Prediction of robotic neurorehabilitation functional ambulatory outcome in patients with neurological disorders.

INTRODUCTION: Conflicting results persist regarding the effectiveness of robotic-assisted gait training (RAGT) for functional gait recovery in post-stroke survivors. We used several machine learning algorithms to construct prediction models for the functional outcomes of robotic neurorehabilitation in adult patients. METHODS AND MATERIALS: Data of 139 patients who underwent Lokomat training at Taipei Medical University Hospital were retrospectively collected. After screening for data completeness, records of 91 adult patients with acute or chronic neurological disorders were included in this study. Patient characteristics and quantitative data from Lokomat were incorporated as features to construct prediction models to explore early responses and factors associated with patient recovery. RESULTS: Experimental results using the random forest algorithm achieved the best area under the receiver operating characteristic curve of 0.9813 with data extracted from all sessions. Body weight (BW) support played a key role in influencing the progress of functional ambulation categories. The analysis identified negative correlations of BW support, guidance force, and days required to complete 12 Lokomat sessions with the occurrence of progress, while a positive correlation was observed with regard to speed. CONCLUSIONS: We developed a predictive model for ambulatory outcomes based on patient characteristics and quantitative data on impairment reduction with early-stage robotic neurorehabilitation. RAGT is a customized approach for patients with different conditions to regain walking ability. To obtain a more-precise and clearer predictive model, collecting more RAGT training parameters and analyzing them for each individual disorder is a possible approach to help clinicians achieve a better understanding of the most efficient RAGT parameters for different patients. TRIAL REGISTRATION: Retrospectively registered.

Ets1 Promotes the Differentiation of Post-Selected iNKT Cells through Regulation of the Expression of Vα14Jα18 T Cell Receptor and PLZF.

The transcription factor Ets1 is essential for the development/differentiation of invariant Natural Killer T (iNKT) cells at multiple stages. However, its mechanisms of action and target genes in iNKT cells are still elusive. Here, we show that Ets1 is required for the optimal expression of the Vα14Jα18 T cell receptor (TCR) in post-selected thymic iNKT cells and their immediate differentiation. Ets1 is also critical for maintaining the peripheral homeostasis of iNKT cells, which is a role independent of the expression of the Vα14Jα18 TCR. Genome-wide transcriptomic analyses of post-selected iNKT cells further reveal that Ets1 controls leukocytes activation, proliferation differentiation, and leukocyte-mediated immunity. In addition, Ets1 regulates the expression of ICOS and PLZF in iNKT cells. More importantly, restoring the expression of PLZF and the Vα14Jα18 TCR partially rescues the differentiation of iNKT cells in the absence of Ets1. Taken together, our results establish a detailed molecular picture of how Ets1 regulates the stepwise differentiation of iNKT cells.

Novel design for a dynamic ankle foot orthosis with motion feedback used for training in patients with hemiplegic gait: a pilot study.

BACKGROUND: We designed a novel ankle foot orthosis (AFO), namely, ideal training AFO (IT-AFO), with motion feedback on the hemiparetic lower limb to improve ambulation in individuals with stroke-related hemiplegia. We, therefore sought to compare the kinematic parameters of gait between IT-AFO with and without dynamic control and conventional anterior-type AFO or no AFO. METHODS: Gait parameters were measured using the RehaWatch® system in seven individuals with hemiplegia (mean 51.14 years). The parameters were compared across four conditions: no AFO, conventional anterior AFO, IT-AFO without dynamic control, and IT-AFO with dynamic control, with three trials of a 10-m walk test for each. RESULTS: The dorsiflexion angle increased during the swing phase when the IT-AFO was worn, and it was larger with dynamic control. These data can confirm drop foot improvement; however, the difference between the parameters with- and without-AFO control conditions was not significant in the swing phase. The IT-AFO with or without dynamic control enhanced the loading response to a greater extent between the hemiparetic and unaffected lower limbs than conventional AFO or no AFO. The duration of the stance phase on the hemiparetic lower limb was also longer when using IT-AFO with and without dynamic control than that when using conventional AFO, which improved asymmetry. User comfort and satisfaction was greater with IT-AFO than with the other conditions. CONCLUSIONS: The IT-AFO with dynamic control improved gait pattern and weight shifting to the hemiparetic lower limb, reducing gait asymmetry. The difference with and without dynamic control of IT-AFO is not statistically significant, and it is limited by sample size. However, this study shows the potential of IT-AFO in applying positive motion feedback with gait training. TRIAL REGISTRATION: Taipei Medical University-Joint Institutional Review Board. N201510010 . Registered 12 February 2015. http://ohr.tmu.edu.tw/main.php .

Identification of low-molecular-weight vitellogenin 1 (Vg1)-like proteins as nucleotide excision repair (NER) factors in developing zebrafish (Danio rerio) using a transcription-based DNA repair assay.

Nucleotide excision repair (NER) removes helix-distorting DNA lesions such as UV-induced pyrimidine dimers and cisplatin-induced strand crosslinking. Our earlier studies have identified low-molecular-weight proteins homologous to the 150-kDa vitellogenin 1 (Vg1) as UV-damaged DNA-binding factors expressed in developing zebrafish (Danio rerio). This present study explored if Vg1-like proteins also participated in NER in zebrafish. Immunoblot analysis of affinity-captured 12 h post-fertilization (hpf) zebrafish extract proteins showed a transient binding of a 30-kDa Vg1-like polypeptide to UV-damaged DNA. A transcription-based in vitro repair assay revealed a significant up-regulation of UVC or cisplatin-suppressed transcriptional activity of a marker cDNA driven by a SP6 RNA polymerase-regulated promotor after incubating the damaged plasmid with the extracts of 12 hpf embryos or 96 hpf larvae. The up-regulation of UV or cisplatin-suppressed transcription was abolished in the presence of a monoclonal anti-zebrafish Vg1 antibody. The differential sensitivity of UV-induced repair in 12 and 96 hpf zebrafish extracts to exogenous ATP suggested a development-dependent expression of Vg1-like NER factors. A T4 endonuclease V digestion assay showed no inhibition of the anti-Vg1 antibody on the excision of UV-induced cyclobutane pyrimidine dimers. Our results identified the participation of Vg1-like factors in NER in developing zebrafish, and these factors may function at post-incison steps of NER.

Using non-invasive assessment methods to predict the risk of metabolic syndrome.

This study aimed to develop non-invasive assessment indicators for predicting the risk of metabolic syndrome. A cross-sectional study design with 154 convenient subjects recruited from the family clinics was used for this study. Physical assessment sheet, lifestyle profile, the heart rate variability assessment and standard blood sample tests were used to measure variables. The subjects were categorized into four groups based on the number of factors meeting the criteria for metabolic syndrome. After excluding invasive blood tests, the results of multivariate logistic regression identified non-invasive assessment (blood pressure, body mass index and very lower frequency of heart rate variability) were the significantly predictors of the risks of metabolic syndrome. When invasive blood test cannot be performed, community health care providers can use the non-invasive physical assessments to predict the risk of early-stage metabolic syndrome, consequently enabling them to implement related health education and interventions.

Neuronal population activity in the olivocerebellum encodes the frequency of essential tremor in mice and patients.

Essential tremor (ET) is the most prevalent movement disorder, characterized primarily by action tremor, an involuntary rhythmic movement with a specific frequency. However, the neuronal mechanism underlying the coding of tremor frequency remains unexplored. Here, we used in vivo electrophysiology, optogenetics, and simultaneous motion tracking in the Grid2dupE3 mouse model to investigate whether and how neuronal activity in the olivocerebellum determines the frequency of essential tremor. We report that tremor frequency was encoded by the temporal coherence of population neuronal firing within the olivocerebellums of these mice, leading to frequency-dependent cerebellar oscillations and tremors. This mechanism was precise and generalizable, enabling us to use optogenetic stimulation of the deep cerebellar nuclei to induce frequency-specific tremors in wild-type mice or alter tremor frequencies in tremor mice. In patients with ET, we showed that deep brain stimulation of the thalamus suppressed tremor symptoms but did not eliminate cerebellar oscillations measured by electroencephalgraphy, indicating that tremor-related oscillations in the cerebellum do not require the reciprocal interactions with the thalamus. Frequency-disrupting transcranial alternating current stimulation of the cerebellum could suppress tremor amplitudes, confirming the frequency modulatory role of the cerebellum in patients with ET. These findings offer a neurodynamic basis for the frequency-dependent stimulation of the cerebellum to treat essential tremor.

Recommendations and guidance for herpes zoster vaccination for adults in Taiwan.

Herpes zoster (HZ) is a painful, vesicular, cutaneous eruption from reactivation of varicella zoster virus (VZV), which can lead to potentially debilitating complications. The lifetime risk of HZ is estimated to be 20%-30% in the general population, with an increased risk in the elderly and immunocompromised populations. The most effective strategy to prevent HZ and its complications is by vaccination. Two types of HZ vaccines, zoster vaccine live and recombinant zoster vaccine, have been approved for use. This guidance offers recommendations and suggestions for HZ vaccination in adults, aiming to reduce the disease burden of HZ and its complications. It is intended as a guide to first-line healthcare providers, but does not supersede clinical judgement when assessing risk and providing recommendations to individuals. The Working Group on Adult Immunization Practice was appointed by the Infectious Diseases Society of Taiwan (IDST) and recommendations were drafted after a full literature review, using the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system. The recommendations were reviewed and revised by expert review panels during a series of consensus meetings and endorsed by the IDST, Taiwan Association of Family Medicine, the Taiwanese Dermatological Association, the Taiwan Oncology Society, the Taiwan Society of Blood and Marrow Transplantation, the Transplantation Society of Taiwan, the Taiwan AIDS Society, and the Taiwan College of Rheumatology. This guidance describes the epidemiology of HZ and provides recommendations for HZ vaccination in adults with varying levels of risk, differing history of previous VZV infection and past varicella or zoster vaccinations.

Enormous Asymptomatic Intraoral Sialolithiasis: A Case Report.

Sialolithiasis is one of the most common diseases of salivary glands. More than 80% of the sialoliths occur in the submandibular gland. While most of the calculi are less than 10 mm in size, 7.6% are larger than 15 mm and are classified as giant sialoliths. We demonstrate a rare case of asymptomatic giant sialolith in the left Wharton's duct with a total atrophy of the left submandibular salivary gland. A 48-year-old female patient presented with lumping sensation for 1 month. A left mouth floor mass was found accidentally during examination and was later revealed to be a painless sialolithiasis. Image study revealed a giant sialolith in the left Wharton's duct with duct dilatation and left submandibular gland total atrophy. She underwent transoral sialolithotomy with removal of a huge stone, measuring 3.5 × 1.4 cm in size. Sialolithiasis usually presents with typical symptoms of the involved salivary gland, and the size of calculi is usually less than 20 mm. This is a rare case report of an asymptomatic giant sialolith in the Wharton's duct, causing left submandibular salivary gland total atrophy, and its diagnosis and management.

Sample-to-answer sensing technologies for nucleic acid preparation and detection in the field.

Efficient sample preparation and accurate disease diagnosis under field conditions are of great importance for the early intervention of diseases in humans, animals, and plants. However, in-field preparation of high-quality nucleic acids from various specimens for downstream analyses, such as amplification and sequencing, is challenging. Thus, developing and adapting sample lysis and nucleic acid extraction protocols suitable for portable formats have drawn significant attention. Similarly, various nucleic acid amplification techniques and detection methods have also been explored. Combining these functions in an integrated platform has resulted in emergent sample-to-answer sensing systems that allow effective disease detection and analyses outside a laboratory. Such devices have a vast potential to improve healthcare in resource-limited settings, low-cost and distributed surveillance of diseases in food and agriculture industries, environmental monitoring, and defense against biological warfare and terrorism. This paper reviews recent advances in portable sample preparation technologies and facile detection methods that have been / or could be adopted into novel sample-to-answer devices. In addition, recent developments and challenges of commercial kits and devices targeting on-site diagnosis of various plant diseases are discussed.

Extended-Spectrum ß-Lactamases (ESBL) Producing Bacteria in Animals.

Animals have been identified as potential reservoirs and vectors of resistance genes, with studies showing that Gram-negative bacteria can acquire resistance through the horizontal transmission of resistance genes on plasmids. It is important to understand the distribution of antimicrobial-resistant bacteria and their drug-resistant genes in animals. Previous review articles mostly focused on a single bacterium or a single animal. Our objective is to compile all ESBL-producing bacteria isolated from various animals in recent years and provide a comprehensive viewpoint. Using a thorough PubMed literature search spanning from 1 January 2020 to 30 June 2022, studies exploring extended-spectrum beta-lactamase (ESBL) producing bacteria in animals were included. ESBL-producing bacteria are present in animals from various countries around the world. The most common sources of these bacteria were farm animals, and the most frequently isolated bacteria were Escherichia coli and Klebsiella pneumoniae. The most detected ESBL genes were blaTEM, blaSHV, and blaCTX-M. The presence of ESBL-producing bacteria in animals highlights the importance of the One Health approach to address the issue of antibiotic resistance. Further research is needed to better understand the epidemiology and mechanisms of the spread of ESBL-producing bacteria in animal populations and their potential impact on human and animal health.

Identification of combinatorial mutations associated with colistin resistance in Shewanella algae.

Colistin is a last-resort antibiotic used to treat infections caused by drug-resistant gram-negative bacteria. However, the genetic mechanisms underlying colistin resistance in Shewanella algae are not well understood. In this study, we sequenced and compared the genomes of 23 mcr-negative colistin-resistant and sensitive S. algae samples from various sources. We applied a computational approach to identify combinatorial mutations associated with colistin resistance. Our analysis revealed a combination of three mutations (PmrB 451, PmrE168, PmrH292) that were strongly associated with colistin resistance in S. algae. This study provides insights into the genetic mechanisms of colistin resistance in S. algae and demonstrates the utility of a computational approach for identifying epistatic interactions among mutations. Identifying the genetic mutations responsible for colistin resistance in S. algae can inform the development of new treatments or strategies to combat infections caused by this emerging pathogen.

Comparative Genomics Identified PenR E151V Substitution Associated with Carbapenem-Resistance Burkholderia cepacia Complex and a Novel Burkholderia cepacia Complex Specific OXA-1043 Subgroup.

Purpose: Burkholderia cepacia complex (Bcc) is a known significant opportunistic pathogen causing morbidity and mortality, particularly in those with cystic fibrosis, chronic granulomatous disease, or immunocompromising host. Mortality of Bcc bloodstream infections among non-cystic fibrosis patients remained high. The antibiotic treatment for Bcc infection is quite challenging due to its intrinsic resistance to most antibiotics, and the resistance to carbapenems was the biggest concern among them. We aimed to realize the mechanism of carbapenem resistance in Bcc. Patients and Methods: Ten strains of Bcc were identified by the MALDI-TOF MS, and the drug susceptibility test was using VITEK 2 system. The Burkholderia cepacia complex genomes were sequenced via Nanopore GridIon. We also downloaded another ninety-five strains of Bcc from the National Center for Biotechnology Information database to evaluate the divergence between carbapenem-resistance and carbapenem-sensitive strains. Results: The genetic organization between carbapenem-sensitive and carbapenem-resistant strains of Bcc showed no difference. However, in the carbapenem-sensitive strain, E151V substitution in PenR was detected. In addition, a novel specific OXA family subgroup, blaOXA-1043 in Burkholderia cenocepacia was discovered. Conclusion: The E151V substitution in PenR may be associated with carbapenem-sensitive in Bcc. Moreover, the V151E mutation in PenR may be related to the activation of PenB, leading to Bcc resistance to carbapenems. Besides, a novel OXA family subgroup, blaOXA-1043, was found in Burkholderia cenocepacia, which differs from the previous OXA family.

Diagnosis of Legionnaires' Disease Assisted by Next-Generation Sequencing in a Patient with COVID-19.

Coinfection in COVID-19 patients is associated with worsening outcome. Among patients with COVID-19, Legionella pneumophila, a common cause of pneumonia, has been reported as a co-occurring respiratory infection. A nonspecific clinical presentation, however, makes an early diagnosis difficult. Bronchoalveolar lavage fluid was collected from a patient suffering from COVID-19 and presenting with pneumonia and sent for metagenomic analysis. Differential abundance analysis was carried out by comparing each taxon reads per million between the bronchoalveolar lavage fluid sample and the negative control. Two replicates of metagenomic sequencing were conducted on bronchoalveolar lavage fluid samples. Within each replicated sequencing, one negative control was sequenced for comparison of taxon abundance in the BALF sample. In both replicates, Legionella pneumophila was the only taxon with significantly higher abundance when compared with the negative control. PCR of the bronchoalveolar further confirmed the presence of L. pneumophila. Several studies have estimated that the incidence of Legionnaires' disease co-infection in patients with COVID-19 infection is approximately 0% to 1.5%. There are some common characteristics of COVID-19 and co-infection with Legionnaires' disease, making it difficult to diagnose bacterial infection early. The diagnosis of these cases is important due to the different treatments used. Current diagnostic tests for Legionnaires' disease include conventional culture, urinary antigen for L. pneumophila serogroup 1, polymerase chain reaction, direct fluorescent antibody stain, and paired serology. The current study demonstrated that metagenomics is a promising approach that facilitated the diagnosis of Legionnaires' disease.

Identification of Cutibacterium modestum in Spondylitis by Metagenomics Analysis.

BACKGROUND/AIM: Identifying pathogens with culture-negative pyogenic spondylitis is difficult. Shotgun metagenomic sequencing is an unbiased and culture-free approach in the diagnosis of infectious diseases. There are, however, a variety of contaminating factors that can confound the precision of metagenomic sequencing. CASE REPORT: In a 65-year-old man suffering from culture-negative L3-5 spondylitis, metagenomics was applied to facilitate the diagnosis. The patient underwent percutaneous endoscopic lumbar discectomy. We applied metagenomic sequencing with a robust contamination-free protocol to the bone biopsy. By comparing the abundance for each taxon between the replicates and negative controls, we reliably identified Cutibacterium modestum as having a statistically higher abundance in all replicates. The patient's antibiotic therapy was switched to penicillin and doxycycline based upon the resistome analysis; the patient fully recovered. CONCLUSION: This application of next-generation sequencing provides a new perspective in the clinical approach to spinal osteomyelitis and illustrates the potential of this technique in rapid etiological diagnosis.

Is moderate resistance training adequate for older adults with sarcopenia? A systematic review and network meta-analysis of RCTs.

BACKGROUND: Resistance training (RT) and nutritional supplementation are recommended for the management of sarcopenia in older adults. However, optimal RT intensity for the treatment of sarcopenia has not been well investigated. METHODS: This network meta-analysis aims to determine the comparative effectiveness of interventions for sarcopenia, taking RT intensity into consideration. RT intensity was classified into light-to-moderate intensity RT(LMRT), moderate intensity RT(MRT), and moderate-to-vigorous intensity RT(MVRT) based on percentage of one repetition maximum (%1RM) and/or rating of perceived exertion. RESULTS: A total of 50 RCTs (N = 4,085) were included after screening 3,485 articles. The results confirmed that RT with or without nutrition was positively associated with improved measures of muscle strength and physical performance. Regarding RT intensity, LMRT only demonstrated positive effects on hand grip (aerobic training + LMRT + nutrition: mean difference [MD] = 2.88; 95% credential intervals [CrI] = 0.43,5.32). MRT provided benefits on improvement in the 30-s chair stand test (repetitions) (MRT: MD = 2.98, 95% CrI = 0.35,5.59), timed up and go test (MRT: MD = -1.74, 95% CrI: = -3.34,-0.56), hand grip (MRT: MD = 2.44; 95% CrI = 0.03,5.70), and leg press (MRT: MD = 8.36; 95% CrI = 1.87,13.4). MVRT also improved chair stand test repetitions (MVRT: MD = 5.64, 95% CrI = 0.14,11.4), gait speed (MVRT + nutrition: MD = 0.21, 95% CrI = 0.003,0.48), appendicular skeletal muscle index (MVRT + nutrition: MD = 0.25, 95% CrI = 0.01,0.5), and leg press (MVRT: MD = 14.7, 95% CrI: 5.96,22.4; MVRT + nutrition: MD = 17.8, 95% CrI: 7.55,28.6). CONCLUSION: MVRT had greater benefits on muscle mass, lower extremity strength, and physical performance compared to MRT. Increasing RT intensity may be recommended for sarcopenic older adults.

Effect of N-acetyl-cysteine in prevention of noise-induced hearing loss: a systematic review and meta-analysis of randomized controlled trials.

Introduction: Noise-induced hearing loss is one of the most prevalent causes of hearing impairment and occupational diseases. Although multiple factors lead to noise-induced hearing loss, prevention and protection strategies remain limited. Studies in the past decade have employed antioxidants, especially N-acetyl-cysteine, to prevent noise-induced hearing loss. Therefore, this systematic review and meta-analysis of randomized controlled trials evaluated the effect of N-acetyl-cysteine on the prevention of noise-induced hearing loss. Material and methods: This systematic review and meta-analysis included relevant studies from the Cochrane Library, EMBASE, PubMed, ScienceDirect, Scopus, and Web of Science by using related terms. The study only included randomized controlled trials in meta-analyses and assessed the quality of the identified randomized controlled trials by using the Cochrane Risk of Bias tool. Two authors extracted and calculated data on characteristics and hearing threshold. The results are presented as weighted mean difference (WMD) with 95% confidence interval (CI). Results: This study identified five randomized controlled trials that randomized 1,115 patients into N-acetyl-cysteine and control groups. The meta-analysis evidenced that N-acetyl-cysteine has greater protective effects against hearing threshold shifts than the control in the 0 to 4 kHz (WMD = -3.39, 95% CI: -6.56 to -0.22) and 0 to 6 kHz (MD = -3.49, 95% CI: -6.57 to -0.41) subgroups. Conclusions: The present review and meta-analysis recommends that N-acetyl-cysteine may be considered as an option for protective therapy for noise-induced hearing loss. Nonetheless, larger randomized controlled trials are requisite for further investigation and verification.

COVID-19 Screening for Hospitalized Patients: The Role of Expanded Hospital Surveillance in a Low Prevalence Setting.

PURPOSE: The COVID-19 pandemic poses a serious threat to healthcare workers and hospitalized patients. Early detection of COVID-19 cases is essential to control the spread in healthcare facilities. However, real-world data on the screening criteria for hospitalized patients remain scarce. We aimed to explore whether patients with negative results of pre-hospital screening for COVID-19 should be rescreened after admission in a low-prevalence (less than 3% of the world average) setting. PATIENTS AND METHODS: We retrospectively included patients in central Taiwan who were negative at the first screening but were newly diagnosed with pneumonia or had a body temperature above 38 degrees Celsius during their hospitalization. Each patient might be included as an eligible case several times, and the proportions of cases who were rescreened for COVID-19 and those diagnosed with COVID-19 were calculated. A logistic regression model was constructed to identify factors associated with rescreening. Reverse transcription-polymerase chain reaction tests were used to confirm the diagnosis of COVID-19. RESULTS: A total of 3549 cases eligible for COVID-19 rescreening were included. There were 242 cases (6.8%) who received rescreening. In the multivariable analysis, cases aged 75 years or older, those with potential exposure to SARS-CoV-2, or patients visiting specific departments, such as the Cardiovascular Center and Department of Neurology, were more likely to be rescreened. None was diagnosed with COVID-19 after rescreening. There was no known cluster infection outbreak in the hospital or in the local community during the study period and in the following two months. CONCLUSION: In Taiwan, a country with a low COVID-19 prevalence, it was deemed safe to rescreen only high-risk hospitalized patients. This strategy was effective and reduced unnecessary costs.

Real-World Experience with Coformulated Ledipasvir and Sofosbuvir for HIV-Positive Patients with HCV Genotype 2 Infection: A Multicenter, Retrospective Study.

INTRODUCTION: While coformulated ledipasvir (90 mg)/sofosbuvir (400 mg) (LDV/SOF) is approved for the treatment of hepatitis C virus (HCV) genotype 2 (GT2) infection in Taiwan, Japan, and New Zealand, data regarding its use for HIV (Human Immunodeficiency Virus)-positive patients infected with HCV GT2 are sparse. We aimed to assess the effectiveness and tolerability of LDV/SOF for HIV-positive patients with HCV GT2 coinfection. METHODS: From January 2019 to July 2020, consecutive HIV-positive Taiwanese patients infected with HCV GT2 who received LDV/SOF were retrospectively included for analysis. The effectiveness was determined by sustained virologic response 12 weeks off-therapy (SVR12). RESULTS: Of the 114 patients (mean age, 38.6 years) initiating LDV/SOF during the study period, 0.9% had liver cirrhosis and 4.4% were HCV treatment-experienced. All patients had estimated glomerular filtration rate (eGFR) > 30 ml/min/1.73 m2 and were receiving antiretroviral therapy with 98.2% having CD4 counts ≥ 200 cells/mm3 and 93.9% plasma HIV RNA load < 50 copies/ml. Antiretrovirals prescribed included tenofovir alafenamide/emtricitabine in 42.1%, tenofovir disoproxil fumarate (TDF)/emtricitabine 18.4%, other nucleoside reverse transcriptase inhibitors (NRTIs) 39.5%, non-NRTIs 12.3%, protease inhibitors 13.2%, and integrase inhibitors 74.6%. All patients had undetectable plasma HCV RNA load at the end of treatment, and 96.5% achieved SVR12 in intention-to-treat analysis. The on-treatment eGFR decline was more pronounced in those receiving TDF-containing antiretroviral therapy (mean change, - 8.33 ml/min/1.73 m2), which was reversible after discontinuation of LDV/SOF. None of the patients interrupted LDV/SOF during the 12-week treatment course. CONCLUSION: Similar to the response observed among HIV-negative patients, LDV/SOF is effective for HIV-positive patients coinfected with HCV GT2.

2019 novel coronavirus disease (COVID-19) in Taiwan: Reports of two cases from Wuhan, China.

We reported two cases with community-acquired pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who returned from Wuhan, China in January, 2020. The reported cases highlight non-specific clinical presentations of 2019 novel coronavirus disease (COVID-19) as well as the importance of rapid laboratory-based diagnosis.

Discovery of T-1101 tosylate as a first-in-class clinical candidate for Hec1/Nek2 inhibition in cancer therapy.

Highly expressed in cancer 1 (Hec1) plays an essential role in mitosis and is correlated with cancer formation, progression, and survival. Phosphorylation of Hec1 by Nek2 kinase is essential for its mitotic function, thus any disruption of Hec1/Nek2 protein-protein interaction has potential for cancer therapy. We have developed T-1101 tosylate (9j tosylate, 9j formerly known as TAI-95), optimized from 4-aryl-N-pyridinylcarbonyl-2-aminothiazole of scaffold 9 by introducing various C-4' substituents to enhance potency and water solubility, as a first-in-class oral clinical candidate for Hec1 inhibition with potential for cancer therapy. T-1101 has good oral absorption, along with potent in vitro antiproliferative activity (IC50: 14.8-21.5 nM). It can achieve high concentrations in Huh-7 and MDA-MB-231 tumor tissues, and showed promise in antitumor activity in mice bearing human tumor xenografts of liver cancer (Huh-7), as well as of breast cancer (BT474, MDA-MB-231, and MCF7) with oral administration. Oral co-administration of T-1101 halved the dose of sorafenib (25 mg/kg to 12.5 mg/kg) required to exhibit comparable in vivo activity towards Huh-7 xenografts. Cellular events resulting from Hec1/Nek2 inhibition with T-1101 treatment include Nek2 degradation, chromosomal misalignment, and apoptotic cell death. A combination of T-1101 with either of doxorubicin, paclitaxel, and topotecan in select cancer cells also resulted in synergistic effects. Inactivity of T-1101 on non-cancerous cells, a panel of kinases, and hERG demonstrates cancer specificity, target specificity, and cardiac safety, respectively. Subsequent salt screening showed that T-1101 tosylate has good oral AUC (62.5 µM·h), bioavailability (F = 77.4%), and thermal stability. T-1101 tosylate is currently in phase I clinical trials as an orally administered drug for cancer therapy.