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BACKGROUND: Functional MRI combined with electromyography (EMG-fMRI) is a new technique to investigate the functional association of movement to brain activations. Thalamic stereotactic surgery is effective in reducing tremor. However, while some patients have satisfying benefit, others have only partial or temporary relief. This could be due to suboptimal targeting in some cases. By identifying tremor-related areas, EMG-fMRI could provide more insight into the pathophysiology of tremor and be potentially useful in refining surgical targeting. OBJECTIVE: Aim of the study was to evaluate whether EMG-fMRI could detect blood oxygen level dependent brain activations associated with tremor in patients with Essential Tremor. Second, we explored whether EMG-fMRI could improve the delineation of targets for stereotactic surgery. METHODS: Simultaneous EMG-fMRI was performed in six Essential Tremor patients with unilateral thalamotomy. EMG was recorded from the trembling arm (non-operated side) and from the contralateral arm (operated side). Protocols were designed to study brain activations related to voluntary muscle contractions and postural tremor. RESULTS: Analysis with the EMG regressor was able to show the association of voluntary movements with activity in the contralateral motor cortex and supplementary motor area, and ipsilateral cerebellum. The EMG tremor frequency regressor showed an association between tremor and activity in the ipsilateral cerebellum and contralateral thalamus. The activation spot in the thalamus varied across patients and did not correspond to the thalamic nucleus ventralis intermedius. CONCLUSION: EMG-fMRI is potentially useful in detecting brain activations associated with tremor in patients with Essential Tremor. The technique must be further developed before being useful in supporting targeting for stereotactic surgery.

Introduction: Quality of life (QoL), mental wellbeing, and physical function are often diminished among people with chronic disease. Tai Chi is a moderate form of exercise that may be effective in improving chronic disease management. This protocol paper outlines a trial to determine the therapeutic effects of a Tai Chi program on chronic disease management., Methods and Analysis: This study will be a pilot, interventional, single-blind, two-armed, randomised, parallel, and controlled trial involving a 12-week Tai Chi program for Australian adults. Forty people aged 18 years and older, diagnosed with one or more chronic disease from general community will be recruited. All participants will be randomised to either a 12-week Tai Chi program or a waiting list control group. The Tai Chi program will involve 12 weeks of group Tai Chi sessions, with 45 minutes per session, twice a week. The primary outcome will be QoL as measured by mean scores on the 12-item Short Form Health Survey (SF-12v2) and the EuroQoL (EQ-5D). The secondary outcomes will include anxiety as measured by mean score on the generalised anxiety disorder 7 (GAD-7) survey; depression as measured by mean score on the patient health questionnaire (PHQ-9); work productivity and activity assessment (WPAI:SHP); pain (if any) as measured by mean scores on the visual analogue scale (VAS) and the McGill pain questionnaire (MPQ). These primary and secondary outcomes will be self-administered via two online assessments prior to (T0) and post-intervention (T1). Objective measures as additional secondary outcomes, will also be carried out by the research team including flexibility as measured by the finger to floor distance (FFD); obesity as measured by mean scores on body mass index (BMI); vital signs (blood pressure, heart rate, respiratory rate, temperate, and oxygen saturation) as measured by a blood pressure monitor, tympanic, and pulse oximetry device, and these outcomes will be measured at T0 and T1 in the ECU Holistic Health Research Clinic. People diagnosed with pre-diabetes or diabetes, their glycosylated haemoglobin (HbA1C) and fasting (before breakfast) blood glucose level (BGL) will also be measured via test kits at T0 and T1 in the clinic. Linear mixed modelling will be conducted to assess changes in outcomes. Statistical significance will be set at an alpha level of 0.05 with a medium effect size. All analyses will be conducted using R version 4.1. Qualitative data will be analysed using template thematic analysis., Ethics and Dissemination: Ethical approval has been obtained from the Edith Cowan University (ECU) Human Research Ethics Committee (2021-03042-WANG). Research findings will be disseminated to the public, health professionals, researchers, and healthcare providers through conference presentations, lay summaries, and peer-reviewed publications. This study will provide an updated evidence on a safe, sustainable, and inexpensive non-pharmacological approach in the management of chronic disease, the number one burden of disease in Australia., Trial Registration: Trial registration number: ACTRN12622000042741p., Competing Interests: The authors have declared that no competing interests exist.

Background: Shoulder and neck pain (SNP) is common in office workers and represents a serious public health problem given its detrimental impact on quality of life, physical functioning, personal finances, employers, and the health care system. Management with painkillers has adverse implications such as tolerance, addiction, and opioid abuse. Safe, sustainable, cost-effective, and evidence-based solutions are urgently needed. The non-invasive, painless, non-infectious, and safe modality of low-level laser acupuncture (LLLA) has shown promise for SNP management., Objective: The overarching aim of this study is to provide evidence of the feasibility and therapeutic efficacy of LLLA for office workers with SNP., Methods: This is a pilot, single-blind, double-armed, randomised controlled trial on the feasibility and therapeutic efficacy of a two-week LLLA therapy for office workers with SNP, aged 18 to 65 years. Each of the two study groups will contain 35 participants: the intervention group will receive LLLA from a licensed acupuncturist at the researchers' university clinic (10-20 min/session, 3 sessions/week) for two weeks; the control group will receive usual care without painkillers. Outcomes will be measured at baseline, throughout the two-week intervention, and at trial end. Surveys including open-ended questions will be completed. The primary outcome of this study is to evaluate the feasibility of a two-week LLLA therapy for office workers with SNP, as measured by recruitment and completion rates, patient safety, and treatment adherence and compliance. Participants' attitudes, motivation, and challenges to participation, intervention non-compliance, and experience of participating in the trial will be investigated via qualitative data. The secondary outcome is to evaluate the therapeutic efficacy of LLLA on SNP using the visual analogue scale (VAS) and the Short-Form McGill Pain Questionnaire (SF-MPQ); the work productivity and activity assessment (WPAI:SHP); 12-Item Short Form Survey (SF-12) for quality of life assessment; and the past 3-month out-of-pocket (OOP) cost for prescription and non-prescription SNP therapy, which is an indicative of the economic burden of SNP on patients and health care systems. This study was approved by Edith Cowan University's Human Research Ethics Committee (No. 2021-02225-WANG)., Results: Data collection will commence in December 2021 with anticipated completion by December 2022., Conclusions: Safe, sustainable, cost-effective, evidence-based interventions are needed to minimise the negative implications of SNP in office workers. LLLA is a promising modality in managing SNP. However, more consolidated evidence is required to provide insight regarding the effectiveness of LLLA. This study is expected to contribute to the challenging work of reducing the burden of SNP in office workers., Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12621000426886p; https://www.anzctr.org.au/ACTRN12621000426886p.aspx., Competing Interests: The authors have declared that no competing interests exist.

Background: Tai Chi (TC) mind-body exercise has been shown to reduce falls and improve balance and gait, however, few studies have evaluated the role of lower extremity muscle activation patterns in the observed benefits of TC on mobility., Purpose: To perform an exploratory analysis of the association between TC training and levels of lower extremity muscle co-contraction in healthy adults during walking under single-task (ST) and cognitive dual-task (DT) conditions., Methods: Surface electromyography of the anterior tibialis and lateral gastrocnemius muscles was recorded during 90 sec trials of overground ST (walking normally) and DT (walking with verbalized serial subtractions) walking. A mean co-contraction index (CCI), across all strides, was calculated based on the percentage of total muscle activity when antagonist muscles were simultaneously activated. A hybrid study design investigated long-term effects of TC via a cross-sectional comparison of 27 TC experts and 60 age-matched TC-naïve older adults. A longitudinal comparison assessed the shorter-term effects of TC; TC-naïve participants were randomly allocated to either 6 months of TC training or to usual care., Results: Across all participants at baseline, greater CCI was correlated with slower gait speed under DT (β(95% CI) = -26.1(-48.6, -3.7)) but not ST (β(95% CI) = -15.4(-38.2, 7.4)) walking. Linear models adjusting for age, gender, BMI and other factors that differed at baseline indicated that TC experts exhibited lower CCI compared to TC naives under DT, but not ST conditions (ST: mean difference (95% CI) = -7.1(-15.2, 0.97); DT: mean difference (95% CI) = -10.1(-18.1, -2.4)). No differences were observed in CCI for TC-naive adults randomly assigned to 6 months of TC vs. usual care., Conclusion: Lower extremity muscle co-contraction may play a role in the observed benefit of longer-term TC training on gait and postural control. Longer-duration and adequately powered randomized trials are needed to evaluate the effect of TC on neuromuscular coordination and its impact on postural control., Trial Registration: The randomized trial component of this study was registered at ClinicalTrials.gov (NCT01340365)., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Peter Wayne is the founder and sole owner of the Tree of Life Tai Chi Center. Peter Wayne's interests were reviewed and managed by the Brigham and Women's Hospital and Partner's HealthCare in accordance with their conflict of interest policies. This does not alter our adherence to PLOS ONE policies on sharing data and materials. No other authors have any potential conflicts to disclose.

In December 2016, the Nigerian Federal Ministry of Health updated its HIV guidelines to a Treat All approach, expanding antiretroviral therapy (ART) eligibility to all individuals with HIV infection, regardless of CD4+ cell count, and recommending ART be initiated within two weeks of HIV diagnosis (i.e., the Test and Treat strategy). The Test and Treat policy was first piloted in 32 local government areas (LGAs). The primary objective of this study was to evaluate the clinical outcomes of adult patients initiated on ART within two weeks of HIV diagnosis during this pilot. We conducted a retrospective cohort analysis of patients who initiated ART within two weeks of new HIV diagnosis between October 2015 and September 2016 in eight randomly selected LGAs participating in the Test and Treat pilot study. 2,652 adults were newly diagnosed and initiated on ART within two weeks of HIV diagnosis. Of these patients, 8% had documentation of a 12-month viral load measurement, and 13% had documentation of a six-month viral load measurement. Among Test and Treat patients with a documented viral load, 79% were suppressed (≤400 copies/ml) at six months and 78% were suppressed at 12 months. By 12 months post-ART initiation, 34% of the patients who initiated ART under the Test and Treat strategy were lost to follow-up. The median CD4 cell count among patients initiating ART within two weeks of HIV diagnosis was 323 cells/mm3 (interquartile range, 161-518). While randomized controlled trials have demonstrated that Test and Treat strategies can improve patient retention and increase viral suppression compared to standard of care, these findings indicate that the effectiveness of Test and Treat in some settings may be far lower than the efficacy demonstrated in randomized controlled trials. Significant attention to the way Test and Treat strategies are implemented, monitored, and improved particularly related to early retention, can help expand access to ART for all patients., Competing Interests: The authors have declared that no competing interests exist.

Unlabelled: The aim of this study was to develop an automatic orientation calibration and reproduction method for recording the natural head position (NHP) in stereo-photogrammetry (SP). A board was used as the physical reference carrier for true verticals and NHP alignment mirror orientation. Orientation axes were detected and saved from the digital mesh model of the board. They were used for correcting the pitch, roll and yaw angles of the subsequent captures of patients' facial surfaces, which were obtained without any markings or sensors attached onto the patient. We tested the proposed method on two commercial active (3dMD) and passive (DI3D) SP devices. The reliability of the pitch, roll and yaw for the board placement were within ±0.039904°, ±0.081623°, and ±0.062320°; where standard deviations were 0.020234°, 0.045645° and 0.027211° respectively., Conclusion: Orientation-calibrated stereo-photogrammetry is the most accurate method (angulation deviation within ±0.1°) reported for complete NHP recording with insignificant clinical error.

Objective: Genome-wide association studies have uncovered a large number of genetic variants associated with type 2 diabetes or related phenotypes. In many cases the causal gene or polymorphism has not been identified, and its impact on response to anti-hyperglycemic medications is unknown. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH, NCT01762046) is a novel resource of genetic and biochemical data following glipizide and metformin administration. We describe recruitment, enrollment, and phenotyping procedures and preliminary results for the first 668 of our planned 1,000 participants enriched for individuals at risk of requiring anti-diabetic therapy in the future., Methods: All individuals are challenged with 5 mg glipizide × 1; twice daily 500 mg metformin × 2 days; and 75-g oral glucose tolerance test following metformin. Genetic variants associated with glycemic traits and blood glucose, insulin, and other hormones at baseline and following each intervention are measured., Results: Approximately 50% of the cohort is female and 30% belong to an ethnic minority group. Following glipizide administration, peak insulin occurred at 60 minutes and trough glucose at 120 minutes. Thirty percent of participants experienced non-severe symptomatic hypoglycemia and required rescue with oral glucose. Following metformin administration, fasting glucose and insulin were reduced. Common genetic variants were associated with fasting glucose levels., Conclusions: SUGAR-MGH represents a viable pharmacogenetic resource which, when completed, will serve to characterize genetic influences on pharmacological perturbations, and help establish the functional relevance of newly discovered genetic loci to therapy of type 2 diabetes., Trial Registration: ClinicalTrials.gov NCT01762046.

Background: Various pathways have been implicated in the pathogenesis of heart failure (HF) with preserved ejection fraction (HFPEF). Inflammation in response to comorbid conditions, such as hypertension and diabetes, may play a proportionally larger role in HFPEF as compared to HF with reduced ejection fraction (HFREF)., Methods and Results: This study investigated inflammation mediated by the tumor necrosis factor-alpha (TNFα) axis in community-based cohorts of HFPEF patients (n = 100), HFREF patients (n = 100) and healthy controls (n = 50). Enzyme-linked immunosorbent assays were used to investigate levels of TNFα, its two receptors (TNFR1 and TNFR2), and a non-TNFα cytokine, interleukin-6 (IL-6), in plasma derived from peripheral blood samples. Plasma levels of TNFα and TNFR1 were significantly elevated in HFPEF relative to controls, while levels of TNFR2 were significantly higher in HFPEF than both controls and HFREF. TNFα, TNFR1 and TNFR2 were each significantly associated with at least two of the following: age, estimated glomerular filtration rate, hypertension, diabetes, smoking, peripheral vascular disease or history of atrial fibrillation. TNFR2 levels were also significantly associated with increasing grade of diastolic dysfunction and severity of symptoms in HFPEF., Conclusions: Inflammation mediated through TNFα and its receptors, TNFR1 and TNFR2, may represent an important component of a comorbidity-induced inflammatory response that partially drives the pathophysiology of HFPEF.

A rapid heuristic ratiometric analysis for estimating tissue hemoglobin concentration and oxygen saturation from measured tissue diffuse reflectance spectra is presented. The analysis was validated in tissue-mimicking phantoms and applied to clinical measurements in head and neck, cervical and breast tissues. The analysis works in two steps. First, a linear equation that translates the ratio of the diffuse reflectance at 584 nm and 545 nm to estimate the tissue hemoglobin concentration using a Monte Carlo-based lookup table was developed. This equation is independent of tissue scattering and oxygen saturation. Second, the oxygen saturation was estimated using non-linear logistic equations that translate the ratio of the diffuse reflectance spectra at 539 nm to 545 nm into the tissue oxygen saturation. Correlations coefficients of 0.89 (0.86), 0.77 (0.71) and 0.69 (0.43) were obtained for the tissue hemoglobin concentration (oxygen saturation) values extracted using the full spectral Monte Carlo and the ratiometric analysis, for clinical measurements in head and neck, breast and cervical tissues, respectively. The ratiometric analysis was more than 4000 times faster than the inverse Monte Carlo analysis for estimating tissue hemoglobin concentration and oxygen saturation in simulated phantom experiments. In addition, the discriminatory power of the two analyses was similar. These results show the potential of such empirical tools to rapidly estimate tissue hemoglobin in real-time spectral imaging applications.

In the pentameric ligand-gated ion channel family, transmitter binds in the extracellular domain and conformational changes result in channel opening in the transmembrane domain. In the muscle nicotinic receptor and other heteromeric members of the family one subunit does not contribute to the canonical agonist binding site for transmitter. A fundamental question is whether conformational changes occur in this subunit. We used records of single channel activity and rate-equilibrium free energy relationships to examine the β1 (non-ACh-binding) subunit of the muscle nicotinic receptor. Mutations to residues in the extracellular domain have minimal effects on the gating equilibrium constant. Positions in the channel lining (M2 transmembrane) domain contribute strongly and relatively late during gating. Positions thought to be important in other subunits in coupling the transmitter-binding to the channel domains have minimal effects on gating. We conclude that the conformational changes involved in channel gating propagate from the binding-site to the channel in the ACh-binding subunits and subsequently spread to the non-binding subunit.

A dramatic increase in the frequency of the H275Y mutation in the neuraminidase (NA), conferring resistance to oseltamivir, has been detected in human seasonal influenza A/H1N1 viruses since the influenza season of 2007-2008. The resistant viruses emerged in the ratio of 14.3% and quickly reached 100% in Taiwan from September to December 2008. To explore the mechanisms responsible for emergence and spread of the resistant viruses, we analyzed the complete genome sequences of 25 viruses collected during 2005-2009 in Taiwan, which were chosen from various clade viruses, 1, 2A, 2B-1, 2B-2, 2C-1 and 2C-2 by the classification of hemagglutinin (HA) sequences. Our data revealed that the dominant variant, clade 2B-1, in the 2007-2008 influenza emerged through an intra-subtype 4+4 reassortment between clade 1 and 2 viruses. The dominant variant acquired additional substitutions, including A206T in HA, H275Y and D354G in NA, L30R and H41P in PB1-F2, and V411I and P453S in basic polymerase 2 (PB2) proteins and subsequently caused the 2008-2009 influenza epidemic in Taiwan, accompanying the widespread oseltamivir-resistant viruses. We also characterized another 3+5 reassortant virus which became double resistant to oseltamivir and amantadine. Comparison of oseltamivir-resistant influenza A/H1N1 viruses belonging to various clades in our study highlighted that both reassortment and mutations were associated with emergence and spread of these viruses and the specific mutation, H275Y, conferring to antiviral resistance, was acquired in a hitch-hiking mechanism during the viral evolutionary processes.

Background: Flavivirus infected cells produce infectious virions and subviral particles, both of which are formed by the assembly of prM and E envelope proteins and are believed to undergo the same maturation process. Dengue recombinant subviral particles have been produced in cell cultures with either modified or chimeric proteins but not using the native forms of prM and E., Methodology/principal Findings: We have used a codon optimization strategy to obtain an efficient expression of native viral proteins and production of recombinant subviral particles (RSPs) for all four dengue virus (DV) serotypes. A stable HeLa cell line expressing DV1 prME was established (HeLa-prME) and RSPs were analyzed by immunofluorescence and transmission electron microscopy. We found that E protein is mainly present in the endoplasmic reticulum (ER) where assembly of RSPs could be observed. Biochemical characterization of DV1 RSPs secretion revealed both prM protein cleavage and homodimerization of E proteins before their release into the supernatant, indicating that RSPs undergo a similar maturation process as dengue virus. Pulse chase experiment showed that 8 hours are required for the secretion of DV1 RSPs. We have used HeLa-prME to develop a semi-quantitative assay and screened a human siRNA library targeting genes involved in membrane trafficking. Knockdown of 23 genes resulted in a significant reduction in DV RSP secretion, whereas for 22 others we observed an increase of RSP levels in cell supernatant., Conclusions/significance: Our data describe the efficient production of RSPs containing native prM and E envelope proteins for all dengue serotypes. Dengue RSPs and corresponding producing cell lines are safe and novel tools that can be used in the study of viral egress as well as in the development of vaccine and drugs against dengue virus.