Transcutaneous fluorescence spectroscopy: development and characterization of a compact, portable, and fiber-optic sensor.

Significance: The integrity of the intestinal barrier is gaining recognition as a significant contributor to various pathophysiological conditions, including inflammatory bowel disease, celiac disease, environmental enteric dysfunction (EED), and malnutrition. EED, for example, manifests as complex structural and functional changes in the small intestine leading to increased intestinal permeability, inflammation, and reduced absorption of nutrients. Despite the importance of gut function, current techniques to assess intestinal permeability (such as endoscopic biopsies or dual sugar assays) are either highly invasive, unreliable, and/or difficult to perform in certain patient populations (e.g., infants). Aim: We present a portable, optical sensor based on transcutaneous fluorescence spectroscopy to assess gut function (in particular, intestinal permeability) in a fast and noninvasive manner. Approach: Participants receive an oral dose of a fluorescent contrast agent, and a wearable fiber-optic probe detects the permeation of the contrast agent from the gut into the blood stream by measuring the fluorescence intensity noninvasively at the fingertip. We characterized the performance of our compact optical sensor by comparing it against an existing benchtop spectroscopic system. In addition, we report results from a human study in healthy volunteers investigating the impact of skin tone and contrast agent dose on transcutaneous fluorescence signals. Results: The first study with eight healthy participants showed good correlation between our compact sensor and the existing benchtop spectroscopic system [correlation coefficient (r)>0.919, p<0.001]. Further experiments in 14 healthy participants revealed an approximately linear relationship between the ingested contrast agent dose and the collected signal intensity. Finally, a parallel study on the impact of different skin tones showed no significant differences in signal levels between participants with different skin tones (p>0.05). Conclusions: In this paper, we demonstrate the potential of our compact transcutaneous fluorescence sensor for noninvasive monitoring of intestinal health.

Changes in mental health services in response to the COVID-19 pandemic in high-income countries: a rapid review.

BACKGROUND: Severe deterioration in mental health and disrupted care provision during the COVID-19 increased unmet needs for mental health. This review aimed to identify changes in mental health services for patients in response to the pandemic and understand the impact of the changes on patients and providers. METHODS: Following the Cochrane guidance for rapid reviews, Cochrane CENTRAL, MEDLINE, Embase and PsycInfo were searched for empirical studies that investigated models of care, services, initiatives or programmes developed/evolved for patients receiving mental health care during COVID-19, published in English and undertaken in high-income countries. Thematic analysis was conducted to describe the changes and an effect direction plot was used to show impact on outcomes. RESULTS: 33 of 6969 records identified were included reporting on patients' experiences (n = 24), care providers' experiences (n = 7) and mixed of both (n = 2). Changes reported included technology-based care delivery, accessibility, flexibility, remote diagnostics and evaluation, privacy, safety and operating hours of service provision. These changes had impacts on: (1) care access; (2) satisfaction with telehealth; (3) comparability of telehealth with face-to-face care; (4) treatment effectiveness; (5) continuity of care; (6) relationships between patients and care providers; (7) remote detection and diagnostics in patients; (8) privacy; (9) treatment length and (10) work-life balance. CONCLUSIONS: A shift to telecommunication technologies had a significant impact on patients and care providers' experiences of mental health care. Improvements to care access, flexibility, remote forms of care delivery and lengths of operating service hours emerged as crucial changes, which supported accessibility to mental health services, increased attendance and reduced dropouts from care. The relationships between patients and care providers were influenced by service changes and were vastly depending on technological literacy and context of patients and availability and care access ranging from regular contact to a loss of in-person contact. The review also identified an increase in care inequality and a feeling of being disconnected among marginalised groups including homeless people, veterans and ethic minority groups. Telehealth in mental care could be a viable alternative to face-to-face service delivery with effective treatment outcomes. Further research is needed to better understand the impact of the changes identified particularly on underserved populations.

Broadening and strengthening the health providers caring for patients with chronic hepatitis C may improve continuity of care.

BACKGROUND: Direct-acting antiviral (DAA) therapies for hepatitis C virus infection (HCV) lead to excellent rates of sustained virological response (SVR). However, loss to follow-up (LTFU) for SVR testing remains a challenge. We examine factors associated with LTFU in a real-world setting. METHODS: Adults who received DAA therapy for HCV in one of 26 centers across Australia during 2016-2021 were followed up for 2 years. Data sources included the patient medical records and the national Pharmaceutical and Medicare Benefits Schemes. Linkage to Medicare provided utilization data of other health-care providers and re-treatment with DAAs. LTFU was defined as no clinic attendance for SVR testing by at least 52 weeks after DAA treatment commencement. Multivariable logistic regression assessed factors associated with LTFU. RESULTS: In 3619 patients included in the study (mean age 52.0 years; SD = 10.5), 33.6% had cirrhosis (69.4% Child-Pugh class B/C), and 19.3% had HCV treatment prior to the DAA era. Five hundred and fifteen patients (14.2%) were LTFU. HCV treatment initiation in 2017 or later (adj-OR = 2.82, 95% confidence interval [CI] 2.25-3.54), younger age (adj-OR = 2.63, 95% CI 1.80-3.84), Indigenous identification (adj-OR = 1.99, 95% CI 1.23-3.21), current injection drug use or opioid replacement therapy (adj-OR = 1.66, 95% CI 1.25-2.20), depression treatment (adj-OR = 1.49, 95% CI 1.17-1.90), and male gender (adj-OR = 1.31, 95% CI 1.04-1.66) were associated with LTFU. CONCLUSIONS: These findings stress the importance of strengthening the network of providers caring for patients with HCV. In particular, services targeting vulnerable groups of patients such as First Nations Peoples, youth health, and those with addiction and mental health disorders should be equipped to treat HCV.

Selective recording of physiologically evoked neural activity in a mixed autonomic nerve using a minimally invasive array.

Real-time closed-loop control of neuromodulation devices requires long-term monitoring of neural activity in the peripheral nervous system. Although many signal extraction methods exist, few are both clinically viable and designed for extracting small signals from fragile peripheral visceral nerves. Here, we report that our minimally invasive recording and analysis technology extracts low to negative signal to noise ratio (SNR) neural activity from a visceral nerve with a high degree of specificity for fiber type and class. Complex activity was recorded from the rat pelvic nerve that was physiologically evoked during controlled bladder filling and voiding, in an extensively characterized in vivo model that provided an excellent test bed to validate our technology. Urethane-anesthetized male rats (n = 12) were implanted with a four-electrode planar array and the bladder instrumented for continuous-flow cystometry, which measures urodynamic function by recording bladder pressure changes during constant infusion of saline. We demonstrated that differential bipolar recordings and cross-correlation analyses extracts afferent and efferent activity, and discriminated between subpopulations of fibers based on conduction velocity. Integrated Aδ afferent fiber activity correlated with bladder pressure during voiding (r2: 0.66 ± 0.06) and was not affected by activating nociceptive afferents with intravesical capsaicin (r2: 0.59 ± 0.14, P = 0.54, and n = 3). Collectively, these results demonstrate our minimally invasive recording and analysis technology is selective in extracting mixed neural activity with low/negative SNR. Furthermore, integrated afferent activity reliably correlates with bladder pressure and is a promising first step in developing closed-loop technology for bladder control.

Spread of activation and interaction between channels with multi-channel optogenetic stimulation in the mouse cochlea.

For individuals with severe to profound hearing loss resulting from irreversibly damaged hair cells, cochlear implants can be used to restore hearing by delivering electrical stimulation directly to the spiral ganglion neurons. However, current spread lowers the spatial resolution of neural activation. Since light can be easily confined, optogenetics is a technique that has the potential to improve the precision of neural activation, whereby visible light is used to stimulate neurons that are modified with light-sensitive opsins. This study compares the spread of neural activity across the inferior colliculus of the auditory midbrain during electrical and optical stimulation in the cochlea of acutely deafened mice with opsin-modified spiral ganglion neurons (H134R variant of the channelrhodopsin-2). Monopolar electrical stimulation was delivered via each of four 0.2 mm wide platinum electrode rings at 0.6 mm centre-to-centre spacing, whereas 453 nm wavelength light was delivered via each of five 0.22 × 0.27 mm micro-light emitting diodes (LEDs) at 0.52 mm centre-to-centre spacing. Channel interactions were also quantified by threshold changes during simultaneous stimulation by pairs of electrodes or micro-LEDs at different distances between the electrodes (0.6, 1.2 and 1.8 mm) or micro-LEDs (0.52, 1.04, 1.56 and 2.08 mm). The spread of activation resulting from single channel optical stimulation was approximately half that of monopolar electrical stimulation as measured at two levels of discrimination above threshold (p<0.001), whereas there was no significant difference between optical stimulation in opsin-modified deafened mice and pure tone acoustic stimulation in normal-hearing mice. During simultaneous micro-LED stimulation, there were minimal channel interactions for all micro-LED spacings tested. For neighbouring micro-LEDs/electrodes, the relative influence on threshold was 13-fold less for optical stimulation compared electrical stimulation (p<0.05). The outcomes of this study show that the higher spatial precision of optogenetic stimulation results in reduced channel interaction compared to electrical stimulation, which could increase the number of independent channels in a cochlear implant. Increased spatial resolution and the ability to activate more than one channel simultaneously could lead to better speech perception in cochlear implant recipients.

Examining the impact of a universal social and emotional learning intervention (Passport) on internalising symptoms and other outcomes among children, compared to the usual school curriculum: study protocol for a school-based cluster randomised trial.

BACKGROUND: School-based universal social and emotional learning (SEL) interventions implemented during the transition to adolescence may be efficacious in preventing the development of mental health difficulties. This protocol describes a two-arm parallel cluster randomised controlled trial to investigate the impact of a universal SEL intervention (Passport, compared to usual provision) on internalising symptoms (primary outcome), emotion regulation, well-being, loneliness, social support, bullying, academic attainment, and health-related quality of life in English primary school pupils aged 9-11 years. A developer-led trial demonstrated the feasibility, acceptability, and utility of Passport; this will be the first independent trial. METHODS: Sixty primary schools will be recruited across the Greater Manchester city region and surrounding areas, involving 2400 pupils aged 8-9 at baseline. Schools will be allocated to the intervention arm to implement Passport over 18 weekly sessions or to the control arm to implement the usual school curriculum. Random allocation will be at school level following completion of baseline measures, with minimisation to ensure balance across trial arms in school size and free school meal eligibility. Measures will be collected at baseline, post-intervention (12 months post-baseline), and at 12 months follow-up (24 months post-baseline). The primary outcome analysis (intervention effects on internalising symptoms at post-intervention) will comprise a two-level (school, child) hierarchical linear model, following the intention-to-treat principle. Additional analyses will be undertaken to assess intervention effects on secondary outcomes, maintenance effects for all outcomes, intervention compliance moderator effects, subgroup moderator effects, and mechanisms underpinning intervention effects on the primary outcome. A mixed-methods implementation and process evaluation will examine factors that influence implementation, and a health economic evaluation will assess the cost-effectiveness of the intervention. DISCUSSION: Findings will provide educators with crucial knowledge of whether and how increasing emotion regulation through a universal intervention impacts internalising symptoms and a range of related outcomes. Findings will also inform policy related to the promotion of mental health among children and young people. If the intervention is found to be efficacious in reducing internalising symptoms and is also cost-effective, it may offer high potential as a preventative intervention for widespread implementation. TRIAL REGISTRATION: ISRCTN12875599; registered on 24 November 2022.

Characterization of bacteria swarming effect under plasmonic optical fiber illumination.

Significance: Plasmo-thermo-electrophoresis (PTEP) involves using plasmonic microstructures to generate both a large-scale convection current and a near-field attraction force (thermo-electrophoresis). These effects facilitate the collective locomotion (i.e., swarming) of microscale particles in suspension, which can be utilized for numerous applications, such as particle/cell manipulation and targeted drug delivery. However, to date, PTEP for ensemble manipulation has not been well characterized, meaning its potential is yet to be realized. Aim: Our study aims to provide a characterization of PTEP on the motion and swarming effect of various particles and bacterial cells to allow rational design for bacteria-based microrobots and drug delivery applications. Approach: Plasmonic optical fibers (POFs) were fabricated using two-photon polymerization. The particle motion and swarming behavior near the tips of optical fibers were characterized by image-based particle tracking and analyzing the spatiotemporal concentration variation. These results were further correlated with the shape and surface charge of the particles defined by the zeta potential. Results: The PTEP demonstrated a drag force ranging from a few hundred fN to a few tens of pN using the POFs. Furthermore, bacteria with the greater (negative) zeta potential (|ζ|>10 mV) and smoother shape (e.g., Klebsiella pneumoniae and Escherichia coli) exhibited the greatest swarming behavior. Conclusions: The characterization of PTEP-based bacteria swarming behavior investigated in our study can help predict the expected swarming behavior of given particles/bacterial cells. As such, this may aid in realizing the potential of PTEP in the wide-ranging applications highlighted above.

Combined optogenetic and electrical stimulation of the sciatic nerve for selective control of sensory fibers.

Introduction: Electrical stimulation offers a drug-free alternative for the treatment of many neurological conditions, such as chronic pain. However, it is not easy to selectively activate afferent or efferent fibers of mixed nerves, nor their functional subtypes. Optogenetics overcomes these issues by controlling activity selectively in genetically modified fibers, however the reliability of responses to light are poor compared to electrical stimulation and the high intensities of light required present considerable translational challenges. In this study we employed a combined protocol of optical and electrical stimulation to the sciatic nerve in an optogenetic mouse model to allow for better selectivity, efficiency, and safety to overcome fundamental limitations of electrical-only and optical-only stimulation. Methods: The sciatic nerve was surgically exposed in anesthetized mice (n = 12) expressing the ChR2-H134R opsin via the parvalbumin promoter. A custom-made peripheral nerve cuff electrode and a 452 nm laser-coupled optical fiber were used to elicit neural activity utilizing optical-only, electrical-only, or combined stimulation. Activation thresholds for the individual and combined responses were measured. Results: Optically evoked responses had a conduction velocity of 34.3 m/s, consistent with ChR2-H134R expression in proprioceptive and low-threshold mechanoreceptor (Aα/Aß) fibers which was also confirmed via immunohistochemical methods. Combined stimulation, utilizing a 1 ms near-threshold light pulse followed by an electrical pulse 0.5 ms later, approximately halved the electrical threshold for activation (p = 0.006, n = 5) and resulted in a 5.5 dB increase in the Aα/Aß hybrid response amplitude compared to the electrical-only response at equivalent electrical levels (p = 0.003, n = 6). As a result, there was a 3.25 dB increase in the therapeutic stimulation window between the Aα/Aß fiber and myogenic thresholds (p = 0.008, n = 4). Discussion: The results demonstrate that light can be used to prime the optogenetically modified neural population to reside near threshold, thereby selectively reducing the electrical threshold for neural activation in these fibers. This reduces the amount of light needed for activation for increased safety and reduces potential off-target effects by only stimulating the fibers of interest. Since Aα/Aß fibers are potential targets for neuromodulation in chronic pain conditions, these findings could be used to develop effective strategies to selectively manipulate pain transmission pathways in the periphery.

Differential Methylation of Telomere-Related Genes Is Associated with Kidney Disease in Individuals with Type 1 Diabetes.

Diabetic kidney disease (DKD) represents a major global health problem. Accelerated ageing is a key feature of DKD and, therefore, characteristics of accelerated ageing may provide useful biomarkers or therapeutic targets. Harnessing multi-omics, features affecting telomere biology and any associated methylome dysregulation in DKD were explored. Genotype data for nuclear genome polymorphisms in telomere-related genes were extracted from genome-wide case-control association data (n = 823 DKD/903 controls; n = 247 end-stage kidney disease (ESKD)/1479 controls). Telomere length was established using quantitative polymerase chain reaction. Quantitative methylation values for 1091 CpG sites in telomere-related genes were extracted from epigenome-wide case-control association data (n = 150 DKD/100 controls). Telomere length was significantly shorter in older age groups (p = 7.6 × 10-6). Telomere length was also significantly reduced (p = 6.6 × 10-5) in DKD versus control individuals, with significance remaining after covariate adjustment (p = 0.028). DKD and ESKD were nominally associated with telomere-related genetic variation, with Mendelian randomisation highlighting no significant association between genetically predicted telomere length and kidney disease. A total of 496 CpG sites in 212 genes reached epigenome-wide significance (p ≤ 10-8) for DKD association, and 412 CpG sites in 193 genes for ESKD. Functional prediction revealed differentially methylated genes were enriched for Wnt signalling involvement. Harnessing previously published RNA-sequencing datasets, potential targets where epigenetic dysregulation may result in altered gene expression were revealed, useful as potential diagnostic and therapeutic targets for intervention.

Non-invasive assessment of intestinal permeability in healthy volunteers using transcutaneous fluorescence spectroscopy.

The permeability of the intestinal barrier is altered in a multitude of gastrointestinal conditions such as Crohn's and coeliac disease. However, the clinical utility of gut permeability is currently limited due to a lack of reliable diagnostic tests. To address this issue, we report a novel technique for rapid, non-invasive measurement of gut permeability based on transcutaneous ('through-the-skin') fluorescence spectroscopy. In this approach, participants drink an oral dose of a fluorescent dye (fluorescein) and a fibre-optic fluorescence spectrometer is attached to the finger to detect permeation of the dye from the gut into the blood stream in a non-invasive manner. To validate this technique, clinical trial measurements were performed in 11 healthy participants. First, after 6 h of fasting, participants ingested 500 mg of fluorescein dissolved in 100 ml of water and fluorescence measurements were recorded at the fingertip over the following 3 h. All participants were invited back for a repeat study, this time ingesting the same solution but with 60 g of sugar added (known to transiently increase intestinal permeability). Results from the two study datasets (without and with sugar respectively) were analysed and compared using a number of analysis procedures. This included both manual and automated calculation of a series of parameters designed for assessment of gut permeability. Calculated values were compared using Student's T-tests, which demonstrated significant differences between the two datasets. Thus, transcutaneous fluorescence spectroscopy shows promise in non-invasively discriminating between two differing states of gut permeability, demonstrating potential for future clinical use.

Assessment of the cobas® HBV RNA investigational assay in the setting of nucleoside analog therapy cessation.

HBV RNA is used as a marker of cccDNA transcription and is applicable in the setting of nucleos(t)ide analog (NA) treatment, which suppresses HBV DNA. Traditional assays for quantification of HBV RNA rely on labor-intensive 3'RACE assays targeting the polyA tail. In this study, the high-throughput Roche cobas®HBV RNA investigational assay was assessed on the Roche cobas® 6800 automated platform. Of 969 samples collected for a NA treatment cessation trial, and tested on the cobas assay, 249 were analyzed for sensitivity, reproducibility, sample type applicability, and results were compared to a RACE-based assay. Results of 97 paired serum and plasma samples demonstrated an excellent correlation of 0.98. However, 14.5% of plasma samples yielded detectable (below the limit of quantification) results, when the paired serum was undetectable, and plasma was shown to yield a statistically significant (p < 0.001) greater mean 0.119 log10 copies/ml. Quantification of 152 samples showed good correlation (0.91) between the cobas and RACE assays. The cobas assay demonstrated superior lower limit of quantification, 10 copies/ml, which resulted in detection of 13.2% more samples than the RACE assay. Reproducibility and linear range of the automated assay were also confirmed. The Roche cobas assay for HBV RNA is sensitive and highly recommended.

The measurement and modification of hypoxia in colorectal cancer: overlooked but not forgotten.

Tumour hypoxia is the inevitable consequence of a tumour's rapid growth and disorganized, inefficient vasculature. The compensatory mechanisms employed by tumours, and indeed the absence of oxygen itself, hinder the ability of all treatment modalities. The clinical consequence is poorer overall survival, disease-free survival, and locoregional control. Recognizing this, clinicians have been attenuating the effect of hypoxia, primarily with hypoxic modification or with hypoxia-activated pro-drugs, and notable success has been demonstrated. However, in the case of colorectal cancer (CRC), there is a general paucity of knowledge and evidence surrounding the measurement and modification of hypoxia, and this is possibly due to the comparative inaccessibility of such tumours. We specifically review the role of hypoxia in CRC and focus on the current evidence for the existence of hypoxia in CRC, the majority of which originates from indirect positron emission topography imaging with hypoxia selective radiotracers; the evidence correlating CRC hypoxia with poorer oncological outcome, which is largely based on the measurement of hypoxia inducible factor in correlation with clinical outcome; the evidence of hypoxic modification in CRC, of which no direct evidence exists, but is reflected in a number of indirect markers; the prognostic and monitoring implications of accurate CRC hypoxia quantification and its potential in the field of precision oncology; and the present and future imaging tools and technologies being developed for the measurement of CRC hypoxia, including the use of blood-oxygen-level-dependent magnetic resonance imaging and diffuse reflectance spectroscopy.

Seven-day in vivo testing of a novel, low-resistance, pumpless pediatric artificial lung for long-term support.

INTRODUCTION: For children with end-stage lung disease that cannot wean from extracorporeal life support (ECLS), a wearable artificial lung would permit extubation and provide a bridge to recovery or transplantation. We evaluate the function of the novel Pediatric MLung-a low-resistance, pumpless artificial lung developed specifically for children-in healthy animal subjects. METHODS: Adolescent "mini sheep" weighing 12-20 kg underwent left thoracotomy, cannulation of the main pulmonary artery (PA; inflow) and left atrium (outflow), and connection to the MLung. RESULTS: Thirteen sheep were studied; 6 were supported for 7 days. Mean PA pressure was 23.9 ± 6.9 mmHg. MLung blood flow was 633±258 mL/min or 30.0 ± 16.0% of CO. MLung pressure drop was 4.4 ± 3.4 mmHg. Resistance was 7.2 ± 5.2 mmHg/L/min. Device outlet oxygen saturation was 99.0 ± 3.3% with inlet saturation 53.8 ± 7.3%. Oxygen delivery was 41.1 ± 18.4 mL O2/min (maximum 84.9 mL/min) or 2.8 ± 1.5 mL O2/min/kg. Platelet count significantly decreased; no platelet transfusions were required. Plasma free hemoglobin significantly increased only on day 7, at which point 2 of the animals had plasma free hemoglobin levels above 50 mg/dL. CONCLUSION: The MLung provides adequate gas exchange at appropriate blood flows for the pediatric population in a PA-to-LA configuration. Further work remains to improve the biocompatibility of the device. LEVEL OF EVIDENCE: N/A.

Combination treatments including the small-interfering RNA JNJ-3989 induce rapid and sometimes prolonged viral responses in patients with CHB.

BACKGROUND & AIMS: RNA interference therapy has been shown to reduce hepatitis B surface antigen (HBsAg) levels in preclinical models, which could confer functional cure in patients with chronic hepatitis B. This phase IIa trial (ClinicalTrials.gov Identifier: NCT03365947) assessed the safety and efficacy of the small-interfering RNA JNJ-73763989 (JNJ-3989) plus a nucleos(t)ide analogue (NA), with/without the capsid assembly modulator JNJ-56136379 (JNJ-6379) in patients with chronic hepatitis B. METHODS: Treatment-naïve and NA-suppressed patients received 3 subcutaneous JNJ-3989 doses every week (QW; 100, 200, or 300 mg), 2 weeks (Q2W; 100 mg) or 4 weeks (Q4W; 25, 50, 100, 200, 300, or 400 mg), or JNJ-3989 Q4W (200 mg) plus oral JNJ-6379 250 mg daily for 12 weeks. Patients received NAs throughout. RESULTS: Eighty-four patients were recruited. All treatments were well tolerated, with all 5 serious adverse events considered unrelated to study drugs. JNJ-3989 100 to 400 mg Q4W resulted in HBsAg reductions ≥1 log10 IU/ml from baseline in 39/40 (97.5%) patients at the nadir. All patients receiving the triple combination (n = 12) had HBsAg reductions ≥1 log10 IU/ml from baseline at the nadir. HBsAg reductions were similar for HBeAg-positive (n = 21) and HBeAg-negative (n = 47) patients in all JNJ-3989 Q4W treatment arms, including the triple combination (n = 68). Smaller HBsAg reductions were seen with 25 mg (n = 8) and 50 mg (n = 8) than with 100 to 400 mg (n = 40). Shorter dosing intervals (QW [n = 12] and Q2W [n = 4]) did not improve response vs. Q4W dosing. HBsAg reductions ≥1 log10 IU/ml from baseline persisted in 38% of patients 336 days after the last JNJ-3989 dose. CONCLUSIONS: JNJ-3989 plus an NA, with/without JNJ-6379, was well tolerated and resulted in HBsAg reductions up to 336 days after the last JNJ-3989 Q4W dose. CLINICAL TRIAL NUMBER: NCT03365947. LAY SUMMARY: Hepatitis B virus affects people's livers and produces particles called hepatitis B surface antigen (HBsAg) that damage a person's liver and can help the virus infect a person for a long time, known as chronic hepatitis B (CHB). In this study, a new treatment called JNJ-3989 was assessed (in combination with normal treatment known as nucleos(t)ide analogues), for its safety and effectiveness in reducing the number of HBsAg particles in people with CHB. The results of this study showed that treatment with JNJ-3989 could be safe for people with CHB, lowered their HBsAg levels, and kept HBsAg levels lowered for 336 days in 38% of patients after receiving their last dose of JNJ-3989.

A Parametric Analysis of Capillary Height in Single-Layer, Small-Scale Microfluidic Artificial Lungs.

Microfluidic artificial lungs (µALs) are being investigated for their ability to closely mimic the size scale and cellular environment of natural lungs. Researchers have developed µALs with small artificial capillary diameters (10-50 µm; to increase gas exchange efficiency) and with large capillary diameters (~100 µm; to simplify design and construction). However, no study has directly investigated the impact of capillary height on µAL properties. Here, we use Murray's law and the Hagen-Poiseuille equation to design single-layer, small-scale µALs with capillary heights between 10 and 100 µm. Each µAL contained two blood channel types: capillaries for gas exchange; and distribution channels for delivering blood to/from capillaries. Three designs with capillary heights of 30, 60, and 100 µm were chosen for further modeling, implementation and testing with blood. Flow simulations were used to validate and ensure equal pressures. Designs were fabricated using soft lithography. Gas exchange and pressure drop were tested using whole bovine blood. All three designs exhibited similar pressure drops and gas exchange; however, the µAL with 60 µm tall capillaries had a significantly higher wall shear rate (although physiologic), smaller priming volume and smaller total blood contacting surface area than the 30 and 100 µm designs. Future µAL designs may need to consider the impact of capillary height when optimizing performance.

Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation.

The chromokinesin KIF22 generates forces that contribute to mitotic chromosome congression and alignment. Mutations in the α2 helix of the motor domain of KIF22 have been identified in patients with abnormal skeletal development, and we report the identification of a patient with a novel mutation in the KIF22 tail. We demonstrate that pathogenic mutations do not result in a loss of KIF22's functions in early mitosis. Instead, mutations disrupt chromosome segregation in anaphase, resulting in reduced proliferation, abnormal daughter cell nuclear morphology, and, in a subset of cells, cytokinesis failure. This phenotype could be explained by a failure of KIF22 to inactivate in anaphase. Consistent with this model, constitutive activation of the motor via a known site of phosphoregulation in the tail phenocopied the effects of pathogenic mutations. These results suggest that the motor domain α2 helix may be an important site for regulation of KIF22 activity at the metaphase to anaphase transition. In support of this conclusion, mimicking phosphorylation of α2 helix residue T158 also prevents inactivation of KIF22 in anaphase. These findings demonstrate the importance of both the head and tail of the motor in regulating the activity of KIF22 and offer insight into the cellular consequences of preventing KIF22 inactivation and disrupting force balance in anaphase.

Understanding how to live with hepatitis B: a qualitative investigation of peer advice for Chinese people living with hepatitis B in Australia.

BACKGROUND: Hepatitis B is a chronic viral infection, a leading cause of primary liver cancer and identified as a major public health priority by the World Health Organization. Despite a high proportion of people in Australia who have been diagnosed with hepatitis B, significant gaps remain in health care access and in accurate knowledge about hepatitis B. Most people with hepatitis B in Australia were born in China, where the infection has an intergenerational impact with significant social implications resulting from the infection. Understanding how people of Chinese ethnicity with hepatitis B understand and respond to hepatitis B is imperative for reducing morbidity, mortality, and the personal and social impact of the infection. METHODS: Qualitative semi-structured interviews with people with hepatitis B of Chinese ethnicity recruited through a specialist service identified the advice people with hepatitis B thought was important enough to inform the experience of people newly diagnosed with hepatitis B. A thematic analysis of the data privileged the lived experience of participants and their personal, rather than clinical, explanations of the virus. RESULTS: Hepatitis B infection had psychological and physical consequences that were informed by cultural norms, and to which people had responded to with significant behavioural change. Despite this cohort being engaged with specialist clinical services with access to the most recent, comprehensive, and expert information, much of the advice people with hepatitis B identified as important for living with hepatitis B was not based on biomedical understandings. Key suggestions from people with hepatitis B were to form sustainable clinical relationships, develop emotional resilience, make dietary changes, regulate energy, and issues related to disclosure. CONCLUSIONS: The study highlights conflicts between biomedical and public health explanations and the lived experience of hepatitis B among people of Chinese ethnicity in Australia. Beliefs about hepatitis B are embedded within cultural understandings of health that can conflict with bio-medical explanations of the infection. Acknowledging these perspectives provides for insightful communication between health services and their clients, and the development of nuanced models of care informed by the experience of people with hepatitis B.

Quantifying Changes in Chromosome Position to Assess Chromokinesin Activity.

The chromokinesin KIF22 (Kid, kinesin-10 family) is the primary generator of polar ejection forces, which contribute to chromosome positioning and alignment in mitotic cells. Assessment of KIF22 function requires quantitative comparison of relative polar ejection forces between experimental conditions. This is facilitated by the generation of monopolar spindles to reduce the impact of bioriented microtubule attachment at kinetochores on chromosome positions and increase the dependence of chromosome positions on chromokinesin activity. Radial profile plots measure the intensity of chromatin signal in concentric circles around the poles of monopolar cells and represent an expedient quantitative measure of relative polar ejection forces. As such, this assay can be used to measure changes in polar ejection forces resulting from chromokinesin depletion or perturbation.