The emerging spectrum of fetal acetylcholine receptor antibody-related disorders (FARAD).

In utero exposure to maternal antibodies targeting the fetal acetylcholine receptor isoform (fAChR) can impair fetal movement, leading to arthrogryposis multiplex congenita (AMC). Fetal AChR antibodies have also been implicated in apparently rare, milder myopathic presentations termed fetal acetylcholine receptor inactivation syndrome (FARIS). The full spectrum associated with fAChR antibodies is still poorly understood. Moreover, since some mothers have no myasthenic symptoms, the condition is likely underreported, resulting in failure to implement effective preventive strategies. Here we report clinical and immunological data from a multicentre cohort (n = 46 cases) associated with maternal fAChR antibodies, including 29 novel and 17 previously reported with novel follow-up data. Remarkably, in 50% of mothers there was no previously established myasthenia gravis (MG) diagnosis. All mothers (n = 30) had AChR antibodies and, when tested, binding to fAChR was often much greater than that to the adult AChR isoform. Offspring death occurred in 11/46 (23.9%) cases, mainly antenatally due to termination of pregnancy prompted by severe AMC (7/46, 15.2%), or during early infancy, mainly from respiratory failure (4/46, 8.7%). Weakness, contractures, bulbar and respiratory involvement were prominent early in life, but improved gradually over time. Facial (25/34; 73.5%) and variable peripheral weakness (14/32; 43.8%), velopharyngeal insufficiency (18/24; 75%) and feeding difficulties (16/36; 44.4%) were the most common sequelae in long-term survivors. Other unexpected features included hearing loss (12/32; 37.5%), diaphragmatic paresis (5/35; 14.3%), CNS involvement (7/40; 17.5%) and pyloric stenosis (3/37; 8.1%). Oral salbutamol used empirically in 16/37 (43.2%) offspring resulted in symptom improvement in 13/16 (81.3%). Combining our series with all previously published cases, we identified 21/85 mothers treated with variable combinations of immunotherapies (corticosteroids/intravenous immunoglobulin/plasmapheresis) during pregnancy either for maternal MG symptom control (12/21 cases) or for fetal protection (9/21 cases). Compared to untreated pregnancies (64/85), maternal treatment resulted in a significant reduction in offspring deaths (P < 0.05) and other complications, with treatment approaches involving intravenous immunoglobulin/ plasmapheresis administered early in pregnancy most effective. We conclude that presentations due to in utero exposure to maternal (fetal) AChR antibodies are more common than currently recognized and may mimic a wide range of neuromuscular disorders. Considering the wide clinical spectrum and likely diversity of underlying mechanisms, we propose 'fetal acetylcholine receptor antibody-related disorders' (FARAD) as the most accurate term for these presentations. FARAD is vitally important to recognize, to institute appropriate management strategies for affected offspring and to improve outcomes in future pregnancies. Oral salbutamol is a symptomatic treatment option in survivors.

Mitochondrial diseases in Hong Kong: prevalence, clinical characteristics and genetic landscape.

OBJECTIVE: To determine the prevalence of mitochondrial diseases (MD) in Hong Kong (HK) and to evaluate the clinical characteristics and genetic landscape of MD patients in the region. METHODS: This study retrospectively reviewed the phenotypic and molecular characteristics of MD patients from participating public hospitals in HK between January 1985 to October 2020. Molecularly and/or enzymatically confirmed MD cases of any age were recruited via the Clinical Analysis and Reporting System (CDARS) using relevant keywords and/or International Classification of Disease (ICD) codes under the HK Hospital Authority or through the personal recollection of treating clinicians among the investigators. RESULTS: A total of 119 MD patients were recruited and analyzed in the study. The point prevalence of MD in HK was 1.02 in 100,000 people (95% confidence interval 0.81-1.28 in 100,000). 110 patients had molecularly proven MD and the other nine were diagnosed by OXPHOS enzymology analysis or mitochondrial DNA depletion analysis with unknown molecular basis. Pathogenic variants in the mitochondrial genome (72 patients) were more prevalent than those in the nuclear genome (38 patients) in our cohort. The most commonly involved organ system at disease onset was the neurological system, in which developmental delay, seizures or epilepsy, and stroke-like episodes were the most frequently reported presentations. The mortality rate in our cohort was 37%. CONCLUSION: This study is a territory-wide overview of the clinical and genetic characteristics of MD patients in a Chinese population, providing the first available prevalence rate of MD in Hong Kong. The findings of this study aim to facilitate future in-depth evaluation of MD and lay the foundation to establish a local MD registry.

Performance evaluation of online motion synchronizing systems for patient-specific respiratory movements with helical tomotherapy.

Background and purpose.The introduction of online motion synchronizing system on helical tomotherapy paves way for robust motion tracking. A recent upgrade launches modifications on both hardware and software of the kV tracking system. An evaluation on the kV subsystems, prior (Version1) and post upgrade (Version2), was performed to compare tracking accuracy by means of fiducial tracking error and resulted root-mean-square (RMS). Impacts influenced by various patient-specific breathing pattern regularities and target movements were also investigated to refine motion tracking error estimations upon future selection of possible candidates.Materials and methods.Respiratory patterns from twenty-five lung cases were imported individually into a commercial dynamic platform model. Situating a phantom implanted with gold fiducial markers on the platform, superior-inferior (SI) movements of corresponding targets were simulated. Each case was delivered via an identical treatment plan in Version1 and was repeated in Version2. Motion tracking accuracy, by means of discrepancies between subsystem predicted model and raw data motion recorded in patient CT simulation, was analyzed statistically. Wilcoxon signed ranked test was employed to evaluate the difference in tracking error range between the two versions. Statistical model was fitted to inspect the dependence of internal target movement towards fiducial tracking errors.Results.A small difference of ±1 mm was exhibited in 99% of fiducial tracking errors for all cases experimented under both versions. RMS errors were all below 0.5 mm. Version2 demonstrated a greater extremity in fiducial tracking error (p = 0.04). A positive correlation was depicted between internal target amplitudes and 95% interval of fiducial tracking errors (p < 0.02). Overall, irregular respiratory patterns tended to have greater fiducial tracking errors.Conclusions.The excellent tracking performance in both kV subsystem versions offers motion compensations benefits, yet Version1 outperformed Version2 in fiducial tracking accuracy. It is noticeable that greater magnitude in internal target movement and irregular breathing patterns yield greater tracking error.

The Value of Hepatic Scintigraphy in the Diagnosis of Biliary Atresia.

Introduction: Biliary Atresia (BA) requires prompt diagnosis and surgical intervention to optimize its outcome. The aim of this study was to evaluate the accuracy of EHIDA in distinguishing between BA and other causes of cholestatic jaundice. Methods: This was a retrospective study of all patients who underwent EHIDA in a tertiary center from 1997 to 2019. The sensitivity, specificity, Negative Predictive Value (NPV) and Positive Predictive Value (PPV) of EHIDA were evaluated. Factors that can potentially affect its accuracy were also analyzed. Results: During the study period, 93 patients aged 10 to 110 days with cholestasis and suspected BA underwent EHIDA. The sensitivity and NPV were 91.2 and 85.3% while specificity and PPV were 80.6 and 88.1%. These results suggested that EHIDA is suboptimal in both diagnosing or excluding BA. Out of 59 patients who showed no tracer activities in the intestines after 24 h, 56 were subjected to surgical exploration and 52 (92.9%) were eventually diagnosed BA. The accuracy of EHIDA scan were different by the maturity of the patient, age at testing and severity of cholestasis. Conclusions: EHIDA has a limited accuracy and surgical exploration remains the gold standard to establish the diagnosis of BA. Potential confounding factors that may affect the accuracy of EHIDA were identified but require further studies with larger sample sizes to validate.

Dosimetric impact of phase shifts on Radixact Synchrony tracking system with patient-specific breathing patterns.

PURPOSE: The Synchrony tracking system of Radixact is capable of real-time tumor tracking by building a correlation model between external light-emitting diodes on the patient's chest and an internal marker. A phase shift between the chest wall and a lung tumor has been reported. Hence, this study focused on evaluating the accuracy of the tracking system, especially under a patient-specific breathing pattern with respiratory phase shifts. METHODS: A phantom containing fiducial markers was placed on a moving platform. The intrinsic delivery accuracy was verified with a patient-specific breathing pattern. Three patient-specific breathing patterns were then implemented, for which phase shifts, φ, were introduced. Phase shifts with +0.3 s and +1 s were tested for dosimetric aspects, whereas ±0.3, ±0.6, and ±0.8 s shifts were used for tracking accuracy. The resultant dose distributions were analyzed by γ comparison. Dose profiles in the superior-inferior and lateral directions were compared. Logfiles of the tracking information were extracted from the system and compared with the input breathing pattern. The root mean square (RMS) difference was used to quantify the consistency. RESULTS: When the φ value was as large as 1 s, a severe inconsistency was observed. The target was significantly underdosed, down to 89% of the originally planned dose. γ analysis revealed that the failed portion was concentrated in the target region. The RMS of the tracking difference was close to 1 mm when φ was ±0.3 s and approximately 4 mm when φ was ±0.8 s. Tracking errors increased with an increase in the degree of phase shifts. CONCLUSION: Phase shifts between the patient chest wall and the internal target may hamper treatment delivery and jeopardize treatment using Synchrony Tracking. Hence, a larger planning target volume (PTV) may be necessary if a large phase shift is observed in a patient, especially when an external surrogate shows a lag in motion when compared with the tumor.

X-chromosome inactivation and PCDH19-associated epileptic encephalopathy: A novel PCDH19 variant in a Chinese family.

BACKGROUND: Developmental and epileptic encephalopathy 9 (DEE9, MIM #300088) is an early onset seizure disorder associated with cognitive impairment and behavioral disturbances. It is caused by mutation in protocadherin 19 with an unusual X-linked inheritance selectively involving heterozygous females or mosaic hemizygous males, while hemizygous males are unaffected. Cellular interference was the postulated mechanism underlying the unusual inheritance pattern. CASE REPORT: We report a Chinese girl who presented with severe treatment refractory seizures at 26 months of age and was found heterozygous for a novel likely pathogenic missense variant NM_001184880.2:c.488T>A p.(Val163Glu) in PCDH19. Her younger sister, who was also heterozygous for the variant, was asymptomatic with normal development at the time of reporting at 37 months of age. X-chromosome inactivation study by androgen receptor gene methylation assay in DNA from peripheral leukocytes was performed which demonstrated somewhat skewed X-chromosome inactivation in the proband and extremely skewed X-chromosome inactivation in the asymptomatic younger sibling. CONCLUSION: PCDH19-related seizure disorder has incomplete penetrance and variable expressivity. Further studies are required to determine the potential role of X-chromosome inactivation on the phenotypic variability and patient outcomes. Liberal referral for PCDH19 testing among female patients with early-onset seizures should be considered to enhance case detection.

Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial.

BACKGROUND: Dengue infection is the most common mosquito-borne viral disease worldwide, but no suitable antiviral drugs are available. We tested the α-glucosidase inhibitor celgosivir as a treatment for acute dengue fever. METHODS: To establish eligibility for inclusion in a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial, individuals aged 21-65 years who had had a fever (≥38°C) for less than 48 h, met at least two criteria indicating probable dengue infection, and had a positive result on a dengue point-of-care test kit or PCR assay were referred for screening at a centre in Singapore between July 30, 2012, and March 4, 2013. Using a web-based system, we randomly assigned patients who met full inclusion criteria after screening (1:1; random permuted block length four) to celgosivir (initial 400 mg loading dose within 6 h of randomisation, followed by 200 mg every 12 h for a total of nine doses) or matched placebo. Patients and the entire study team were masked to group assignment. The primary endpoints were mean virological log reduction (VLR) from baseline for days 2, 3, and 4, and area under the fever curve (AUC) for a temperature above 37°C from 0 h to 96 h. Efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01619969. FINDINGS: We screened 69 patients and randomly assigned 50 (24 to celgosivir, 26 to placebo). Mean VLR was greater in the celgosivir group (-1·86, SD 1·07) than in the placebo group (-1·64, 0·75), but the difference was non-significant (-0·22, 90% CI -0·65 to 0·22; one-sided p=0·203). The mean AUC was also higher in the celgosivir group (54·92, SD 31·04) than in the placebo group (40·72, 18·69), but again the difference was non-significant (14·20, 90% CI 2·16-26·25; one-sided p=0·973). We noted similar incidences of adverse events between groups. INTERPRETATION: Although generally safe and well tolerated, celgosivir does not seem to reduce viral load or fever burden in patients with dengue. FUNDING: STOP Dengue Translational Clinical Research.

A nuclear transport inhibitor that modulates the unfolded protein response and provides in vivo protection against lethal dengue virus infection.

BACKGROUND: Dengue virus (DENV) is estimated to cause 390 million infections each year, but there is no licensed vaccine or therapeutic currently available. METHODS: We describe a novel, high-throughput screen to identify compounds inhibiting the interaction between DENV nonstructural protein 5 and host nuclear transport proteins. We document the antiviral properties of a lead compound against all 4 serotypes of DENV, antibody-dependent enhanced (ADE) infection, and ex vivo and in vivo DENV infections. In addition, we use quantitative reverse-transcription polymerase chain reaction to examine cellular effects upon compound addition. RESULTS: We identify N-(4-hydroxyphenyl) retinamide (4-HPR) as effective in protecting against DENV-1-4 and DENV-1 ADE infections, with 50% effective concentrations in the low micromolar range. 4-HPR but not the closely related N-(4-methoxyphenyl) retinamide (4-MPR) could reduce viral RNA levels and titers when applied to an established infection. 4-HPR but not 4-MPR was found to specifically upregulate the protein kinase R-like endoplasmic reticulum kinase arm of the unfolded protein response. Strikingly, 4-HPR but not 4-MPR restricted infection in peripheral blood mononuclear cells and in a lethal ADE-infection mouse model. CONCLUSIONS: 4-HPR is a novel antiviral that modulates the unfolded protein response, effective against DENV1-4 at concentrations achievable in the plasma in a clinical setting, and provides protection in a lethal mouse model.

Effect of a prodrug of the green tea polyphenol (-)-epigallocatechin-3-gallate on the growth of androgen-independent prostate cancer in vivo.

Epigallocatechin-3-gallate (EGCG) is the major and most potent polyphenol compound of green tea that has been shown to have anticancer effects against various types of cancers. In this study, in addition to the EGCG compound, a synthetic derivative, the peracetate of EGCG (EGCG-P), was used to investigate the inhibitory effects on growth of androgen-independent prostate cancer in vivo. The advantage of EGCG-P is that it may act as a prodrug, leading to higher bioavailability than EGCG itself. The aim of our study was to compare the differences between EGCG and EGCG-P on their inhibitory effect on androgen-independent prostate cancer, CWR22R, xenograft model in nude mice. The mice were administrated daily with solvent dimethyl sulfoxide, EGCG, and EGCG-P separately through intraperitoneal injection for 20 days. Tumor volume and body weight of nude mice were recorded daily. Serum prostate-specific antigen (PSA) levels were also measured before and after the treatment. The effects of both EGCG and EGCG-P on tumor cell proliferation were assessed by immunohistochemical (IHC) method using antibodies against Ki-67 and proliferating cell nuclear antigen. The apoptotic effect was evaluated by IHC against B-cell non-Hodgkin lymphoma-2 and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay by in situ apoptosis detection kit. Moreover, the potential suppression of angiogenesis by EGCG and EGCG-P on prostate cancer was examined by IHC against CD31. Our results revealed that treatment of EGCG and EGCG-P compounds suppressed the growth of CWR22R xenografts without causing any detectable side effects in nude mice. The suppression of growth of the tumor was correlated with the decrease of serum PSA level together with the reduction in tumor angiogenesis and an increase in apoptosis on prostate cancer cells. The results showed that treatment of EGCG and EGCG-P inhibited tumor growth and angiogenesis while promoting apoptosis of the prostate cancer cells in vivo. Our results suggest that EGCG-P may be a more stable and useful compound for increasing the therapeutic anticancer effects in androgen-independent prostate cancer.

Effect of a home exercise program based on tai chi in patients with end-stage renal disease.

OBJECTIVE: Previous reports have documented the benefits of exercise on the well-being of renal patients. However, fewer than 50% of our end-stage renal disease (ESRD) patients engage in regular exercise. To promote exercise, we implemented a home-based exercise program. The aim of the program was to reduce barriers to exercise by helping patients to exercise at their convenience and without the need to travel. The effect of the program was evaluated 3 months after implementation. PATIENTS AND METHODS: Each study participant received a videotape that demonstrated 30 minutes of low-capacity aerobic exercise. Participants were advised to exercise by following the demonstration on the videotape. Encouragement was given over the telephone. Self-reports on practice were recorded in a log book that was also provided. The effect of the program was evaluated by comparing outcomes data before, and 3 months after, implementation of the program. Outcomes assessment included functional mobility (timed "Up & Go" test), muscle flexibility ("Sit & Reach" test), physical capacity ("Six-Minute Walk"), and quality of life [Kidney Disease Quality of Life Short Form (KDQOL-SF)]. RESULTS: The program began with 72 participants. Over time, 39 dropped out. The remaining 33 participants included 11 men and 22 women with a mean age of 52.8 +/- 9.8 years. They exercised 3 - 7 times weekly. Significant improvements were observed in the timed "Up & Go" (p = 0.003) and "Sit & Reach" (p < 0.001) tests. Improvements in the "Six-Minute Walk" (p = 0.130) and in KDQOL-SF scores for emotional well-being (p = 0.456), pain (p = 0.100), burden of kidney disease (p = 0.061), and general health (p = 0.085) were statistically insignificant. CONCLUSIONS: Physically, patients with ESRD benefit from home-based low-capacity aerobic exercise. A home-based program provides an alternative to outdoor and group exercise. In view of a high drop-out rate, intensive promotion and encouragement should be considered to achieve a positive outcome.

Comparison of clinical outcome and ease of handling in two double-bag systems in continuous ambulatory peritoneal dialysis: a prospective, randomized, controlled, multicenter study.

BACKGROUND: We performed a prospective, randomized, controlled, multicenter study on the use of two double-bag disconnect systems: Stay-Safe (SS; Fresenius Deutschland GmbH2) and Ultrabag (UB; Baxter Healthcare, Deerfield, IL) to assess the ease of handling, peritonitis rate, exit-site infection rate, and clinical outcome. METHODS: We enrolled 110 new continuous ambulatory peritoneal dialysis (CAPD) patients; 55 patients were randomized to SS treatment, and 55 patients, to UB treatment. RESULTS: Patients using the UB and SS systems were followed up for 946 and 846 patient-months, respectively. There were 21 episodes of peritonitis in 18 patients in the UB group and 23 episodes in 18 patients in the SS group. No significant difference was observed in peritonitis rates between the two systems, which were 45 and 36.8 patient-months per episode for the UB and SS groups, respectively. At 12 months, 82.1% of patients in the UB group and 72.1% in the SS group were free of peritonitis; at 18 months, 71.1% and 62.2% were free of peritonitis for the UB and SS groups, respectively (P = 0.559). Gram-positive organisms accounted for 28.6% of infections in the UB group and 39.1% in the SS group. Exit-site infection rates were one episode per 21 patient-months versus 19.2 patient-months in the UB and SS groups, respectively (P = 0.743). Patients perceived SS as easier to handle in 4 of the 13 steps immediately post-CAPD training. However, there was no significant difference in rankings between the two systems after 1 month of adaptation. Median training periods were 4 and 5 days for the SS and UB groups, respectively (P = 0.640). CONCLUSION: The two double-bag systems (UB and SS) have similar incidences of peritonitis and exit-site infection. Both systems showed comparably good clinical outcome. The SS system is easier to learn during the initial training period, but the difference is not significant after 1 month's adaptation.