Effects of chronic dichlorodiphenyldichloroethylene exposure on testosterone secretion and steroidogenic pathway in the male gonad.

Endocrine disrupting chemicals are present in the environment and/or in consumer products. These agents have the capacity to mimic and/or antagonize endogenous hormones and thus perturb the endocrine axis. The male reproductive tract expresses steroid hormone (androgen and estrogen) receptors at high levels and is a major target for endocrine disrupting chemicals. In this study, Long-Evans male rats were exposed to dichlorodiphenyldichloroethylene, a metabolite of dichlorodiphenyltrichloroethane and a chemical present in the environment, in drinking water at 0.1 and 10 µg/L for 4 weeks. At the end of exposure, we measured steroid hormone secretion and analyzed steroidogenic proteins, including 17ß-hydroxysteroid dehydrogenase, 3ß-hydroxysteroid dehydrogenase, steroidogenic acute regulatory protein, aromatase, and the LH receptor. We also analyzed Leydig cell apoptosis (poly-(ADP-ribose) polymerase) and caspase-3 in the testes. Testicular testosterone (T) and 17ß-estradiol (E2) were both affected by exposure to dichlorodiphenyldichloroethylene by displaying altered steroidogenic enzyme expression. Dichlorodiphenyldichloroethylene exposure also increased the expression of enzymes mediating the pathway for programmed cell death, including caspase 3, pro-caspase 3, PARP, and cleaved PARP. Altogether, the present results demonstrate that dichlorodiphenyldichloroethylene directly and/or indirectly can target specific proteins involved in steroid hormone production in the male gonad and suggest that exposure to environmentally relevant dichlorodiphenyldichloroethylene levels has implications for male reproductive development and function.

First Dark Matter Search Results from the LUX-ZEPLIN (LZ) Experiment.

The LUX-ZEPLIN experiment is a dark matter detector centered on a dual-phase xenon time projection chamber operating at the Sanford Underground Research Facility in Lead, South Dakota, USA. This Letter reports results from LUX-ZEPLIN's first search for weakly interacting massive particles (WIMPs) with an exposure of 60 live days using a fiducial mass of 5.5 t. A profile-likelihood ratio analysis shows the data to be consistent with a background-only hypothesis, setting new limits on spin-independent WIMP-nucleon, spin-dependent WIMP-neutron, and spin-dependent WIMP-proton cross sections for WIMP masses above 9 GeV/c^{2}. The most stringent limit is set for spin-independent scattering at 36 GeV/c^{2}, rejecting cross sections above 9.2×10^{-48} cm at the 90% confidence level.

Development of a Preliminary Question Prompt List as a Communication Tool for Adults With Achalasia: A Modified Delphi Study.

BACKGROUND: Question prompt lists (QPLs) are structured sets of disease-specific questions that enhance patient-physician communication by encouraging patients to ask questions during consultations. AIM: The aim of this study was to develop a preliminary achalasia-specific QPL created by esophageal experts. METHODS: The QPL content was derived through a modified Delphi method consisting of 2 rounds. In round 1, experts provided 5 answers to the prompts "What general questions should patients ask when given a new diagnosis of achalasia" and "What questions do I not hear patients asking, but given my expertise, I believe they should be asking?" In round 2, experts rated questions on a 5-point Likert scale. Questions considered "essential" or "important" were accepted into the QPL. Feedback regarding the QPL was obtained in a pilot study wherein patients received the QPL before their consultation and completed surveys afterwards. RESULTS: Nineteen esophageal experts participated in both rounds. Of 148 questions from round 1, 124 (83.8%) were accepted into the QPL. These were further reduced to 56 questions to minimize redundancy. Questions were categorized into 6 themes: "What is achalasia," "Risks with achalasia," "Symptom management in achalasia," "Treatment of achalasia," "Risk of reflux after treatment," and "Follow-up after treatment." Nineteen patients participated in the pilot, most of whom agreed that the QPL was helpful (84.2%) and recommended its wider use (84.2%). CONCLUSIONS: This is the first QPL developed specifically for adults with achalasia. Although well-received in a small pilot, follow-up studies will incorporate additional patient feedback to further refine the QPL content and assess its usability, acceptability, and feasibility.

Effects of different DDE exposure paradigms on testicular steroid hormone secretion and hepatic oxidative stress in male Long-Evans rats.

Chronic exposure to low doses of anthropogenic chemicals in the environment continues to be a major health issue. Due to concerns about the effects in humans and wildlife, use of persistent organic pollutants, such as dichlorodiphenyltrichloroethane (DDT), is prohibited. However, their ubiquitous nature and persistence allows them to remain in the environment at low levels for decades. Dichlorodiphenyldichloroethylene (DDE) is the most persistent metabolite of DDT and has been shown to cause hepatotoxicity, nephrotoxicity, hormonal disorders, and induce oxidative stress in many organisms. Although the effects of acute exposure to DDT and its metabolite DDE have been extensively studied, the chronic effects of sub-lethal DDE exposure at levels comparable to those found in the environment have not been well documented. Long-Evans male rats were used to determine the effect of relatively chronic and short term DDE (doses ranged from 0.001 to 100 µg/L) exposure on endocrine function and oxidative stress at different developmental time points. We found that circulating serum testosterone (T) levels were significantly decreased and T secretion in testicular explants were significantly influenced in a dose dependent manner in both pre-pubertal and pubertal male rats after DDE exposure, with pubertal rats being the most affected contrary to our original prediction. Additionally, exposure to DDE increased expression of protein oxidation indicating a possible increase in cellular damage caused by oxidative stress. This study suggests that chronic exposures to environmentally relevant levels of DDE affected testicular function and decreased T secretion with implications for reproductive capacity.

Effect of the COVID-19 pandemic on blood donations and transfusions in Nigeria - A multi-facility study of 34 tertiary hospitals.

Background: The coronavirus disease 2019 (COVID-19) pandemic affected blood supplies globally. Mobile blood drive campaigns halted, and voluntary blood donations reduced, challenging available blood supplies. Furthermore, fears of virus transmission led to deferrals of elective surgeries and non-urgent clinical procedures with noticeable declines in blood donations and transfusions. Aims: We aimed to assess the effect of the COVID-19 pandemic on the number of blood donations and transfusions across the country by blood product type across various hospital departments. Materials and Methods: A retrospective descriptive study was conducted to determine the impact of the COVID-19 pandemic on blood services in 34 tertiary hospitals in Nigeria, comparing January to July 2019 (pre-COVID-19) to January to July 2020 (peri-COVID-19). Data were collected from the country's web-based software District Health Information System, Version 2 (DHIS2). Results: A 17.1% decline in numbers of blood donations was observed over the study period, especially in April 2020 (44.3%), a 21.7% decline in numbers of blood transfusions, especially in April 2020 (44.3%). The largest declines in transfusion were noted in surgery department for fresh frozen plasma (80.1%) [p = 0.012] and accident and emergency department transfusion of platelets (78.3%) [p = 0.005]. The least decline of statistical significance was observed in internal medicine transfusions of whole blood (19.6%) [p = 0.011]. Conclusions: The COVID-19 pandemic significantly affected the numbers of blood donations and transfusions in Nigeria. Strengthening blood services to provide various blood components and secure safe blood supplies during public health emergencies is therefore critical.

Room temperature mid-infrared fiber lasing beyond 5 µm in chalcogenide glass small-core step index fiber.

This Letter, to the best of our knowledge, reports mid-infrared fiber lasing beyond 5 µm at room temperature for the first time, Ce3+-doped, chalcogenide glass, step index fiber employed in-band pumping with a 4.15 µm quantum cascade laser. The lasing fiber is was 64 mm long, with a calculated numerical aperture of 0.48 at the lasing wavelengths. The core glass was Ge15As21Ga1Se63 atomic % (at. %), doped with 500 parts-per-million-by-weight Ce, with a 9 µm core diameter. The cladding glass was Ge21Sb10Se69 at. % with a 190 µm outer diameter. As pump power increases continuous wave lasing corresponding to the 2F7/2→2F5/2, transition in the Ce3+ ion occurs at 5.14 µm, 5.17 µm, and 5.28 µm.

Small Intestinal Bacterial Overgrowth Syndrome: A Guide for the Appropriate Use of Breath Testing.

The increased availability of noninvasive breath tests, each with limitations, has led to widespread testing for small intestinal bacterial overgrowth (SIBO) in patients with non-specific gastrointestinal complaints. The lactulose breath test (LBT) is based upon an incorrect premise and therefore incorrect interpretations which has resulted in the over-diagnosis of SIBO and the excessive use of antibiotics in clinical practice. Despite limitations, the glucose breath test (GBT) should be exclusively employed when considering SIBO in appropriately chosen patients. This review suggests guidelines for the optimal use and appropriate interpretation of the GBT for suspected SIBO. The LBT should be discarded from future use, and the literature based upon the LBT should be discounted accordingly.

Understanding farmers' and veterinarians' behavior in relation to antimicrobial use and resistance in dairy cattle: A systematic review.

To tackle antimicrobial resistance, it is vital that farmers' and veterinarians' antimicrobial use behaviors and attitudes toward resistance are understood so that we can identify how beliefs and motives influence practices. Current literature details qualitative and quantitative research that explores the knowledge, attitudes and perceptions of dairy farmers and veterinarians with respect to antimicrobial resistance and antimicrobial practices, and the reported findings are varied and conflicting. Our objective was to conduct a systematic review to assess the evidence and knowledge gaps in the published literature. We identified articles via database searches of Embase, Medline, PubMed, Scopus, and Web of Science; we limited findings to published articles available in English with no publication year restrictions. Article screening was conducted at 3 levels: title, abstract, and full text. Of the 349 articles identified, 35 were retained for systematic review. Transparency of reporting was assessed for each study using the Consolidated Criteria for Reporting Qualitative Research (COREQ) framework. Quality was assessed using the Critical Appraisal Skills Programme qualitative checklist. Findings relating to dairy farmers' and veterinarians' knowledge, attitudes, and perceptions on antimicrobial resistance and practices were thematically analyzed. The comprehensiveness of reporting was variable: studies reported 5 to 26 of the 32 COREQ checklist items. Five key themes emerged from the data: knowledge and awareness of antimicrobial resistance; factors influencing farmer and veterinarian decision-making; perceived barriers and facilitators to reduced antimicrobial use; perceived responsibility for antimicrobial resistance; and the role of the farmer and veterinarian relationship in reducing antimicrobial use. Awareness of prudent antimicrobial use was not uniform between studies. Many factors influence farmers' and veterinarians' decisions to use antimicrobials, including animal welfare and available resources. The farmer-veterinarian relationship is a potential barrier or facilitator of reduced antimicrobial use, depending on the perceived relationship dynamic. Encouraging collaboration between farmers and veterinarians could lead to shared responsibility for reducing antimicrobial use. This review provided a coherent picture of what is currently known and identified gaps in the current knowledge to inform future behavioral intervention research. Increased knowledge, skill development, resources, engagement, and further research to address the gaps we identified are the main recommendations to effectively overcome barriers, elicit appropriate behavior change, and achieve reduced antimicrobial use in dairy cattle.

Motility Patterns Following Esophageal Pharmacologic Provocation With Amyl Nitrite or Cholecystokinin During High-Resolution Manometry Distinguish Idiopathic vs Opioid-Induced Type 3 Achalasia.

BACKGROUND & AIMS: In some patients, the type 3 achalasia (A3) motor pattern may be an effect of chronic use of high-dose opioids. No motor findings have been identified to differentiate opioid-induced A3 (OA3) from idiopathic A3 (IA3). We investigated whether OA3 could be distinguished from IA3 on the basis of differences in esophageal motor responses to amyl nitrite, cholecystokinin, or atropine. METHODS: We performed a retrospective study of patients who received pharmacologic provocation during esophageal high-resolution manometry from 2007 through 2017 at a tertiary referral center. We identified 26 patients with IA3 (9 women; mean age, 68 ± 13 years) and 24 patients with OA3 (15 women; mean age, 59 ± 10 years). We compared pressure topography metrics during deglutition and after administration of amyl nitrite, cholecystokinin, or atropine between patients with OA3 vs IA3. RESULTS: Amyl nitrite induced a similar relaxation response in both groups, but the rebound contraction of the lower esophageal sphincter during amyl nitrite recovery, and the paradoxical esophageal contraction during the first phase of cholecystokinin response, were both significantly attenuated in patients with OA3. The second phase of cholecystokinin response in patients with OA3 was 100% relaxation, when present, in contrast to only 26% of patients with IA3. There was no significant difference between groups in inhibition of lower esophageal sphincter tone or esophageal body contractility by cholinergic receptor blockade. CONCLUSIONS: Nearly half of patients with an A3 pattern of dysmotility are chronic, daily users of opioids with manometry patterns indistinguishable from those of patients with IA3. Patients with OA3 differ from patients with IA3 in responses to amyl nitrite and cholecystokinin. These findings might be used to identify patients with dysmotility resulting from opioid use.

Clinical Functional Lumen Imaging Probe Testing in Esophageal Disorders: A Need for Better Quality Evidence.

In their article "Use of the Functional Lumen Imaging Probe in Clinical Esophagology," Savarino et al. report the outcomes of a Grading of Recommendations Assessment, Development, and Evaluation analysis performed by experts in the use of functional lumen imaging probe (FLIP) evaluation of esophageal disorders. For essentially all clinical indications, the recommendation for use was conditional with a very low quality of evidence. FLIP is an expensive, invasive technology examining limited aspects of esophageal function. Its role in complementing or replacing existing technology is uncertain, particularly when compared with manometric testing with additional provocative studies. Performing properly designed studies to demonstrate FLIP's true effectiveness and cost-effectiveness will be costly.

Regulation of the neuroendocrine axis in male rats by soy-based diets is independent of age and due specifically to isoflavone action†.

Soy-based foods are consumed for their health beneficial effects, implying that the population is exposed to soy isoflavones in the diet. Herein, male rats at 21, 35, and 75 days of age were maintained either on a casein control diet, soybean meal (SBM), or control diet supplemented with daidzin and genistin (G + D) for 14 days. Feeding of SBM and G + D diets decreased testicular testosterone (T) secretion regardless of age. Altered androgen secretion was due to decreased (P < 0.05) Star and Hsd17ß protein in the testes and was associated with increased (P < 0.05) Lhß and Fshß subunit protein expression in pituitary glands. Second, male rats were fed either a casein control diet, control diet + daidzin, control diet + genistin, or control diet + genistin + daidzin (G + D). Compared to control, feeding of all isoflavone-containing diets decreased (P < 0.05) testicular T concentrations, and more so in the G + D diet group. Interestingly, Esr1 and androgen receptor protein and pituitary Fshß with Lhß subunit protein were increased (P < 0.05) by feeding of genistin and G + D diets, but not the daidzin diet. However, daidzein and genistein both caused a concentration dependent inhibition (P < 0.05) of T secretion by Leydig cells in vitro with IC50 of 184 ηM and 36 ηM, respectively. Results demonstrated that altered testicular steroidogenic capacity and pituitary FSHß and LHß subunit expression due to soy-based diets result from specific actions by genistein and daidzein. Experiments to assess effects of isoflavone regulation of intratesticular androgen concentrations on male fertility are warranted.

A standard set of person-centred outcomes for diabetes mellitus: results of an international and unified approach.

AIMS: To select a core list of standard outcomes for diabetes to be routinely applied internationally, including patient-reported outcomes. METHODS: We conducted a structured systematic review of outcome measures, focusing on adults with either type 1 or type 2 diabetes. This process was followed by a consensus-driven modified Delphi panel, including a multidisciplinary group of academics, health professionals and people with diabetes. External feedback to validate the set of outcome measures was sought from people with diabetes and health professionals. RESULTS: The panel identified an essential set of clinical outcomes related to diabetes control, acute events, chronic complications, health service utilisation, and survival that can be measured using routine administrative data and/or clinical records. Three instruments were recommended for annual measurement of patient-reported outcome measures: the WHO Well-Being Index for psychological well-being; the depression module of the Patient Health Questionnaire for depression; and the Problem Areas in Diabetes scale for diabetes distress. A range of factors related to demographic, diagnostic profile, lifestyle, social support and treatment of diabetes were also identified for case-mix adjustment. CONCLUSIONS: We recommend the standard set identified in this study for use in routine practice to monitor, benchmark and improve diabetes care. The inclusion of patient-reported outcomes enables people living with diabetes to report directly on their condition in a structured way.

Flip Technology for Assessing Esophageal Structural and Motor Disorders: a Skeptic's View.

PURPOSE OF REVIEW: Functional lumen impedance (FLIP) technology has become commercially available to assess structural and motor abnormalities of the esophagus. Increasing numbers of papers have described novel findings with this technology. This review examines the validity of the FLIP technique, how it compares with existing diagnostic modalities, and evidence to date on diagnostic accuracy. RECENT FINDINGS: FLIP studies require deep sedation at the time of endoscopy to complete. They assess a simulated state of esophageal obstruction in only a distal part of the esophagus rather than deglutitive motor function of the entire esophagus. The available normative dataset is small and not matched to the older age of patients typically being evaluated. The test-retest agreement in health and disease is unknown, as is the operator dependence on performing and interpreting findings. Studies to date have largely excluded patients with structural disorders, which FLIP cannot reliably distinguish from motor disorders. FLIP is an expensive technology that has been made clinically available without its true utility being established. For FLIP to be deemed a device ready for widespread clinical use, additional studies on validity, diagnostic accuracy, and outcomes need to be performed. Prospective clinical studies need to include all patients and assess the incremental cost-effectiveness of FLIP over more innovative use of existing technology, such as high-resolution manometry with provocative challenges.

Androgen and mineralocorticoid receptors are present on the germinal disc region in laying hens: Potential mediators of sex ratio adjustment in birds?

Female birds skew offspring sex ratios based on environmental and social stimuli; however, the mechanism mediating this phenomenon remains unknown. Growing evidence suggests that testosterone and corticosterone may influence meiosis, as they skew sex ratios when given immediately before chromosomal segregation. It is unclear if these hormones act on the germinal disc (GD) or through a downstream mediator. It is also unknown whether the GD contains receptors for these hormones. If testosterone and/or corticosterone act on the GD to skew sex ratios, then the GD should have receptors for them and that receptor levels should be higher in the GD regions compared to other follicular regions. Furthermore, fluctuations of receptor levels should occur near meiotic segregation. We collected ovarian follicles at 5 h pre-ovulation (just before meiotic segregation) and 20 h pre-ovulation (when sex chromosomes are arrested), and measured androgen receptor (AR) and mineralocorticoid receptor (MR) protein levels via Western blot. ARs and MRs were on the follicle in the GD and non-GD regions, and at 5 h and 20 h pre-ovulation. Both AR and MR protein levels were higher in the GD region than the non-GD region at both time points, but did not differ between time points. These results suggest that hen ovarian follicles have receptors for testosterone and corticosterone, and that the ability for testosterone to respond may be specifically higher in the GD-region, providing further support for the role of testosterone in the alteration of meiotic segregation.

Presence of Irritable Bowel Syndrome Symptoms in Quiescent Inflammatory Bowel Disease Is Associated with High Rate of Anxiety and Depression.

BACKGROUND: Inflammatory bowel disease (IBD; Crohn's disease, CD and Ulcerative colitis, UC) and irritable bowel syndrome (IBS) have overlapping symptoms. Few prevalence studies of IBS in quiescent IBD have used colonoscopy with histology to confirm inactive disease. The aims were (1) to determine the percentage of IBD patients in deep remission whose persistent IBS-like symptoms (IBD/IBS+) would cause them to be classified as having active disease, based on the calculation of Harvey Bradshaw Index (HBI) or UC disease activity index (UCDAI); (2) to identify demographic and disease characteristics that are associated with IBD/IBS+. METHODS: This was a prospective study at a single tertiary care IBD center. 96/112 patients with colonoscopy and histology confirmed quiescent disease consented and completed Rome III criteria for IBS Survey, and the hospital anxiety and depression scale (HADS). Other demographic and disease specific data were collected. RESULTS: 36% (28/77) and 37% (7/19) of CD and UC patients, respectively, met diagnostic criteria for IBS. Significantly higher HBI/UCDAI scores (p = 0.005) and low short inflammatory bowel disease questionnaire (SIBDQ) scores (p ≤ 0.0001) were seen in IBD/IBS+ patients. 29% of patients in deep remission were mis-categorized by HBI/UCDAI as having active disease when they fulfilled Rome III criteria for IBS. Psychiatric diagnosis (OR 3.53 95% CI 1.2-10.2) and earlier onset of IBD (OR 1.056 95% CI 1.015-1.096) were associated with IBD/IBS+. Patients fulfilling IBS criteria had higher hospital anxiety and depression scale (HADS). CONCLUSION: IBD/IBS+ affect scoring of IBD disease activity scales and become less useful in guiding treatment plans.

Modeling of resonantly pumped mid-infrared Pr3+-doped chalcogenide fiber amplifier with different pumping schemes.

We propose a model for resonantly pumped Pr3+-doped chalcogenide fiber amplifiers, which includes excited state absorption and the full spectral amplified spontaneous emission spanning from 2 µm to 6 µm. Based on this model, the observed near- and mid-infrared photoluminescence generated from Pr3+-doped chalcogenide fiber is explained. Then the output properties of a 4.1 µm resonantly pumped Pr3+-doped chalcogenide fiber amplifier are simulated in both co- and counter-pumping schemes. Results show that the 4.1 µm counter-pumped fiber amplifier can achieve a power conversion efficiency (PCE) of over 62.8% for signal wavelengths ranging from 4.5 µm to 5.3 µm. This is, to our best knowledge, the highest simulated PCE for a Pr3+-doped chalcogenide fiber amplifier.

Sub-20 nm Stable Micelles Based on a Mixture of Coiled-Coils: A Platform for Controlled Ligand Presentation.

Ligand-functionalized, multivalent nanoparticles have been extensively studied for biomedical applications from imaging agents to drug delivery vehicles. However, the ligand cluster size is usually heterogeneous and the local valency is ill-defined. Here, we present a mixed micelle platform hierarchically self-assembled from a mixture of two amphiphilic 3-helix and 4-helix peptide-polyethylene glycol (PEG)-lipid hybrid conjugates. We demonstrate that the local multivalent ligand cluster size on the micelle surface can be controlled based on the coiled-coil oligomeric state. The oligomeric states of mixed peptide bundles were found to be in their individual native states. Similarly, mixed micelles indicate the orthogonal self-association of coiled-coil amphiphiles. Using differential scanning calorimetry, fluorescence recovery spectroscopy, and coarse-grained molecular dynamics simulation, we studied the distribution of coiled-coil bundles within the mixed micelles and observed migration of coiled-coils into nanodomains within the sub-20 nm mixed micelle. This report provides important insights into the assembly and formation of nanophase-separated micelles with precise control over the local multivalent state of ligands on the micelle surface.

Kinetic Pathway of 3-Helix Micelle Formation.

A subtle but highly pertinent factor in the self-assembly of hierarchical nanostructures is the kinetic landscape. Self-assembly of a hierarchical multicomponent system requires the intricate balance of noncovalent interactions on a similar energy scale that can result in several self-assembly processes occurring at different time scales. We seek to understand the hierarchical assemblies within an amphiphilic 3-helix peptide-PEG-lipid conjugate system in the formation process of highly stable 3-helix micelles (3HMs). 3HM self-assembles through multiple parallel processes: helix folding, coiled-coil formation, micelle assembly, and packing of alkyl chains. Our results show that the kinetic pathway of 3HM formation is mainly governed by two confounding factors: lateral diffusion of amphiphiles to form coiled-coils within the micelle corona and packing of alkyl tails within the hydrophobic micelle core. 3HM has exhibited highly desirable attributes as a drug delivery nanocarrier; understanding the role of individual components in the kinetic pathway of 3HM formation will allow us to exert better control over the kinetic pathway, as well as to enhance future design and eventually manipulate the kinetic intermediates for potential drug delivery applications.