Real-world use of long-acting cabotegravir and rilpivirine: 12-month results of the inJectable Antiretroviral therapy feasiBility Study (JABS).

OBJECTIVES: The inJectable Antiretroviral feasiBility Study (JABS) aimed to evaluate the implementation of long-acting regimens in a 'real world' Australian setting, with inclusion of participants with complex medical needs, social vulnerability and/or historical non-adherence. METHODS: JABS was a 12-month, single-centre, single-arm, open-label phase IV study of long-acting cabotegravir 600 mg plus rilpivirine 900 mg administered intramuscularly every 2 months to adults with treated HIV-1 infection. The primary endpoint was the proportion of attendances and administration of injections within a 14-day dosing window over 12 months, out of the total prescribed doses. Secondary endpoints included proportions of missed appointments, use of oral bridging, discontinuations, virological failures, adverse events and participant-reported outcomes. A multidisciplinary adherence programme embedded in the clinical service known as REACH provided support to JABS participants. RESULTS: Of 60 participants enrolled by May 2022, 60% had one or more complexity or vulnerability factors identified, including absence of social supports (50%), mental health issues, alcohol or drug use (30%) and financial hardship or instability (13%), among others. Twenty-seven per cent of participants had historical non-adherence to antiretroviral therapy. Out of 395 prescribed doses, 97.2% of injections were administered within correct dosing windows at clinic visits. Two courses of short-term oral bridging were required. The rate of injection site reactions was 29%, the majority being grade 1-2. There were no virological failures, no serious adverse events and only one injection-related study discontinuation. High baseline treatment satisfaction and acceptability of injections increased by month 12. Those with vulnerability factors had similar adherence to injections as those without such factors. Ninety-eight per cent of the participants who completed 12 months on the study have maintained long-acting therapy, virological suppression and retention in care. CONCLUSIONS: Long-acting cabotegravir plus rilpivirine was associated with very high adherence, maintenance of virological suppression, safety and treatment satisfaction in a diverse Australian clinic population, comparable to results of phase III randomized clinical trials. Individuals with vulnerability factors can achieve adherence to injections with individualized support. Long-acting therapies in this group can increase the subsequent engagement in clinical care.

Size-Controlled and Shelf-Stable DNA Particles for Production of Lentiviral Vectors.

Polyelectrolyte complex particles assembled from plasmid DNA (pDNA) and poly(ethylenimine) (PEI) have been widely used to produce lentiviral vectors (LVVs) for gene therapy. The current batch-mode preparation for pDNA/PEI particles presents limited reproducibility in large-scale LVV manufacturing processes, leading to challenges in tightly controlling particle stability, transfection outcomes, and LVV production yield. Here we identified the size of pDNA/PEI particles as a key determinant for a high transfection efficiency with an optimal size of 400-500 nm, due to a cellular-uptake-related mechanism. We developed a kinetics-based approach to assemble size-controlled and shelf-stable particles using preassembled nanoparticles as building blocks and demonstrated production scalability on a scale of at least 100 mL. The preservation of colloidal stability and transfection efficiency was benchmarked against particles generated using an industry standard protocol. This particle manufacturing method effectively streamlines the viral manufacturing process and improves the production quality and consistency.

Adaptable transmitter for discrete and continuous variable quantum key distribution.

We present a versatile transmitter capable of performing both discrete variable and continuous variable quantum key distribution protocols (DV-QKD and CV-QKD, respectively). Using this transmitter, we implement a time-bin encoded BB84 DV-QKD protocol over a physical quantum channel of 47 km and a GG02 CV-QKD protocol with true local oscillator over a 10.5 km channel, achieving secret key rates of 4.1 kbps and 1 Mbps for DV- and CV-QKD, respectively. The reported transmitter scheme is particularly suitable for re-configurable optical networks where the QKD protocol is selected to optimize the performance according to the parameters of the links.

Technical note: Evaluation of a commercial on-farm milk leukocyte differential tester to identify subclinical mastitis cases in dairy cows.

The objective of this study was to validate the precision and accuracy of a milk leukocyte differential tester to identify subclinical mastitis cases in dairy cows. Milk samples from individual quarters (n = 320) of 80 Holstein cows were aseptically collected and analyzed in this study. Each sample was divided into 2 replicate samples after mixing. One replicate was analyzed for somatic cell count (SCC) using the current gold standard of flow cytometry immediately after milking. The second sample was evaluated using the on-farm milk leukocyte differential tester directly after milking, where total leukocyte count (TLC; cells/mL) was obtained. The SCC and TLC were used to calculate somatic cell score (SCS) and TLC score [TLS = log2 (TLC/100,000) + 3]. Two subclinical mastitis thresholds were set: >200,000 (low) and >400,000 (high) cells/mL. First, precision was determined between the 2 methods. Total leukocyte count and calculated TLS from the milk leukocyte differential device were compared with the gold standard using correlation and regression coefficient of determination analyses. Correlation coefficients (r) were 0.97 for TLC and SCC and 0.90 for TLS and SCS. The coefficient of determination for regression (R2) was 0.94 for TLC and SCC and 0.80 for TLS and SCS. Slopes of regression for scores and measures were 0.36 [95% confidence interval (CI): 0.35-0.37] and 0.69 (CI: 0.65-0.73), respectively; both were significantly different from 1. Sensitivity, specificity, and diagnostic accuracy were calculated for correct diagnosis of the 2 SCC thresholds using the gold standard as reference. The sensitivity of the on-farm test was 58% (95% CI: 44 to 71%) and 73% (95% CI: 56 to 86%) for the low and high thresholds, respectively. The specificities for the on-farm test were 100% (95% CI: 99 to 100%) and 100% (95% CI: 98 to 100%) for the low and high thresholds, respectively. Subclinical diagnosis accuracies were 93% (95% CI: 89 to 95%) and 96% (95% CI: 92 to 98%) for the low and high thresholds, respectively. The on-farm milk leukocyte differential tester was precise but not overall accurate for total cell counts; it had high specificity and accuracy for diagnosis compared with a standard diagnostic tool. These results suggest that the tested system is a promising technology to detect subclinical mastitis on-farm.

Pro-Oxidative and Proinflammatory Effects After Traveling From Los Angeles to Beijing: A Biomarker-Based Natural Experiment.

BACKGROUND: Exposure to air pollution increases cardiovascular morbidity and mortality. Preventing chronic cardiovascular diseases caused by air pollution relies on detecting the early effects of pollutants on the risk of cardiovascular disease development, which is limited by the lack of sensitive biomarkers. We have previously identified promising biomarkers in experimental animals but comparable evidence in humans is lacking. METHODS: Air pollution is substantially worse in Beijing than in Los Angeles. We collected urine and blood samples from 26 nonsmoking, healthy adult residents of Los Angeles (mean age, 23.8 years; 14 women) before, during, and after spending 10 weeks in Beijing during the summers of 2014 and 2015. We assessed a panel of circulating biomarkers indicative of lipid peroxidation and inflammation. Personal exposure to polycyclic aromatic hydrocarbons (PAHs), a group of combustion-originated air pollutants, was assessed by urinary PAH metabolite levels. RESULTS: Urinary concentrations of 4 PAH metabolites were 176% (95% CI, 103% to 276%) to 800% (95% CI, 509% to 1780%) greater in Beijing than in Los Angeles. Concentrations of 6 lipid peroxidation biomarkers were also increased in Beijing, among which 5-, 12-, and 15-hydroxyeicosatetraenoic acid and 9- and 13-hydroxyoctadecadienoic acid levels reached statistical significance (false discovery rate <5%), but not 8-isoprostane (20.8%; 95% CI, -5.0% to 53.6%). The antioxidative activities of paraoxonase (-9.8%; 95% CI, -14.0% to -5.3%) and arylesterase (-14.5%; 95% CI, -22.3% to -5.8%) were lower and proinflammatory C-reactive protein (101%; 95% CI, 3.3% to 291%) and fibrinogen (48.3%; 95% CI, 4.9% to 110%) concentrations were higher in Beijing. Changes in all these biomarkers were reversed, at least partially, after study participants returned to Los Angeles. Changes in most outcomes were associated with urinary PAH metabolites (P<0.05). CONCLUSIONS: Traveling from a less-polluted to a more-polluted city induces systemic pro-oxidative and proinflammatory effects. Changes in the levels of 5-, 12-, and 15-hydroxyeicosatetraenoic acid and 9- and 13-hydroxyoctadecadienoic acid as well as paraoxonase and arylesterase activities in the blood, in association with exposures to PAH metabolites, might have important implications in preventive medicine as indicators of increased cardiovascular risk caused by air pollution exposure.

Comparing dairy farm milk yield and components, somatic cell score, and reproductive performance among United States regions using summer to winter ratios.

Heat stress abatement is a challenge for dairy producers in the United States, especially in the southern states. Thus, managing heat stress is critical to maintain dairy cow performance in the summer. The ability to employ a metric to measure heat stress and evaluate abatement strategies may benefit dairy producers by providing meaningful feedback on the effectiveness of current and future management strategies with the goal of improving heat stress management. Therefore, this study aimed to explore the use of the summer to winter performance ratio metric to quantify and compare farm performance variables among regions of the United States. Monthly performance data recorded by the Dairy Herd Improvement Association from 2007 to 2016, for all US Dairy Herd Improvement Association herds processing records through Dairy Records Management Systems (Raleigh, NC), were obtained. Season dates were based on the astronomical definition of the Northern Hemisphere with summer as June 21 to September 21 and winter as December 21 to March 19. States were grouped into regions based on climate zone classification. Performance records included a total of 16,573 herds [Northeast (n = 7,955), Midwest (n = 6,555), Northern Plains (n = 305), Southeast (n = 1,370), and Southern Plains (n = 388) regions]. Herd test day performance variables energy-corrected milk, somatic cell score, milk fat and protein percentage, conception rate, heat detection rate, and pregnancy rate in summer and winter were used to calculate summer to winter ratios for each region. The MIXED procedure of SAS 9.4 (SAS Institute Inc., Cary, NC) was used to compare test day performance variables. The effects of year, mean days in milk, mean 150-d milk, mean herd size, and number of milkings per day were included as covariates in the models. Dairy cattle performance in all climate regions was negatively affected by summer heat stress, but some regions greater than others. A difference was also observed among regions when comparing summer to winter ratios for each performance parameter. This indicates that summer performance varies by climate region identified by the summer to winter ratio and demonstrates usefulness of the metric to monitor degree of heat stress based on performance.

Novel Surgical and Radiologic Risk Factors for Progression or Recurrence of Pediatric Pilocytic Astrocytoma.

INTRODUCTION: Pilocytic astrocytomas (PA) are a common, benign childhood tumor known for their slow growth rates and excellent prognosis. The aim of our study was to characterize patient, tumor, and imaging-related risk factors for recurrence and progression of disease. METHODS: We identified 116 patients with PA who underwent surgery at our institution between 2000 and 2015. Data were collected retrospectively from the clinical charts. RESULTS: The mean age at resection was 7 ± 5 years (range 0.5-31) and mean follow-up was 6 ± 3 years. Initial resection was complete in 33 patients (29%), subtotal in 78 patients (67%), and biopsy in 5 patients (4%). A total of 45/116 (40%) patients experienced either recurrence or progression after initial resection with a mean time to recurrence or progression of 2.2 years. Bivariate analysis identified subtotal resection, tumor location, age at diagnosis, and imaging features (i.e., T2 invasion, exophytic component, hemorrhage, and solid tumors) as factors significantly associated with recurrence or progression (p < 0.05). Conversely, PAs that were completely resected, predominately cystic, and located in the cerebellum were significantly associated with no recurrence or progression (p < 0.05). Multivariate regression analysis narrowed down 4 robust risk factors: extent of resection, T2 invasion, predominantly solid lesions, and presence of an exophytic component (p < 0.05). CONCLUSION: Total surgical removal of PA has been the most important prognostic factor for the clinical course of PA. Our study reveals additional risk factors for the recurrence or progression of disease: tumor invasion, solid composition, and tumors with an exophytic component.

Sigma-1 receptor ligands inhibit catecholamine secretion from adrenal chromaffin cells due to block of nicotinic acetylcholine receptors.

Adrenal chromaffin cells (ACCs) are the neuroendocrine arm of the sympathetic nervous system and key mediators of the physiological stress response. Acetylcholine (ACh) released from preganglionic splanchnic nerves activates nicotinic acetylcholine receptors (nAChRs) on chromaffin cells causing membrane depolarization, opening voltage-gated Ca2+ channels (VGCC), and exocytosis of catecholamines and neuropeptides. The serotonin transporter is expressed in ACCs and interacts with 5-HT1A receptors to control secretion. In addition to blocking the serotonin transporter, some selective serotonin reuptake inhibitors (SSRIs) are also agonists at sigma-1 receptors which function as intracellular chaperone proteins and can translocate to the plasma membrane to modulate ion channels. Therefore, we investigated whether SSRIs and other sigma-1 receptor ligands can modulate stimulus-secretion coupling in ACCs. Escitalopram and fluvoxamine (100 nM to 1 µM) reversibly inhibited nAChR currents. The sigma-1 receptor antagonists NE-100 and BD-1047 also blocked nAChR currents (≈ 50% block at 100 nM) as did PRE-084, a sigma-1 receptor agonist. Block of nAChR currents by fluvoxamine and NE-100 was not additive suggesting a common site of action. VGCC currents were unaffected by the drugs. Neither the increase in cytosolic [Ca2+ ] nor the resulting catecholamine secretion evoked by direct membrane depolarization to bypass nAChRs was altered by fluvoxamine or NE-100. However, both Ca2+ entry and catecholamine secretion evoked by the cholinergic agonist carbachol were significantly reduced by fluvoxamine or NE-100. Together, our data suggest that sigma-1 receptors do not acutely regulate catecholamine secretion. Rather, SSRIs and other sigma-1 receptor ligands inhibit secretion evoked by cholinergic stimulation because of direct block of Ca2+ entry via nAChRs.

Circulating immune cells in multiple sclerosis.

Circulating T and B lymphocytes contribute to the pathogenesis of the neuroinflammatory autoimmune disease, multiple sclerosis (MS). Further progress in the development of MS treatments is dependent upon a greater understanding of the immunological disturbances that underlie the disease. Analyses of circulating immune cells by flow cytometry have revealed MS-associated alterations in the composition and function of T and B cell subsets, including temporal changes associated with disease activity. Disturbances in circulating immune populations reflect those observed in the central nervous system and include skewing towards proinflammatory CD4+ and CD8+ T cells and B cells, greater proportions of follicular T helper cells and functional defects in the corresponding T and B regulatory subsets. Utilizing the analytical power of modern flow cytometers, researchers are now well positioned to monitor immunological changes associated with disease activity or intervention, describe immunological signatures with predictive value and identify targets for therapeutic drug development. This review discusses the contribution of various T and B lymphocyte subsets to MS pathogenesis, provides current and relevant phenotypical descriptions to assist in experimental design and highlights areas of future research.

Determinants of residual viraemia during combination HIV treatment: Impacts of baseline HIV RNA levels and treatment choice.

OBJECTIVES: Effective HIV therapy reflects suppression of plasma HIV RNA levels below assay detection thresholds, although lower levels of "residual viraemia" have also been demonstrated over extended periods of effective antiretroviral treatment. Here we examine the determinants of HIV RNA suppression below the standard assay threshold (40 HIV-1 RNA copies/mL) as well as factors associated with detectable HIV RNA below this reported detection limit. METHODS: Between 2007 and 2010, 11 575 consecutive viral load (VL) tests were obtained from 1540 patients, including 356 on effective antiretroviral therapy followed since initiation (1996-2001: n = 165; 2002-2009: n = 191). Analyses modelled the probability of an undetectable VL given successful suppression to < 200 copies/mL, and the probability of residual viraemia given an undetectable result. RESULTS: Detectable HIV RNA amplification was demonstrated in 20% of samples with a VL result < 40 copies/mL. Longitudinal analyses from 356 patients revealed that the likelihood of achieving results < 40 copies/mL was increased with current nonnucleoside reverse transcriptase inhibitor (NNRTI) therapy [odds ratio (OR) 2.0; P < 0.05] and reduced with prior virological rebound (OR 0.5; P < 0.05). In contrast, the presence of detectable HIV RNA < 40 copies/mL was strongly associated with pretreatment HIV RNA levels among those on current protease inhibitor (PI) treatment (OR 1.5 per log10 copies/mL increase; P = 0.02) as well as those on NNRTIs (OR 1.7; P = 0.002). CONCLUSIONS: While HIV treatment history was associated with plasma HIV RNA levels below the detection limit, residual viraemia results were dominantly determined by pretreatment VL. These findings support the concept of a stable, long-lived reservoir of latently infected cells as a source of residual viraemia despite effective HIV treatment.

Detection and characterization of viruses of the genus Megalocytivirus in ornamental fish imported into an Australian border quarantine premises: an emerging risk to national biosecurity.

This report documents an emerging trend of identification of Megalocytivirus-like inclusions in a range of ornamental fish species intercepted during quarantine detention at the Australian border. From September 2012 to February 2013, 5 species of fish that had suffered mortality levels in excess of 25% whilst in the post-entry quarantine and had Megalocytivirus-like inclusion bodies in histological sections were examined by PCR. The fish had been imported from Singapore, Malaysia and Sri Lanka. Ninety-seven of 111 individual fish from affected tanks of fish tested were positive for the presence of Megalocytivirus by PCR. Sequence analysis of representative PCR products revealed an identical sequence of 621 bp in all cases which was identical to a previously characterized Megalocytivirus (Sabah/RAA1/2012 strain BMGIV48). Phylogenetic analysis of available Megalocytivirus major capsid protein (MCP) sequences confirmed the existence of 3 major clades of Megalocytivirus. The virus detected in this study was identified as a member of Genotype II. The broad host range and pathogenicity of megalocytiviruses, coupled to the documented spread of ornamental fish into the environment, render this a significant and emerging biosecurity threat to Australia.

Combining HLA-DR risk alleles and anti-Epstein-Barr virus antibody profiles to stratify multiple sclerosis risk.

BACKGROUND: Risk factors for multiple sclerosis (MS) include human leukocyte antigen (HLA)-DR and Epstein-Barr virus (EBV)-specific antibody responses, including an epitope within EBV nuclear antigen 1 (EBNA-1) that is of recent interest. OBJECTIVE: The objective of this paper is to assess case-control associations between MS risk and anti-EBV antibody levels as well as HLA-DR profiles, gender and age in a population-based cohort. METHODS: Serological responses to EBV were measured in 426 MS patients and 186 healthy controls. HLA-DR typing was performed using sequence-based methods. RESULTS: MS patients had significantly higher levels of antibodies against epitope-specific and polyspecific EBNA-1 and viral capsid antigen (VCA), compared with controls (all p < 10(-15)). In regression analyses, anti-EBNA-1 and anti-VCA antibody levels, protective HLA-DR*04/07/09 alleles and gender (all p < 0.003) contributed independently to a model that classified cases and controls with an odds ratio > 20 (sensitivity 92%, specificity 64%). Notably, the strong influence of high-risk HLA-DR alleles was abrogated after inclusion of EBV serology results. CONCLUSIONS: The ability to discriminate MS cases and controls can be substantially enhanced by including anti-EBV serology as well as HLA-DR risk profiles. These findings support the relevance of EBV-specific immunity in MS pathogenesis, and implicate both HLA-dependent and HLA-independent immune responses against EBNA-1 as prominent disease risk factors.

The use of quantitative clinical pharmacology approaches to support moxidectin dosing recommendations in lactation.

Moxidectin is approved by the US Food and Drug Administration (US FDA) for the treatment of onchocerciasis (river-blindness) due to Onchocerca volvulus in patients aged 12 years and older. In onchocerciasis-endemic areas, mass drug administration (MDA) programs with ivermectin, with or without vector control, aim to control the disease, reduce morbidity, interrupt transmission, and more recently, achieve elimination. Moxidectin has the potential to be used in MDA programs. In countries where onchocerciasis is endemic, infants are often breastfed up to the age of 2 years, suggesting that some women are likely to be lactating during such periodic MDA programs. Quantitative analyses of non-clinical and clinical data using non-compartmental analysis and population based pharmacokinetic (popPK) modeling as well as physiologically based pharmacokinetic modeling (PBPK) were performed to determine the amount of moxidectin excreted in breast milk and subsequent exposures in the infant. The results of the analyses were similar. Concentrations of moxidectin in breast milk followed a similar pattern to those in plasma, with maximum concentrations occurring approximately 4 hours after dosing followed by a rapid decline in both breast milk and plasma. As early as two days after dosing, concentrations of moxidectin in breast milk were below the threshold for acceptable daily intake levels established by the European Medicines Agency (EMA) and FDA for secondary exposures from veterinary use, and below the WHO recommended relative infant dose (RID) safety threshold. The analyses were conducted to support prescribers and policy makers on dosing recommendations for moxidectin in lactation.

Primary Care Considerations for the Adolescent Wrestler.

PURPOSE OF REVIEW: Adolescent wrestlers undergo intense physical combat. While guidelines are effective in keeping the sport safer, concerns specific to the adolescent wrestler may be missed at primary care visits without knowledge of the unique challenges faced by these athletes. The following review highlights important characteristics of the adolescent wrestler which are of interest to primary care providers. RECENT FINDINGS: Recommendations for concussion management are evolving to gradual return-to-sport after physician clearance rather than total sport removal. Prolonged skin-to-skin contact also places athletes at greater risk of dermatologic infections, which often require removal from competition, treatment, and/or coverage. Finally, adolescent nutritional literature recommends limiting pre-match weight loss to 3-5% body weight due to noted kidney damage that may result from larger deficits. Adolescent wrestlers are more prone to acute injuries than chronic overuse injuries, with most injuries occurring above the trunk. Primary care providers should consider obtaining imaging to rule out severe injuries or referring to specialist providers. Current guidelines for skin infections require frequent pre-match skin checks and mandatory waiting periods when certain infections are identified. However, the primary care provider is well-equipped for more in-depth skin examination, discussion of skin hygiene, and appropriate treatment of skin infections. Athletes attempting to meet lower weight classes may put themselves at risk of acute kidney damage, under-fueling, and eating disorders. Current guidelines attempt to mitigate excessive weight changes in the adolescent wrestler during competition season, but primary care providers should emphasize healthier methods of weight fluctuation and look for indicators of physiological or psychological effects.

CB1R dysfunction of inhibitory synapses in the ACC drives chronic social isolation stress-induced social impairments in male mice.

Social isolation is a risk factor for multiple mood disorders. Specifically, social isolation can remodel the brain, causing behavioral abnormalities, including sociability impairments. Here, we investigated social behavior impairment in mice following chronic social isolation stress (CSIS) and conducted a screening of susceptible brain regions using functional readouts. CSIS enhanced synaptic inhibition in the anterior cingulate cortex (ACC), particularly at inhibitory synapses of cholecystokinin (CCK)-expressing interneurons. This enhanced synaptic inhibition in the ACC was characterized by CSIS-induced loss of presynaptic cannabinoid type-1 receptors (CB1Rs), resulting in excessive axonal calcium influx. Activation of CCK-expressing interneurons or conditional knockdown of CB1R expression in CCK-expressing interneurons specifically reproduced social impairment. In contrast, optogenetic activation of CB1R or administration of CB1R agonists restored sociability in CSIS mice. These results suggest that the CB1R may be an effective therapeutic target for preventing CSIS-induced social impairments by restoring synaptic inhibition in the ACC.

Enhancement of mediodorsal thalamus rescues aberrant belief dynamics in a mouse model with schizophrenia-associated mutation.

Optimizing behavioral strategy requires belief updating based on new evidence, a process that engages higher cognition. In schizophrenia, aberrant belief dynamics may lead to psychosis, but the mechanisms underlying this process are unknown, in part, due to lack of appropriate animal models and behavior readouts. Here, we address this challenge by taking two synergistic approaches. First, we generate a mouse model bearing patient-derived point mutation in Grin2a (Grin2aY700X+/-), a gene that confers high-risk for schizophrenia and recently identified by large-scale exome sequencing. Second, we develop a computationally trackable foraging task, in which mice form and update belief-driven strategies in a dynamic environment. We found that Grin2aY700X+/- mice perform less optimally than their wild-type (WT) littermates, showing unstable behavioral states and a slower belief update rate. Using functional ultrasound imaging, we identified the mediodorsal (MD) thalamus as hypofunctional in Grin2aY700X+/- mice, and in vivo task recordings showed that MD neurons encoded dynamic values and behavioral states in WT mice. Optogenetic inhibition of MD neurons in WT mice phenocopied Grin2aY700X+/- mice, and enhancing MD activity rescued task deficits in Grin2aY700X+/- mice. Together, our study identifies the MD thalamus as a key node for schizophrenia-relevant cognitive dysfunction, and a potential target for future therapeutics.

Restoring thalamocortical circuit dysfunction by correcting HCN channelopathy in Shank3 mutant mice.

Thalamocortical (TC) circuits are essential for sensory information processing. Clinical and preclinical studies of autism spectrum disorders (ASDs) have highlighted abnormal thalamic development and TC circuit dysfunction. However, mechanistic understanding of how TC dysfunction contributes to behavioral abnormalities in ASDs is limited. Here, our study on a Shank3 mouse model of ASD reveals TC neuron hyperexcitability with excessive burst firing and a temporal mismatch relationship with slow cortical rhythms during sleep. These TC electrophysiological alterations and the consequent sensory hypersensitivity and sleep fragmentation in Shank3 mutant mice are causally linked to HCN2 channelopathy. Restoring HCN2 function early in postnatal development via a viral approach or lamotrigine (LTG) ameliorates sensory and sleep problems. A retrospective case series also supports beneficial effects of LTG treatment on sensory behavior in ASD patients. Our study identifies a clinically relevant circuit mechanism and proposes a targeted molecular intervention for ASD-related behavioral impairments.

Development of in silico models to guide the experimental characterisation of penile tissue and inform surgical treatment of erectile dysfunction.

This paper presents a computational study to investigate the mechanical properties of human penile tissues. Different experimental testing regimes, namely indentation and plate-compression tests, are compared to establish the most suitable testing regime for establishing the mechanical properties of the different penile tissues. An idealised MRI-based geometry of the penis, containing different tissue layers, is simulated using the finite element (FE) method to enable realistic predictions of the deformation of the penis. Unlike the linear elastic models used in the literature to-date, hyperelastic isotropic/anisotropic material models are used to capture material nonlinearity and anisotropy. The influence of material properties, morphological variations, material nonlinearity and anisotropy are investigated. Moreover, the implantation of an inflatable penile prosthesis (IPP) is simulated to assess the effects of the implantation procedure, material nonlinearity, and anisotropy on tissue stresses. The results indicate that the interior layers of the penis do not affect the overall stiffness of the penis in the indentation test, while the plate-compression test is able to capture the effects of these layers. Tunica Albuginea (TA) is found to have the most significant contribution to the total stiffness of the penis under load. It can also be observed that buckling occurs in the septum of the penis during the compression tests, and different morphologies dictate different compressive behaviours. There is a clear need for future experimental studies on penile tissues given the lack of relevant test data in the literature. Based on this study, plate-compression testing would offer the most insightful experimental data for such tissue characterisation.

Radiation exposure in multiple hereditary exostoses: A retrospective review.

Background: Exposure to ionizing radiation in patients with Multiple Hereditary Exostoses (MHE) is inevitable and necessary for the diagnosis and treatment of MHE. Radiation exposure has many potentially dangerous consequences, including the increased risk of developing cancer. This is especially concerning in the pediatric patient population since children are more likely to develop adverse effects from radiation than adults. This study aimed to quantify radiation exposure over a five-year period among patients diagnosed with MHE since such information is not currently available in the literature. Methods: Diagnostic radiographs, computed tomography (CT) scans, nuclear medicine studies, and intraoperative fluoroscopy exposures were analyzed for radiation exposure in 37 patients diagnosed with MHE between 2015 and 2020. Results: Thirty-seven patients with MHE underwent 1200 imaging studies, 976 of which were related to MHE and 224 unrelated to MHE. The mean estimated MHE cumulative radiation dose per patient was 5.23 mSv. Radiographs related to MHE contributed the most radiation. Patients from the ages of 10- to 24-years-old received the most imaging studies and exposure to ionizing radiation, especially compared to those under age 10 (P = 0.016). The 37 patients also received a total of 53 surgical-excision procedures, with a mean of 1.4 procedures per person. Conclusions: MHE patients are exposed to increased levels of ionizing radiation secondary to serial diagnostic imaging, with those ages 10-24 years old being exposed to significantly higher doses of radiation. Because pediatric patients are more sensitive to radiation exposure and are at an overall higher risk, the use of radiographs should always be justified in those patients.

Higher order Pancharatnam-Berry phase and the angular momentum of light.

The first experimental demonstration of a new Pancharatnam-Berry phase for light beams with spatially inhomogeneous, or vector, states of polarization referred to as the higher-order Pancharatnam-Berry phase is presented. This new geometric phase is proportional to light's total angular momentum, a sum of spin and higher dimensional orbital angular momentum, sharply contrasting the well-known Pancharatnam-Berry phase associated with the plane wave state of polarization of a spatially homogeneous light beam. The higher-order Pancharatnam-Berry phase is directly related to the rotational symmetry of a vortex-bearing electromagnetic field, associated with the rotational frequency shift of a light beam, and has implications in quantum information science as well as other physical systems such as electron vortex beams.