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BackgroundIn Uganda, cervical cancer (CaCx) is the commonest cancer, accounting for 35.7% of all cancer cases in women. The rates of human papillomavirus vaccination and CaCx screening remain low. Digital health tools and interventions have the potential to improve different aspects of CaCx screening and control in Uganda. ObjectiveThis study aimed to describe stakeholders’ perceptions of the telemedicine system we developed to improve CaCx screening in Uganda. MethodsWe developed and implemented a smartphone-based telemedicine system for capturing and sharing cervical images and other clinical data, as well as an artificial intelligence model for automatic analysis of images. We conducted focus group discussions with health workers at the screening clinics (n=27) and women undergoing screening (n=15) to explore their perceptions of the system. The focus group discussions were supplemented with field observations and an evaluation survey of the health workers on system usability and the overall project. ResultsIn general, both patients and health workers had positive opinions about the system. Highlighted benefits included better cervical visualization, the ability to obtain a second opinion, improved communication between nurses and patients (to explain screening findings), improved clinical data management, performance monitoring and feedback, and modernization of screening service. However, there were also some negative perceptions. For example, some health workers felt the system is time-consuming, especially when it had just been introduced, while some patients were apprehensive about cervical image capture and sharing. Finally, commonplace challenges in digital health (eg, lack of interoperability and problems with sustainability) and challenges in cancer screening in general (eg, arduous referrals, inadequate monitoring and quality control) also resurfaced. ConclusionsThis study demonstrates the feasibility and value of digital health tools in CaCx screening in Uganda, particularly with regard to improving patient experience and the quality of screening services. It also provides examples of potential limitations that must be addressed for successful implementation.

Background: Varicocele repair is a widely used treatment for subfertility. Our aim was to identify and combine the results from randomised controlled trials published to ascertain whether the pregnancy rates after varicocele repair are higher than those with no treatment.Methods: We did a systematic review of seven studies identified by searching Medline and a register of controlled trials. We also searched the contents of specialist journals and the annual meeting programmes of relevant societies by hand. Inclusion criteria were treatment of varicocele in subfertile couples, random allocation to treatment and control groups, and pregnancy or livebirth rates as an outcome measure. We pooled data by use of fixed and random effects models.Findings: None of seven eligible studies published between 1979 and 2002 described a strategy for concealment of the allocation sequence. There were 61 pregnancies among 281 treated couples and 50 pregnancies among 259 controls. The overall relative benefit of treatment was 1.01 (95% CI 0.73-1.40) by the fixed effects model and 1.04 (0.62-1.75) by the random effects model. The overall risk difference was 0.2% (-7 to 7) and 3% (-7 to 14), respectively. In subgroup analyses, varicocele treatment was not effective in trials restricted to male subfertility with clinical varicocele, or in those that included men with subclinical varicocele or normal semen analysis. However, this systematic review, done with a meta-analytical method, might have had insufficient power to detect small effects because of the small number of patients in some subgroups.Interpretation: Varicocele repair does not seem to be an effective treatment for male or unexplained subfertility. [ABSTRACT FROM AUTHOR]

This randomized controlled trial assessed which of three low-intensity ovulation induction protocols was associated with the highest rate of cycle completion among infertile women undergoing intrauterine insemination (IUI) with their husband's spermatozoa. Sixty-three women aged 42 years with normospermic partners participated in the study. The primary diagnosis of infertility was unexplained in 89% of subjects, endometriosis in 6% and tubal factor in 5%. Women were assigned to three groups according to recombinant FSH dosage: group A received two ampoules (75 IU FSH per ampoule) on cycle day 4, and one ampoule on days 6 and 8 (total four ampoules); group B received two ampoules on days 4, 6 and 8 (total six ampoules); group C received two ampoules on days 4, 6, 8 and 10 (total eight ampoules). Daily ultrasound investigations began on cycle day 9-12 and human chorionic gonadotrophin (HCG) 5000 IU was administered when one or two follicles 18 mm were seen. IUI was scheduled for the next day. HCG was given and/or ovulation shown to have occurred in 88 or 109 cycles attempted (81%) with no differences among the three dose groups. Two singleton pregnancies occurred (2.3% per ovulatory cycle and 1.8% per cycle start). There were no significant differences among the three regimes in terms of cycle parameters, suggesting that an individualized and more intensive approach to ovarian stimulation is necessary for many women with unexplained infertility. [ABSTRACT FROM PUBLISHER]

The spontaneous pregnancy prognosis of couples in a primary care situation has never been studied. Prognostic models have been developed for referral populations only. We wished to develop a prognostic model to estimate the likelihood of live birth and the impact of prognostic factors among untreated subfertile couples in a primary care situation. With this aim, we conducted a cohort follow-up study of 726 couples in the peninsula of Walcheren, a geographically isolated, but demographically and socio-economically representative area of an industrialized Western society, The Netherlands. Of the Walcheren population, 9.9% exhibit subfertility complaints at least once during their lifetime. There were 201 live birth conceptions during 9915 months of untreated observation. The cumulative rate of conceptions leading to live births was 52.5% when all of the untreated observations were considered, and 72.0% in the subgroup of 342 couples who remained untreated throughout their follow-up. The relevant prognostic factors in this primary care subfertility population were: abnormal post-coital test, tubal defect, ovulation defect, and duration of subfertility. A prediction score based on these factors would be accurate in approximately 76-79% of cases. Live birth prognosis can be estimated with sufficient accuracy to be useful in counselling subfertility patients, and in planning clinical management. [ABSTRACT FROM AUTHOR]

During a time of war, the federal government passed the National Fitness Act 1941 to improve the fitness of the youth of Australia and better prepare them for roles in the armed services and industry. Implementation of the National Fitness Act made federal funds available at a local level through state-based national fitness councils, which coordinated promotional campaigns, programs, education and infrastructure for physical fitness, with volunteers undertaking most of the work. Specifically focused on children and youth, national fitness councils supported the provision of children's playgrounds, youth clubs and school camping programs, as well as the development of physical education in schools and its teaching and research in universities. By the time the Act was repealed in 1994, fitness had become associated with leisure and recreation rather than being seen as equipping people for everyday life and work. The emergence of the Australian National Preventive Health Agency Act 2010 offers the opportunity to reflect on synergies with its historic precedent. [ABSTRACT FROM AUTHOR]

First of its kind combined atmospheric and ocean profile data were collected by the recently upgraded NASA Langley Research Center’s (LaRC) High Spectral Resolution Lidar (HSRL-1) during the 17 July – 7 August 2014 Ship-Aircraft Bio-Optical Research Experiment (SABOR). This mission sampled over a region that covered the Gulf of Maine, open-ocean near Bermuda, and coastal waters from Virginia to Rhode Island. The HSRL-1 and the Research Scanning Polarimeter from NASA Goddard Institute for Space Studies collected data onboard the NASA LaRC King Air aircraft and flight operations were closely coordinated with the Research Vessel Endeavor that made in situ ocean optical measurements. The lidar measurements provided profiles of atmospheric backscatter and particulate depolarization at 532nm, 1064nm, and extinction (532nm) from approximately 9km altitude. In addition, for the first time HSRL seawater backscatter, depolarization, and diffuse attenuation data at 532nm were collected and compared to both the ship measurements and the Moderate Resolution Imaging Spectrometer (NASA MODIS-Aqua) satellite ocean retrievals.

Abstract Background Proper blood pressure control during surgical procedures such as total joint arthroplasty (TJA) is considered critical to good outcome. There is poor understanding of the pre-operative risk factors for poor intra-operative hemodynamic control. The purpose of this study is to identify risk factors for poor hemodynamic control during TJA. Methods We performed a retrospective cohort analysis of 118 patients receiving TJA in the Dominican Republic. We collected patient demographic and comorbidity data. We developed an a priori definition for poor hemodynamic control: 1) Mean arterial pressure (MAP) 135% of preoperative MAP. We performed bivariate and multivariate analyses to identify risk factors for poor hemodynamic control during TJA. Results Hypertension was relatively common in our study population (76 of 118 patients). Average preoperative mean arterial pressure was 109.0 (corresponding to an average SBP of 149 and DBP of 89). Forty-nine (41.5%) patients had intraoperative blood pressure readings consistent with poor hemodynamic control. Based on multi-variable analysis preoperative hypertension of any type (RR 2.9; 95% CI 1.3-6.3) and an increase in BMI (RR 1.2 per 5 unit increase; 95% CI 1.0-1.5) were significant risk factors for poor hemodynamic control. Conclusions Preoperative hypertension and being overweight/obese increase the likelihood of poor blood pressure control during TJA. Hypertensive and/or obese patients warrant further attention and medical optimization prior to TJA. More work is required to elucidate the relationship between these risk factors and overall outcome.

Abstract Background Experimental examinations of biofluids to measure concentrations of proteins or their fragments or metabolites are being explored as a means of early disease detection, distinguishing diseases with similar symptoms, and drug treatment efficacy. Many studies have produced classifiers with a high sensitivity and specificity, and it has been argued that accurate results necessarily imply some underlying biology-based features in the classifier. The simplest test of this conjecture is to examine datasets designed to contain no information with classifiers used in many published studies. Results The classification accuracy of two fingerprint-based classifiers, a decision tree (DT) algorithm and a medoid classification algorithm (MCA), are examined. These methods are used to examine 30 artificial datasets that contain random concentration levels for 300 biomolecules. Each dataset contains between 30 and 300 Cases and Controls, and since the 300 observed concentrations are randomly generated, these datasets are constructed to contain no biological information. A modest search of decision trees containing at most seven decision nodes finds a large number of unique decision trees with an average sensitivity and specificity above 85% for datasets containing 60 Cases and 60 Controls or less, and for datasets with 90 Cases and 90 Controls many DTs have an average sensitivity and specificity above 80%. For even the largest dataset (300 Cases and 300 Controls) the MCA procedure finds several unique classifiers that have an average sensitivity and specificity above 88% using only six or seven features. Conclusion While it has been argued that accurate classification results must imply some biological basis for the separation of Cases from Controls, our results show that this is not necessarily true. The DT and MCA classifiers are sufficiently flexible and can produce good results from datasets that are specifically constructed to contain no information. This means that a chance fitting to the data is possible. All datasets used in this investigation are available on the web. This work is funded by NCI Contract N01-CO-12400.

Abstract Background Iron-deficiency leads to the induction of genes related to intestinal iron absorption and homeostasis. By analyzing a large GeneChip® dataset from the rat intestine, we identified a large cluster of 228 genes that was induced by iron-deprivation. Only 2 of these genes contained 3' iron-response elements, suggesting that other regulation including transcriptional may be involved. We therefore utilized computational methods to test the hypothesis that some of the genes within this large up-regulated cluster are co-ordinately regulated by common transcriptional mechanisms. We thus identified promoters from the up-regulated gene cluster from rat, mouse and human, and performed enrichment analyses with the Clover program and the TRANSFAC database. Results Surprisingly, we found a strong statistical enrichment for SP1 binding sites in our experimental promoters as compared to background sequences. As the TRANSFAC database cannot distinguish among SP/KLF family members, many of which bind similar GC-rich DNA sequences, we surmise that SP1 or an SP1-like factor could be involved in this response. In fact, we detected induction of SP6/KLF14 in the GeneChip® studies, and confirmed it by real-time PCR. Additional computational analyses suggested that an SP1-like factor may function synergistically with a FOX TF to regulate a subset of these genes. Furthermore, analysis of promoter sequences identified many genes with multiple, conserved SP1 and FOX binding sites, the relative location of which within orthologous promoters was highly conserved. Conclusion SP1 or a closely related factor may play a primary role in the genetic response to iron-deficiency in the mammalian intestine.

Intervertebral disc degeneration is a major risk factor contributing to chronic low back and neck pain. While the etiological factors for disc degeneration vary, age is still one of the most important risk factors. Recent studies have shown the promising role of SIRT6 in mammalian aging and skeletal tissue health, however its role in the intervertebral disc health remains unexplored. We investigated the contribution of SIRT6 to disc health by studying the age-dependent spinal phenotype of mice with conditional deletion of Sirt6 in the disc ( Acan CreERT2 ; Sirt6 fl/fl ). Histological studies showed a degenerative phenotype in knockout mice compared to Sirt6 fl/fl control mice at 12 months which became pronounced at 24 months. RNA-Seq analysis of NP and AF tissues, quantitative histone analysis, and in vitro multiomics employing RNA-seq with ATAC-seq revealed that SIRT6-loss resulted in changes in acetylation and methylation status of specific Histone 3 lysine residues, thereby affecting DNA accessibility and transcriptomic landscape. A decrease in autophagy and an increase in DNA damage were also noted in Sirt6 -deficient cells. Further mechanistic insights revealed that loss of SIRT6 increased senescence and SASP burden in the disc characterized by increased p21, γH2AX, IL-6, and TGF-β abundance. Taken together our study highlights the contribution of SIRT6 in modulating DNA damage, autophagy and cell senescence, and its importance in maintaining disc health during aging thereby underscoring it as a potential therapeutic target to treat intervertebral disc degeneration., Competing Interests: CONFLICT OF INTERESTS Authors of this manuscript do not have conflicts of interest to disclose.

Introduction: Tau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis., Methods: Using head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale., Results: A strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach., Discussion: Preliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification., Highlights: Tested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Extracorporeal Membrane Oxygenation (ECMO) is a life support device for patients with severe heart and/or lung failure. Emergency situations require immediate ECMO response. Primed circuits have become a routine practice, as it may take 30-60 min to assemble and prime. There remains a lack of data to support the sterility of primed and stored ECMO circuits. This bench study assessed the impact of storage environment and priming solution on specific microbial growth of primed ECMO circuits., Methods: Twelve adult ECMO circuits were tested for sterility for 56 days between September-December 2020. Circuits were assembled and primed in a perfusion lab in Chicago, IL. Six were stored in a sterile environment and six in a non-sterile environment, with three circuits primed using normal saline (NaCl) and three with Plasmalyte-A for each environment. Samples were collected on days 0, 3, 7, 14, 28, 42, and 56 in anaerobic bottle cultures testing for potential pathogen growth, such as Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli., Results: Samples obtained from the 12 primed ECMO circuits demonstrated no microbial growth of S. aureus , P. aeruginosa , and E. coli in the bottle cultures. Similarly, there was no difference in the circuit sterility based on the storage environment (sterile vs nonsterile) or priming solution (NaCl vs Plasmalyte-A)., Conclusion: Our findings showed that ECMO circuits can be primed for 56 days without evidence of the specified bacterial growth. Furthermore, the storage conditions and the prime utilized did not affect the sterility of the primed ECMO circuits., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Gyrase and topoisomerase IV are the cellular targets for fluoroquinolones, a critically important class of antibacterial agents used to treat a broad spectrum of human infections. Unfortunately, the clinical efficacy of the fluoroquinolones has been curtailed by the emergence of target-mediated resistance. This is especially true for Neisseria gonorrhoeae , the causative pathogen of the sexually transmitted infection gonorrhea. Spiropyrimidinetriones (SPTs), a new class of antibacterials, were developed to combat the growing antibacterial resistance crisis. Zoliflodacin is the most clinically advanced SPT and displays efficacy against uncomplicated urogenital gonorrhea in human trials. Like fluoroquinolones, the primary target of zoliflodacin in N. gonorrhoeae is gyrase, and topoisomerase IV is a secondary target. Because unbalanced gyrase/topoisomerase IV targeting has facilitated the evolution of fluoroquinolone-resistant bacteria, it is important to understand the underlying basis for the differential targeting of zoliflodacin in N. gonorrhoeae . Therefore, we assessed the effects of this SPT on the catalytic and DNA cleavage activities of N. gonorrhoeae gyrase and topoisomerase IV. In all reactions examined, zoliflodacin displayed higher potency against gyrase than topoisomerase IV. Moreover, zoliflodacin generated more DNA cleavage and formed more stable enzyme-cleaved DNA-SPT complexes with gyrase. The SPT also maintained higher activity against fluoroquinolone-resistant gyrase than topoisomerase IV. Finally, when compared to zoliflodacin, the novel SPT H3D-005722 induced more balanced double-stranded DNA cleavage with gyrase and topoisomerase IV from N. gonorrhoeae , Escherichia coli , and Bacillus anthracis . This finding suggests that further development of the SPT class could yield compounds with a more balanced targeting against clinically important bacterial infections.

Despite the high prevalence of age-dependent intervertebral disc calcification, there is a glaring lack of treatment options for this debilitating pathology. Here, we investigate the efficacy of long-term oral K 3 Citrate supplementation in ameliorating disc calcification in LG/J mice, a model of spontaneous age-associated disc calcification. K 3 Citrate successfully reduced the incidence of disc calcification in LG/J mice without deleterious effects on vertebral bone structure, plasma chemistry, and locomotion. Notably, a positive effect on grip strength was evident in treated mice. Spectroscopic investigation of the persisting calcified nodules indicated K 3 Citrate did not alter the mineral composition and revealed that reactivation of an endochondral differentiation program in endplates may drive LG/J disc calcification. Importantly, K 3 Citrate reduced calcification incidence without altering the pathological endplate chondrocyte hypertrophy, suggesting mitigation of disc calcification primarily occurred through Ca 2+ chelation, a conclusion supported by chondrogenic differentiation and Seahorse metabolic assays. Overall, this study underscores the therapeutic potential of K 3 Citrate as a systemic intervention strategy for disc calcification.

Equids are engaged in myriad types of work across the world, with contexts and industries varying widely between high-, middle- and low-income countries as classified by the World Bank. Through a comprehensive abstract search and literature review, we examined the usage and context of terms associated with working equids in high-income countries (HICs), upper-middle-income countries (UMICs), lower-middle-income countries (LMICs), and low-income countries (LICs). Analysis showed that the search term used was significantly associated with World Bank country income classification. All search terms except two returned a significantly higher number of papers for higher-income countries compared to lower-income countries. The two exceptions were "working equid" and "draft equid", which returned significantly more papers for lower-income countries than higher-income countries. Both terms also returned papers from high-income and upper-middle-income countries, but these were always in the context of low-resource settings and rural or marginalised communities, of which we provide examples in the discussion. We propose that the term "working equid" should be used to describe "any equid engaged in physical labour that provides a significant or direct contribution to the economic livelihood, sustenance or support of the owner/user's family, typically within a low resource setting". Our review highlights the intricate interplay between socioeconomic factors and examines how equids are described in the literature. The lack of a universally accepted definition leads to challenges in policy formulation, resource allocation, and welfare standards development, particularly in LMICs and LICs where working equids are crucial to livelihoods. This study underscores the need for a more inclusive and comprehensive approach to terminology, advocating for future research to bridge linguistic and cultural gaps in understanding working equids globally. Such efforts are vital for equitable and effective welfare standards and policy development for these animals.

Fluoroquinolones make up a critically important class of antibacterials administered worldwide to treat human infections. However, their clinical utility has been curtailed by target-mediated resistance, which is caused by mutations in the fluoroquinolone targets, gyrase and topoisomerase IV. An important pathogen that has been affected by this resistance is Neisseria gonorrhoeae , the causative agent of gonorrhea. Over 82 million new cases of this sexually transmitted infection were reported globally in 2020. Despite the impact of fluoroquinolone resistance on gonorrhea treatment, little is known about the interactions of this drug class with its targets in this bacterium. Therefore, we investigated the effects of the fluoroquinolone ciprofloxacin on the catalytic and DNA cleavage activities of wild-type gyrase and topoisomerase IV and the corresponding enzymes that harbor mutations associated with cellular and clinical resistance to fluoroquinolones. Results indicate that ciprofloxacin interacts with both gyrase (its primary target) and topoisomerase IV (its secondary target) through a water-metal ion bridge that has been described in other species. Moreover, mutations in amino acid residues that anchor this bridge diminish the susceptibility of the enzymes for the drug, leading to fluoroquinolone resistance. Results further suggest that ciprofloxacin primarily induces its cytotoxic effects by enhancing gyrase-mediated DNA cleavage as opposed to inhibiting the DNA supercoiling activity of the enzyme. In conclusion, this work links the effects of ciprofloxacin on wild-type and resistant gyrase to results reported for cellular and clinical studies and provides a mechanistic explanation for the targeting and resistance of fluoroquinolones in N. gonorrhoeae .

Beyond their requisite functions in many critical DNA processes, the bacterial type II topoisomerases, gyrase and topoisomerase IV, are the targets of fluoroquinolone antibacterials. These drugs act by stabilizing gyrase/topoisomerase IV-generated DNA strand breaks and by robbing the cell of the catalytic activities of these essential enzymes. Since their clinical approval in the mid-1980s, fluoroquinolones have been used to treat a broad spectrum of infectious diseases and are listed among the five "highest priority" critically important antimicrobial classes by the World Health Organization. Unfortunately, the widespread use of fluoroquinolones has been accompanied by a rise in target-mediated resistance caused by specific mutations in gyrase and topoisomerase IV, which has curtailed the medical efficacy of this drug class. As a result, efforts are underway to identify novel antibacterials that target the bacterial type II topoisomerases. Several new classes of gyrase/topoisomerase IV-targeted antibacterials have emerged, including novel bacterial topoisomerase inhibitors, Mycobacterium tuberculosis gyrase inhibitors, triazaacenaphthylenes, spiropyrimidinetriones, and thiophenes. Phase III clinical trials that utilized two members of these classes, gepotidacin (triazaacenaphthylene) and zoliflodacin (spiropyrimidinetrione), have been completed with positive outcomes, underscoring the potential of these compounds to become the first new classes of antibacterials introduced into the clinic in decades. Because gyrase and topoisomerase IV are validated targets for established and emerging antibacterials, this review will describe the catalytic mechanism and cellular activities of the bacterial type II topoisomerases, their interactions with fluoroquinolones, the mechanism of target-mediated fluoroquinolone resistance, and the actions of novel antibacterials against wild-type and fluoroquinolone-resistant gyrase and topoisomerase IV.

While our direct observations of the features or behaviours of the stimuli around us tell us much about them (e.g., should they be feared?), the origin of much of our knowledge is often untethered from directly observable properties (e.g., through what we have learned or have been told about them, or "semantic knowledge"). Here, we ask whether otherwise neutral visual stimuli that participants learn to associate with emotional qualities in the lab cause the stimuli to be attended in a similar way as stimuli whose emotional qualities can be discerned through their visual properties. In Experiment 1, participants learned to associate negative or neutral characteristics with neutral faces, which then served as valid or invalid spatial cues to targets in an attentional disengagement paradigm. The performance of participants higher in trait anxiety was consistent with attentional avoidance of faces with learned negative associations, while participants lower in trait anxiety showed a general response slowing in trials with these stimuli, compared to those with neutral associations. In contrast, in Experiment 2, using (visually) expressive (angry) faces, the performance of participants higher in trait anxiety was consistent with difficulty disengaging from visually threatening faces, while the performance of those with lower trait anxiety appeared unaffected by the valence of the stimuli. These findings suggest that (1) emotionality acquired indirectly via learned semantic knowledge impacts how attention is allocated to face stimuli, and this impact is influenced by trait anxiety, and (2) there are differences in the effects of stimulus emotionality depending on whether it is acquired indirectly or directly via the perceptual features of the stimulus. These differences are discussed in the context of the variability of attention bias effects reported in the literature and the time course of impacts of emotionality on stimulus processing.