Exome sequencing and genome-wide association analyses unveils the genetic predisposition in hydroxychloroquine retinopathy.

OBJECTIVES: To unveil the candidate susceptibility genes in chloroquine/hydroxychloroquine (CQ/HCQ) retinopathy using whole exome sequencing (WES) and genome-wide association study (GWAS). METHODS: Patients with a diagnosis of CQ/HCQ retinopathy based on the comprehensive demographic and ocular examination were included. The peripheral blood was extracted for WES and GWAS analyses. The Chinese Han Southern database from 1000 genomes was used as control group to compare the affected percentage. Multivariate logistic regression analysis adjusted for age, HCQ dose, duration and renal disease were used to analyze the correlation between genetic variants and visual outcome. A poor vision outcome was defined as visual acuity <6/12. An abnormal anatomical outcome was defined as disruption of ellipsoid zone in the fovea. RESULTS: Twenty-nine patients with an average age of 60.9 ± 13.4 years, treatment duration of 12.1 ± 6.2 years, daily dose of 8.5 ± 4.1 mg/kg, and the cumulative dose of 1637.5 ± 772.5 g, were genotyped. Several candidate genes associated with CQ/HCQ retinopathy were found, including RP1L1, RPGR and RPE65, with a difference of affected percentage over 50% in mutation between the case and control groups. New foci in CCDC66: rs56616026 (OR = 63.43, p = 1.63 × 10-8) and rs56616023 (OR = 104.7, p = 5.02 × 10-10) were identified significantly associated with HCQ retinopathy. Multivariate analysis revealed increased genetic variants were significantly associated with poor functional (OR = 1.600, p = 0.004) and structural outcome (OR = 1.318, p = 0.043). CONCLUSIONS: Several candidate susceptibility genes including RP1L1, RPGR, RPE65 and CCDC66 were identified to be associated with CQ/HCQ retinopathy. In addition to disease susceptibility, patients with increased genetic variants are more vulnerable to poor visual outcomes.

Does positive feedback or appraisal about medical providers increase patients' trust and lead to better treatment outcomes? A double-blind randomized control trial.

[Purpose] Trust among patients and clinical suppliers is the foundation for achieving appropriate treatment. This double-blind randomized control trial aimed to determine whether providing patients a pre-treatment physical therapists' introductions and positive appraisal can enhance the trust of patients in therapists. [Participants and Methods] This study included patients diagnosed with lumbar spine spondylosis or non-acute lower back muscle strain who were divided into intervention and control groups. The previously recorded video informed the intervention group patients that they were assigned to our best therapist because of their participation. The primary outcome was evaluated twice, once before and once after the treatment, and the secondary outcome was measured using the second time pain inventory evaluation. [Results] A total of 32 patients participated in this study. No significant difference was found in patients' trust in therapists between the two groups, and a lower successful treatment rate with a higher pain influence level to daily life was noted in the intervention group. [Conclusion] Doctors who offer introductions with a positive assessment of physical therapists cannot change the trust of patients on therapists. Furthermore, this action may risk worse treatment outcomes.

The efficient induction of human retinal ganglion-like cells provides a platform for studying optic neuropathies.

Retinal ganglion cells (RGCs) are essential for vision perception. In glaucoma and other optic neuropathies, RGCs and their optic axons undergo degenerative change and cell death; this can result in irreversible vision loss. Here we developed a rapid protocol for directly inducing RGC differentiation from human induced pluripotent stem cells (hiPSCs) by the overexpression of ATOH7, BRN3B, and SOX4. The hiPSC-derived RGC-like cells (iRGCs) show robust expression of various RGC-specific markers by whole transcriptome profiling. A functional assessment was also carried out and this demonstrated that these iRGCs display stimulus-induced neuronal activity, as well as spontaneous neuronal activity. Ethambutol (EMB), an effective first-line anti-tuberculosis agent, is known to cause serious visual impairment and irreversible vision loss due to the RGC degeneration in a significant number of treated patients. Using our iRGCs, EMB was found to induce significant dose-dependent and time-dependent increases in cell death and neurite degeneration. Western blot analysis revealed that the expression levels of p62 and LC3-II were upregulated, and further investigations revealed that EMB caused a blockade of lysosome-autophagosome fusion; this indicates that impairment of autophagic flux is one of the adverse effects of that EMB has on iRGCs. In addition, EMB was found to elevate intracellular reactive oxygen species (ROS) levels increasing apoptotic cell death. This could be partially rescued by the co-treatment with the ROS scavenger NAC. Taken together, our findings suggest that this iRGC model, which achieves both high yield and high purity, is suitable for investigating optic neuropathies, as well as being useful when searching for potential drugs for therapeutic treatment and/or disease prevention.

Ophthalmic characteristics and retinal vasculature changes in Williams syndrome, and its association with systemic diseases.

BACKGROUND: We aim to characterise the ophthalmic findings and retinal vasculature changes in patients with WS, and to analyse the correlation between ophthalmic manifestations and the associated systemic diseases. METHODS: This retrospective case-control study included 27 WS patients and 28 age-matched healthy participants. Stellate pattern of iris, central macular thickness (CMT), foveal width, retinal vessel diameter, superficial vascular density (SVD) of macula and foveal avascular zone (FAZ) were compared between WS patients and healthy participants. RESULTS: Twenty-five patients (93%) had the classic stellate iris presentation. Compared with healthy controls, WS patients had decreased CMT, increased foveal width and a lower SVD of macula (all P < 0.001). Significantly decreased mean retinal arterial (117.9 ± 9.9 µm vs. 133.0 ± 6.7 µm in WS and controls, respectively; p < 0.001) and venous (158.9 ± 11.2 µm vs. 174.0 ± 8.0 µm in WS and controls, respectively; p < 0.001) outer diameters, as well as mean arterial wall thickness (11.2 ± 1.3 µm vs. 12.2 ± 0.8 µm in WS and controls, respectively; p < 0.01) were found in WS. Stellate iris grading was significantly associated with CMT, foveal width, retinal vessel diameter (all p < 0.05), and a significant increase in the odds of having hypertension (Odds ratio (OR), 5.63; P < 0.05). The severity of stellate iris in WS seemed to have the trend of increasing risk of having pulmonary stenosis, tricuspid regurgitation and mitral regurgitation. CONCLUSIONS: This study provides the first in vivo evidence reflecting current knowledge on vessel morphology in WS patients that deficient circumferential growth is the predominant pathophysiologic changes resulting from elastin deficiency. The ophthalmic characteristics may serve as a complementary tool to diagnose and follow-up patients suffering from WS.

Novel mutation of IFT140 in an infant with Mainzer-Saldino syndrome presenting with retinal dystrophy.

A seven-month-old girl presented with bilateral roving nystagmus, hyperopia, and retinal dystrophy, and was brought to our ophthalmology clinic. Visual-evoked potentials (VEPs) were non-recordable in both the eyes. No other systemic symptoms or abnormalities were observed. Whole exome sequencing (WES) identified a compound heterozygous mutation in the IFT140 gene: c.1990G > A (p. Glu664Lys) and c.2214_2217del (p.Asp738GlufsTer47). The genetic results support a diagnosis of Mainzer-Saldino syndrome (MSS). Importantly, c.2214_2217del is a novel mutation in the IFT140 gene. Although the patient presents with isolated retinal dystrophy, it is crucial to monitor renal function overtime. Taken together, our results reinforce the role of IFT140 in syndromic ciliopathies. This report also highlights the role of combined WES approaches in identifying underlying mutations in infants presenting with isolated retinal dystrophy, considering MSS may present differently over time.

Investigating the rate of skeletal muscle atrophy in men and women in the intensive care unit: a prospective observational study.

Muscle atrophy greatly affects the prognosis of patients in the intensive care unit, but the rate of change remains unclear. In this prospective observational study, we used ultrasound to measure the change in muscle thickness of the rectus femoris (RF) and vastus intermedius (VI) in 284 patients who were admitted to the SICU of Taoyuan General Hospital between January 1 and June 30, 2020. Patients were excluded if there is a wound at the right thigh which hinders the ultrasonography probe from placing. Daily rates of muscle atrophy were calculated using linear analysis and the ratios of change were plotted against the period of hospitalization. Patient characteristics were adjusted using propensity score matching and differences between men and women were analyzed. A linear mixed model was used to calculate the influence of other factors on muscle loss. The average daily atrophy rates of the RF and VI were 0.84% and 0.98%, respectively. The rate of atrophy was the highest in the third and fourth weeks. Daily atrophy rates of the RF and VI were approximately three times higher in women than in men. Protective factors of muscle atrophy included higher BMI and lower initial thickness of the RF and VI. Our study depicts the trend of muscle atrophy in the ICU and suggests more discussion in prevention to be conducted especially for women.

Candidate Modifier Genes for the Penetrance of Leber's Hereditary Optic Neuropathy.

Leber's hereditary optic neuropathy (LHON) is a maternally transmitted disease caused by mitochondria DNA (mtDNA) mutation. It is characterized by acute and subacute visual loss predominantly affecting young men. The mtDNA mutation is transmitted to all maternal lineages. However, only approximately 50% of men and 10% of women harboring a pathogenic mtDNA mutation develop optic neuropathy, reflecting both the incomplete penetrance and its unexplained male prevalence, where over 80% of patients are male. Nuclear modifier genes have been presumed to affect the penetrance of LHON. With conventional genetic methods, prior studies have failed to solve the underlying pathogenesis. Whole exome sequencing (WES) is a new molecular technique for sequencing the protein-coding region of all genes in a whole genome. We performed WES from five families with 17 members. These samples were divided into the proband group (probands with acute onset of LHON, n = 7) and control group (carriers including mother and relative carriers with mtDNSA 11778 mutation, without clinical manifestation of LHON, n = 10). Through whole exome analysis, we found that many mitochondria related (MT-related) nuclear genes have high percentage of variants in either the proband group or control group. The MT genes with a difference over 0.3 of mutation percentage between the proband and control groups include AK4, NSUN4, RDH13, COQ3, and FAHD1. In addition, the pathway analysis revealed that these genes were associated with cofactor metabolism pathways. Family-based analysis showed that several candidate MT genes including METAP1D (c.41G > T), ACACB (c.1029del), ME3 (c.972G > C), NIPSNAP3B (c.280G > C, c.476C > G), and NSUN4 (c.4A > G) were involved in the penetrance of LHON. A GWAS (genome wide association study) was performed, which found that ADGRG5 (Chr16:575620A:G), POLE4 (Chr2:7495872T:G), ERMAP (Chr1:4283044A:G), PIGR (Chr1:2069357C:T;2069358G:A), CDC42BPB (Chr14:102949A:G), PROK1 (Chr1:1104562A:G), BCAN (Chr 1:1566582C:T), and NES (Chr1:1566698A:G,1566705T:C, 1566707T:C) may be involved. The incomplete penetrance and male prevalence are still the major unexplained issues in LHON. Through whole exome analysis, we found several MT genes with a high percentage of variants were involved in a family-based analysis. Pathway analysis suggested a difference in the mutation burden of MT genes underlining the biosynthesis and metabolism pathways. In addition, the GWAS analysis also revealed several candidate nuclear modifier genes. The new technology of WES contributes to provide a highly efficient candidate gene screening function in molecular genetics.

Melanoma-associated retinopathy with anti-TRPM1 autoantibodies showing concomitant Off-bipolar cell dysfunction.

BACKGROUND: To report the clinical features of a patient with melanoma-associated retinopathy (MAR) with anti-transient receptor potential cation channel, subfamily M, member 1 (TRPM1) autoantibodies showing concomitant Off-bipolar cell dysfunction. METHODS: We evaluated a patient with a past history of scalp melanoma presented with sudden-onset shimmering photopsia in both eyes. MAR was confirmed with complete ophthalmic examinations, electronegative electroretinogram (ERG), and the presence of anti-TRPM1 autoantibodies by Western blot analysis. S-cone ERG and photopic On-Off ERG were studied in this patient as well. RESULTS: The patient's best-corrected visual acuity was 6/30 in the right eye and 6/8.6 in the left eye. Fundus and OCT findings were unremarkable. Visual field test showed severe constriction in both eyes. His full-field ERG was electronegative. S-cone ERG recorded preservation of L/M-cone-mediated response and undetectable S-cone-mediated response. Photopic On-Off ERG disclosed attenuated On- and Off-response. Western blot analysis confirmed immunoreactivity of the patient's serum to a 30 kDa TRPM1 recombinant protein. Whole-body positron emission tomography scan detected lymph node metastases in the neck. CONCLUSIONS: Anti-TRPM1 autoantibody-positive MAR varies greatly in its presentation and clinical course. We present a case of anti-TRPM1 autoantibody-positive MAR with atypical feature of Off-bipolar cell involvement. A complete electroretinographic study together with identification of the pathogenic antiretinal autoantibodies may help better understand and subclassify the disease in the future.

Leber Hereditary Optic Neuropathy: Molecular Pathophysiology and Updates on Gene Therapy.

Molecular pathophysiology of LHON was reviewed and the current status of gene therapy for LHON is updated.

Astrocytic hamartoma in a patient heterozygous for RIM1 mutation associated-retinal dystrophy.

BACKGROUND: Autosomal-dominant cone-rod dystrophy 7 (CORD7) has been documented in association with RIM1 mutation (c.2459 G>A). We report a patient with retinal dystrophy who was heterozygous for RIM1 missense variant with a newly found point mutation (c.4036 G>T). Clinical findings of this genetic variant manifested differently from a typical CORD7. In addition, astrocytic hamartomas at bilateral optic discs are also a unique feature, which has not been described in CORD previously. MATERIALS AND METHODS: Medical records of this patient were retrospectively reviewed. Genetic testing with whole exon sequencing was performed. RESULTS: This 43-year-old female with history of decreased night vision since childhood came to our hospital complaining of blurred vision in both eyes for more than half a year. Her best-corrected visual acuity was 20/200 in both eyes. Dilated fundoscopic examination revealed symmetric diffuse atrophy of retinal pigment epithelium with peripheral pigmentary clumps. Also, optic disc astrocytic hamartomas were found bilaterally. Optical coherence tomography revealed extensive disruption of inner segment/outer segment junction in both eyes. Visual field test showed severe peripheral defect sparing central vision. Electroretinogram demonstrated both rod and cone cells abnormalities. Subsequent genetic testing reported heterozygosity for the RIM1 (c.4036 G>T) mutation. CONCLUSIONS: This is the first reported case of RIM1 mutation-associated retinal dystrophy with a newly found point mutation (c.4036 G>T), which presented differently from a typical CORD7 and more similarly to the phenotype of RP. Furthermore, our finding of bilateral optic disc astrocytic hamartomas has not been reported in association with CORD previously.

Long-Term Rehabilitation Utilization Pattern Among Stroke Patients Under the National Health Insurance Program.

OBJECTIVE: The aim of this study was to understand the frequency of patients receiving rehabilitation services at various periods after stroke and the possible medical barriers to receiving rehabilitation. DESIGN: A retrospective cohort study was conducted using a nationally representative sample in Taiwan. A total of 14,600 stroke patients between 2005 and 2011 were included. Utilization of physical therapy or occupational therapy at different periods after stroke onset was the outcome variable. Individual and geographic characteristics were investigated to determine their effect on patients' probability of receiving rehabilitation. RESULTS: More severe stroke or more comorbid diseases increased the odds of receiving physical therapy and occupational therapy; older age was associated with decreased odds. Notably, sex and stroke type influenced the odds of rehabilitation only in the early period. Copayment exemption lowered the odds of rehabilitation in the first 6 mos but increased the odds in later periods. Rural and suburban patients had significantly lower odds of receiving physical therapy and occupational therapy, as did patients living in areas with fewer rehabilitation therapists. CONCLUSIONS: Besides personal factors, geographic factors such as urban-rural gaps and number of therapists were significantly associated with the utilization of post-stroke rehabilitation care. Furthermore, the influence of certain factors, such as sex, stroke type, and copayment exemption type, changed over time.

Single nucleotide variants lead to dysregulation of the human mitochondrial NAD(P)+-dependent malic enzyme.

Human mitochondrial NAD(P)+-dependent malic enzyme (ME2) is well recognized to associate with cancer cell metabolism, and the single nucleotide variants (SNVs) of ME2 may play a role in enzyme regulation. Here we reported that the SNVs of ME2 occurring in the allosteric sites lead to inactivation or overactivation of ME2. Two ME2-SNVs, ME2_R67Q and ME2-R484W, that demonstrated inactivating or overactivating enzyme activities of ME2, respectively, have different impact toward the cells. The cells with overactivating SNV enzyme, ME2_R484W, grow more rapidly and are more resistant to cellular senescence than the cells with wild-type or inactivating SNV enzyme, ME2_R67Q. Crystal structures of these two ME2-SNVs reveal that ME2_R67Q was an inactivating "dead form," and ME2_R484W was an overactivating "closed form" of the enzyme. The resolved ME2-SNV structures provide a molecular basis to explain the abnormal kinetic properties of these SNV enzymes.

Recovery of visual field defects following vitrectomy for proliferative diabetic retinopathy: A case report.

RATIONALE: Proliferative diabetic retinopathy (PDR) may lead to severe visual impairment, and visual field (VF) loss in such patients has been reported. Vitrectomy is performed in PDR cases complicated with either vitreous hemorrhage or tractional retinal detachment to restore their visual acuity. However, its effect on VF defects is limited in data. Herein, we report the recovery of VF defects following vitrectomy in a patient with PDR. PATIENT CONCERNS: A 25-year-old female with bilateral PDR and vitreous hemorrhage received 2 monthly intravitreal injections of aflibercept in both eyes. Six months after her last injection, she presented with fibrovascular membrane formation in both eyes and VF defects of -9.02 dB and -20.05 dB in the right and left eye, respectively. DIAGNOSES: Proliferative diabetic retinopathy in both eyes. INTERVENTIONS: The patient underwent vitrectomy for her left eye. OUTCOMES: Although her visual acuity did not improve as expected, results from the Humphrey visual field analyzer showed notably improvement of her left eye (-9.05 dB) after the surgery. LESSONS: Vitrectomy potentially allows recovery of VF defects in patients with PDR.

Chronic rhinosinusitis after radiotherapy in patients with head and neck cancer: a population-based cohort study in Taiwan.

BACKGROUND: Chronic rhinosinusitis (CRS) is a common post-radiotherapy (RT) side effect in patients with nasopharyngeal cancer (NPC). However, whether RT is a risk factor for CRS in patients with other types of head and neck cancer remains unclear. This study investigated the association, if any, between CRS and RT in patients with head and neck cancer. METHODS: This retrospective cohort study included the data of patients newly diagnosed as having head and neck cancer between January 1, 2005, and December 31, 2008, from the 2005 Longitudinal Health Insurance Database. Patients were categorized into the following groups according to the treatment regimens received: RT alone (RT-alone), RT combined with other treatments (any-RT), and treatments without RT (no-RT). The outcome was the occurrence of CRS after treatment. RESULTS: Of the 701 patients, 7% experienced CRS within 5 years after initial treatment. Patients were divided into subgroups according to different treatment policies, and the RT-alone group, any-RT group, and no-RT group had 5-year incidence of CRS of 12%, 9.3%, and 4.5%, respectively. Patients in the RT-alone and any-RT groups exhibited an increased risk of CRS compared with patients in the no-RT group (hazard ratio: 6.76 and 2.91; 95% confidence interval: 2.60 to 17.5 and 1.60 to 5.31, respectively). CONCLUSION: This is the first nationwide population-based cohort study to evaluate the risk of posttreatment CRS in patients with head and neck cancer. Our findings indicate that RT is a major risk factor for CRS. Thus, physicians should consider this potential risk in patients with head and neck cancer after RT.

Optical Coherence Tomography Angiography Evaluation of Retinal Microvasculature Before and After Carotid Angioplasty and Stenting.

The aim of the study was to evaluate the influence of carotid angioplasty and stenting (CAS) on retinal microvasculature using optical coherence tomography angiography (OCTA) in patients with severe carotid stenosis. 20 patients with severe carotid stenosis underwent comprehensive ophthalmic examinations and OCTA before and one month after CAS. Automated algorithms were used to quantify vessel density in the macular superficial vascular complex (SVC), deep vascular complex (DVC), and radial peripapillary capillary (RPC) around the optic disc. Eyes on the operated side constituted the ipsilateral eye group, and the other eye constituted the fellow eye group. In the ipsilateral eye group, the vessel density in the DVC increased significantly after stent implantation (P = 0.010), but the vessel density change in the SVC was not statistically different (P = 0.999). In the fellow eye group, the vessel density in the SVC (P = 0.028) and DVC (P = 0.034) were significantly increased after stent implantation. The vessel density in the RPC did not significantly change in the ipsilateral (P = 0.363) or fellow (P = 0.878) eye groups. This study shows that unilateral CAS for severe carotid stenosis increases macular vessel densities in both eyes.