serotonin reuptake may also be effective. Objective  To evaluate a selective serotonin reuptake inhibitor (paroxetine controlled release [CR]) in treating the vasomotor symptoms displayed by a general cross-section of menopausal women. Design and Setting  Randomized, double-blind, placebo-controlled, parallel group study conducted across 17 US sites, including urban, suburban, and rural clinics. Patients  A total of 165 menopausal women aged 18 years or older experiencing at least 2 to 3 daily hot flashes and must have discontinued any hormone replacement therapy for at least 6 weeks. Women were excluded if they had any signs of active cancer or were undergoing chemotherapy or radiation therapy. Intervention  After a 1-week placebo run-in phase, study participants were randomized to receive placebo or receive 12.5 mg/d or 25.0 mg/d of paroxetine CR (in a 1:1:1 ratio) for 6 weeks. Main Outcome Measures  Mean change from baseline to week 6 in the daily hot flash composite score (frequency x severity). Results  Fifty-six participants were randomly assigned to receive placebo and 51 to receive 12.5 mg/d and 58 to receive 25.0 mg/d of paroxetine CR. The mean reductions in the hot flash frequency composite score from baseline to week 6 were statistically significantly greater for those receiving paroxetine CR than for those receiving placebo. By week 6, the mean daily hot flash frequency went from 7.1 to 3.8 (mean reduction, 3.3) for those in the 12.5-mg/d and from 6.4 to 3.2 (mean reduction, 3.2) for those in the 25-mg/d paroxetine CR groups and from 6.6 to 4.8 (mean reduction, 1.8) for those in the placebo group. Mean placebo-adjusted reduction in hot flash composite scores were -4.7 (95% confidence interval, - 8.1 to -1.3; P = .007) comparing 12.5-mg/d paroxetine CR with placebo; and -3.6 (95% confidence interval, -6.8 to -0.4; P = .03) comparing 25.0-mg/d paroxetine CR with placebo. This corresponded to median reductions of 62.2% for those in the 12.5-mg/d and 64.6% for those in the 25.0-mg/d paroxetine CR groups compared with 37.8% for those in the placebo group. Conclusion  Paroxetine CR may be an effective and acceptable alternative to hormone replacement and other therapies in treating menopausal hot flash symptoms.      

Mortality within 30 days of receiving systemic anti‐cancer therapy at a regional oncology unit: What have we learned?

Aims: Benefits to patients from systemic anti‐cancer therapies (SACT) occur at a cost of significant toxicities that can be life threatening. Published data of SACT mortality outside clinical trials is limited with no published Australia data. We aim to establish local outcomes at a regional Victorian oncology center to allow comparison with limited international data. Methods: An audit was undertaken at Ballarat Health Services to analyze all deaths occurring within 30 and 60 days of receiving SACT (cytotoxic chemotherapy and targeted therapy) for epithelial malignancies and hematological malignancies (excluding acute leukemia), over a 12‐month period. Hormonal therapy was excluded. Results: Between 1 January and 31 December 2008, 378 patients received SACT. In total 13 deaths (3.4%) occurred within 30 days following SACT. Three deaths (23%) were definitely treatment‐related – neutropenic sepsis, pneumocystis pneumonia and bowel perforation, respectively. Eight deaths (62%) were definitely unrelated to treatment. Most deaths were due to disease progression (six patients) For two patients (15%), the cause of death was unknown. Most patients were treated with palliative intent. Most patients were receiving first‐line treatment (seven patients, 50%). A further five deaths (1.3%) occurred 31–60 days after SACT, four of which were due to disease progression. Conclusion: Our local outcome data are comparable to limited current international data. This type of audit reviews local outcomes and identifies factors contributing to mortality in order to improve standards of care. We encourage similar audits to establish national benchmarks of 30‐day mortality rate.     

Imaging Therapeutic PARP Inhibition In Vivo through Bioorthogonally Developed Companion Imaging Agents

A number of small-molecule poly (ADP-ribose) polymerase (PARP) inhibitors are currently undergoing advanced clinical trials. Determining the distribution and target inhibitory activity of these drugs in individual subjects, however, has proven problematic. Here, we used a PARP agent for positron emission tomography-computed tomography (PET-CT) imaging (¹⁸F-BO), which we developed based on the Olaparib scaffold using rapid bioorthogonal conjugation chemistries. We show that the bioorthogonal ¹⁸F modification of the parent molecule is simple, highly efficient, and well tolerated, resulting in a half maximal inhibitory concentration (IC₅₀) of 17.9 ± 1.1 nM. Intravital imaging showed ubiquitous distribution of the drug and uptake into cancer cells, with ultimate localization within the nucleus, all of which were inhibitable. Whole-body PET-CT imaging showed tumoral uptake of the drug, which decreased significantly, after a daily dose of Olaparib. Standard ¹⁸F-fludeoxyglucose imaging, however, failed to detect such therapy-induced changes. This research represents a step toward developing a more generic approach for the rapid codevelopment of companion imaging agents based on small-molecule therapeutic inhibitors.