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Background: To examine the efficacy and safety of patisiran, an RNA interference therapeutic, in patients from Taiwan with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy. Methods: The APOLLO phase 3 trial included patients from Taiwan who received patisiran 0.3 mg/kg intravenously or placebo once every 3 weeks (q3w) for 18 months (18 M), followed by patisiran 0.3 mg/kg q3w in an ongoing global open-label extension (OLE) study. The primary endpoint was change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 18 M. Results: Eighteen Taiwanese patients were enrolled in APOLLO (patisiran, n = 8; placebo, n = 10; all A97S gene variant) and 14 continued in the global OLE. In this Taiwanese sub-population, beneficial treatment effects at 18 M were observed in mNIS+7 (least squares mean difference in change from baseline [patisiran-placebo], −26.5 points; 95% confidence interval: −45.5, −7.5). Patients who switched from placebo to patisiran demonstrated slowing of polyneuropathy progression at month 12 in the global OLE, while those who received patisiran in APOLLO maintained the beneficial treatment effects. Patisiran had an acceptable safety profile in the Taiwanese sub-population. Conclusion: This analysis suggests that patisiran is well tolerated and may provide a substantial clinical benefit for Taiwanese patients with hATTR amyloidosis with polyneuropathy. Trial registration information: The studies were registered on the ClinicalTrials.gov. The APOLLO study ClinicalTrials.gov identifier is NCT01960348 (https://clinicaltrials.gov/ct2/show/NCT01960348), with the registration date of October 10, 2013, and the first patient was enrolled on December 13, 2013. For the global OLE, the ClinicalTrials.gov identifier is NCT02510261 (https://clinicaltrials.gov/ct2/show/NCT02510261) with the registration date of July 29, 2015, and the first patient was enrolled on July 13, 2015. Classification of evidence: This study provides Class II evidence that treatment with patisiran is safe and efficacious in Taiwanese patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy.

Abstract Background To investigate the peripheral nervous system involvement in S sialidosis with typical features of myoclonus, seizure, and giant waves in somatosensory evoked potentials suggesting hyperexcitability in the central nervous system. Methods The clinical presentation of patients with genetically confirmed sialidosis was recorded. Neurophysiological studies, including nerve conduction studies (NCSs), F-wave studies, and needle electromyography (EMG), were performed on these patients. Results Six patients (M/F: 2:4) were recruited. In addition to the classical presentation, intermittent painful paresthesia was noted in four patients, and three of whom reported it as the earliest symptom. In the NCSs, one patient had reduced compound muscle action potential amplitudes in the right ulnar nerve, while another patient had prolonged distal motor latency in the bilateral tibial and peroneal nerves. Prolonged F-wave latency (83.3%), repeater F-waves (50%), and neurogenic polyphasic waves in EMG (in 2 out of 3 examined patients) were also noted. Interestingly, a very late response was noted in the F-wave study of all patients, probably indicating lesions involving the proximal peripheral nerve or spinal cord. Conclusion In addition to the central nervous system, the peripheral nervous system is also involved in sialidosis, with corresponding clinical symptoms. Further study on these phenomena is indicated.

Humans are extensively exposed to organophosphate flame retardants (OPFRs), an emerging group of organic contaminants with potential nephrotoxicity. Nevertheless, the estimated daily intake (EDI) and prognostic impacts of OPFRs have not been assessed in individuals with chronic kidney disease (CKD). In this 2-year longitudinal study of 169 patients with CKD, we calculated the EDIs of five OPFR triesters from urinary biomonitoring data of their degradation products and analyzed the effects of OPFR exposure on adverse renal outcomes and renal function deterioration. Our analysis demonstrated universal OPFR exposure in the CKD population, with a median EDIΣOPFR of 360.45 ng/kg body weight/day (interquartile range, 198.35–775.94). Additionally, our study revealed that high tris(2-chloroethyl) phosphate (TCEP) exposure independently correlated with composite adverse events and composite renal events (hazard ratio [95 % confidence interval; CI]: 4.616 [1.060–20.096], p = 0.042; 3.053 [1.075–8.674], p = 0.036) and served as an independent predictor for renal function deterioration throughout the study period, with a decline in estimated glomerular filtration rate of 4.127 mL/min/1.73 m2 (95 % CI, −8.127–−0.126; p = 0.043) per log ng/kg body weight/day of EDITCEP. Furthermore, the EDITCEP and EDIΣOPFR were positively associated with elevations in urinary 8-hydroxy-2’-deoxyguanosine and kidney injury molecule-1 during the study period, indicating the roles of oxidative damage and renal tubular injury in the nephrotoxicity of OPFR exposure. To conclude, our findings highlight the widespread OPFR exposure and its possible nephrotoxicity in the CKD population.

Background: Treating marginalized populations with HCV infection for elimination is faced with the challenge for the integration of HCV screening service offered for patients often moving across multiple settings. We envisaged a novel collaborative care approach to identify to what extent HCV patients overlapped between and within these multiple institutions and reported the findings of treatment coverage of these marginalized populations after HCV care cascades. Methods: We enrolled 7765 patients residing in the Changhua County, Taiwan offered with HCV screening from correctional institutions, HIV clinics, methadone clinics, and the existing HIV surveillance program (four subgroups including police-arrested people, probationers, non-injection drug user, and high-risk behavior people) between 2019 and 2020. The collaborative care and information were integrated through a teamwork of gastroenterologists, psychologists, infectious disease specialists, and nursing coordinators under the auspices of local health authority. Results: The overall participation rate in HCV screening was 92.65% (7194/7765). The prevalence rate was the highest in methadone clinics (90.17%) followed by correctional institutions (37.67%), HIV clinics (34.60%), and the surveillance program (18.14%). We found 25.41% (77/303) of methadone clinic patients, 17.65% (129/731) of HIV clinic patients, and various proportions for 44.09% (41/93) of deferred prosecuted or probationers under surveillance program were also recruited into other settings. Individuals' patient flow within setting was more frequent than that between setting. After calibrating the overlap of patient flow, a total of 1700 anti-HCV positives out of 4074 after screening were traced with available follow-up information to complete 92.52% treatment coverage of 1177 RNA-positives (77.23%) diagnosed from 1524 undergoing RNA testing with similar findings across multiple settings. Conclusion: A new collaborative integrated care was adopted for elucidating patient flow between and within multiple settings in order to calibrate the accurate demand for HCV care cascades and enhance HCV treatment coverage in marginalized populations.

Background: Diabetic kidney disease (DKD) is one of the most significant public health burdens worldwide. This study explored the renal protections of combined adipose-derived mesenchymal stem cells (ADMSCs) and empagliflozin (EMPA) in DKD rats. Methods: Adult-male-SD rats were equally allocated into group 1 (sham-operated-control), group 2 (DKD), group 3 (DKD + EMPA/20 mg/kg/day since day-14 after CKD-induction), group 4 [DKD + ADMSCs (6.0 × 105/intrarenal-arterial-injection/post-day-28, followed by 1.2 × 106/intravenous injection post-days 35 and 42 after CKD-induction, i.e., defined as repeated administration)] and group 5 (DKD + ADMSCs + EMPA) and kidney was harvested post-day-60 CKD-induction. Results: The result showed that the blood sugar and circulatory levels of BUN/creatinine and the ratio of urine protein/creatinine at day 60 were greatly increased in group 2 as compared the SC (i.e., group 1), significantly increased in groups 3 and 4 than in groups 5, but these parameters showed the similar manner in groups 3 and 4, except for blood sugar that was significantly lower in group 3 than in group 4 (all p

Background: We tested the hypothesis that overexpression of cellular-prion-protein in adipose-derived mesenchymal stem cells (PrPC OE -ADMSCs) effectively protected the kidney against ischemia-reperfusion (IR) injury in rat. Methods: Part I of cell culture was categorized into A1(ADMSCs)/A2(ADMSCs+p-Cresol)/A3(PrPC OE in ADMSCs)/A4 (PrPC OE in ADMSCs+p-Cresol). Part II of cell culture was divided into B1(ADMSCs)/B2[ADMSCs+lipopolysaccharide (LPS)]/B3(PrPC OE in ADMSCs)/B4(PrPC OE in ADMSCs+LPS). Sprague-Dawley (SD) rats (n = 50) were equally categorized into groups 1 (sham-operated-control)/2 (IR)/3 (IR+ADMSCs/6.0 × 10 5 equally divided into bilateral-renal arteries and 6.0 × 10 5 intravenous administration by 1 h after IR)/4 [IR+PrPC OE -ADMSCs (identical dosage administered as group 3)]/5 [IR+silencing PRNP -ADMSCs (identical dosage administered as group 3)], and kidneys were harvested post-day 3 IR injury. Results: Part I results demonstrated that the cell viability at 24/48/72 h, BrdU uptake/number of mitDNA/APT concentration/mitochondrial-cytochrome-C+ cells and the protein expressions of ki67/PrPC at 72 h-cell culturing were significantly higher in PrPC OE -ADMSCs than in ADMSCs (all P < 0.001). The protein expressions of oxidative-stress (NOX-1/NOX2/NOX4/oxidized protein)/mitochondrial-damaged (p22-phox/cytosolic-cytochrome-C)/inflammatory (p-NF-κB/IL-1ß/TNF-α/IL-6)/apoptotic (cleaved caspase-3/cleaved-PARP) biomarkers were lowest in A1/A3 and significantly higher in A2 than in A4 (all P < 0.001). Part II result showed that the protein expressions of inflammatory (p-NF-κB/IL-1ß/TNF-α/IL-6)/apoptotic (cleaved caspase-3/cleaved-PARP) biomarkers exhibited an identical pattern of part I among the groups (all P < 0.001). The protein expressions of inflammatory (p-NF-κB/IL-1ß/TNF-α/MMP-9)/oxidative-stress (NOX-1/NOX-2/oxidized-protein)/mitochondrial-damaged (cytosolic-cytochrome-C/p22-phox)/apoptotic (cleaved caspase-3/cleaved-PARP/mitochondrial-Bx)/autophagic (beclin-1/ratio of LC3B-II/LC3B-I)/fibrotic (Smad3/TGF-ß) biomarkers and kidney-injury-score/creatinine level were lowest in group 1, highest in group 2, significantly higher in group 5 than in groups 3/4 (all P < 0.0001). Conclusion: PrPC OE in ADMSCs rejuvenated these cells and played a cardinal role on protecting the kidney against IR injury.

This paper proposed a fabrication of p-type Germanium (Ge) tri-gate field-effect transistors (Tri-gate FETs) via green nanosecond laser crystallization (GNSLC) and counter doping (CD). By using the GNSLC, the nano-crystalline-Ge (nc-Ge) with a grain size of 80 nm could be turned into polycrystalline Ge (poly-Ge) with that of above $1 ~\mu \text{m}$ . With the increase of laser power, the improved crystallinity and lower hole concentration of poly-Ge were also verified by Raman spectra and Hall measurement. To fabricate the high-performance Ge Tri-gate FETs, the chemical-mechanical planarization (CMP) and counter doping (CD) process would further be utilized. The CMP process eliminated the surface roughness of poly-Ge while the CD process decreased the hole concentration of poly-Ge or even converted that into an N-type one. The effect of the CD on the performance of p-type Ge Tri-gate FETs was further investigated. Consequently, the GNSLC Ge Tri-gate FETs showed threshold voltage (Vth) of −0.41 V, ION of $7.10\times 10\; ^{-6}$ , and IOFF of $1.28\times 10\; ^{-9}$ respectively, indicating better crystallinity of the Ge channel.

Background: Hereditary neuromuscular diseases (NMDs) are a group of rare disorders, and the diagnosis of these diseases is a substantial burden for referral centers. Although next-generation sequencing (NGS) has identified a large number of genes associated with hereditary NMDs, the diagnostic rates still vary across centers. Methods: Patients with a suspected hereditary NMD were referred to neuromuscular specialists at the National Taiwan University Hospital. Molecular diagnoses were performed by employing a capture panel containing 194 genes associated with NMDs. Results: Among the 50 patients referred, 43 had a suspicion of myopathy, and seven had polyneuropathy. The overall diagnostic rate was 58%. Pathogenic variants in 19 genes were observed; the most frequent pathogenic variant found in this cohort (DYSF) was observed in only four patients, and 10 pathogenic variants were observed in one patient each. One case of motor neuron disease was clinically mistaken for myopathy. A positive family history increased the diagnostic rate (positive: 72.7% vs. negative: 56.3%). Fourteen patients with elevated plasma creatine kinase levels remained without a diagnosis. Conclusion: The application of NGS in this single-center study proves the great diversity of hereditary NMDs. A capture panel is essential, but high-quality clinical and laboratory evaluations of patients are also indispensable.

BackgroundWe estimated healthcare resource utilization (HRU) and costs in patients with generalized myasthenia gravis (gMG) in Taiwan.MethodsThis retrospective population-based, matched cohort study used the National Health Insurance Research Database to identify prevalent patients with gMG (cases) in 2019. In total, 2537 cases were matched (1:4) by age, sex, and urbanization level to 10148 randomly selected patients without gMG (comparators). A generalized linear regression model predicted the frequency of HRU and costs among service users. Costs attributable to gMG were obtained by subtracting all-cause HRU costs incurred by comparators from cases.ResultsThe mean age of all patients was 54.99 years and 55.97% were female. Compared with comparators, cases had significantly higher rates of hypertension (33.03%/24.26%), diabetes mellitus (18.92%/11.37%), malignancies (16.00%/4.08%), cardiovascular disease (11.35%/8.12%), thyroid-related conditions (5.99%/1.16%), respiratory illness/disorders (4.38%/1.22%), and neurotic disorders (4.65%/2.6%). Amongst users of healthcare resources, cases had a mean 10 additional outpatient visits, 0.62 inpatient stays, and 0.49 emergency room visits in 2019 compared with comparators (p

BackgroundThe prevalence of myasthenia gravis is increasing in many countries, including Asia. As treatment options expand, population-based information about the disease burden can inform health technology assessments.MethodsWe conducted a population-based retrospective cohort study using the Taiwan National Healthcare Insurance Research database and Death Registry to describe the epidemiology, disease burden and treatment patterns of generalized myasthenia gravis (gMG) from 2009 to 2019. Episodes of hepatitis B virus (HBV) infection or reactivation were explored.ResultsThe number of patients with gMG increased from 1,576 in 2009 to 2,638 in 2019 and the mean (standard deviation) age from 51.63 (17.32) to 55.38 (16.29) years. The female:male ratio was 1.3:1. Frequently reported co-morbidities were hypertension (32–34% of patients), diabetes mellitus (16–21%) and malignancies (12–17%). The prevalence of patients with gMG increased annually from 6.83/100,000 population in 2009 to 11.18/100,000 population in 2019 (p

Abstract Objective Mutations in the colony‐stimulating factor 1 receptor gene (CSF1R) were identified as a cause of adult‐onset inherited leukoencephalopathy. The present study aims at investigating the frequency, clinical characteristics, and functional effects of CSF1R mutations in Taiwanese patients with adult‐onset leukoencephalopathy. Methods Mutational analysis of CSF1R was performed in 149 unrelated individuals with leukoencephalopathy by a targeted resequencing panel covering the entire coding regions of CSF1R. In vitro analysis of the CSF1‐induced autophosphorylation activities of mutant CSF1R proteins was conducted to assess the pathogenicity of the CSF1R mutations. Results Among the eight CSF1R variants identified in this study, five mutations led to a loss of CSF1‐induced autophosphorylation of CSF1R proteins. Four mutations (p.K586*, p.G589R, p.R777Q, and p.R782C) located within the tyrosine kinase domain of CSF1R, whereas the p.T79M mutation resided in the immunoglobulin‐like domain. The five patients carrying the CSF1R mutations developed cognitive decline at age 41, 43, 50, 79, and 86 years, respectively. Psychiatric symptoms and behavior changes were observed in four of the five patients. The executive function and processing speed were severely impaired at an early stage, and their cognitive function deteriorated rapidly within 3–4 years. Diffusion‐restricted lesions at the subcortical regions and bilateral corticospinal tracts were found in three patients. Interpretation CSF1R mutations account for 3.5% (5/149) of the adult‐onset leukoencephalopathy in Taiwan. CSF1R mutations outside the tyrosine kinase domain may also disturb the CSF1R function and lead to the clinical phenotype. Molecular functional validation is important to determine the pathogenicity of novel CSF1R variants.

Abstract Background This study tested whether human induced-pluripotent stem-cell-derived mesenchymal-stem-cells (iPS-MSCs) would offer an additional benefit to the rodent with acute kidney injury (AKI) (ischemia for 1 h followed by reperfusion for 120 h) associated sepsis syndrome (SS) (by cecal-ligation-puncture immediately after AKI-induction) undergoing ciprofloxacin therapy. Results Male-adult SD rats (n = 80) were categorized into group 1 (sham-operated-control, n = 10), group 2 (AKI + SS, n = 24), group 3 (AKI + SS + ciprofloxacin/3 mg/kg, orally for 120 h, n = 12), group 4 (AKI + SS + iPS-MSCs/1.2 × 106/intravenously administered by 3 h after AKI, n = 12), group 5 (AKI + SS + iPS-MSCs/1.2 × 106/intravenously administered by 18 h after AKI, n = 12), group 6 (AKI + SS + iPS-MSCs/1.2 × 106/intravenously administered by 3 h after AKI induction + ciprofloxacin, n = 10] and euthanized by 120 h. The result showed that the mortality was significantly higher in group 2 than in other groups (all p

Background: Identification and treatment for latent tuberculosis infection (LTBI) are of great epidemiological importance of controlling tuberculosis (TB) worldwide. Identification in high-risk population on dialysis and treatment with 12-week weekly rifapentine plus isoniazid (3HP) help improve prevention outcomes effectively. Methods: We conducted a single-center, nonrandomized follow-up study on end-stage renal disease patients on hemodialysis. The interferon-gamma release assay (IGRA) was used for the diagnosis of LTBI. Participants were treated with 3HP, and treatment responses were recorded and analyzed. Results: A total of 123 of the 641 patients showed positive IGRA results. The male sex, age >60 years, low serum albumin level ( 10.2 mg/dL) were associated with IGRA positivity. Seventy-five patients were treated with 3HP, with a completion rate of 66.67%. The male sex, albumin level >4.0 g/dL, and absence of adverse drug reaction were associated with increased completion rates. Adverse drug reactions included dizziness, fatigue, nausea and vomiting, fever, and hypertension. Conclusion: Risk factors for LTBI in dialysis patients were identified to prioritize LTBI screening and initiate early treatment. The completion rate in dialysis patients were approximately 2 of 3 patients with mild adverse drug reaction, leading to discontinuation of the treatment.

Abstract Background This study tested the hypothesis that combined melatonin (Mel) and adipose-derived mesenchymal stem cells (ADMSCs) treatment was superior to either one alone on protecting the testis against acute testicular torsion-induced ischemia-reperfusion (TTIR) injury. Methods and results Male adult SD rats (n = 30) were equally categorized into group 1 (sham-operated control), group 2 [TTIR/by torsion of right/left testis (i.e., ischemia) with rotated 720° counterclockwise for 2 h, then detorsion (i.e., reperfusion) to the original position for 72 h], group 3 (TTIR + Mel/intraperitoneal administration/50 mg/kg at 30 min after ischemia, followed by 20 mg at 3 h and days 1/2/3 after TTIR), group 4 (TTIR + ADMSCs/1.2 × 106 cells/by tail-vein administration at 30 min after ischemia, followed by days 1/2 TTIR), and group 5 (TTIR + Mel + ADMSCs/tail-vein administration). The result showed that the protein expressions of oxidative-stress (NOX-1/NOX-2/oxidized-protein), apoptotic/mitochondrial-damaged (mitochondrial-Bax/cleaved-caspase3/cleaved-PARP/cytosolic-cytochrome C), and fibrotic (TGF-ß/Smad3) biomarkers as well as testicular damage scores were lowest in group 1, highest in group 2, and significantly higher in groups 3/4 than in group 5, but they showed no difference between groups 3/4, whereas the protein expressions of androgen receptor (AR) and vimentin showed an opposite pattern of oxidative stress (all p < 0.0001). The cellular levels of inflammation (MMP-9/MPO/CD68) exhibited an identical pattern, whereas the numbers of Sertoli cells, α-tubulin, AR and vimentin as well as thickness of seminiferous tubule exhibited an opposite pattern of oxidative stress among the groups (all p < 0.0001). Conclusion Mel-ADMSCs effectively protected the testis against TTIR injury.

Background/Purpose: Multiple sclerosis is classified as a rare disease in Taiwan. This study evaluated the safety and effectiveness of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS) from routine clinical practice in Taiwan. Methods: In this retrospective, multicentre, observational study, we collected clinical data of patients treated with fingolimod 0.5 mg/day in routine clinical practice between September 2012 and December 2015. Primary outcome was the overall safety of fingolimod; secondary outcome was the annualized relapse rate (ARR). Results: Overall, 62/69 (86.1%) patients were on fingolimod by the end of data collection period. Mean age (±standard deviation [SD]) at inclusion was 37.7 ± 10.10 years; mean duration of MS was 5.4 ± 4.52 years and mean duration of fingolimod exposure was 135.8 patient-years. The most common adverse events (AEs) were bradycardia (21.7%; first-dose related), upper respiratory tract infection, dizziness, and hypoaesthesia (numbness) (11.6% each), followed by urinary tract infection and back pain (7.2% each). Seven patients had liver enzyme-related AEs. Eight patients had absolute lymphocyte counts

Li et al. show that dipeptidyl peptidase 4 (DPP4) promotes peritoneal fibrosis whereas the inhibition of DPP4 protects the patients from failure of peritoneal dialysis. This study provides mechanistic insights into the effects of DPP4 on peritoneal fibrosis and the translational potential of these effects.

Abstract Background This was a randomized, open‐label, controlled phase II clinical trial to investigate the safety, efficacy, and outcomes of intrarenal artery infusion of autologous peripheral‐blood‐derived CD34+ cells for patients with chronic kidney disease (CKD; ie, stage III or IV). Materials and Methods Between October 2016 and July 2018, 52 consecutive patients with CKD at stage III or IV were randomly allocated into a treatment group (TG; 2.5 × 107 cells for each intrarenal artery; n = 26) and a control group (CG; standardized pharmacotherapy only; n = 26). The primary endpoints included safety and change of creatinine level/creatinine clearance. The secondary endpoints were 12‐month combined unfavorable clinical outcomes (defined as dialysis or death), improvement in proteinuria, and CD34+ cell‐related adverse events. Results All patients were uneventfully discharged after CD34+ cell therapy. The baseline endothelial progenitor cell (EPC) populations did not differ between TG and CG (P > .5). Flow cytometric analysis showed increases in circulating EPC (ie, CD34+KDR+CD45dim/ CD34+CD133+CD45dim/CD31+CD133+CD45dim/CD34+CD133+KDR+/CD133+) and hematopoietic stem cell (CD34+) populations after granulocyte‐colony stimulating factor treatment (all P .1). Conclusion CD34+ cell therapy was safe and improved 1‐year outcome.

Background: The cardiac manifestations of late-onset hereditary transthyretin amyloidosis with p.A97S variant have not been extensively studied, and the prognostic factors remain unclear. Methods: The clinical profile, echocardiography, and ECG of patients diagnosed with ATTR p.A97S polyneuropathy between 2000 and 2016 were retrospectively collected. 67 patients with ATTR p.A97S were collected. Results: A total of 82% of patients met the criteria for left ventricular (LV) hypertrophy. Reduced global longitudinal strain (GLS) was noted in 42.1% of patients, and 14% of patients had a relative apical sparing pattern. A low voltage pattern in the ECG was observed in 31.3% of patients, while 64.2% presented with a pseudoinfarction pattern. End-systolic LV inner dimension (HR: 2.25 (95% CI: 1.01–5.01), p = 0.048), reduced GLS (HR: 5.26 (1.08–25.0), p = 0.039), relative apical longitudinal strain (RALS>1, HR: 8.57 (1.69–43.3), p = 0.009), increased E/A ratio (HR: 6.51 (1.17–36.4), p = 0.033), and increased QRS duration (HR: 1.02 (1.00–1.04), p = 0.05) were correlated with reduced survival in univariate analysis. Multivariate analysis revealed reduced RALS was significantly correlated with reduced survival (HR: 13.00 (1.81–93.45), p = 0.011). Conclusion: Our findings reveal that ATTR p.A97S is a cardiomyopathy as well as a polyneuropathic syndrome. Routine use of more contemporary echocardiographic techniques are recommended to identify cardiac amyloidosis and provide prognostic information. Keywords: Hereditary transthyretin amyloidosis, Familial amyloidotic polyneuropathy, p.A97S, Global longitudinal strain

This study tested the hypothesis that intrarenal arterial transfusion of oxidized low-density lipoprotein (ox-LDL) jeopardized the residual renal function and kidney architecture in rat chronic kidney disease ((CKD), i.e., induced by 5/6 nephrectomy) that was reversed by rosuvastatin. Cell culture was categorized into A1 (NRK-52E cells), A2 (NRK-52E + TGF-β), A3 (NRK-52E + TGF-β + ox-LDL) and A4 (NRK-52E + TGF-β + ox-LD). The result of in vitro study showed that cell viability (at 24, 48 and 72 h), NRK-52E ox-LDL-uptake, protein expressions of epithelial–mesenchymal–transition (EMT) markers (i.e., p-Smad2/snail/α-SMA/FSP1) and cell migratory and wound healing capacities were significantly progressively increased from A1 to A4 (all p < 0.001). SD rats were categorized into group 1 (sham-operated control), group 2 (CKD), group 3 (CKD + ox-LDL/0.2 mg/rat at day 14 after CKD induction) and group 4 (CKD + ox-LDL-treated as group 3+ rosuvastatin/10 mg/kg/day by days 20 to 42 after CKD induction) and kidneys were harvested at day 42. The circulatory levels of BUN and creatinine, ratio of urine-protein to urine-creatinine and the protein expressions of the above-mentioned EMT, apoptotic (cleaved-caspase3/cleaved-PARP/mitochondrial-Bax) and oxidative-stress (NOX-1/NOX-2/oxidized-protein) markers were lowest in group 1, highest in group 3 and significantly higher in group 4 than in group 2 (all p < 0.0001). Histopathological findings demonstrated that the kidney injury score, fibrotic area and kidney injury molecule-1 (KIM-1) displayed an identical pattern, whereas the cellular expression of podocyte components (ZO-1/synaptopodin) exhibited an opposite pattern of EMT markers (all p < 0.0001). In conclusion, ox-LDL damaged the residual renal function and kidney ultrastructure in CKD mainly through augmenting oxidative stress, EMT and fibrosis that was remarkably reversed by rosuvastatin.

A 25-year-old man complained of progressive diplopia and limb weakness for 3 years. Mitochondrial myopathy was suspected according to clinical presentation, elevated serum lactate concentration, and muscle histopathology. However, next-generation mtDNA sequencing (mtDNA NGS) of the blood only revealed a likely benign variant in the MT-CO1 gene (m.6510G > A). An mtDNA NGS study on the muscle sample revealed a large mtDNA deletion (m.5788–m.16071). The patient was diagnosed as having CPEO-plus syndrome related to the large mtDNA deletion. Notably, magnetic resonance spectroscopy revealed a doublet peak at 1–2 ppm in his edematous right vastus lateralis, which indicated lactate accumulation. Thus, muscle imaging and appropriate genetic tests facilitated the diagnosis of mitochondrial myopathy.

Abstract Background Migraine ranks as the third most prevalent disease and the seventh most common cause of disability worldwide. To better understand the impact of migraine on the quality of life of individuals with this diagnosis, and how these might differ from one country or culture to another, reliable and valid measures of quality of life that are available in different languages are needed. To address this need, here we (1) translated the Migraine-Specific Quality of Life Questionnaire into Chinese (MSQv2.1-C), and (2) examined the psychometric properties of the measure. Methods Forward and backward translation was conducted using four bilingual experts. One native speaker finalized the translation. Cognitive testing was performed by interviewing 11 monolingual migraineurs, and modifications were made to the MSQv2.1-C, as appropriate. Next, 174 individuals with a history of migraine completed the MSQv2.1-C, along with the SF-12, Migraine Disability Assessment Scale, and numerical rating scale s assessing pain intensity. We then evaluated the reliability and validity of the MSQv2.1-C by performing analyses to evaluate its internal consistency, test-retest reliability, convergent validity, criterion validity, and construct validity. Results The MSQv2.1-C scales demonstrated (1) good internal consistency (Cronbach’s alpha s ≥ 0.81); (2) good 1-week test-retest reliability (intra-class coefficients ≥0.69 and Spearman’s rho correlation coefficients ≥0.74); (3) convergent validity (positive correlations with the MSQ and SF-12 scales [rho range = 0.27 to 0.37, ps 0.5]). Conclusions The MSQv2.1-C exhibited satisfactory reliability and validity in a sample of individuals with migraine who speak Chinese. The availability of this measure will facilitate research, including cross-cultural research, on the quality of life of individuals with migraine.

Background: Endothelial cell dysfunction plays the crucial role in initiation and propagation of obstructive arteriosclerosis which ultimately causes arterial obstructive syndrome. Additionally, severe endothelial progenitor cells (EPC) dysfunction is always found in those of end-stage renal disease (ESRD) patients. This study tested the hypothesis that a novel method, named “quality and quantity (QQ) culture”, could successfully improve the EPC proliferation and function in ESRD patients. Materials and methods: Peripheral blood mononuclear cells (PBMNCs) were isolated from age-matched control subjects (i.e., normal renal function) (group 1) and ESRD patients (group 2), followed by culture in either conventional EPC culture for one month or in QQ culture for 7 days, respectively. The result showed that as compared to the conventional EPC culture method, the EPC population and M2-like population/ratio (M2/M1) were significantly enriched in QQ culture both in groups 1 and 2 (all p

Abstract Development of manufacture trend for TFTs technologies has focused on improving electrical properties of films with the cost reduction to achieve commercialization. To achieve this goal, high-performance sub-50 nm TFTs-based MOSFETs with ON-current (Ion)/subthreshold swing (S.S.) of 181 µA/µm/107 mV/dec and 188 µA/µm/98 mV/dec for NMOSFETs and PMOSFETs in a monolithic 3D circuit were demonstrated by a low power with low thermal budget process. In addition, a stackable static random access memory (SRAM) integrated with TFTs-based MOSFET with static noise margins (SNM) equals to 390 mV at VDD = 1.0 V was demonstrated. Overall processes include a low thermal budget via ultra-flat and ultra-thin poly-Si channels by solid state laser crystallization process, chemical-mechanical polishing (CMP) planarization, plasma-enhanced atomic layer deposition (ALD) gate stacking layers and infrared laser activation with a low thermal budget. Detailed material and electrical properties were investigated. The advanced 3D architecture with closely spaced inter-layer dielectrics (ILD) enables high-performance stackable MOSFETs and SRAM for power-saving IoT/mobile products at a low cost or flexible substrate.

We introduce a single-grain gate-all-around (GAA) Si nanowire (NW) FET using the location-controlled-grain technique and several innovative low-thermal budget processes, including green nanosecond laser crystallization, far-infrared laser annealing, and hybrid laser-assisted salicidation, that keep the substrate temperature (Tsub) lower than 400 °C for monolithic three-dimensional integrated circuits (3D-ICs). The detailed process verification of a low-defect GAA nanowire and electrical characteristics were investigated in this article. The GAA Si NW FETs, which were intentionally fabricated within the controlled Si grain, exhibit a steeper subthreshold swing (S.S.) of about 65 mV/dec., higher driving currents of 327 µA/µm (n-type) and 297 µA/µm (p-type) @ Vth ± 0.8 V, and higher Ion/Ioff (>105 @|Vd| = 1 V) and have a narrower electrical property distribution. In addition, the proposed Si NW FETs with a GAA structure were found to be less sensitive to Vth roll-off and S.S. degradation compared to the omega(Ω)-gate Si FETs. It enables ultrahigh-density sequentially stackable integrated circuits with superior performance and low power consumption for future mobile and neuromorphic applications.

ImportanceCIS to MS conversion rates vary depending on population cohorts, initial manifestations, and durations of follow-up.ObjectiveTo investigate conversion rate of patients from CIS to MS and the prognostic significance of demographic and clinical variables in Taiwanese population.DesignNationwide, prospective, multi-centric, observational study from November 2008 to November 2014 with 4 years follow-up.SettingMulti-centre setting at 5 institutions in Taiwan.Participants152 patients having single clinical event potentially suggestive of MS in last 2 years were enrolled as consecutive sample. 33 patients were lost to follow-up and 16 patients did not complete the study.103 patients completed the study.Intervention(s) (for clinical trials) or exposure(s) (for observational studies)Natural progression from first episode of CIS to MS or NMO was observed.Main outcome(s) and measure(s)Variables analysed were 'proportion of patients converting to MS or NMO after first episode of CIS', 'duration between first episode of neurological event and diagnosis of MS', 'status of anti-AQP4 IgG' and 'length of longest contiguous spinal cord lesion in MS patients'. Association between baseline characteristics and progression to MS from CIS was analyzed using multiple logistic regression. Multivariate time dependent effect of baseline characteristics on progression to MS was plotted.Results14.5% patients with CIS converted to MS after 1.1 ± 1.0 years with greater predisposition (18.8%) in those having syndromes referable to the cerebral hemispheres. Conversion rate from ON to MS was 9.7%. 90.9% patients had mild disease course. 46.7% patients had abnormal MRIs at baseline, with 0.6±0.5 contrast enhanced lesions. 'Below normal BMI' and 'MRI lesion load (≥ 4 lesions)' were identified as risk indicators for the development of MS. Amongst the patients who developed NMO as diagnosed by modern criteria, 80% were positive for anti-AQP4 IgG antibody.Conclusions and relevance'Below normal BMI' and 'number of demyelinating lesions (≥4)' are significant predictors of conversion from CIS to MS. A low conversion rate to MS in Taiwanese CIS patients and majority of them having a mild course and minimal disability suggest the roles of geographic, genetic and ethnic factors.Trial registrationNon-trial observational study.

Two parts of work are included in this paper. In the first part, the novel Ge gate-all-around field effect transistors (GAA FETs) are introduced and discussed. Fabrication of Ge GAA FETs requires only simple top-down dry etching and blanket Ge epitaxy techniques readily available in mass production. First, a novel process to etch away the defective Ge near Ge/Si interface from epitaxial Ge grown on SOI achieves a nearly defect-free channel, good gate control triangular gate, larger effective width than rectangular fin, and have low punch-through current through the Si substrate. By dislocation removal, the defect-free Ge channel can be formed on nothing. The p-channel triangular Ge GAA FET with fin width (Wfin) of 52 nm and Lg of 183 nm has Ion/Ioff = 105, SS = 130 mV/dec, and Ion = 235 μA/μm at -1 V. Next, due to the highest electron mobility (2200 cm2/Vs) on (111) Ge surface, the n-channel triangular Ge GAA FET with (111) sidewalls on Si and Lg = 350 nm shows 2 times enhanced Ion with respect to the devices with near (110) sidewalls. Electrostatic control of SS = 94 mV/dec (at 1 V) can be further improved if superior gate stack than EOT = 5.5 nm and Dit = 1×1012 cm-2·eV-1 is used. The Ion can be further enhanced if the line edge roughness (LER) can be reduced. Second, a feasible pathway to scale the Ge MOSFET technology by using a novel diamond-shaped Ge GAA FET with four {111} facets is also reviewed. The proposed dry etching process involves three isotropic/anisotropic etching steps with different Cl2/HBr ratios for forming the suspended diamond-shaped channel. Taking advantages of the GAA configuration, favorable carrier mobility of the {111} surface, and nearly defect-free suspended channel, nFET and pFET with excellent performance have been demonstrated, including an Ion/Ioff ratio exceeding 108, the highest ever reported for Ge-based pFETs. The TMD FinFET devices are reviewed in the second part of this paper. The TMD FinFET channel is deposited by CVD. MoS2 covered on Si fin and nanowire resulted in improved (+25%) Ion of the FinFET and nanowire FET. The PFETs also operated effectively and the N/P device Vth are low and matched perfectly. The proposed heterogeneous Si/TMD 3DFETs can be useful in future electronics. Furthermore, a 4 nm thin transition-metal dichalcogenide (TMD) body FinFET with back gate control is also proposed and reviewed. Hydrogen plasma treatment of TMD is employed to lower the series resistance. The 2 nm thin back gate oxide enables 0.5 V of Vth shift with 1.2 V change in back bias for correcting device variations and dynamically configuring a device as a high performance or low leakage device. TMD can potentially provide sub-nm thin monolayer body needed for 2 nm node FinFET.

Bimetallic Pt–Au and Fe–Pt nanoparticles are successfully fabricated by high-intensity laser irradiation of aqueous solution without any chemical reducing agent. The mechanism of the formation of bimetallic nanoalloys by laser irradiation of the solution without using any reducing agent was mainly attributed to the optically induced decomposition of water molecule. When an intense femtosecond laser field is focused in an aqueous solution containing metal ions, the free electrons will be produced by the dissociation of water molecules, these free electrons and hydrogen radicals contained in the plasma might be caught by H+ or OH− ions to form the bubbles of H2 and O2 gases or they can be trapped by metal ions, resulting in the formation of metal atoms during the femtosecond laser irradiation process. The average size of the bimetallic nanoparticles increases with irradiation time. This technique is simple and ‘green’ process without using any chemicals except for metal salt and dispersing agent.

Background: In the face of increasing treatment options for extended-spectrum beta-lactamase-producing Klebsiella pneumoniae (ESBL-Kp) hemodialysis (HD) access-related bacteremia, the difference in clinical effectiveness between ertapenem and flomoxef remains unclear. We conducted this retrospective study to determine their efficacies and treatment outcomes. Methods: Patients on maintenance HD with fistula-, graft-, or catheter-related ESBL-Kp bacteremia were enrolled. Data related to clinical features and antibiotic treatments were collected. Outcome was determined by mortality resulting from bacteremia during the 14-day period after the collection of the first positive blood culture for flomoxef-susceptible ESBL-Kp. Results: The 64 patients studied had severe septicemia as determined by the Pitt bacteremia score; 50% (32/64) were in the intensive care unit (ICU) at the time of bacteremia. Old age (>65 years; 57.8%), malnutrition (albumin 30 days; 75%) were also highly prevalent. The study population comprised nine fistula-, 10 graft-, and 45 HD catheter-related bacteremia cases, and the mortality rate was high (38/64, 59.4%). The mortality rate was significantly higher in the flomoxef treatment group than in the ertapenem treatment group (22/30, 73% vs. 16/34, 47%, p

Metal and metal alloy nanopowders were prepared by using the microwave plasma synthesis method. The microwave plasma was operated in atmospheric pressure at a frequency of 2.45 GHz. The precursor decomposed thermally in the plasma reaction region and the products were then condensed in the heat exchanger, were separated from the gas by the powder filter, and then finally collected in the powder collector. The effect of various processing parameters such as plasma gas, carrier gas, cooling gas, precursor raw materials and feeding rate were studied in this work. Cu, Mo, W, Mo-Ni and Fe-Co nanopowders were successfully prepared by using the microwave plasma synthesis method. The processing conditions can be tuned to manipulate the particle size of the nanopowders.

Niemann-Pick type C disease (NPC) is a rare autosomal recessive lipid storage disorder caused by impaired cellular functions in processing and transporting low-density lipoprotein-cholesterol. In this report, we present magnetic resonance imaging (MRI), magnetic resonance spectrography (MRS) and 18-fluoro-2-deoxyglucose positron emission tomography (PET) imaging results for a 22-year-old male NPC patient. The patient's two MRI studies (at age 19 years and 22 years) demonstrated progressive changes of brain atrophy that were more prominent at the frontal lobes, and hyperintense signals in bilateral parietal-occipital periventricular white matter. MRS (at age 19 years) revealed no significant decrease in N-acetyl aspartate/choline ratio in the left frontal central white matter. PET (at age 22 years) showed significant bilateral hypometabolism in the prefrontal cortex and dorsomedial thalamus, and hypermetabolism in the parietal-occipital white matter, lenticular nucleus of the basal ganglia, cerebellum and pons. The imaging findings noted by MRI, MRS and 18-fluoro-2-deoxyglucose PET offered a possible supplementary explanation for the clinical neurological symptoms of this NPC patient.

Sarcoidosis is a chronic inflammatory disease that involves multiple systems. Complications in the nervous system are rare, especially in Asia. This report describes an unusual case of neurosarcoidosis affecting the spinal cord and other systems in a 53-year-old Taiwanese women patient. The patient presented with subacute onset of right arm radicular pain followed by quadriparesis. Magnetic resonance imaging revealed a hyperintense lesion on T2WI in the cervical spinal cord. The patient also had a history of facial neuropathy, bilateral parotid enlargement, intrathoracic lymphadenopathy, hypercalcemia, nephrocalcinosis, and renal function impairment. Parotid gland biopsy showed granulomatous lesion with multinucleated giant cells. Sarcoidosis was diagnosed after other possibilities were excluded. Oral steroid treatment resulted in initial significant clinical improvement. Awareness of the systemic and neurological presentations of sarcoidosis can prompt the correct diagnosis and treatment.

Nephrogenic systemic fibrosis (NSF) is an idiopathic, progressive, systemic fibrosis that occurs in patients with renal diseases. Recently, gadolinium-containing contrast (Gd-contrast) has become a suspected causal factor for NFS. This report discusses two female patients with end-stage renal disease, aged 70 and 51 years, respectively, who developed histologically proven NSF after exposure to Gd-contrast. Clinically, both patients were characterized by fibrosis and induration of skin and muscle mainly in the limbs with joint contracture. In the first case, NSF developed gradually after undergoing evaluation by Gd-contrast magnetic resonance imaging (MRI) and subsequent surgery for her urothelial carcinoma. In the second patient, NSF developed after undergoing evaluation by Gd-contrast MRI for her right shoulder bursitis with calcification, and the conditions of NSF continued to worsen after the surgical treatment of this right shoulder lesion. Although the role of Gd-contrast in NSF is still not well known, the correlation in our cases strongly suggests that it should be used with cautioned in patients with end-stage renal disease. Both of our patients underwent surgery before or during the development of NSF, indicating that the surgical procedure may be a contributing factor.

Familial amyloid polyneuropathy (FAP) caused by a mutation in transthyretin (TTR) gene is an autosomal dominant inherited disorder. The aim of this study is to explore the pathophysiological mechanism of FAP. We prospectively recruited 12 pauci-symptomatic carriers, 18 patients who harbor a TTR mutation, p.A97S, and two-age matched control groups. Data of nerve excitability test (NET) from ulnar motor and sensory axons were collected.NET study of ulnar motor axons of patients shows increased threshold and rheobase, reduced threshold elevation during hyperpolarizing threshold electrotonus (TE), and increased refractoriness. In sensory nerve studies, there are increased threshold reduction in depolarizing TE, lower slope of recovery and delayed time to overshoot after hyperpolarizing TE, increased refractoriness and superexcitability in recovery cycle. NET profiles obtained from the ulnar nerve of carriers show the increase of threshold and rheobase, whereas no significant threshold changes in hyperpolarizing TE and superexcitability. The regression models demonstrate that the increase of refractoriness and prolonged relative refractory period are correlated to the disease progression from carriers to patients. The marked increase of refractoriness at short-width stimulus suggests a defect in sodium current which may represent an early, pre-symptomatic pathophysiological change in TTR-FAP. Focal disruption of basal lamina and myelin may further increase the internodal capacity, manifested by the lower slope of recovery and delayed time to overshoot after hyperpolarization TE as well as the increase of superexcitability. NET could therefore make a pragmatic tool for monitoring disease progress from the very early stage of TTR-FAP.

In Drosophila imaginal epithelia, cells mutant for the endocytic neoplastic tumor suppressor gene vps25 stimulate nearby untransformed cells to express Drosophila Inhibitor-of-Apoptosis-Protein-1 (DIAP-1), conferring resistance to apoptosis non-cell autonomously. Here, we show that the non-cell autonomous induction of DIAP-1 is mediated by Yorkie, the conserved downstream effector of Hippo signaling. The non-cell autonomous induction of Yorkie is due to Notch signaling from vps25 mutant cells. Moreover, activated Notch in normal cells is sufficient to induce non-cell autonomous Yorkie activity in wing imaginal discs. Our data identify a novel mechanism by which Notch promotes cell survival non-cell autonomously and by which neoplastic tumor cells generate a supportive microenvironment for tumor growth.

BackgroundSpinal muscular atrophy (SMA) is the most common neuromuscular autosomal recessive disorder. The American College of Medical Genetics has recently recommended routine carrier screening for SMA because of the high carrier frequency (1 in 25-50) as well as the severity of that genetic disease. Large studies are needed to determine the feasibility, benefits, and costs of such a program.Methods and findingsThis is a prospective population-based cohort study of 107,611 pregnant women from 25 counties in Taiwan conducted during the period January 2005 to June 2009. A three-stage screening program was used: (1) pregnant women were tested for SMA heterozygosity; (2) if the mother was determined to be heterozygous for SMA (carrier status), the paternal partner was then tested; (3) if both partners were SMA carriers, prenatal diagnostic testing was performed. During the study period, a total of 2,262 SMA carriers with one copy of the SMN1 gene were identified among the 107,611 pregnant women that were screened. The carrier rate was approximately 1 in 48 (2.10%). The negative predictive value of DHPLC coupled with MLPA was 99.87%. The combined method could detect approximately 94% of carriers because most of the cases resulted from a common single deletion event. In addition, 2,038 spouses were determined to be SMA carriers. Among those individuals, 47 couples were determined to be at high risk for having offspring with SMA. Prenatal diagnostic testing was performed in 43 pregnant women (91.49%) and SMA was diagnosed in 12 (27.91%) fetuses. The prevalence of SMA in our population was 1 in 8,968.ConclusionThe main benefit of SMA carrier screening is to reduce the burden associated with giving birth to an affected child. In this study, we determined the carrier frequency and genetic risk and provided carrier couples with genetic services, knowledge, and genetic counseling.

BACKGROUND: Charcot-Marie-Tooth disease type 2 (CMT2) is a clinically and genetically heterogeneous group of inherited axonal neuropathies. The aim of this study was to extensively investigate the mutational spectrum of CMT2 in a cohort of patients of Han Chinese. METHODOLOGY AND PRINCIPAL FINDINGS: Genomic DNA from 36 unrelated Taiwanese CMT2 patients of Han Chinese descent was screened for mutations in the coding regions of the MFN2, RAB7, TRPV4, GARS, NEFL, HSPB1, MPZ, GDAP1, HSPB8, DNM2, AARS and YARS genes. Ten disparate mutations were identified in 14 patients (38.9% of the cohort), including p.N71Y in AARS (2.8%), p.T164A in HSPB1 (2.8%), and p.[H256R]+[R282H] in GDAP1 (2.8%) in one patient each, three NEFL mutations in six patients (16.7%) and four MFN2 mutations in five patients (13.9%). The following six mutations were novel: the individual AARS, HSPB1 and GDAP1 mutations and c.475-1G>T, p.L233V and p.E744M mutations in MFN2. An in vitro splicing assay revealed that the MFN2 c.475-1G>T mutation causes a 4 amino acid deletion (p.T159_Q162del). Despite an extensive survey, the genetic causes of CMT2 remained elusive in the remaining 22 CMT2 patients (61.1%). CONCLUSIONS AND SIGNIFICANCE: This study illustrates the spectrum of CMT2 mutations in a Taiwanese CMT2 cohort and expands the number of CMT2-associated mutations. The relevance of the AARS and HSPB1 mutations in the pathogenesis of CMT2 is further highlighted. Moreover, the frequency of the NEFL mutations in this study cohort was unexpectedly high. Genetic testing for NEFL and MFN2 mutations should, therefore, be the first step in the molecular diagnosis of CMT2 in ethnic Chinese.