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Legacy data in the form of historical aerial imagery can be used to investigate geomorphological change over time. This data can be used to improve research about the preservation and visibility of the archaeological record, and it can also aid heritage management. This paper presents a composite Image-Based Modelling workflow to generate 3D models, historical orthophotos, and historical digital elevation models from images from the 1970s. This was done to improve the interpretation of survey data from the early Roman colony of Aesernia. The main challenge was the lack of high-resolution recent digital elevation models and ground control points, and a general lack of metadata. Therefore, spatial data from various sources had to be combined. To assess the accuracy of the final 3D model, the RMSE was calculated. While the workflow appears effective, the low accuracy of the initial data limits the usefulness of the model for the study of geomorphological change. However, it can be implemented to aid sample area selection when preparing archaeological fieldwork. Additionally, when working with existing survey datasets, areas with a high bias risk resulting from post-depositional processes can be indicated.

Background: Next generation sequencing studies have revealed an ever-increasing number of causes for genetic disorders of central nervous system white matter. A substantial number of disorders are identifiable from their specific pattern of biochemical and/or imaging findings for which single gene testing may be indicated. Beyond this group, the causes of genetic white matter disorders are unclear and a broader approach to genomic testing is recommended. Aim: This study aimed to identify the genetic causes for a group of individuals with unclassified white matter disorders with suspected genetic aetiology and highlight the investigations required when the initial testing is non-diagnostic. Methods: Twenty-six individuals from 22 families with unclassified white matter disorders underwent deep phenotyping and genome sequencing performed on trio, or larger, family groups. Functional studies and transcriptomics were used to resolve variants of uncertain significance with potential clinical relevance. Results: Causative or candidate variants were identified in 15/22 (68.2%) families. Six of the 15 implicated genes had been previously associated with white matter disease (COL4A1, NDUFV1, SLC17A5, TUBB4A, BOLA3, DARS2). Patients with variants in the latter two presented with an atypical phenotype. The other nine genes had not been specifically associated with white matter disease at the time of diagnosis and included genes associated with monogenic syndromes, developmental disorders, and developmental and epileptic encephalopathies (STAG2, LSS, FIG4, GLS, PMPCA, SPTBN1, AGO2, SCN2A, SCN8A). Consequently, only 46% of the diagnoses would have been made via a current leukodystrophy gene panel test. Discussion: These results confirm the importance of broad genomic testing for patients with white matter disorders. The high diagnostic yield reflects the integration of deep phenotyping, whole genome sequencing, trio analysis, functional studies, and transcriptomic analyses. Conclusions: Genetic white matter disorders are genetically and phenotypically heterogeneous. Deep phenotyping together with a range of genomic technologies underpin the identification of causes of unclassified white matter disease. A molecular diagnosis is essential for prognostication, appropriate management, and accurate reproductive counseling.

In Mycobacterium tuberculosis, bedaquiline and clofazimine resistance occurs primarily through Rv0678 variants, a gene encoding a repressor protein that regulates mmpS5/mmpL5 efflux pump gene expression. Despite the shared effect of both drugs on efflux, little else is known about other pathways affected. We hypothesized that in vitro generation of bedaquiline- or clofazimine-resistant mutants could provide insight into additional mechanisms of action. We performed whole-genome sequencing and determined phenotypic MICs for both drugs on progenitor and mutant progenies. Mutants were induced through serial passage on increasing concentrations of bedaquiline or clofazimine. Rv0678 variants were identified in both clofazimine- and bedaquiline-resistant mutants, with concurrent atpE SNPs occurring in the latter. Of concern was the acquisition of variants in the F420 biosynthesis pathway in clofazimine-resistant mutants obtained from either a fully susceptible (fbiD: del555GCT) or rifampicin mono-resistant (fbiA: 283delTG and T862C) progenitor. The acquisition of these variants possibly implicates a shared pathway between clofazimine and nitroimidazoles. Pathways associated with drug tolerance and persistence, F420 biosynthesis, glycerol uptake and metabolism, efflux, and NADH homeostasis appear to be affected following exposure to these drugs. Shared genes affected by both drugs include Rv0678, glpK, nuoG, and uvrD1. Genes with variants in the bedaquiline resistant mutants included atpE, fadE28, truA, mmpL5, glnH, and pks8, while clofazimine-resistant mutants displayed ppsD, fbiA, fbiD, mutT3, fadE18, Rv0988, and Rv2082 variants. These results show the importance of epistatic mechanisms as a means of responding to drug pressure and highlight the complexity of resistance acquisition in M. tuberculosis. In Mycobacterium tuberculosis, bedaquiline and clofazimine resistance occurs primarily through Rv0678 variants, a gene encoding a repressor protein that regulates mmpS5/mmpL5 efflux pump gene expression. Despite the shared effect of both drugs on efflux, little else is known about other pathways affected.

Supplementary Figures S1-S5; Supplementary Methods; Supplementary Tables S1-S2.

Purpose: Chromosomal gain at 7q21 is a frequent event in esophageal adenocarcinoma (EAC). However, this event has not been mapped with fine resolution in a large EAC cohort, and its association with clinical endpoints and functional relevance are unclear.Experimental Design: We used a cohort of 116 patients to fine map the 7q21 amplification using SNP microarrays. Prognostic significance and functional role of 7q21 amplification and its gene expression were explored.Results: Amplification of the 7q21 region was observed in 35% of tumors with a focal, minimal amplicon containing six genes. 7q21 amplification was associated with poor survival and analysis of gene expression identified cyclin-dependent kinase 6 (CDK6) as the only gene in the minimal amplicon whose expression was also associated with poor survival. A low-level amplification (10%) was observed at the 12q13 region containing the CDK6 homologue cyclin-dependent kinase 4 (CDK4). Both amplification and expression of CDK4 correlated with poor survival. A combined model of both CDK6 and CDK4 expressions is a superior predictor of survival than either alone. Specific knockdown of CDK4 and/or CDK6 by siRNAs shows that they are required for proliferation of EAC cells and that their function is additive. PD-0332991 targets the kinase activity of both molecules and suppresses proliferation and anchorage independence of EAC cells through activation of the pRB pathway.Conclusions: We suggest that CDK6 is the driver of 7q21 amplification and that both CDK4 and CDK6 are prognostic markers and bona fide oncogenes in EAC. Targeting these molecules may constitute a viable new therapy for this disease. Clin Cancer Res; 17(13); 4513–22. ©2011 AACR.

Inspired by the observation of a distributed time delay in the nonlinear response of an optical resonator, we investigate the effects of a similar delay on a noise-driven mechanical oscillator. For a delay time that is commensurate with the inverse dissipation rate, we find stable limit cycles. For longer delays, we discover a regime of chaotic dynamics associated with a double scroll attractor. We also analyze the effects of time delay on the spectrum and oscillation amplitude of the oscillator. Our results point to new opportunities for nonlinear energy harvesting, provided that a nonlinearity with distributed time delay can be implemented in mechanical systems., Comment: 4 figures, 7 pages

A constructivist grounded theory approach was used to understand how some people living with stigmatized health conditions develop positive deviance to overcome stigma. We examined interviews from 13 identified positive deviants living with four different stigmatized health conditions (HIV, leprosy, schizophrenia, and diabetes) in Indonesia. Positive deviance develops in the form of psychological empowerment through improvement of self-belief and perception (intrapersonal component), development of understanding and skill to exert control in life (interactional component), and self-discovery of successful behaviors and strategies to avert stigma (behavioral component). Positive deviants, after being empowered, start empowering others affected by sharing their knowledge and fostering social awareness and acceptance. The findings revealed the presence of problem-solving ability and agency within the community of stigmatized individuals in Indonesia and warrant researchers to partner with the community to expedite the diffusion of transferable positive deviant strategies within and outside the communities.

Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

Despite the growing interest in public and patient involvement in research, best practices in the leprosy context have yet to be explored. This mixed-method study aimed to explore the interpretation, barriers and opportunities of meaningful engagement of persons affected by leprosy in research through: (i) an exploratory phase consisting of key informant interviews with experts in public and patient involvement (n = 2) and experts-by-experience (i.e., persons affected by leprosy; n = 4), and (ii) an in-depth phase among leprosy researchers consisting of an online survey (n = 21) and key informant interviews (n = 7). Qualitative data were thematically analyzed. Basic descriptive statistics were used to summarize the survey data. Key informant interviewees unanimously agreed to the importance of engagement in research. Survey results indicated that the level of engagement differed across research stages. Identified barriers included a lack of skills for or awareness of engagement among both experts-by-experience and researchers, stigma and limited time and resources. Opportunities included capacity strengthening, creating a shared understanding, building rapport, and establishing a safe environment. In conclusion, this exploratory study emphasized the importance of engagement of experts-by-experience in leprosy research and identified ways forward that include, but are not limited to, the acknowledgement of its value and creating a shared understanding.

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The sympathetic nervous system fight-or-flight response is characterized by a rapid increase in heart rate, which is mediated by an increase in the spontaneous action potential (AP) firing rate of pacemaker cells in the sinoatrial node. Sympathetic neurons stimulate sinoatrial myocytes (SAMs) by activating β adrenergic receptors (βARs) and increasing cAMP. The funny current (If) is among the cAMP-sensitive currents in SAMs. If is critical for pacemaker activity, however, its role in the fight-or-flight response remains controversial. In this study, we used AP waveform analysis, machine learning, and dynamic clamp experiments in acutely isolated SAMs from mice to quantitatively define the AP waveform changes and role of If in the fight-or-flight increase in AP firing rate. We found that while βAR stimulation significantly altered nearly all AP waveform parameters, the increase in firing rate was only correlated with changes in a subset of parameters (diastolic duration, late AP duration, and diastolic depolarization rate). Dynamic clamp injection of the βAR-sensitive component of If showed that it accounts for ∼41% of the fight-or-flight increase in AP firing rate and 60% of the decrease in the interval between APs. Thus, If is an essential contributor to the fight-or-flight increase in heart rate.

Chronic obstructive pulmonary disease (COPD) is characterised by the occurrence of exacerbations triggered by infections. The aim of this study was to determine the composition of the lung microbiome and lung virome in patients with COPD in an African setting and to compare their composition between the stable and exacerbated states. Twenty-four adult COPD patients were recruited from three hospitals. Sputum was collected and bacterial DNA was extracted. Targeted metagenomics was performed to determine the microbiome composition. Viral DNA and RNA were extracted from selected samples followed by cDNA conversion. Shotgun metagenomics sequencing was performed on pooled DNA and RNA. The most abundant phyla across all samples were Firmicutes and Proteobacteria. The following genera were most prevalent: Haemophilus and Streptococcus. There were no considerable differences for alpha and beta diversity measures between the disease states. However, a difference in the abundances between disease states was observed for: (i) Serratia (3% lower abundance in exacerbated state), (ii) Granulicatella (2.2% higher abundance in exacerbated state), (iii) Haemophilus (5.7% higher abundance in exacerbated state) and (iv) Veillonella (2.5% higher abundance in exacerbated state). Virome analysis showed a high abundance of the BeAn 58058 virus, a member of the Poxviridae family, in all six samples (90% to 94%). This study is among the first to report lung microbiome composition in COPD patients from Africa. In this small sample set, no differences in alpha or beta diversity between stable and exacerbated disease state was observed, but an unexpectedly high frequency of BeAn 58058 virus was observed. These observations highlight the need for further research of the lung microbiome of COPD patients in African settings.

Background The vaginal microbiota (VMB) are the set of microorganisms residing in the human vagina. During pregnancy, their composition is Lactobacillus-dominant in most Caucasian women. Previous studies suggest that the VMB of women with African ancestry is more likely to be non-Lactobacillus dominant (dysbiotic) compared to other populations, and possibly relate to the high incidence of pregnancy complications, such as preterm birth. This work reviewed the literature on VMB composition in pregnant women from sub-Saharan Africa. Methods A search was conducted in PubMed and Embase databases following PRISMA guidelines. Observational and intervention studies analysing VMB communities from sub-Saharan African pregnant women using molecular techniques were included. Results Ten studies performed in seven sub-Saharan African countries were identified. They independently showed that Lactobacillus-dominant VMB (particularly L. iners or L. crispatus) or VMB containing Lactobacilli are the most prevalent, followed by a more diverse anaerobe-dominant VMB, in the studied populations. The majority of pregnant women with a sexually-transmitted infection had a Lactobacillus-dominant VMB, but with a significantly higher presence of anaerobic species. Conclusion In agreement with studies performed in other populations, Lactobacillus species are the most prevalent VMB species during pregnancy in sub-Saharan African women. The frequency of diverse anaerobe-dominant VMB is high in these populations. In Africa, studies on VMB in pregnancy are scant, heterogeneous in methodology, and knowledge remains limited. More insights on VMB composition and their possible sequalae among these populations is needed.

Circadian regulation of autonomic reflex pathways pairs physiological function with the daily light cycle. The brainstem nucleus of the solitary tract (NTS) is a key candidate for rhythmic control of the autonomic nervous system. Here we investigated circadian regulation of NTS neurotransmission and synaptic throughput using patch-clamp electrophysiology in brainstem slices from mice. We found that spontaneous quantal glutamate release on to NTS neurons showed strong circadian rhythmicity, with the highest rate of release during the light phase and the lowest in the dark, that were sufficient to drive day / night differences in constitutive postsynaptic action potential firing. In contrast, afferent-evoked action potential throughput was enhanced during the dark and diminished in the light. Afferent-driven synchronous release pathways showed a similar decrease in release probability that did not explain the enhanced synaptic throughput during the night. However, analysis of postsynaptic membrane properties revealed diurnal changes in conductance; which, when coupled with the circadian changes in glutamate release pathways, tuned synaptic throughput between the light and dark phases. These coordinated pre- / postsynaptic changes encode nuanced control over synaptic performance and pair NTS action potential firing and vagal throughput with time of day.

Objective The objective of the review was to identify, appraise, and synthesise qualitative studies on the lived experience of individuals diagnosed with leprosy, the impact of the disease, and how they coped with the disease burden. Introduction Leprosy is a chronic disease with long-term biopsychosocial impact and is a leading cause of preventable disabilities. It traps the individuals with leprosy in a vicious circle of disease, stigma, and poverty. The efforts to reduce stigma and discrimination and improve their quality of life have not kept pace with the success of the multidrug treatment. Inclusion criteria This review considered published literature on the lived experience of individuals diagnosed with leprosy. There were no limitations on gender, background, or country. All qualitative or mixed-methods studies were accepted. Methods The review followed the JBI meta-aggregation approach for qualitative systematic reviews. A structured literature search was undertaken using multiple electronic databases: PubMed, Embase, Web of Science, and CINAHL. Results The search identified 723 publications, and there were 446 articles after deduplication. Forty-nine studies met the inclusion criteria. The final 173 findings were synthesised into ten categories and aggregated into four synthesised findings: biophysical impact, social impact, economic impact, and mental and emotional impact. These synthesised findings were consistent across the included studies from a patient’s perspective. The way people coped with leprosy depended on their interpretation of the disease and its treatment. It affected their help-seeking behaviour and their adherence to treatment and self-care. The review has identified a multi-domain effect on the affected individuals, which goes beyond the biological and physical effects, looking at the social issues, specific difficulties, emotions, and economic hardships. Conclusions The researchers, health professionals, and policymakers could use the synthesised findings to address the concerns and needs of the leprosy-affected individuals and offer appropriate support to manage their lives. Systematic review registration number PROSPERO Registration number: CRD42021243223

The SARS-CoV-2 prefusion spike protein is characterized by a high degree of flexibility and temporal transformations associated with its multifunctional behavior. In this study, we have examined the dynamics of the Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein in detail. Its primary, binding subdomain with human Angiotensin Covering Enzyme II includes a highly conspicuous flap or loop that is part of a beta hairpin loop structural motif. Dynamic details of the RBD obtained through RMSF and Order Parameter calculations are consistent with structural details including the stability of “glue” points or dominant interaction energy residues of the RBD in the Up and Down states with its neighboring N-terminal domain (NTD) protomer. The RBD flap in the Up state protomer periodically obstructs the binding site on an approximate 70 nanosecond time interval and is reminiscent of an HIV-1 protease polypeptide flap that opens and closes to modulate that enzymes activity. No claim is made here regarding the possible modulating role of the flap; however, the flap may be a potential site for therapeutic targeting aimed at keeping it in the closed state, as previously demonstrated in the inhibition of the HIV-1 protease polypeptide. The RBD primary binding subdomain is further shown to have not only similar dynamics but, also, an approximate 30% sequence similarity to the HIV-1 protease polypeptide.

This study aims to assess the potential association of MBL2 gene single nucleotide polymorphisms (SNPs) to Chlamydia trachomatis infection. We analysed a selected sample of 492 DNA and serum specimens from Dutch Caucasian women. Women were categorized into four groups of infection status based on the results of DNA and antibody tests for C. trachomatis: Ct-DNA+/IgG+, Ct-DNA+/IgG−, Ct-DNA−/IgG+, and Ct-DNA−/IgG−. We compared six MBL2 SNPs (−619G > C (H/L), −290G > C (Y/X), −66C > T (P/Q), +154C > T (A/D), +161A > G (A/B), and +170A > G (A/C)) and their respective haplotypes in relation to these different subgroups. The −619C (L) allele was less present within the Ct-DNA−/IgG+ group compared with the Ct-DNA−/IgG− group (OR = 0.49; 95% CI: 0.28–0.83), while the +170G (C) allele was observed more in the Ct-DNA+/IgG+ group as compared with the Ct-DNA−/IgG− group (OR = 2.4; 95% CI: 1.1–5.4). The HYA/HYA haplotype was more often present in the Ct-DNA−/IgG− group compared with the Ct-DNA+/IgG+ group (OR = 0.37; 95% CI: 0.16–0.87). The +170G (C) allele was associated with increased IgG production (p = 0.048) in C. trachomatis PCR-positive women. This study shows associations for MBL in immune reactions to C. trachomatis. We showed clear associations between MBL2 genotypes, haplotypes, and individuals’ stages of C. trachomatis DNA and IgG positivity.

Background: Traumatic cardiac arrest (TCA) is a severe and life-threatening situation that mandates urgent action. Outcomes after on-scene treatment of TCA in the Netherlands are currently unknown. The aim of the current study was to investigate the rate of survival to discharge in patients who suffered from traumatic cardiac arrest and who were subsequently treated on-scene by the Dutch Helicopter Emergency Medical Services (HEMS). Methods: A retrospective cohort study was performed including patients ≥ 18 years with TCA for which the Dutch HEMS were dispatched between January 1 st 2014 and December 31 st 2018. Patients with TCA after hanging, submersion, conflagration or electrocution were excluded. The primary outcome measure was survival to discharge after prehospital TCA. Secondary outcome measures were return of spontaneous circulation (ROSC) on-scene and neurological status at hospital discharge. Results: Nine-hundred-fifteen patients with confirmed TCA were included. ROSC was achieved on-scene in 261 patients (28.5%). Thirty-six (3.9%) patients survived to hospital discharge of which 17 (47.2%) had a good neurological outcome. Age < 70 years (0.7% vs. 5.2%; p=0.041) and a shockable rhythm on first ECG (OR 0.65 95%CI 0.02-0.28; p

Background: Sexually transmitted infections (STIs) can be transmitted from mother to neonate. We determined the frequency of mother-to-child transmission (MTCT) of Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis to the newborn nasopharynx. Methods: This study was nested in a cohort study of etiologic testing versus syndromic management for STIs among pregnant women living with human immunodeficiency virus in South Africa. Mothers were tested for STIs using the GeneXpert platform within 60 days after delivery. Nasopharyngeal swabs were obtained from newborns of mothers with a positive STI test; these were then tested by Xpert® on the same day based on the maternal STI diagnosis. Results. We tested nasopharyngeal swabs from 85 STI-exposed newborns; 74 (87%) were tested within 2 weeks after birth (median five; range 2–12 days). MTCT frequency of any STI was 30/74 (41%); 43% (23/53) for C. trachomatis, 29% (2/7) for N. gonorrhoeae, and 24% (6/25) for T. vaginalis. Also, 4/11 (36%) swabs obtained between 14 and 60 days after delivery tested positive for STI. Conclusions: There was a high frequency of MTCT of STIs to the nasopharynx of newborns in our setting. The impact of nasopharyngeal colonization and the benefits of STI testing on newborn health remain to be determined.

ObjectivesMacrolide resistance in Mycoplasma genitalium is emerging globally. There is paucity of data from sub-Saharan Africa where syndromic management is used to treat sexually transmitted infections (STIs). We conducted a molecular epidemiological study to determine the prevalence of azithromycin resistance and epidemic diversity of M. genitalium infections in South Africa.MethodsWe analysed 90 M. genitalium-positive specimens that had been collected consecutively from men and women (50% symptomatic) from geographically diverse communities across the northern part of South Africa between 2015 and 2019. Melting curve analysis followed by targeted sequencing of the 23S rRNA gene was performed to detect azithromycin resistance. Molecular typing was done through single nucleotide polymorphism (SNP) analysis of the MG191 gene and short tandem repeats (STR) assessment of the MG309 gene. An overview of all published M. genitalium sequence types was generated and novel sequence types identified in this study were allocated numbers accordingly.ResultsAzithromycin resistance was detected in 1/90 M. genitalium-positive specimens (1.1%; 95% CI 0% to 3.3%) as conferred by A2071G mutation; this strain also harboured a C234T mutation in the parC gene with wild type gyrA gene. SNP typing and STR assessment was successful in 38/90 specimens (42%) and showed a genetically diverse epidemic, without geographic clustering, with eight novel sequence types identified.ConclusionThis is the first study that determines resistance in M. genitalium infection since introduction of azithromycin in the syndromic management regimen for STIs in South Africa in 2015. Despite a well-established epidemic, azithromycin-resistant M. genitalium infection is still uncommon in the public healthcare sector. However, it has the potential to undermine the effectiveness of syndromic management. Introduction of molecular diagnostics and continuous surveillance are warranted for early detection emergence of resistance.

Cellulite is a common condition, and laxity in the superficial fascial system contributes significantly to its appearance in the thigh and buttock areas. Components of the superficial fascial system such as the fibrous septae and adipose tissue are targets for an effective treatment to improve the appearance of cellulite. This preliminary report demonstrates the use of radiofrequency-assisted lipolysis as a novel treatment approach to improve the appearance of cellulite by tightening the superficial fascial system. Ten female patients with grade 2 and grade 3 cellulite of the thighs or buttocks were included in this study. Minimally invasive application of bipolar radiofrequency energy to the affected areas was performed. Predetermined internal thermal endpoints at multiple tissue levels and different directions were reached in the treated tissues. Aspiration of the coagulated adipose tissue was performed using a small-diameter cannula to minimize damage to the connective tissues. Pretreatment and 6-month postoperative photographs of 70 different body areas were randomized and scored by five blinded evaluators. Using the Photonumeric Cellulite Severity Scale, scoring of preoperative and postoperative photographs revealed statistically significant differences in all body area comparisons. The magnitudes of the differences in all scored body areas were considered large, and mean differences were all positive, indicating an improvement across time. Grade 2 and grade 3 cellulite of the thighs and buttocks can be effectively treated using radiofrequency-assisted lipolysis technology to decrease the laxity of the superficial fascial system.

This study aims to assess the potential association of

Study question What is the predictive value of the menstrual cycle pattern in adolescence on fertility, cardiovascular- and metabolic health at age 40 years Summary answer Adolescents with oligomenorrhea are more often treated to conceive, but, are as likely to have children as those with regular menstrual cycles. What is known already Polycystic ovary syndrome(PCOS) is the main endocrine disorder in women of reproductive age. Adolescents with oligomenorrhea have a high risk for PCOS and potential subfertility due to ovulatory disorders. PCOS is also associated with pregnancy complications as pregnancy induced hypertension, pre-eclampsia and gestational diabetes. Furthermore PCOS is related to long-term health risks such as cardiovascular disease and diabetes. Studies on longitudinal implications of adolescent oligomenorrhea for fertility are lacking. Data on long-term health consequences of PCOS usually describe the development of these diseases in adult PCOS patients and lack longitudinal input starting at adolescence. Study design, size, duration This is a long-term follow-up study based on a unique adolescent study on menstrual irregularities performed between 1990-1997, the Pubertal onset of Menstrual Cycle abnormalities, a prospective study, the POMP study. We contacted stratified samples of this studycohort two decades after the initial study for a questionnaire assessing PCOS features, fertility history, pregnancy outcome, metabolic and cardiovascular health. Participants/materials, setting, methods 160 of 271 of the invited adult participants completed the questionnaire; the mean adolescent age was 15.3 years and the women were 39.6 years at time of follow-up. 92 had a regular menstrual cycle as adolescent and also as adult (REGREG); 15 changed to oligomenorrhea in adulthood (REGOL); 21 oligoamenorrheic adolescents remained oligomenorrheic (OLOL),and 31 oligomenorrheic girls developed a regular menstrual cycle pattern (OLREG). Main results and the role of chance Of those with adolescent regular menstrual cycles(REGREG+REGOL) 12 never tried to conceive, 4 tried but never conceived and 92 of 96(95,8%) conceived, 89 of 96(92,7%) delivered at least one living child. The mean time to pregnancy (TTP) in the REGREG subgroup was 7.2(SD 11.2) months with 14.6% subfertility (TTP > 12 months) compared to a TTP of 14.9 (SD 19.5) months with 35.7% subfertility in the REGOLsubgroup. 47 of 52 adolescents with oligomenorrhea (OLOL+OLREG) tried to conceive and 45(95,6%) succeeded to have at least one full term pregnancy. The mean TTP was 12.8 months (SD 19.8) in the OLOL subgroup versus 13.6 (SD 18.2) months in the OLREG subgoup, respectively 30 % and 24 % had a TTP > 12 months (p = 0.17). The median number of children was two in all subgroups. The OLOL subgroup had more fertility treatments -40%- than the other subgroups (14-22%) (p = 0.08). BMI did not differ between the four subgroups. The risk for pregnancy induced hypertension or pre-eclampsia was comparable among all subgroups (14-20%). Gestational diabetes developed in 3 participants all part of the OLOLsubgroup. Adult diabetes (0-5%), hypertension(3-10%), hypercholesterolaemia(0-5%) were diagnosed most frequently in the OLOLsubgroup, Cardiovascular disease(0-1%) in the REGREG subgroup Limitations, reasons for caution The numbers in the study are small. However the small difference between the percentage with a least one living child of those with adolescent oligomenorhea versus those with adolescent regular menstrual cycles is reassuring. Time to pregnancy data may have been biased by early treatment of oligomenorrheic adults. Wider implications of the findings Oligomenorrheic adolescents may be reassured for their chance to have a live birth being comparable with those with a regular menstrual cycle. Trial registration number NTR5871

Background Leprosy reactions, Type-1 and erythema nodosum leprosum, are immune-mediated complications of leprosy, which play a significant role in the morbidity associated with the disease. A considerable amount of literature has been published on the impact of leprosy in general but few studies focus specifically on leprosy reactions. This study aimed to investigate the impact of leprosy reactions on physical, psychological, and social aspects of the lives of people affected by analysing their life experiences and perspectives about leprosy reactions. Methods/Principal findings This qualitative study involved people affected by leprosy reactions and their family members in two leprosy endemic countries. The data were collected through 66 interviews and 9 focus group discussions (4–6 participants each) in Surabaya, Indonesia, and Purulia, India. Content analysis and conversational analysis were performed. This study found that both types of leprosy reactions were perceived as an unpredictable and painful condition. Leprosy reactions restricted physical activities of the participants, such as going to bathroom, sleeping, eating, and cooking. In the interviews, the respondents expressed a range of emotions and feelings including confusion, sadness, anxiety, and anger. Some recounted that they felt stigmatized and lost opportunities to socialise and earn money. Differences between the two settings were identified. The majority of Indonesian participants preferred to stay at home, and some concealed the diagnosis of leprosy, while most of the Indian respondents continued working up to the time of hospitalization. Conclusion Leprosy reactions are a distressing complication of leprosy and adversely affect the lives of those affected. Individuals reported physical discomfort, distress, anxiety, stigma, and financial hardship and these negative impacts in the physical, psychological, and social spheres reinforced each other. These findings provide important information about a need for early detection and sustained commitment to follow-up care for people with a history of leprosy reactions. More research on new drugs for reactional episodes, tools to measure knowledge, attitude, and practice, and costing study on leprosy reactions treatment are needed. We recommend the development and testing of holistic strategies to improve the management of leprosy reactions.

While stigmatisation is universal, stigma research in low- and middle-income countries (LMIC) is limited. LMIC stigma research predominantly concerns health-related stigma, primarily regarding HIV/AIDS or mental illness from an adult perspective. While there are commonalities in stigmatisation, there are also contextual differences. The aim of this study in DR Congo (DRC), as a formative part in the development of a common stigma reduction intervention, was to gain insight into the commonalities and differences of stigma drivers (triggers of stigmatisation), facilitators (factors positively or negatively influencing stigmatisation), and manifestations (practices and experiences of stigmatisation) with regard to three populations: unmarried mothers, children formerly associated with armed forces and groups (CAAFAG), and an indigenous population. Group exercises, in which participants reacted to statements and substantiated their reactions, were held with the ‘general population’ (15 exercises, n = 70) and ‘populations experiencing stigma’ (10 exercises, n = 48). Data was transcribed and translated, and coded in Nvivo12. We conducted framework analysis. There were two drivers mentioned across the three populations: perceived danger was the most prominent driver, followed by perceived low value of the population experiencing stigma. There were five shared facilitators, with livelihood and personal benefit the most comparable across the populations. Connection to family or leaders received mixed reactions. If unmarried mothers and CAAFAG were perceived to have taken advice from the general population and changed their stereotyped behaviour this also featured as a facilitator. Stigma manifested itself for the three populations at family, community, leaders and services level, with participation restrictions, differential treatment, anticipated stigma and feelings of scapegoating. Stereotyping was common, with different stereotypes regarding the three populations. Although stigmatisation was persistent, positive interactions between the general population and populations experiencing stigma were shared as well. This study demonstrated utility of a health-related stigma and discrimination framework and a participatory exercise for understanding non-health related stigmatisation. Results are consistent with other studies regarding these populations in other contexts. This study identified commonalities between drivers, facilitators and manifestations—albeit with population-specific factors. Contextual information seems helpful in proposing strategy components for stigma reduction.

The sympathetic nervous system fight-or-flight response is characterized by a rapid increase in heart rate, which is mediated by an increase in the spontaneous action potential (AP) firing rate of pacemaker cells in the sinoatrial node. Sympathetic neurons stimulate sinoatrial myocytes (SAMs) by activating β adrenergic receptors (βARs) and increasing cAMP. The funny current (If) is among the cAMP-sensitive currents in SAMs. If is critical for pacemaker activity, however, its role in the fight-or-flight response remains controversial. In this study, we used AP waveform analysis, machine learning, and dynamic clamp experiments in acutely-isolated SAMs from mice to quantitatively define the AP waveform changes and role of If in the fight-or-flight response. We found that while βAR stimulation significantly altered nearly all AP waveform parameters, the increase in AP firing rate was only correlated with changes in a subset of parameters (diastolic duration, late AP duration, and diastolic depolarization rate). Dynamic clamp injection of the βAR-sensitive component of If showed that it accounts for approximately 41% of the fight-or-flight increase in AP firing rate and 60% of the decrease in the interval between APs. Thus, If is an essential contributor to the fight-or-flight increase in heart rate.

Background Sexually transmitted infections (STIs) during pregnancy are associated with adverse birth outcomes, including preterm birth, low birth weight, perinatal death, and congenital infections such as increased mother-to-child HIV transmission. Prevalence of STIs among pregnant women in South Africa remains high, with most women being asymptomatic for their infection(s). Unfortunately, most STIs remain undetected and untreated due to standard practice syndromic management in accordance with World Health Organization (WHO) guidelines. Although lab-based and point-of-care molecular tests are available, optimal screening strategies during pregnancy, their health impact, and cost-effectiveness are unknown. Methods We will implement a 3-arm (1:1:1) type-1 hybrid effectiveness-implementation randomized-controlled trial (RCT). We will enroll 2500 pregnant women attending their first antenatal care (ANC) visit for their current pregnancy at participating health facilities in Buffalo City Metro District, Eastern Cape Province, South Africa. Participants allocated to arms 1 and 2 (intervention) will receive GeneXpert® point-of-care diagnostic testing for Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis, with same-day treatment for detected infection(s). Arm 1 will additionally receive a test-of-cure 3 weeks post-treatment, while Arm 2 will receive a repeat test at 30–34 weeks’ gestation. Those allocated to Arm 3 will receive syndromic management (standard-of-care). The RE-AIM framework will be used to guide collection of implementation indicators to inform potential future scale up. Primary outcome measures include (1) frequency of adverse birth outcomes among study arms, defined by a composite measure of low birth weight and pre-term delivery, and (2) change in STI prevalence between baseline and birth outcome among intervention arms and compared to standard-of-care. Estimates and comparative costs of the different screening strategies relative to standard-of-care and the costs of managing adverse birth outcomes will be calculated. Cost-effectiveness will be assessed per STI and disability-adjusted life year averted. Discussion This trial is the first RCT designed to identify optimal, cost-effective screening strategies that decrease the burden of STIs during pregnancy and reduce adverse birth outcomes. Demonstrating the impact of diagnostic screening and treatment, compared to syndromic management, on birth outcomes will provide critical evidence to inform changes to WHO guidelines for syndromic management of STIs during pregnancy. Trial registration ClinicalTrials.gov NCT04446611. Registered on 25 June 2020.