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Over the past several years, there has been an increasing interest in the biology of bone repair and potential technologies for enhancing fracture-healing. Part of this interest is derived from the growing age of the population and the recognition that increased age carries an increased risk of complications after fracture. Although use of locally implanted or injected growth factors has received the most attention, systemic treatments for the enhancement of bone repair, especially for situations in which bone repair may be diminished or delayed, are now under investigation. Since the approval of parathyroid hormone (PTH) as an anabolic treatment for osteoporosis, there has been an increasing interest in other potential clinical uses for this compound in musculoskeletal conditions. It is now widely recognized that PTH administration is an effective therapy to increase bone mineral density and prevent fractures in patients with osteoporosis. More recently, a growing body of evidence has supported the conclusion that PTH will also be an effective anabolic therapy for the enhancement of bone repair after fracture. This review focuses on the recent research demonstrating the potential of PTH in the management of bone repair in a number of fracture models and also highlights the ongoing studies into the mechanisms of PTH actions on endochondral bone repair. [ABSTRACT FROM AUTHOR]

Rationale: Treatment of latent tuberculosis (TB) infection with weekly rifapentine and isoniazid is a potentially effective alternative to current therapies.Objectives: To compare the efficacy of weekly rifapentine/isoniazid to daily rifampin/pyrazinamide in preventing TB in household contacts of patients with pulmonary TB in Brazil.Methods: Contacts of patients with TB were randomized to rifapentine 900 mg/isoniazid 900 mg once weekly for 12 wk or rifampin 450-600 mg/pyrazinamide 750-1,500 mg daily for 8 wk and followed for at least 2 yr.Measurements: TB rates, adverse events, and adherence to therapy.Main Results: A total of 399 household contacts were enrolled, 206 in the rifapentine/isoniazid arm and 193 in the rifampin/pyrazinamide arm. The median age was 34 yr, median weight was 63 kg, 60% of participants were female, and only one patient was HIV infected. Rifapentine/isoniazid was well tolerated, but the trial was halted by the investigators before completion because of unanticipated hepatotoxicity in the rifampin/pyrazinamide arm. Twenty of 193 participants (10%) receiving rifampin/pyrazinamide experienced grade 3 or 4 hepatotoxicity, compared with 2 of 206 participants (1%) on rifapentine/isoniazid (p<0.001). There were no hospitalizations or deaths due to hepatotoxicity, and all participants' liver enzyme levels returned to normal during follow-up. During follow-up, four cases of active TB developed, three in the rifapentine/isoniazid group and one in the rifampin/pyrazinamide group (1.46 vs. 0.52%; difference, 0.94%; 95% confidence interval, -1.6 to 3.7%).Conclusions: Rifapentine/isoniazid was better tolerated than rifampin/pyrazinamide and was associated with good protection against TB. Rifapentine/isoniazid weekly for 12 wk is likely a promising therapy for latent TB infection. [ABSTRACT FROM AUTHOR]

We report the discovery of MED6-189, an analog of the kalihinol family of isocyanoterpene natural products that is effective against drug-sensitive and drug-resistant Plasmodium falciparum strains, blocking both asexual replication and sexual differentiation. In vivo studies using a humanized mouse model of malaria confirm strong efficacy of the compound in animals with no apparent hemolytic activity or toxicity. Complementary chemical, molecular, and genomics analyses revealed that MED6-189 targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses revealed that a mutation in PfSec13 , which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. Its high potency, excellent therapeutic profile, and distinctive mode of action make MED6-189 an excellent addition to the antimalarial drug pipeline.

Internalising symptoms are elevated in autism compared to the general population. Few studies have investigated emotional dysregulation (ED) as a potential mediator between specific transdiagnostic processes and anxiety and depression symptoms in autistic youth. In a sample of 94 autistic young people aged 5-18 years referred to a specialist clinic for an autism evaluation, we tested the effects of ED as a mediator between cognitive inflexibility (CI), intolerance of uncertainty (IU) and alexithymia with anxiety and depression symptoms, using structural equation modelling. Effect sizes were compared to a non-autistic comparison group (n = 84). CI and alexithymia did not significantly predict depression symptoms in autistic young people, directly nor via ED. Relationships between CI/alexithymia and depression were fully mediated by ED in the non-autistic sample. There was a direct effect of CI on anxiety in the non-autistic group but not in those with a diagnosis. IU predicted depression symptoms in the autism group; and ED mediated this relationship only in those who did not receive a diagnosis. IU directly predicted anxiety in both groups and this relationship did not occur via ED. The finding of a direct pathway from IU to anxiety and depression in autistic youth is consistent with the literature. The finding that CI did not predict anxiety or depression in those with autism is novel, as was the finding that ED mediated relationships between alexithymia and anxiety/depression symptoms in both samples. The findings may have important implications for the delivery of psychological interventions for autistic youth., (© 2024. The Author(s).)

Background: Childhood trauma is a risk factor for psychosis. It is proposed this is due to traumatic events giving rise to psychological mechanisms that are implicated in the development and maintenance of symptoms. Investigation of the psychological mechanisms accounting for relationships between trauma and psychosis will be assisted by focusing on specific trauma profiles, hallucination modalities, and delusion subtypes., Study Design: In 171 adults with schizophrenia-spectrum diagnoses and high-conviction delusions, associations between childhood trauma classes, and hallucination and delusion factors, were tested using structural equation models (SEMs). Anxiety, depression, and negative schema were examined as potential mediators of trauma class-psychosis symptom factor links., Study Results: Significant associations were found between the emotional abuse/neglect and poly-victimization classes with persecutory delusions and delusions of influence, that were all mediated through anxiety (β = 1.24-0.23, P  = < .05). There was an association between the physical abuse class and grandiose/religious delusions that was not explained by the mediators (β = 1.86, P  = < .05). Trauma class was not significantly associated with any hallucination modality (β = 0.004-1.46, P  = > .05)., Conclusions: In a sample of people with strongly held delusions, this study demonstrates that childhood victimization is associated with delusions of influence and grandiose beliefs, as well as with persecutory delusions in psychosis. Consistent with previous findings, the potent, mediating role of anxiety supports affective pathway theories and the utility of targeting threat-related processes when treating trauma effects in psychosis., Competing Interests: The authors have no conflicts of interest to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.)

A radical/polar crossover annulation between allyl-substituted arenes and electron-deficient alkenes is described. Cobalt-catalyzed hydrogen atom transfer (HAT) facilitates tandem radical C-C bond formation that generates functionalized tetralin products in the face of potentially problematic hydrofluorination, hydroalkoxylation, hydrogenation, alkene isomerization, and radical polymerization reactions. The reactions proceed under mild conditions that tolerate many functional groups, leading to a broad substrate scope. This powerful ring-forming reaction very quickly assembles complex tetralins that are the formal products of the largely infeasible Diels-Alder cycloadditions of styrenes., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

We offer a new biogenetic proposal for the origin of the complex alkaloid alstonlarsine A, through rearrangement of the Strychnos alkaloids alstolucines B and F. Further, we provide evidence of the chemical feasibility of this proposal in the facile conversion of synthetic alstolucines into alstonlarsine A through a short, efficient sequence of N-methylation, β-elimination, and a cascade 1,7-hydride shift/Mannich cyclization. We believe that this is the first biogenetic proposal involving the "tert-amino effect", a hydride-shift-based internal redox trigger of a Mannich cyclization. A further interesting feature of the cascade is that its stereochemical outcome most likely originates in conformational preferences during the hydride shift., (© 2022 Wiley-VCH GmbH.)

Background: Tuberculosis preventive therapy (TPT) is recommended for people with HIV infection, including during pregnancy. The effect of TPT exposure at conception and during pregnancy is poorly documented., Methods: We report pregnancy outcomes among South African women with HIV enrolled in a randomized trial of 4 TPT regimens (two 3-month regimens, rifapentine/isoniazid [3HP] or rifampin/isoniazid [3HR], isoniazid for 6 months, or isoniazid continuously). Descriptive statistics and risk ratios were assessed to examine relationships between study regimens and outcomes., Results: 216/896 women (24%) conceived during the study. Women who conceived were younger (27.9 vs 31.3 years) and had higher mean CD4 counts (589.1 vs 536.7). The odds of pregnancy were higher in women in the rifamycin-isoniazid arms than those in the isoniazid arms (3HP: relative risk [RR] 1.73, P = 0.001; 3HR:RR 1.55, P = 0.017) despite increased contraceptive use compared with the standard 6H therapy. Thirty-four women became pregnant while taking preventive treatment (8 rifamycin and 26 isoniazid monotherapy). Pregnancy outcomes in these women were as follows: 17 (50%) mother/baby healthy, 3 (9%) spontaneous abortions, 6 (18%) elective abortions, 1 (3%) premature delivery, 2 (6%) neonatal deaths [1 rifamycin-isoniazid and 1 isoniazid], and 5 (15%) unknown., Conclusions: Pregnancy was common in women who had received TPT and more frequent in women who had received rifamycin-isoniazid-based regimens., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Rotavirus is a major cause of gastroenteritis in children <5 years of age. The disease burden in older children, adults, and the elderly is underappreciated. This study describes rotavirus disease and genotypic diversity in the Australian population comprising children ≥5 years of age and adults., Methods: Rotavirus positive fecal samples were collected from laboratories Australia-wide participating in the Australian Rotavirus Surveillance Program between 2010 and 2018. Rotavirus samples were genotyped using a heminested multiplex reverse-transcription polymerase chain reaction. Notification data from the National Notifiable Diseases Surveillance System were also analyzed., Results: Rotavirus disease was highest in children aged 5-9 years and adults ≥85 years. G2P[4] was the dominant genotype in the population ≥5 years of age. Genotype distribution fluctuated annually and genotypic diversity varied among different age groups. Geographical differences in genotype distribution were observed based on the rotavirus vaccine administered to infants <1 year of age., Conclusions: This study revealed a substantial burden of rotavirus disease in the population ≥5 years of age, particularly in children 5-9 years and the elderly. This study highlights the continued need for rotavirus surveillance across the population, despite the implementation of efficacious vaccines., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Debates within health care and public spheres have, at times, created a seeming 'divide' between biological and psychosocial determinants and management of mental health difficulties. The phrase 'medical model' is often held up as an example and is sometimes used pejoratively to infer over-reliance on biology and medication. Our objective was to explore inpatient mental health clinicians' perceptions of the definition and the application of a 'medical model' in contemporary mental health care. In this qualitative study, eighteen clinicians working in adult inpatient teams participated in three mixed focus groups. Data were analysed using framework analysis. Three core themes were identified: (i) power of a 'medical model' and authority of the medic; (ii) responsibility within, and reliance on, a 'medical model'; and (iii) integrated models of contemporary mental health care. Subthemes arose around organisational culture and low resources affecting the power of a 'medical model' and the value of multidisciplinary and person-centred approaches. The findings highlight the importance of recognising inter-professional dynamics and power gradients in mental health teams and organisations, as we begin to move towards more integrated models of collaboration and distributed leadership within the NHS., (© 2022 John Wiley & Sons Australia, Ltd.)

Rationale: Carbapenems are recommended for treatment of drug-resistant tuberculosis. Optimal dosing remains uncertain. Objectives: To evaluate the 14-day bactericidal activity of meropenem, at different doses, with or without rifampin. Methods: Individuals with drug-sensitive pulmonary tuberculosis were randomized to one of four intravenous meropenem-based arms: 2 g every 8 hours (TID) (arm C), 2 g TID plus rifampin at 20 mg/kg once daily (arm D), 1 g TID (arm E), or 3 g once daily (arm F). All participants received amoxicillin/clavulanate with each meropenem dose. Serial overnight sputum samples were collected from baseline and throughout treatment. Median daily fall in colony-forming unit (CFU) counts per milliliter of sputum (solid culture) (EBA CFU0-14 ) and increase in time to positive culture (TTP) in liquid media were estimated with mixed-effects modeling. Serial blood samples were collected for pharmacokinetic analysis on Day 13. Measurements and Main Results: Sixty participants enrolled. Median EBA CFU0-14 counts (2.5th-97.5th percentiles) were 0.22 (0.12-0.33), 0.12 (0.057-0.21), 0.059 (0.033-0.097), and 0.053 (0.035-0.081); TTP increased by 0.34 (0.21-0.75), 0.11 (0.052-0.37), 0.094 (0.034-0.23), and 0.12 (0.04-0.41) (log 10 h), for arms C-F, respectively. Meropenem pharmacokinetics were not affected by rifampin coadministration. Twelve participants withdrew early, many of whom cited gastrointestinal adverse events. Conclusions: Bactericidal activity was greater with the World Health Organization-recommended total daily dose of 6 g daily than with a lower dose of 3 g daily. This difference was only detectable with solid culture. Tolerability of intravenous meropenem, with amoxicillin/clavulanate, though, was poor at all doses, calling into question the utility of this drug in second-line regimens. Clinical trial registered with www.clinicaltrials.gov (NCT03174184).

Purpose: Neurocognitive difficulties and early childhood speech/motor delays are well documented amongst older adolescents and young adults considered at risk for psychosis-spectrum diagnoses. We aimed to test associations between unusual or psychotic-like experiences (PLEs), co-occurring distress/emotional symptoms, current cognitive functioning and developmental delays/difficulties in young people (aged 8-18 years) referred to Child and Adolescent Mental Health Services in South London, UK., Methods: Study 1 examined receptive language, verbal learning and caregiver-reported speech and motor delays/difficulties in a sample of 101 clinically-referred children aged 8-14 years, comparing those reporting no PLEs (n = 19), PLEs without distress (n = 16), and PLEs with distress (n = 66). Study 2 tested associations of severity of distressing PLEs with vocabulary, perceptual reasoning, word reading and developmental delays/difficulties in a second sample of 122 adolescents aged 12-18 years with distressing PLEs., Results: In Study 1, children with distressing PLEs had lower receptive language and delayed recall and higher rates of developmental delays/difficulties than the no-PLE and non-distressing PLE groups (F values: 2.3-2.8; p values: < 0.005). Receptive language (β = 0.24, p = 0.03) and delayed recall (β = - 0.17, p = 0.02) predicted PLE distress severity. In Study 2, the cognitive-developmental variables did not significantly predict PLE distress severity (β values = 0.01-0.22, p values: > 0.05)., Conclusion: Findings may be consistent with a cognitive-developmental model relating distressing PLEs in youth with difficulties in cognitive functioning. This highlights the potential utility of adjunctive cognitive strategies which target mechanisms associated with PLE distress. These could be included in cognitive-behavioural interventions offered prior to the development of an at-risk mental state in mental health, educational or public health settings., (© 2021. The Author(s).)

Background: People with psychosis experience higher rates of childhood victimisation compared to the general population, which may impact on mental health and recovery. This study aimed to identify childhood victimisation profiles in a clinical sample to inform recommendations for routine care., Methods: Participants were 146 adults (ages 19-65 years; M = 42.2) with schizophrenia-spectrum diagnoses reporting trauma. Childhood trauma was assessed using two retrospective measures, and a latent class analysis (LCA) was performed on four trauma types (sexual abuse, emotional abuse, physical abuse and neglect). Multinomial logistic regression investigated demographic differences between the classes., Results: Four distinct childhood trauma classes were identified: Emotional abuse/neglect (n = 29); physical abuse (n = 14); sexual abuse (n = 19); and poly-victimisation (n = 84). There were no differences between the classes in terms of age, ethnicity, relationship status, education or current employment (relative risk (RR) = 0.85-1.27, p > 0.05). Participants in the poly-victimisation class were significantly more likely to be female (RR = 0.22-0.28, p < 0.04)., Discussion: Adults with psychosis, particularly females, are likely to report poly-victimisation in childhood. This highlights the need to comprehensively but concisely assess experiences of abuse and neglect in clinical care, in line with trauma-informed approaches., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

We report the results of experiments, simulations, and DFT calculations that focus on describing the reaction dynamics observed within the collision-induced dissociation of l-lysine-H + and its side-chain methylated analogues, N ε -methyl-l-lysine-H + (Me 1 -lysine-H + ), N ε , N ε -dimethyl-l-lysine-H + (Me 2 -lysine-H + ), and N ε , N ε , N ε -trimethyl-l-lysine-H + (Me 3 -lysine-H + ). The major pathways observed in the experimental measurements were m / z 130 and 84, with the former dominant at low collision energies and the latter at intermediate to high collision energies. The m / z 130 peak corresponds to loss of N(CH 3 ) n H 3- n , while m / z 84 has the additional loss of H 2 CO 2 likely in the form of H 2 O + CO. Within the time frame of the direct dynamics simulations, m / z 130 and 101 were the most populous peaks, with the latter identified as an intermediate to m / z 84. The simulations allowed for the determination of several reaction pathways that result in these products. A graph theory analysis enabled the elucidation of the significant structures that compose each peak. Methylation results in the preferential loss of the side-chain amide group and a reduction of cyclic structures within the m / z 84 peak population in simulations.

AutoMeKin2021 is an updated version of tsscds2018, a program for the automated discovery of reaction mechanisms (J. Comput. Chem. 2018, 39, 1922). This release features a number of new capabilities: rare-event molecular dynamics simulations to enhance reaction discovery, extension of the original search algorithm to study van der Waals complexes, use of chemical knowledge, a new search algorithm based on bond-order time series analysis, statistics of the chemical reaction networks, a web application to submit jobs, and other features. The source code, manual, installation instructions and the website link are available at: https://rxnkin.usc.es/index.php/AutoMeKin., (© 2021 The Authors. Journal of Computational Chemistry published by Wiley Periodicals LLC.)

Purpose: Existing reviews of trauma and psychosis have identified associations between childhood emotional abuse (CEA) and psychosis. However, conceptual issues relating to assessment of CEA limit the conclusions that can be drawn from the literature. The aim of this review was to identify and evaluate studies reporting an association between childhood experiences of caregiver antipathy (i.e. criticism, hostility, coldness, or rejection from a parental figure experienced prior to age 17 years) and psychosis symptoms/diagnosis., Methods: Five databases were systematically searched for articles published until May 2020. Studies were evaluated against inclusion/exclusion criteria, and a narrative synthesis of findings was completed. Study quality was assessed by two independent raters., Results: Fourteen studies comprised of 1,848 participants met inclusion criteria. Twelve of these studies found significant associations between caregiver antipathy and psychosis, and two did not. There was evidence that adults with schizophrenia-spectrum diagnoses report more severe caregiver antipathy in childhood than non-clinical controls and that caregiver antipathy severity is positively correlated with psychosis symptom severity. Most studies received weak or moderate quality ratings and all used cross-sectional or case-control designs which showed associations, rather than causal relationships, between childhood caregiver antipathy and later psychosis., Conclusions: Future research would benefit from more rigorous and valid assessment of CEA, use of multivariate methods to account for possible patterns of co-occurrence, and longitudinal study designs to make more robust causal claims. The findings may have important implications for the delivery of psychological care for people with psychosis who report adverse caregiving experiences., Practitioner Points: People with schizophrenia-spectrum diagnoses may report more severe caregiver antipathy in childhood than non-clinical controls. Caregiver antipathy severity appears to be positively correlated with psychosis symptom severity in clinical and non-clinical populations. Clinicians should consider the possible impact of caregiver antipathy on psychosis symptoms, their content and distress maintenance. Clinicians should also recognise the potential impact of adverse caregiving experiences on therapeutic relationships, patterns of help-seeking and service engagement. Best practice in clinical services would be to adopt individual, formulation-based approaches within trauma-informed models of care., (© 2021 The Authors. Psychology and Psychotherapy: Theory, Research and Practice published by John Wiley & Sons Ltd on behalf of British Psychological Society.)

Background: Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability. Methods: Patients were randomized to one of four treatment groups: meropenem 2 g three times daily plus oral rifampicin 20 mg/kg once daily, meropenem 2 g three times daily, meropenem 1 g three times daily, and meropenem 3 g once daily. Meropenem was administered by intravenous infusion over 0.5-1 h. All patients also received oral amoxicillin/clavulanate together with each meropenem dose, and treatments continued daily for 14 days. Intensive plasma pharmacokinetics sampling over 8 h was conducted on the 14th day of the study. Nonlinear mixed-effects modeling was used for data analysis. The best model was chosen based on likelihood metrics, goodness-of-fit plots, and parsimony. Covariates were tested stepwise. Results: A total of 404 concentration measurements from 49 patients were included in the analysis. A two-compartment model parameterized with clearance (CL), inter-compartmental clearance (Q), and central (V1) and peripheral (V2) volumes of distribution fitted the data well. Typical values of CL, Q, V1, and V2 were 11.8 L/h, 3.26 L/h, 14.2 L, and 3.12 L, respectively. The relative standard errors of the parameter estimates ranged from 3.8 to 35.4%. The covariate relations included in the final model were creatinine clearance on CL and allometric scaling with body weight on all disposition parameters. An effect of age on CL as previously reported could not be identified. Conclusion: A two-compartment model described meropenem population pharmacokinetics in patients with pulmonary tuberculosis well. Covariates found to improve model fit were creatinine clearance and body weight but not rifampicin treatment. The final model will be used for an integrated pharmacokinetics/pharmacodynamics analysis linking meropenem exposure to early bactericidal activity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Abulfathi, de Jager, van Brakel, Reuter, Gupte, Vanker, Barnes, Nuermberger, Dorman, Diacon, Dooley and Svensson.)

Background: Tuberculosis is a top-10 cause of under-5 mortality, despite policies promoting tuberculosis preventive therapy (TPT). We previously conducted a cluster randomized trial to evaluate the effectiveness of symptom-based versus tuberculin skin-based screening on child TPT uptake. Symptom-based screening did not improve TPT uptake and nearly two-thirds of child contacts were not identified or not linked to care. Here we qualitatively explored healthcare provider perceptions of factors that impacted TPT uptake among child contacts., Methods: Sixteen in-depth interviews were conducted with key informants including healthcare providers and administrators who participated in the trial in Matlosana, South Africa. The participants' experience with symptom-based screening, study implementation strategies, and ongoing challenges with child contact identification and linkage to care were explored. Interviews were systematically coded and thematic content analysis was conducted., Results: Participants' had mixed opinions about symptom-based screening and high acceptability of the study implementation strategies. A key barrier to optimizing child contact screening and evaluation was the supervision and training of community health workers., Conclusions: Symptom screening is a simple and effective strategy to evaluate child contacts, but additional pediatric training is needed to provide comfort with decision making. New clinic-based child contact files were highly valued by providers who continued to use them after trial completion. Future interventions to improve child contact management will need to address how to best utilize community health workers in identifying and linking child contacts to care., Trial Registration: The results presented here were from research related to NCT03074799 , retrospectively registered on 9 March 2017.

We present the results of direct dynamics simulations and DFT calculations aimed at elucidating the effect of O -sulfonation on the collision-induced dissociation for serine. Toward this end, direct dynamics simulations of both serine and sulfoserine were performed at multiple collision energies and theoretical mass spectra obtained. Comparisons to experimental results are favorable for both systems. Peaks related to the sulfo group are identified and the reaction dynamics explored. In particular, three significant peaks ( m / z 106, 88, and 81) seen in the theoretical mass spectrum directly related to the sulfo group are analyzed as well as major peaks shared by both systems. Our analysis shows that the m / z 106 peaks result from intramolecular rearrangements, intermolecular proton transfer among complexes composed of initial fragmentation products, and at high energy side-chain fragmentation. The m / z 88 peak was found to contain multiple constitutional isomers, including a previously unconsidered, low energy structure. It was also observed that the RM1 semiempirical method was not able to obtain all of the major peaks seen in experimens for sulfoserine. In contrast, PM6 did obtain all major experimental peaks.

Formally, the Farming/Language Dispersal hypothesis as applied to Japan relates to the introduction of agriculture and spread of the Japanese language (between ca. 500 BC-AD 800). We review current data from genetics, archaeology, and linguistics in relation to this hypothesis. However, evidence bases for these disciplines are drawn from different periods. Genetic data have primarily been sampled from present-day Japanese and prehistoric Jōmon peoples (14,000-300 BC), preceding the introduction of rice agriculture. The best archaeological evidence for agriculture comes from western Japan during the Yayoi period (ca. 900 BC-AD 250), but little is known about northeastern Japan, which is a focal point here. And despite considerable hypothesizing about prehistoric language, the spread of historic languages/ dialects through the islands is more accessible but difficult to relate to prehistory. Though the lack of Yayoi skeletal material available for DNA analysis greatly inhibits direct study of how the pre-agricultural Jōmon peoples interacted with rice agriculturalists, our review of Jōmon genetics sets the stage for further research into their relationships. Modern linguistic research plays an unexpected role in bringing Izumo (Shimane Prefecture) and the Japan Sea coast into consideration in the populating of northeastern Honshu by agriculturalists beyond the Kantō region., Competing Interests: None of the authors have conflicts of interest to declare., (© The Author(s) 2020.)

Background: Tuberculosis preventive therapy (TPT) is highly effective at preventing tuberculosis disease in household child contacts (<5 years), but is poorly implemented worldwide. In 2006, the World Health Organization recommended symptom-based screening as a replacement for tuberculin skin testing (TST) to simplify contact evaluation and improve implementation. We aimed to determine the effectiveness of this recommendation., Methods: We conducted a pragmatic, cluster-randomized trial to determine whether contact evaluation using symptom screening improved the proportion of identified child contacts who initiated TPT, compared to TST-based screening, in Matlosana, South Africa. We randomized 16 clinics to either symptom-based or TST-based contact evaluations. Outcome data were abstracted from customized child contact management files., Results: Contact tracing identified 550 and 467 child contacts in the symptom and TST arms, respectively (0.39 vs 0.32 per case, respectively; P = .27). There was no significant difference by arm in the adjusted proportion of identified child contacts who were screened (52% in symptom arm vs 60% in TST arm; P = .39). The adjusted proportion of identified child contacts who initiated TPT or tuberculosis treatment was 51.5% in the symptom clinics and 57.1% in the TST clinics (difference -5.6%, 95% confidence interval -23.7 to 12.6; P = .52). Based on the district's historic average of 0.7 child contacts per index case, 14% and 15% of child contacts completed 6 months of TPT in the symptom and TST arms, respectively (P = .89)., Conclusions: Symptom-based screening did not improve the proportion of identified child contacts evaluated or initiated on TPT, compared to TST-based screening. Further research is needed to identify bottlenecks and evaluate interventions to ensure all child contacts receive TPT., Clinical Trials Registration: NCT03074799., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

In this article, a perspective is given of chemical dynamics simulations of collisions of biological ions with surfaces and of collision-induced dissociation (CID) of ions. The simulations provide an atomic-level understanding of the collisions and, overall, are in quite good agreement with experiment. An integral component of ion/surface collisions is energy transfer to the internal degrees of freedom of both the ion and the surface. The simulations reveal how this energy transfer depends on the collision energy, incident angle, biological ion, and surface. With energy transfer to the ion's vibration fragmentation may occur, i.e. surface-induced dissociation (SID), and the simulations discovered a new fragmentation mechanism, called shattering, for which the ion fragments as it collides with the surface. The simulations also provide insight into the atomistic dynamics of soft-landing and reactive-landing of ions on surfaces. The CID simulations compared activation by multiple "soft" collisions, resulting in random excitation, versus high energy single collisions and nonrandom excitation. These two activation methods may result in different fragment ions. Simulations provide fragmentation products in agreement with experiments and, hence, can provide additional information regarding the reaction mechanisms taking place in experiment. Such studies paved the way on using simulations as an independent and predictive tool in increasing fundamental understanding of CID and related processes.

Background: Tuberculosis (TB) remains the leading cause of death among human immunodeficiency virus (HIV)-infected individuals globally. Screening for TB at the point of HIV diagnosis with a high-sensitivity assay presents an opportunity to reduce mortality., Methods: We performed a cluster randomized trial of TB screening among adults newly diagnosed with HIV in 12 primary health clinics in rural Thyolo, Malawi. Clinics were allocated in a 1:1 ratio to perform either point-of-care Xpert MTB/RIF assay (Xpert) or point-of-care light-emitting diode fluorescence microscopy (LED-FM) for individuals screening positive for TB symptoms. Asymptomatic participants were offered isoniazid preventive therapy in both arms. Investigators, but not clinic staff or participants, were masked to allocation. Our primary outcome was the incidence rate ratio (RR) of all-cause mortality within 12 months of HIV diagnosis., Results: Prevalent TB was diagnosed in 24 of 1001 (2.4%) individuals enrolled in clinics randomized to Xpert, compared with 10 of 841 (1.2%) in clinics randomized to LED-FM. All-cause mortality was 22% lower in the Xpert arm than in the LED-FM arm (6.7 vs 8.6 per 100 person-years; RR, 0.78 [95% confidence interval {CI}, .58-1.06]). A planned subgroup analysis suggested that participants with more advanced HIV (World Health Organization clinical stage 3 or 4) disease had lower mortality in clinics randomized to Xpert than to LED-FM (RR, 0.43 [95% CI, .22-.87])., Conclusions: In rural Malawi, using point-of-care Xpert MTB/RIF to test symptomatic patients for TB at the time of HIV diagnosis reduced all-cause 12-month mortality among individuals with advanced HIV., Clinical Trials Registration: NCT01450085., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective/Background: Our aim was to qualitatively explore the experiences of people who attended a one-day sleep workshop six years previously. Participants: Of the 95 people who originally attended the workshop and a three-month follow-up, 14 individuals (mean age = 63.6 years) participated. Methods: Semi-structured interviews were used to explore: participants' experiences of insomnia since the workshop, memories of the techniques and information provided and the perceived impact of the workshop on their lives. Qualitative data were analyzed using the principles of Framework Analysis. Results: Interviews produced rich accounts of attributions of changes in sleep, the application of taught strategies and general experiences of the workshop. Conclusions: This research highlights which aspects of a large-scale intervention may be most helpful for individuals experiencing sleep difficulties and what factors may contribute to changes in sleep over time.

The effect of secondary structure on the soft landing process is investigated through direct dynamics simulations of AcA 7 K and AcKA 7 colliding with a fluorinated, organic self-assembled monolayer (FSAM) surface. The α-helical (AcA 7 K) and globular (AcKA 7 ) peptides each exhibited a similar probability of soft landing with normal incidence at all collision energies considered. Rapid conformational changes were quantified through the calculation of the time dependent, conformational entropy production that took place during the collision events, which is consistent with the prior structural measurements made by Laskin and co-workers on these systems. AcA 7 K produces more entropy during the collisions than AcKA 7 .

Background: Introduction of rotavirus vaccines into national immunization programs (NIPs) could result in strain selection due to vaccine-induced selective pressure. This study describes the distribution and diversity of rotavirus genotypes before and after rotavirus vaccine introduction into the Australian NIP. State-based vaccine selection facilitated a unique comparison of diversity in RotaTeq and Rotarix vaccine states., Methods: From 1995 to 2015, the Australian Rotavirus Surveillance Program conducted genotypic analysis on 13051 rotavirus-positive samples from children <5 years of age, hospitalized with acute gastroenteritis. Rotavirus G and P genotypes were determined using serological and heminested multiplex reverse-transcription polymerase chain reaction assays., Results: G1P[8] was the dominant genotype nationally in the prevaccine era (1995-2006). Following vaccine introduction (2007-2015), greater genotype diversity was observed with fluctuating genotype dominance. Genotype distribution varied based on the vaccine implemented, with G12P[8] dominant in states using RotaTeq, and equine-like G3P[8] and G2P[4] dominant in states and territories using Rotarix., Conclusions: The increased diversity and differences in genotype dominance observed in states using RotaTeq (G12P[8]), and in states and territories using Rotarix (equine-like G3P[8] and G2P[4]), suggest that these vaccines exert different immunological pressures that influence the diversity of rotavirus strains circulating in Australia.

Setting: To reduce the risk of tuberculosis (TB) among individuals with human immunodeficiency virus (HIV) infection, the World Health Organization recommends at least 6 months of isoniazid preventive therapy (IPT). Completion of IPT remains a major challenge in resource-limited settings., Objective: To evaluate predictors of IPT completion in individuals newly diagnosed with HIV., Design: Predictors of IPT completion among adults newly diagnosed with HIV in rural Malawi were evaluated using a multilevel logistic regression model., Results: Of 974 participants who screened negative for active TB and were started on IPT, 732 (75%) completed treatment. Only one IPT-eligible individual refused treatment. Participants who were aged <25 years (compared with those aged 45 years, adjusted OR [aOR] 0.33, 95%CI 0.18-0.60) and male (compared to non-pregnant females, aOR 0.57, 95%CI 0.37-0.88) had lower odds of IPT completion., Conclusion: IPT provision at the time of initial HIV diagnosis was highly acceptable in rural Malawi; three quarters of those who initiated IPT successfully completed therapy. We observed lower odds of completion among males and among female participants aged <25 years. Additional efforts may be needed to ensure IPT completion among males and young females who have recently been diagnosed with HIV.

Setting: Ten primary health clinics in rural Thyolo District, Malawi., Objective: Tuberculosis (TB) is a common initial presentation of human immunodeficiency virus (HIV) infection. We investigated the time from TB symptom onset to HIV diagnosis to describe TB health-seeking behaviour in adults newly diagnosed with HIV., Design: We asked adults (18 years) about the presence and duration of TB symptoms at the time of receiving a new HIV diagnosis. Associations with delayed health seeking (defined as >30 and >90 days from the onset of TB symptoms) were evaluated using multivariable logistic regression., Results: TB symptoms were reported by 416 of 1265 participants (33%), of whom 36% (150/416) had been symptomatic for >30 days before HIV testing. Most participants (260/416, 63%) were below the poverty line (US$0.41 per household member per day). Patients who first sought care from informal providers had an increased odds of delay of >30 days (adjusted odds ratio [aOR] 1.6, 95%CI 0.9-2.8) or 90 days (aOR 2.0, 95%CI 1.1-3.8)., Conclusions: Delayed health seeking for TB-related symptoms was common. Poverty was ubiquitous, but had no clear relationship to diagnostic delay. HIV-positive individuals who first sought care from informal providers were more likely to experience diagnostic delays for TB symptoms.

Background: A strategy of administering a neonatal rotavirus vaccine at birth to target early prevention of rotavirus gastroenteritis may address some of the barriers to global implementation of a rotavirus vaccine., Methods: We conducted a randomized, double-blind, placebo-controlled trial in Indonesia to evaluate the efficacy of an oral human neonatal rotavirus vaccine (RV3-BB) in preventing rotavirus gastroenteritis. Healthy newborns received three doses of RV3-BB, administered according to a neonatal schedule (0 to 5 days, 8 weeks, and 14 weeks of age) or an infant schedule (8 weeks, 14 weeks, and 18 weeks of age), or placebo. The primary analysis was conducted in the per-protocol population, which included only participants who received all four doses of vaccine or placebo within the visit windows, with secondary analyses performed in the intention-to-treat population, which included all participants who underwent randomization., Results: Among the 1513 participants in the per-protocol population, severe rotavirus gastroenteritis occurred up to the age of 18 months in 5.6% of the participants in the placebo group (28 of 504 babies), in 1.4% in the neonatal-schedule vaccine group (7 of 498), and in 2.7% in the infant-schedule vaccine group (14 of 511). This resulted in a vaccine efficacy of 75% (95% confidence interval [CI], 44 to 91) in the neonatal-schedule group (P<0.001), 51% (95% CI, 7 to 76) in the infant-schedule group (P=0.03), and 63% (95% CI, 34 to 80) in the neonatal-schedule and infant-schedule groups combined (combined vaccine group) (P<0.001). Similar results were observed in the intention-to-treat analysis (1649 participants); the vaccine efficacy was 68% (95% CI, 35 to 86) in the neonatal-schedule group (P=0.001), 52% (95% CI, 11 to 76) in the infant-schedule group (P=0.02), and 60% (95% CI, 31 to 76) in the combined vaccine group (P<0.001). Vaccine response, as evidenced by serum immune response or shedding of RV3-BB in the stool, occurred in 78 of 83 participants (94%) in the neonatal-schedule group and in 83 of 84 participants (99%) in the infant-schedule group. The incidence of adverse events was similar across the groups. No episodes of intussusception occurred within the 21-day risk period after administration of any dose of vaccine or placebo, and one episode of intussusception occurred 114 days after the third dose of vaccine in the infant-schedule group., Conclusions: RV3-BB was efficacious in preventing severe rotavirus gastroenteritis when administered according to a neonatal or an infant schedule in Indonesia. (Funded by the Bill and Melinda Gates Foundation and others; Australian New Zealand Clinical Trials Registry number, ACTRN12612001282875 .).

Background: HIV-infected individuals have increased risk of developing obstructive lung disease (OLD). Studies from developed countries report high viral load, low CD4 counts, and anti-retroviral therapy (ART) to be associated with OLD; but these findings may not be generalizable to populations in resource-limited settings., Methods: We conducted a prospective cohort study of lung function in 730 HIV-infected black South African adults. Pre-bronchodilator spirometry was performed at enrollment and repeated annually for three years. Logistic regression models were used to identify factors associated with OLD, defined as FEV1/FVC<0.70, at enrollment. Excess annual declines in FEV1 and FVC were modelled as the product-term of follow-up time and exposures using random effects regression., Results: Median (IQR) age at enrollment was 36 (32-41) years, 85% were female and 30% ever-smoked with a median (IQR) exposure of 3 (1-6) pack-years. Median (IQR) CD4 count and viral load at enrollment were 372 (261-518) cells/mm3 and 2655 (91-13,548) copies/mL respectively. Overall, 25% were receiving ART at enrollment, 16% of whom reported at least 6 months of ART receipt. OLD was found in 35 (5%) at enrollment. Increasing age (aOR = 2.08 per 10-years [95%CI 1.22-3.57], p = 0.007), current smoking (aOR = 3.55 [95%CI 1.20-10.53], p = 0.02), and CRP (aOR = 1.01 per unit-increase [95%CI 1.00-1.03], p = 0.04) were significantly associated with OLD at enrollment; while increasing CD4 count (aOR = 1.02 per-100 cells/mm3 [95%CI 0.85-1.22], p = 0.82), viral load (aOR = 0.67 per log-increase [95%CI 0.43-1.10], p = 0.12) and receipt of ART (aOR = 0.57 [95%CI 0.18-1.75], p = 0.32) were not. The median (IQR) follow-up time was 18 (12-24) months. Participants with a history of tuberculosis (TB) had a 35 mL (95%CI 2-68, p = 0.03) and 57 mL (95%CI 19-96, p = 0.003) per year excess loss of FEV1 and FVC respectively., Conclusion: Prevalent OLD was associated with older age, current smoking and higher CRP levels, but not CD4 counts and ART, in HIV-infected South African adults. Better understanding of the long-term effects of TB, smoking and inflammation on lung function in HIV-infected populations is urgently needed.

In a direct dynamics simulation, the technologies of chemical dynamics and electronic structure theory are coupled so that the potential energy, gradient, and Hessian required from the simulation are obtained directly from the electronic structure theory. These simulations are extensively used to (1) interpret experimental results and understand the atomic-level dynamics of chemical reactions; (2) illustrate the ability of classical simulations to correctly interpret and predict chemical dynamics when quantum effects are expected to be unimportant; (3) obtain the correct classical dynamics predicted by an electronic structure theory; (4) determine a deeper understanding of when statistical theories are valid for predicting the mechanisms and rates of chemical reactions; and (5) discover new reaction pathways and chemical dynamics. Direct dynamics simulation studies are described for bimolecular S N 2 nucleophilic substitution, unimolecular decomposition, post-transition-state dynamics, mass spectrometry experiments, and semiclassical vibrational spectra. Also included are discussions of quantum effects, the accuracy of classical chemical dynamics simulation, and the methodology of direct dynamics.

Direct dynamics simulations, utilizing the RM1 semiempirical electronic structure theory, were performed to study the thermal dissociation of the doubly protonated tripeptide threonine-isoleucine-lysine ion, TIK(H + ) 2 , for temperatures of 1250-2500 K, corresponding to classical energies of 1778-3556 kJ/mol. The number of different fragmentation pathways increases with increase in temperature. At 1250 K there are only three fragmentation pathways, with one contributing 85% of the fragmentation. In contrast, at 2500 K, there are 61 pathways, and not one dominates. The same ion is often formed via different pathways, and at 2500 K there are only 14 m/z values for the product ions. The backbone and side-chain fragmentations occur by concerted reactions, with simultaneous proton transfer and bond rupture, and also by homolytic bond ruptures without proton transfer. For each temperature the TIK(H + ) 2 fragmentation probability versus time is exponential, in accord with the Rice-Ramsperger-Kassel-Marcus and transition state theories. Rate constants versus temperature were determined for two proton transfer and two bond rupture pathways. From Arrhenius plots activation energies E a and A-factors were determined for these pathways. They are 62-78 kJ/mol and (2-3) × 10 12 s -1 for the proton transfer pathways and 153-168 kJ/mol and (2-4) × 10 14 s -1 for the bond rupture pathways. For the bond rupture pathways, the product cation radicals undergo significant structural changes during the bond rupture as a result of hydrogen bonding, which lowers their entropies and also their E a and A parameters relative to those for C-C bond rupture pathways in hydrocarbon molecules. The E a values determined from the simulation Arrhenius plots are in very good agreement with the reaction barriers for the RM1 method used in the simulations. A preliminary simulation of TIK(H + ) 2 collision-induced dissociation (CID), at a collision energy of 13 eV (1255 kJ/mol), was also performed to compare with the thermal dissociation simulations. Though the energy transferred to TIK(H + ) 2 in the collisions is substantially less than the energy for the thermal excitations, there is substantial fragmentation as a result of the localized, nonrandom excitation by the collisions. CID results in different fragmentation pathways with a significant amount of short time nonstatistical fragmentation. Backbone fragmentation is less important, and side-chain fragmentation is more important for the CID simulations as compared to the thermal simulations. The thermal simulations provide information regarding the long-time statistical fragmentation.