Differences between bacteria and eukaryotes in clamp loader mechanism, a conserved process underlying DNA replication.

Clamp loaders are pentameric ATPases that place circular sliding clamps onto DNA, where they function in DNA replication and genome integrity. The central activity of a clamp loader is the opening of the ring-shaped sliding clamp and the subsequent binding to primer-template (p/t)-junctions. The general architecture of clamp loaders is conserved across all life, suggesting that their mechanism is retained. Recent structural studies of the eukaryotic clamp loader replication factor C (RFC) revealed that it functions using a crab-claw mechanism, where clamp opening is coupled to a massive conformational change in the loader. Here we investigate the clamp loading mechanism of the Escherichia coli clamp loader at high resolution using cryo-electron microscopy. We find that the E. coli clamp loader opens the clamp using a crab-claw motion at a single pivot point, whereas the eukaryotic RFC loader uses motions distributed across the complex. Furthermore, we find clamp opening occurs in multiple steps, starting with a partly open state with a spiral conformation, and proceeding to a wide open clamp in a surprising planar geometry. Finally, our structures in the presence of p/t-junctions illustrate how the clamp closes around p/t-junctions and how the clamp loader initiates release from the loaded clamp. Our results reveal mechanistic distinctions in a macromolecular machine that is conserved across all domains of life.

Executive function in individuals who are compliant and non-compliant with the conditions of a community-based sentence.

Executive function encompasses multiple processes (e.g. regulating emotions, managing behaviours, problem-solving) essential in daily living. A growing body of neuropsychological research shows a relationship between executive dysfunction and criminal behaviour. However, is executive functioning relevant to sentence management? We examined relationships between self-reported executive functioning and community supervision sentence compliance. Sixty-four individuals serving community-based supervision sentences completed the Behavior Rating Inventory of Executive Function-Adult Version, and their compliance data for six months were collected from probation officer notes. The sample's mean scores were significantly higher (i.e. poorer executive functioning) than those for the normative sample. Those who complied with sentence conditions had higher mean scores than those who were non-compliant. Subsequent exploratory analyses showed that those with poorer executive functioning received more probation officer support to comply with sentence conditions. Attention to responsivity issues like executive function problems may help avoid entrapping people in the criminal justice system.

Acceptability of Early Antiretroviral Therapy Among South African Women.

WHO guidelines recommend immediate initiation of antiretroviral therapy (ART) for all individuals at HIV diagnosis regardless of CD4 count, but concerns remain about potential low uptake or poor adherence among healthy patients with high CD4 counts, especially in resource-limited settings. This study assessed the acceptability of earlier treatment among HIV-positive South African women, median age at enrollment 25 (IQR 22-30), in a 10 year prospective cohort study by (i) describing temporal CD4 count trends at initiation in relation to WHO guidance, (ii) virological suppression rates post-ART initiation at different CD4 count thresholds, and (iii) administration of a standardized questionnaire. 158/232 (68.1%) participants initiated ART between 2006 and 2015. Mean CD4 count at initiation was 217 cells/µl (range 135-372) before 2010, and increased to 531 cells/µl (range 272-1095) by 2015 (p < 0.001). Median viral load at ART initiation decreased over this period from 5.2 (IQR 4.6-5.6) to 4.1 (IQR 3.4-4.6) log copies/ml (p = 0.004). Virological suppression rates at 3, 6, 12 and 18 months were consistently above 85% with no statistically significant differences for participants starting ART at different CD4 count thresholds. A questionnaire assessing uptake of early ART amongst ART-naïve women, median age 28 (IQR 24-33), revealed that 40/51 (78.4%) were willing to start ART at CD4 ≥500. Of those unwilling, 6/11 (54.5%) started ART within 6 months of questionnaire administration. Temporal increases in CD4 counts, comparable virological suppression rates, and positive patient perceptions confirm high acceptability of earlier ART initiation for the majority of patients.

The association between self-reported traumatic brain injury, neuropsychological function, and compliance among people serving community sentences.

BACKGROUND: Traumatic brain injury is overrepresented in incarcerated samples and has been linked to a number of poor correctional outcomes. Despite this, no research has explored the impact of a recent TBI on compliance outcomes for individuals serving community-based. METHOD: We screened for a history of TBI in 106 adults on community sentences and collected compliance (arrests, sentence violations) and related variables (e.g., risk scores, substance use) over 6 months. Sixty-four participants also completed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Comprehensive Trail Making Test and Color-Word Inference Test. RESULTS: A TBI in the last year predicted a significantly higher likelihood of arrest, even when controlling for risk of reconviction and current substance use, but was not associated with non-compliance with sentence conditions nor with performance on the neuropsychological tests. In addition, no significant associations were found between performance on neuropsychological tests and measures of non-compliance. CONCLUSIONS: TBI in the last year was an independent predictor of arrest. This result suggests that those with a recent TBI on a community sentence may need additional monitoring or support to reduce the risk of reoffending.

Differences in clamp loader mechanism between bacteria and eukaryotes.

Clamp loaders are pentameric ATPases that place circular sliding clamps onto DNA, where they function in DNA replication and genome integrity. The central activity of a clamp loader is the opening of the ring-shaped sliding clamp, and the subsequent binding to primer-template (p/t)-junctions. The general architecture of clamp loaders is conserved across all life, suggesting that their mechanism is retained. Recent structural studies of the eukaryotic clamp loader Replication Factor C (RFC) revealed that it functions using a crab-claw mechanism, where clamp opening is coupled to a massive conformational change in the loader. Here we investigate the clamp loading mechanism of the E. coli clamp loader at high resolution using cryo-electron microscopy (cryo-EM). We find that the E. coli clamp loader opens the clamp using a crab-claw motion at a single pivot point, whereas the eukaryotic RFC loader uses motions distributed across the complex. Furthermore, we find clamp opening occurs in multiple steps, starting with a partly open state with a spiral conformation, and proceeding to a wide open clamp in a surprising planar geometry. Finally, our structures in the presence of p/t-junctions illustrate how clamp closes around p/t-junctions and how the clamp loader initiates release from the loaded clamp. Our results reveal mechanistic distinctions in a macromolecular machine that is conserved across all domains of life.

TIR-1/SARM1 inhibits axon regeneration and promotes axon degeneration.

Growth and destruction are central components of the neuronal injury response. Injured axons that are capable of repair, including axons in the mammalian peripheral nervous system and in many invertebrate animals, often regenerate and degenerate on either side of the injury. Here we show that TIR-1/dSarm/SARM1, a key regulator of axon degeneration, also inhibits regeneration of injured motor axons. The increased regeneration in tir-1 mutants is not a secondary consequence of its effects on degeneration, nor is it determined by the NADase activity of TIR-1. Rather, we found that TIR-1 functions cell-autonomously to regulate each of the seemingly opposite processes through distinct interactions with two MAP kinase pathways. On one side of the injury, TIR-1 inhibits axon regeneration by activating the NSY-1/ASK1 MAPK signaling cascade, while on the other side of the injury, TIR-1 simultaneously promotes axon degeneration by interacting with the DLK-1 mitogen-activated protein kinase (MAPK) signaling cascade. In parallel, we found that the ability to cell-intrinsically inhibit axon regeneration is conserved in human SARM1. Our finding that TIR-1/SARM1 regulates axon regeneration provides critical insight into how axons coordinate a multidimensional response to injury, consequently informing approaches to manipulate the response toward repair.

Return to Sport Using Corticosteroid Injections for Knee Pain in Triathletes.

Introduction Despite the prevalence of corticosteroid injections in athletes, little is known about their efficacy in triathletes. We aim to assess attitudes, use, subjective effectiveness, and time to return to sport with corticosteroid injections compared to alternative methods in triathletes with knee pain. Methods This is an observational study during the COVID-19 pandemic. Triathletes answered a 13-question survey posted to three triathlon-specific websites. Results Sixty-one triathletes responded, 97% of whom experienced knee pain at some point in their triathlete career; 63% with knee pain received a corticosteroid injection as treatment (average age 51 years old). The most popular attitude (44.3%) regarding corticosteroid injections was "tried them, with good improvement". Most found the cortisone injection helpful for two to three months (28.6%), or more than one year (28.6%); of individuals who found the injections useful for more than one year, four-eight (50%) had received multiple injections during that same period. After injection, 80.6% returned to sport within one month. The average age of people using alternative treatment methods was 39 years old; most returned to sport within one month (73.7%). Compared to alternative methods, there was an ~80% higher odds of returning to sport within one month using corticosteroid injections; however, this relationship was not significant (OR=1.786, p=0.480, 95% CI:0.448-7.09). Conclusion This is the first study to examine corticosteroid use in triathletes. Corticosteroid use is more common in older triathletes and results in subjective pain improvement. A strong association does not exist for a quicker return to sport using corticosteroid injections compared to alternative methods. Triathletes should be counseled on the timing of injections, duration of side effects, and be aware of potential risks.

Parental Programming of Offspring Health: The Intricate Interplay between Diet, Environment, Reproduction and Development.

As adults, our health can be influenced by a range of lifestyle and environmental factors, increasing the risk for developing a series of non-communicable diseases such as type 2 diabetes, heart disease and obesity. Over the past few decades, our understanding of how our adult health can be shaped by events occurring before birth has developed into a well-supported concept, the Developmental Origins of Health and Disease (DOHaD). Supported by epidemiological data and experimental studies, specific mechanisms have been defined linking environmental perturbations, disrupted fetal and neonatal development and adult ill-health. Originally, such studies focused on the significance of poor maternal health during pregnancy. However, the role of the father in directing the development and well-being of his offspring has come into recent focus. Whereas these studies identify the individual role of each parent in shaping the long-term health of their offspring, few studies have explored the combined influences of both parents on offspring well-being. Such understanding is necessary as parental influences on offspring development extend beyond the direct genetic contributions from the sperm and oocyte. This article reviews our current understanding of the parental contribution to offspring health, exploring some of the mechanisms linking parental well-being with gamete quality, embryo development and offspring health.

Integrins Have Cell-Type-Specific Roles in the Development of Motor Neuron Connectivity.

Formation of the nervous system requires a complex series of events including proper extension and guidance of neuronal axons and dendrites. Here we investigate the requirement for integrins, a class of transmembrane cell adhesion receptors, in regulating these processes across classes of C. elegans motor neurons. We show α integrin/ina-1 is expressed by both GABAergic and cholinergic motor neurons. Despite this, our analysis of hypomorphic ina-1(gm144) mutants indicates preferential involvement of α integrin/ina-1 in GABAergic commissural development, without obvious involvement in cholinergic commissural development. The defects in GABAergic commissures of ina-1(gm144) mutants included both premature termination and guidance errors and were reversed by expression of wild type ina-1 under control of the native ina-1 promoter. Our results also show that α integrin/ina-1 is important for proper outgrowth and guidance of commissures from both embryonic and post-embryonic born GABAergic motor neurons, indicating an ongoing requirement for integrin through two phases of GABAergic neuron development. Our findings provide insights into neuron-specific roles for integrin that would not be predicted based solely upon expression analysis.

Beyond syndromic management: Opportunities for diagnosis-based treatment of sexually transmitted infections in low- and middle-income countries.

INTRODUCTION: In light of the limited impact the syndromic management approach has had on the global sexually transmitted infection (STI) epidemic, we assessed a care model comprising point-of-care (POC) STI testing, immediate treatment, and expedited partner therapy (EPT) among a cohort of young women at high HIV risk in South Africa. METHODS AND FINDINGS: HIV negative women presenting for STI care underwent POC testing for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV), and swabs were sent for NG culture and susceptibility testing. Results were available within 2 hours and women with STIs were immediately treated and offered EPT packs, including medication, condoms, and information for sexual partners. An EPT questionnaire was administered after one week, and women retested for STIs after 6 and 12 weeks. 267 women, median age 23 (IQR 21-26), were recruited and 88.4% (236/267) reported genital symptoms. STI prevalence was CT 18.4% (95%CI 13.7-23.0), NG 5.2% (95%CI 2.6-7.9) and TV 3.0% (95%CI 1.0-5.0). After 12 weeks, all but one NG and two CT infections were cleared. No cephalosporin-resistant NG was detected. Of 63/267 women (23.6%) diagnosed with STIs, 98.4% (62/63) were offered and 87.1% (54/62) accepted EPT. At one week 88.9% (48/54) stated that their partner had taken the medication. No allergic reactions or social harms were reported. Of 51 women completing 6-week follow up, detection rates were lower amongst women receiving EPT (2.2%, 1/46) compared to those who did not (40.0%, 2/5), p = 0.023. During focus group discussions women supported the care model, because they received a rapid, specific diagnosis, and could facilitate their partners' treatment. CONCLUSIONS: POC STI testing and EPT were acceptable to young South African women and their partners, and could play an important role in reducing STI reinfection rates and HIV risk. Larger studies should evaluate the feasibility and cost-effectiveness of implementing this strategy at population level.

Gnathodiaphyseal dysplasia.

Gnathodiaphyseal dysplasia (GDD) is an orthopedic condition involving cemento-osseous lesions of jaw bones, sclerosis, bowing of tubular bones, and overall bone fragility. This is a case report of GDD in which an 18-year-old female presented with a several-year history of bony abnormalities of the jaw and long bones. Radiographs demonstrated endosteal thickening, bowing of long bones, and abnormalities of the skull. These findings, along with the patient's known maxillary region cementoma, led to a diagnosis of GDD.

Primary contact physiotherapy in emergency departments can reduce length of stay for patients with peripheral musculoskeletal injuries compared with secondary contact physiotherapy: a prospective non-randomised controlled trial.

OBJECTIVE: To evaluate if direct physiotherapy assessment and management of patients presenting to emergency departments with musculoskeletal injuries (primary contact physiotherapy) results in reduced length of stay without any increase in adverse effects compared with secondary contact physiotherapy, where patients are seen by a physiotherapist after initial assessment by a doctor. DESIGN: Prospective non-randomised controlled trial. SETTING: Three metropolitan emergency departments. PARTICIPANTS: Adults (n=315) presenting to emergency departments with peripheral musculoskeletal injuries were allocated to primary or secondary contact physiotherapy; 306 participants completed the study. Patients with serious pathology, open fractures and spinal pain were excluded. INTERVENTION: A single episode of physiotherapy. MAIN OUTCOME MEASURES: Primary outcome measures were patient length of stay, waiting time and treatment time. Secondary outcome measures were re-presentations to the emergency department, imaging referrals, patient satisfaction and emergency department staff acceptance. RESULTS: Primary contact physiotherapy resulted in a reduction in length of stay of 59.5 minutes [95% confidence interval (CI) 38.4 to 80.6] compared with secondary contact physiotherapy, with a reduced waiting time of 25.0 minutes (95%CI 12.1 to 38.0) and a reduced treatment time of 34.9 minutes (95%CI 16.2 to 53.6). There were no differences between the groups in imaging referrals or re-presentations. Patients strongly agreed (≥82%) that they were satisfied with their management, and 96% of emergency department staff agreed that primary contact physiotherapists had appropriate skills and knowledge to provide emergency care. CONCLUSION: Experienced musculoskeletal physiotherapists working in emergency departments can be the first point of contact for patients with simple, semi-urgent and non-urgent peripheral musculoskeletal injuries, resulting in decreased waiting times and length of stay for patients without any adverse effects.

An exercise and education program improves well-being of new mothers: a randomized controlled trial.

OBJECTIVE: The purpose of this study was to evaluate the effect of a physical therapy exercise and health care education program on the psychological well-being of new mothers. DESIGN: This was a randomized controlled trial. PARTICIPANTS: Primiparous and multiparous English-speaking women ready for discharge from The Angliss Hospital postnatal ward were eligible for this study. Women who were receiving psychiatric care were excluded. One hundred sixty-one women were randomized into the trial. INTERVENTION: The experimental group (n=62) received an 8-week "Mother and Baby" (M&B) program, including specialized exercise provided by a women's health physical therapist combined with parenting education. The other group (education only [EO], n=73) received only the same educational material as the experimental group. MAIN OUTCOME MEASURES: Psychological well-being (Positive Affect Balance Scale), depressive symptoms (Edinburgh Postnatal Depression Scale), and physical activity levels were assessed at baseline, after 8 weeks (post-program), and then 4 weeks later. RESULTS: There was significant improvement in well-being scores and depressive symptoms of the M&B group compared with the EO group over the study period. More specifically, there was a significant positive effect on well-being scores and depressive symptoms at 8 weeks, and this effect was maintained 4 weeks after completion of the program. The number of women identified as "at risk" for postnatal depression pre-intervention was reduced by 50% by the end of the intervention. LIMITATIONS: Although this study provides promising short-term (4-week) outcomes, further work is needed to explore whether the intervention effects are maintained as sustained psychological and behavioral benefits at 6 months. CONCLUSIONS: A physical therapy exercise and health education program is effective in improving postnatal well-being. Routine use of this program may reduce longer-term problems such as postnatal depression.

Intervertebral disk cyst: a case report.

This case describes a patient who presented with chronic low back pain which developed over the course of 1 year. Imaging revealed a 1.1-cm cystic lesion at the L4-L5 vertebral level posterior to the intervertebral disk. Following both magnetic resonance and computed tomography imaging, diagnosis of intervertebral disk cyst was confirmed by both imaging modalities. A computed tomography-guided aspiration of the lesion was performed, and the patient was given a course of steroid injections with complete resolution of the lesion.

Effect of a consultation teaching behaviour modification on sleep performance in infants: a randomised controlled trial.

OBJECTIVE: To evaluate the effect of a behaviour modification program, taught to parents in a single visit to a trained nurse, in improving sleep performance in newborn infants, Australia. DESIGN: Randomised controlled trial. SETTING AND PARTICIPANTS: 268 families with normal newborn infants in the community, recruited between October 1996 and March 1997 from birth notices published in a South Australian daily newspaper. INTERVENTION: A 45-minute consultation with a nurse 2-3 weeks after the birth, including a tutorial discussion on normal sleep patterns in newborn infants, supported by retained written material and, for infants with weight gain < 30 g daily, referral to their usual postnatal care provider. MAIN OUTCOME MEASURES: Hours of daytime sleep (0600-1800), night sleep (1800-0600) and total sleep per 24 h; and number of daily records with total sleep >/= 15 h per 24 h, assessed by 7-day sleep diary at ages 6 and 12 weeks. RESULTS: 268 families returned at least one sleep diary (137/171 intervention, 131/175 control), recording 3273 days. Two intervention infants were referred for low weight gain. Total sleep time was 15 h or more per 24 h on 62% of recorded days in the intervention group, compared with 36% in the control group (P < 0.001). At 6 weeks of age, intervention infants slept a mean 1.3 h per day more than control infants (95% CI, 0.95-1.65), comprising a mean 0.5 h more night sleep (95% CI, 0.32-0.69) and 0.8 h more daytime sleep (95% CI, 0.56-1.07). At 12 weeks, intervention infants slept a mean 1.2 h per day more (95% CI, 0.94-2.14), comprising 0.64 h more night sleep (95% CI, 0.19-0.89) and 0.58 h more daytime sleep (95% CI, 0.39-1.03). There was no significant difference in crying time between the groups. CONCLUSIONS: A single consultation supported by written material in the first 3 weeks of a child's life improves sleep performance at 6 weeks of age. This improvement is maintained at 3 months.