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Pun Yuet Lam,1 Shing Chuen Chow,1 Wai Ching Lam,1,2 Loraine Lok Wan Chow,1,2 Nicholas Siu Kay Fung1,2 1The Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; 2Queen Mary Hospital & Grantham Hospital, Hong KongCorrespondence: Nicholas Siu Kay Fung Room 301, Level 3 Block B, Cyberport 4 100 Cyberport Road, Hong KongTel + 852 3962 1405Email vitreoretinal@hku.hkBackground and Objective: Diabetic retinopathy, a microvascular complication of diabetes mellitus, is one of the most important causes of visual loss in developed countries. Our objective is to evaluate the efficacy of intensive versus conventional glycemic control of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) patients in terms of ophthalmologic outcome, pathogenesis of the early worsening of diabetic retinopathy, risk factors for early worsening and diabetic retinopathy progression.Methods: A literature search on publications concerning glycaemic control in diabetic retinopathy and management of newly diagnosed diabetes mellitus by intensive versus conventional glycaemic control.Results: A total of 22 articles were reviewed after curation by the authors for relevance. Nineteen articles are randomized control trial, 2 articles are observational studies and 1 is clinical trial. Fifteen articles investigated the glycaemic control in T1DM-related diabetic retinopathy and 8 on T2DM-related diabetic retinopathy. The level of glycemia (in terms of HbA1c level) is significantly related to the diabetic retinopathy progression in both T1DM and T2DM. Intensive glycemic control was found to reduce the development of severe diabetic retinopathy, including severe non-proliferative diabetic retinopathy, neovascularization, clinically significant macular edema and loss of vision. Early worsening of diabetic retinopathy commonly occurs during the first year of intensive treatment, especially those initially present with proliferative or severe non-proliferative retinopathy. However, most patients with early worsening can recover and their long-term ophthalmologic outcomes are better when compared to conventional glycemic control.Conclusion: The current guideline on HbA1c level is considered sufficient for the minimization of diabetic retinopathy progression. More frequent monitoring for early worsening should be recommended for newly diagnosed diabetes cases already presenting with retinopathy.Keywords: diabetic retinopathy, insulin dependent diabetes mellitus, non insulin dependent diabetes mellitus, intense glycemic control, conventional glycemic control

Pear Pongsachareonnont,1,2 Michael Ying Kit Mak,2 Cameron Paul Hurst,3 Wai-Ching Lam2,4 1Vitreo-Retinal Research Unit, Department of Ophthamology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand; 2Department of Ophthalmology and Vision Sciences, University of Toronto Faculty of Medicine, Toronto, ON, Canada; 3Biostatistics Center, Department of Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; 4Department of Ophthalmology, University of Hong Kong, Hong Kong, China Purpose: To determine the levels of interleukin (IL)-6, vascular endothelial growth factor-A, platelet-derived growth factor, placental growth factor (PLGF), and other cytokines in the aqueous fluid of patients with neovascular age-related macular degeneration who respond poorly to ranibizumab. Patients and methods: This is an observational, prospective study. Thirty-two eyes from 30 patients were included in the study: 11 patients who responded poorly to ranibizumab and were switched to aflibercept (AF group), 8 patients who received ranibizumab and photodynamic therapy (PDT group), and 13 patients who responded to ranibizumab (control group). Aqueous fluid samples were collected for analysis of cytokine levels at baseline and after 1, 2, and 3 months of treatment. The effect of treatment on cytokine levels was compared between the study groups and between different time points using a linear mixed-effect regression model. Results: In the AF group, there was an increase in vascular endothelial growth factor-C, IL-7, and angiopoeitin-2 levels (P=0.01) and a decrease in intercellular adhesion molecule and IL-17 levels (P=0.01) between baseline and 3 months. After adjustment for age, sex, race, and type of lesion at baseline, the PLGF level was higher (P=0.02) and the IL-7 level was lower (P=0.04) in the ranibizumab non-responder group than in the ranibizumab responder group. Conclusion: Switching from ranibizumab to aflibercept did not reduce intraocular levels of angiogenesis cytokines, but resulted in improvement of central subfield thickness. PLGF levels were higher in poor responders to ranibizumab. The response of lesions to medication might be related to the stage of choroidal neovascularization. Trial registration: www.ClinicalTrial.gov (NCT02218177c). Keywords: neovascular age-related macular degeneration, choroidal neovascularization, anti-VEGF non-responder, poor responder, ranibizumab and AMD

Wai-Ching Lam,1 David A Albiani,2 Pradeepa Yoganathan,3 John Chanchiang Chen,4 Amin Kherani,5 David AL Maberley,6 Alejandro Oliver,7 Theodore Rabinovitch,3 Thomas G Sheidow,8 Eric Tourville,9 Leah A Wittenberg,10 Chris Sigouin,11 Darryl C Baptiste12 1Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, 2West Coast Retinal Consultants, Vancouver, BC, 3North Toronto Eye Care, North York, ON, 4Department of Ophthalmology, McGill University, Montreal, QC, 5Southern Alberta Eye Center, Calgary, AB, 6Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC, 7Timmins and District Hospital, Timmins, ON, 8Ivey Eye Institute, London, ON, 9Center Oculaire de Quebec, Quebec City, QC, 10Retina Surgical Associates, New Westminster, BC, 11Clinwest Research Inc, Burlington, ON, 12Allergan Inc., Markham, ON, Canada Background: The purpose of this study was to evaluate the real-world use, efficacy, and safety of one or more dexamethasone intravitreal implant(s) 0.7 mg (DEX implant) in patients with macular edema (ME).Methods: This was a retrospective cohort study of patients with ME secondary to retinal disease treated at ten Canadian retina practices, including one uveitis center. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), intraocular pressure (IOP), glaucoma and cataract surgery, and safety data were collected from the medical charts of patients with ≥3 months of follow-up after the initial DEX implant.Results: One hundred and one patient charts yielded data on 120 study eyes, including diagnoses of diabetic ME (DME) (n=34), retinal vein occlusion (RVO, n=30; branch in 19 and central in 11), and uveitis (n=23). Patients had a mean age of 60.9 years, and 73.3% of the study eyes had ME for a duration of ≥12 months prior to DEX implant injection(s). Baseline mean (± standard error) BCVA was 0.63±0.03 logMAR (20/86 Snellen equivalents) and mean CRT was 474.4±18.2 µm. The mean number of DEX implant injections was 1.7±0.1 in all study eyes; 44.2% of eyes had repeat DEX implant injections (reinjection interval 2.3–4.9 months). The greatest mean peak changes in BCVA lines of vision occurred in study eyes with uveitis (3.3±0.6, P0.05). Significant decreases in CRT were observed: -255.6±43.6 µm for uveitis, -190.9±23.5 µm for DME, and -160.7±39.6 µm for RVO (P

Traditional Chinese Medicine (TCM) has been used in patients with atopic dermatitis (AD), but its therapeutic effects are debatable. We evaluated the clinical and biochemical effects of a TCM capsule (PentaHerbs capsule) in children with AD. After a run-in period of 4 weeks, children old enough to manage oral medication were admitted and their disease severity was evaluated by the SCORing Atopic Dermatitis (SCORAD) index. Blood was obtained for complete blood count, total and allergen-specific immunoglobulin E (IgE), biochemical studies and inflammatory markers of AD severity [serum cutaneous T cell-attracting chemokine (CTACK), macrophage-derived chemokine (MDC), thymus and activation-regulated chemokine (TARC) and eosinophil cationic protein (ECP)] prior to, and after 3 months of, TCM use. Three PentaHerbs capsules twice a day were prescribed for 4 months. Patients were followed monthly to ensure compliance, and SCORAD scores were obtained at each visit. Five boys and four girls participated in the study. All patients had detectable food or inhalant-specific IgE in serum. There was significant improvement in the overall and component SCORAD scores. There were no significant differences between the pre- and post-treatment values of the serum CTACK, MDC, TARC and ECP levels but CTACK showed a decreasing trend (p = 0.069). No clinical or biochemical evidence of any adverse drug reaction was observed during the study period. The PentaHerbs capsules were well tolerated by the children and apparent beneficial effects were noted clinically. A larger, randomized placebo-controlled study is required to confirm the efficacy of this formulation for AD. [ABSTRACT FROM AUTHOR]

Purpose To investigate the association between retinal vascular function and kidney function in non‐proliferative diabetic retinopathy (NPDR). Methods 10 control subjects (mean age 55±12yrs), 22 type 2 patients with mild‐to‐moderate NPDR (61±9yrs) and 14 type 2 patients with moderate‐to‐severe (62±11yrs) NPDR were recruited. Retinal vessel diameter, velocity, velocity pulse amplitude and blood flow were assessed in the supero‐temporal arteriole using bi‐directional laser Doppler flowmetry and simultaneous vessel reflectometry. Retinal vascular reactivity (VR) was quantified as the difference in hemodynamic parameters between baseline and isocapnic hyperoxia. Forearm blood samples were taken to derive plasma sodium, creatinine, albumin, glomerular filtration rate (GFR) and hemoglobin (A1c) levels. Urine samples were taken to derive albumin:creatinine ratio (A:C ratio) and microalbumin. All parameters were compared between groups and VR was correlated with systemic markers. Results VR for vessel diameter, velocity, pulse amplitude and blood flow were not different between groups. A:C ratio (ANOVA, p=0.010), microalbumin (p=0.005) and A1c (p=0.006) were elevated in patients with diabetes. The magnitude of VR for retinal vessel diameter was weakly correlated with GFR across the pooled groups (r=‐0.3992, p=0.006). Within the moderate‐to‐severe NPDR group, VR for vessel diameter was strongly correlated with GFR (r=‐0.8551, p=0.001). VR for pulse amplitude was also found to be moderately related to plasma Na levels in moderate‐to‐severe NPDR group (r=‐0.6809, p=0.007). Conclusion Disturbance of retinal VR was related to kidney function in patients with NPDR, especially in the moderate‐to‐severe group. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the facial emotion recognition ability in local children with attention-deficit hyperactivity disorder (ADHD) and the effect of inattention and impulsivity on such ability. Participants and Methods: Eight-seven Chinese children (45 controls and 42 with ADHD) of primary 1 to 3 were recruited. They were matched for age, sex, intelligence, and family income. The subjects were shown facial emotion pictures developed by Matsumoto and Ekman (1998) together with emotional story vignettes. Conners' Continuous Performance Test II was used to evaluate the attention / impulsivity level of the subjects. Results: The difference in performance in facial emotion recognition between the 2 groups was not statistically significant. There was also no significant correlation between the accuracy of facial emotion recognition and the inattention / impulsivity level. Intelligence level correlated significantly with the facial emotion recognition ability. Conclusions: The ability to recognise facial emotion is affected by multiple factors. A single diagnostic label is unlikely to be fully predictive. Further research on the influence of co-morbidities and presence of different ADHD subtypes should be considered. [ABSTRACT FROM AUTHOR]

Background/objectives: To investigate demographic enrolment characteristics in age-related macular degeneration (AMD) trials., Subjects/methods: Clinicaltrials.gov was searched with "age-related macular degeneration" to identify RCTs with double, triple, or quadruple masking. Trial (e.g., study location, phase, masking, trial initiation year, and sponsor origin) and patient demographic data were collected. Sex-based AMD disease burdens were retrieved from the Global Burden of Disease database to calculate pooled female population-to-prevalence ratios (PPRs). Equitable trial enrolment was defined as PPR between 0.8-1.2. Demographic proportions were evaluated across trial characteristics using the Kruskal-Wallis test (alpha = 0.05) followed by post hoc comparisons. Secondary outcomes included absolute number of enrolled female, racial, and ethnic groups, and the association of trial characteristics with these demographics., Results: We included 106 trials (77,939 patients; 46.3% female), spanning 1990-2020. The pooled female PRR was 0.88 (95% confidence interval [CI]: 0.82, 0.94). PPR values were inconclusive studies with quadruple blinding; phase I, III, IV, or not applicable status; foreign (non-US) site; US-only and foreign-only sponsor; and an initiation year before 2010. There was no significant difference in PPR between sublevels of analysed trial characteristics. Of the 74 (69.8%) trials that adequately detailed race, White participants comprised the largest group (N = 57,917; 82% of total participants). Thirty-seven (34.9%) trials adequately detailed ethnicity. The absolute enrolment of race and ethnic groups did not generally exhibit significant difference between sublevels of analysed trial characteristics., Conclusions: Female enrolment was commensurate to their disease burden across all trial characteristics. Race and ethnicity were under-reported. Future trials should prioritise equitable study enrolment strategies., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: Under article 2.4 of the Tri-Council Policy Statement, institutional review board approval was waived since all data were sources from published primary research and publicly available registries. No identifiable information was generated by this work., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

The management of vision-threatening retinal diseases remains challenging due to the lack of an effective drug delivery system. Encapsulated cell therapy (ECT) offers a promising approach for the continuous delivery of therapeutic agents without the need for immunosuppressants. In this context, an injectable and terminable collagen-alginate composite (CAC) ECT gel, designed with a Tet-on pro-caspase-8 system, was developed as a safe intraocular drug delivery platform for the sustained release of glial-cell-line-derived neurotrophic factor (GDNF) to treat retinal degenerative diseases. This study examined the potential clinical application of the CAC ECT gel, focusing on its safety, performance, and termination through doxycycline (Dox) administration in the eyes of healthy New Zealand White rabbits, as well as its therapeutic efficacy in rabbits with sodium-iodate (SI)-induced retinal degeneration. The findings indicated that the CAC ECT gel can be safely implanted without harming the retina or lens, displaying resistance to degradation, facilitating cell attachment, and secreting bioactive GDNF. Furthermore, the GDNF levels could be modulated by the number of implants. Moreover, Dox administration was effective in terminating gel function without causing retinal damage. Notably, rabbits with retinal degeneration treated with the gels exhibited significant functional recovery in both a-wave and b-wave amplitudes and showed remarkable efficacy in reducing photoreceptor apoptosis. Given its biocompatibility, mechanical stability, controlled drug release, terminability, and therapeutic effectiveness, our CAC ECT gel presents a promising therapeutic strategy for various retinal diseases in a clinical setting, eliminating the need for immunosuppressants.

The global burden of infections due to the pathogenic fungus Cryptococcus is substantial in persons with low CD4 + T-cell counts. Previously, we deleted three chitin deacetylase genes from Cryptococcus neoformans to create a chitosan-deficient, avirulent strain, designated as cda1∆2∆3∆ , which, when used as a vaccine, protected mice from challenge with virulent C. neoformans strain KN99. Here, we explored the immunological basis for protection. Vaccine-mediated protection was maintained in mice lacking B cells or CD8 + T cells. In contrast, protection was lost in mice lacking α/β T cells or CD4 + T cells. Moreover, CD4 + T cells from vaccinated mice conferred protection upon adoptive transfer to naive mice. Importantly, while monoclonal antibody-mediated depletion of CD4 + T cells just prior to vaccination resulted in complete loss of protection, significant protection was retained in mice depleted of CD4 + T cells after vaccination but prior to challenge. Vaccine-mediated protection was lost in mice genetically deficient in interferon-γ (IFNγ), tumor necrosis factor alpha (TNFα), or interleukin (IL)-23p19. A robust influx of leukocytes and IFNγ- and TNFα-expressing CD4 + T cells was seen in the lungs of vaccinated and challenged mice. Finally, a higher level of IFNγ production by lung cells stimulated ex vivo correlated with lower fungal burden in the lungs. Thus, while B cells and CD8 + T cells are dispensable, IFNγ and CD4 + T cells have overlapping roles in generating protective immunity prior to cda1∆2∆3∆ vaccination. However, once vaccinated, protection becomes less dependent on CD4 + T cells, suggesting a strategy for vaccinating HIV + persons prior to loss of CD4 + T cells., Importance: The fungus Cryptococcus neoformans is responsible for >100,000 deaths annually, mostly in persons with impaired CD4 + T-cell function such as AIDS. There are no approved human vaccines. We previously created a genetically engineered avirulent strain of C. neoformans , designated as cda1∆2∆3∆ . When used as a vaccine, cda1∆2∆3∆ protects mice against a subsequent challenge with a virulent C. neoformans strain. Here, we defined components of the immune system responsible for vaccine-mediated protection. We found that while B cells and CD8 + T cells were dispensible, protection was lost in mice genetically deficient in CD4 + T cells and the cytokines IFNγ, TNFα, or IL-23. A robust influx of cytokine-producing CD4 + T cells was seen in the lungs of vaccinated mice following infection. Importantly, protection was retained in mice depleted of CD4 + T cells following vaccination, suggesting a strategy to protect persons who are at risk of future CD4 + T-cell dysfunction., Competing Interests: The authors declare no conflict of interest.

Importance: Acupuncture has been used to treat neurological and neuropsychiatric symptoms in China and other parts of the world. These symptoms, such as fatigue, headache, cognitive impairment, anxiety, depression, and insomnia, are common in people experiencing long COVID., Objective: This study aims to explore the feasibility of acupuncture in the treatment of neurological and neuropsychiatric symptoms in long COVID patients., Data Sources: A systematic search was conducted in four English and four Chinese databases from inception to 23 June 2023. Literature selection and data extraction were conducted by two pairs of independent reviewers., Study Selection: Randomized controlled trials (RCTs) that explored the effect of acupuncture on fatigue, depression, anxiety, cognitive abnormalities, headache, and insomnia were included., Data Extraction and Synthesis: RCTs that explored the effect of acupuncture on fatigue, depression, anxiety, cognitive abnormalities, headache, and insomnia were included. A meta-analysis was performed using R software. Heterogeneity was measured using I 2 . Subgroup analyses were performed focusing on the duration of treatment and acupuncture modalities. The systematic review protocol was registered on PROSPERO (registration number: CRD42022354940)., Main Outcomes and Measures: Widely adopted clinical outcome scales included the Fatigue Scale for assessing fatigue, the Hamilton Depression Rating Scale for evaluating depression, the Mini-Mental State Examination for assessing cognitive impairment, the Visual Analog Scale for headache severity, and the Pittsburgh Sleep Quality Index for measuring insomnia., Results: A total of 110 RCTs were included in the systematic review and meta-analysis. Overall, acupuncture was found to improve the scores of the Fatigue Scale (vs. medication: mean differences (MD): -2.27, P < 0.01; vs. sham acupuncture: MD: -3.36, P < 0.01), the Hamilton Depression Rating Scale (vs. medication: MD: -1.62, 95%, P < 0.01; vs. sham acupuncture: MD: -9.47, P < 0.01), the Mini-Mental State Examination (vs. medication: MD: 1.15, P < 0.01; vs. sham acupuncture: MD: 1.20, P < 0.01), the Visual Analog Scale (vs. medication: MD: -1.05, P < 0.01; vs. waitlist: MD: -0.48, P=0.04), and the Pittsburgh Sleep Quality Index (vs. medication: MD: -2.33, P < 0.01; vs. sham acupuncture: MD: -4.19, P < 0.01)., Conclusion and Relevance: This systematic review suggested acupuncture as a potentially beneficial approach for the treatment of neurological and neuropsychiatric symptoms, as assessed using clinical scales, and it may have applicability in long COVID patients. Further well-designed clinical studies specifically targeting long COVID patients are needed to validate the role of acupuncture in alleviating long COVID symptoms., Systematic Review Registration: PROSPERO, identifier [CRD42022354940]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Lam, Wei, Li, Yao, Zhang, Lai, Zheng, Yeung, Lau, Lyu, Bian, Cheung and Zhong.)

Diabetic retinopathy (DR) is a major vision-threatening disease among the working-age population worldwide. Present therapeutic strategies such as intravitreal injection of anti-VEGF and laser photocoagulation mainly target proliferative DR. However, there is a need for early effective management in patients with early stage of DR before its progression into the more severe sight-threatening proliferative stage. Nutraceuticals, natural functional foods with few side effects, have been proposed to be beneficial in patients with DR. Over the decades, many studies, either in vitro or in vivo, have demonstrated the advantages of a number of nutraceuticals in DR with their antioxidative, anti-inflammatory, neuroprotective, or vasoprotective effects. However, only a few clinical trials have been conducted, and their outcomes varied. The low bioavailability and instability of many nutraceuticals have indeed hindered their utilization in clinical use. In this context, nanoparticle carriers have been developed to deliver nutraceuticals and to improve their bioavailability. Despite its preclinical nature, research of interventive nutraceuticals for DR may yield promising information in their clinical applications., Competing Interests: The authors declare no conflicts of interest.

Objectives: To evaluate the efficacy and safety of CHM in the prevention of COVID-19 infection and treatment for COVID-19 related symptoms., Design: Prospective open-label randomized controlled trial., Setting: Participants' home in Hong Kong., Participants: Participants who had household close contact with COVID-19-infected family members., Interventions: Close contacts were stratified into 4 groups (cohort A, B, C, D) based on symptoms and infection status and were randomized in 4:1 ratio to receive CHM granules (9g/sachet, two times daily) or blank control for 7 days with 2 weeks of follow-up., Main Outcome Measures: The primary outcome measure was the rate of positive nucleic acid tests. Secondary outcomes were the proportion of developed COVID-19 related symptoms and adverse events during the whole 3-week study period. Subgroup analysis was used to evaluate demographic factors associated with positive infection rates., Results: A total of 2163 contacts were enrolled and randomly assigned to the CHM group (1720 contacts) and blank control (443 contacts) group. During the 21 days, the rate of PCR-positive cases in cohort A was markedly lower in the CHM group (3.6%) compared to the control group (7.0%) ( P =0.036). Overall, the rate of infection in the CHM group was significantly lower than that in the control group (10.69% vs . 6.03%; RR 0.56, 95% CI 0.39-0.82) after 7-day treatment. No serious adverse events were reported during the medication period., Conclusion: The preliminary findings indicate that CHM may be effective and safe in preventing COVID-19. Future double-blind, randomized controlled trials and long-term follow-up are needed to fully evaluate the efficacy of CHM in a larger contact population., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT05269511., Competing Interests: The authors declare the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Du, Lam, Leung, Li, Lyu, Yuen, Cheung, Lam, Bian and Zhong.)

Background: Traumatic brain injury (TBI) adversely affects both young and old and is a growing public health concern. The common functional, psychological, and cognitive changes associated with TBI and recent trends in its management, such as recommending sub-threshold aerobic activity, and multi-modal treatment strategies including vestibular rehabilitation, suggest that Tai Chi/Qigong could be beneficial for TBI. Tai Chi and Qigong are aerobic mind-body practices with known benefits for maintaining health and mitigating chronic disease. To date, no systematic review has been published assessing the safety and effectiveness of Tai Chi/Qigong for traumatic injury., Methods: The following databases were searched: MEDLINE, CINAHL Cochrane Library, Embase, China National Knowledge Infrastructure Database, Wanfang Database, Chinese Scientific Journal Database, and Chinese Biomedical Literature Database. All people with mild, moderate, or severe TBI who were inpatients or outpatients were included. All Types of Tai Chi and Qigong, and all comparators, were included. All measured outcomes were included. A priori, we chose "return to usual activities" as the primary outcome measure as it was patient-oriented. Cochrane-based risk of bias assessments were conducted on all included trials. Quality of evidence was assessed using the grading of recommendation, assessment, development, and evaluation (GRADE) system., Results: Five trials were assessed; three randomized controlled trials (RCTs) and two non-RCTs; only two trials were conducted in the last 5 years. No trial measured "return to normal activities" or vestibular status as an outcome. Four trials - two RCTs and two non-RCTS - all found Tai Chi improved functional, psychological and/or cognitive outcomes. One RCT had a low risk of bias and a high level of certainty; one had some concerns. One non-RCTs had a moderate risk of bias and the other a serious risk of bias. The one Qigong RCT found improved psychological outcomes. It had a low risk of bias and a moderate level of certainty. Only one trial reported on adverse events and found that none were experienced by either the exercise or control group., Conclusion: Based on the consistent finding of benefit in the four Tai Chi trials, including one RCT that had a high level of certainty, there is a sufficient signal to merit conducting a large, high quality multi-centre trial on Tai Chi for TBI and test it against current trends in TBI management. Based on the one RCT on TBI and Qigong, an additional confirmatory RCT is indicated. Further research is indicated that reflects current management strategies and includes adverse event documentation in both the intervention and control groups. However, these findings suggest that, in addition to Tai Chi's known health promotion and chronic disease mitigation benefits, its use for the treatment of injury, such as TBI, is potentially a new frontier., Systematic Review Registration: PROSPERO [ CRD42022364385 ]., (© 2024. The Author(s).)

Background: Previous literature on dairy products and risk of breast cancer is inconsistent, and the relationship may depend on the life-period of dietary assessment., Objective: We examined dairy consumption from adolescence through later adulthood and incidence of breast cancer by menopausal status and tumor molecular subtypes in the Nurses' Health Study (NHS), a prospective cohort study., Methods: We analyzed data from 63,847 females in the NHS collected from 1980 to 2018. Average intake of dairy products during adulthood was assessed by validated semiquantitative food frequency questionnaires throughout follow-up. Participants recalled adolescent dietary intake in 1986. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) relating dairy product consumption to breast cancer risk overall, by menopausal status, and by subtypes., Results: We documented 5733 incident cases of invasive breast cancer during 32 y of follow-up (n = 5298 postmenopausal). Lifetime, adolescent, adulthood, and postmenopausal total dairy and milk intakes were not associated with overall breast cancer risk (nonsignificant HRs comparing highest with lowest quintile range = 0.97-1.08), although there was a suggestive positive association between adolescent milk intake and breast cancer risk (HR: 1.09; 95% CI: 1.00, 1.18). Higher lifetime and premenopausal cheese intakes were associated with modestly lower risks of breast cancer (comparing highest with lowest quintile, HR for lifetime cheese intake: 0.90; 95% CI: 0.82, 0.98; HR for premenopausal cheese intake: 0.89; 95% CI: 0.79, 1.00). Results varied by tumor subtype and some evidence for heterogeneity was observed for an association between premenopausal milk intake and breast cancer (HR for estrogen receptor [ER]-positive: 0.84; 95% CI: 0.72, 0.99; ER-negative: 1.36; 95% CI: 1.00, 1.84; P heterogeneity = 0.04)., Conclusions: These findings suggest that overall dairy consumption was not associated with risk of breast cancer. However, heterogeneity was observed for type of dairy food, period of life, and tumor subtypes., Competing Interests: Conflicts of interest ER is a Technical Editor for the American Journal for Clinical Nutrition (AJCN) and did not contribute to the decision-making or reviewing of this manuscript at AJCN. All other authors have declared no conflicts of interest., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

The cell wall of the fungal pathogens Cryptococcus neoformans and C. gattii is critical for cell wall integrity and signaling external threats to the cell, allowing it to adapt and grow in a variety of changing environments. Chitin is a polysaccharide found in the cell walls of fungi that is considered to be essential for fungal survival. Chitosan is a polysaccharide derived from chitin via deacetylation that is also essential for cryptococcal cell wall integrity, fungal pathogenicity, and virulence. Cryptococcus has evolved mechanisms to regulate the amount of chitin and chitosan during growth under laboratory conditions or during mammalian infection. Therefore, levels of chitin and chitosan have been useful phenotypes to define mutant Cryptococcus strains. As a result, we have developed and/or refined various qualitative and quantitative methods for measuring chitin and chitosan. These techniques include those that use fluorescent probes that are known to bind to chitin (e.g., calcofluor white and wheat germ agglutinin), as well as those that preferentially bind to chitosan (e.g., eosin Y and cibacron brilliant red 3B-A). Techniques that enhance the localization and quantification of chitin and chitosan in the cell wall include (i) fluorescence microscopy, (ii) flow cytometry, (iii) and spectrofluorometry. We have also modified two highly selective biochemical methods to measure cellular chitin and chitosan content: the Morgan-Elson and the 3-methyl-2-benzothiazolone hydrazine hydrochloride (MBTH) assays, respectively., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Creating a safe and effective vaccine against infection by the fungal pathogen Cryptococcus neoformans is an appealing option that complements the discovery of new small molecule antifungals. Recent animal studies have yielded promising results for a variety of vaccines that include live-attenuated and heat-killed whole-cell vaccines, as well as subunit vaccines formulated around recombinant proteins. Some of the recombinantly engineered cryptococcal mutants in the chitosan biosynthesis pathway are avirulent and very effective at conferring protective immunity. Mice vaccinated with these avirulent chitosan-deficient strains are protected from a lethal pulmonary infection with C. neoformans strain KN99. Heat-killed derivatives of the vaccination strains are likewise effective in a murine model of infection. The efficacy of these whole-cell vaccines, however, is dependent on a number of factors, including the inoculation dose, route of vaccination, frequency of vaccination, and the specific mouse strain used in the study. Here, we present detailed methods for identifying and optimizing various factors influencing vaccine potency and efficacy in various inbred mouse strains using a chitosan-deficient cda1Δcda2Δcda3Δ strain as a whole-cell vaccine candidate. This chapter describes the protocols for immunizing three different laboratory mouse strains with vaccination regimens that use intranasal, orotracheal, and subcutaneous vaccination routes after the animals were sedated using two different types of anesthesia., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Choroidal neovascularization (CNV) is the key pathological event of wet age-related macular degeneration (wAMD) leading to irreversible vision loss. Currently, anti-angiogenic therapy with anti-vascular endothelial growth factor (VEGF) agents has become the standard treatment for wAMD, while it is still subject to several limitations, including the safety concerns of monthly intravitreal administration and insufficient efficacy for neovascular occlusion. Combined therapy with photodynamic therapy (PDT) and anti-angiogenic agents has emerged as a novel treatment paradigm. Herein, a novel and less-invasive approach is reported to achieve anti-angiogenic and photodynamic combination therapy of wAMD by intravenous administration of a photoactivatable nanosystem (Di-DAS-VER NPs). The nanosystem is self-assembled by reactive oxygen species (ROS)-sensitive dasatinib (DAS) prodrug and photosensitizer verteporfin (VER). After red-light irradiation to the diseased eyes, intraocular release of anti-angiogenic DAS is observed, together with selective neo-vessels occlusion by VER-generated ROS. Notably, Di-DAS-VER NPs demonstrates promising therapeutic efficacy against CNV with minimized systemic toxicity. The study enables an efficient intravenous wAMD therapy by integrating a photoactivation process with combinational therapeutics into one simple nanosystem., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background: Serum C-reactive protein (CRP) is commonly used by surgeons to raise suspicion of anastomotic leakage and other infectious complications, but most studies on optimal cut-off values are retrospective with a small sample of patients. The aim of this study was to determine the accuracy and optimal cut-off value of CRP for anastomotic leakage in patients following esophagectomy for cancer., Materials and Methods: Consecutive minimally invasive esophagectomy for esophageal cancer patients was included in this prospective study. Anastomotic leakage was confirmed if a defect or leakage of oral contrast was seen on a CT scan, by endoscopy or if saliva was draining from the neck incision. Diagnostic accuracy of CRP was assessed by receiver operator curve (ROC) analysis. Youden's index was adopted to determine the cut-off value., Results: A total of 200 patients were included between 2016 and 2018. Postoperative day 5 showed the highest area under the ROC (0.825) and optimal cut-off value of 120 mg/L. This resulted in a sensitivity of 75%, specificity of 82%, negative predicting value of 97%, and positive predicting value of 32%., Conclusions: CRP on postoperative day 5 can be used as a negative predictor for and can be used as a marker to raise suspicion of anastomotic leakage following esophagectomy for esophageal cancer. When CRP exceeds 120 mg/L on postoperative day 5, additional investigations should be considered., (© 2023. The Author(s).)

Purpose: This study aims to compare the performance of the 25+® UltraVit® 5000 cuts per minute (cpm) vitrectomy probe versus the 25+ ® Ultravit 10,000 cpm® beveled tip, dual drive vitrectomy probe., Method: In this prospective randomised controlled clinical trial, 52 eyes of 52 consecutive patients were randomized into either the 10,000 cpm (25 patients) or 5000 cpm vitrectomy group (27 patients). Patients were evaluated preoperatively, intraoperatively, and postoperatively on the first day, and at 1 week, 1 month and 3 months. The main outcome measures were vitrectomy time, and secondary endpoints were time to induction of posterior vitreous detachment, intraoperative complications, and number of instruments used., Results: The vitrectomy time was shorter in the 10,000 cpm group (413.7 s) compared to the 5000 cpm group (463.4 s), although there was no significant difference (p = 0.5999). One patient had an iatrogenic retinal break in the 10,000 cpm group while two patients had an iatrogenic retinal break in the 5000 cpm group. The time for posterior vitreous detachment (PVD) induction and the number of instruments used were not significantly different between the two groups., Conclusion: The difference in vitrectomy times between the 10,000 cpm vitrectomy probe and the 5000 cpm cutter were not statistically significant. This may suggest that other factors affect efficiency rather than the limitations of equipment., (© 2023. The Author(s).)

Background: Traumatic brain injury (TBI) adversely affects both young and old and is a growing public health issue. A number of recent trends in managing TBI, such as recommending sub-threshold aerobic activity, tailoring multi-modal treatment strategies, and studying the possible role of low-grade inflammation in those with persistent symptoms, all suggest that the physical and cognitive exercise of tai chi/qigong could have benefit., Method: Designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the following databases will be searched: MEDLINE, CINAHL, Cochrane Library, Embase, China National Knowledge Infrastructure Database, Wanfang Database, Chinese Scientific Journal Database, and Chinese Biomedical Literature Database. All clinical trials on mild, moderate and/or severe TBI with tai chi and/or qigong as the treatment group and any comparison group, in any setting will be included. Four reviewers will independently select studies; two reviewers for the English and two for the Chinese databases. Cochrane-based risk of bias assessments will be conducted on all included studies. An analysis will then be conducted with the grading of recommendation, assessment, development, and evaluation (GRADE) instrument., Results: This review will summarize the clinical trial evidence on tai chi/qigong for TBI including type of TBI, age/sex of participants, type and length of intervention and comparator, outcome measures, and any adverse events. The risk of bias will be considered, and the strengths and weaknesses of each trial will be analyzed., Discussion: The results of this review will be considered with respect to whether there is enough evidence of benefit to merit a more definitive randomized controlled trial. Systematic Review Registration: PROSPERO [CRD42022364385]., Competing Interests: The authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Laskosky, Huston, Lam, Anderson, Zheng and Zhong.)

Competing Interests: None

Purpose: Clinical phenotypes in Immunoglobulin G4-related disease (IgG4-RD) according to the patterns of affecting organs have different risks of malignancies. We attempt to determine the association of malignancies with IgG4-related ophthalmic disease (IgG4-ROD)., Design: Retrospective cohort study., Methods: Review of medical records, orbital images and histopathology reports in a territory-wide cohort of biopsy proven IgG4-ROD patients from 2005-2019., Findings: Among 122 patients who had biopsies taken from adnexal lesions including lacrimal glands (n = 108), orbital mass (n = 30), infiltrated orbital fat (n = 10), conjunctiva (n = 2) or extraocular muscles (n = 3), 13% (16/122) developed malignancies over 73 ± 48months' follow-up. There were 9 cases of ocular adnexal lymphoma (OAL) and 7 extra-orbital malignancies. Compared with the general population, the incidence of OAL was significantly higher (standardized incidence ratios, SIRs = 10.0, 95%CI = 4.5-17.6) while that of extra-orbital malignancies was similar. The SIRs was highest within the first year (SIR = 46.7, 95%CI = 18.5-87.6) when 7 OAL were concomitantly diagnosed. Patients who developed OAL or extra-orbital malignancies were older than other patients at IgG4-ROD diagnosis (64.9 ± 7.1, 68.3 ± 8.5 versus 55.2 ± 15.0 years, P < 0.05). Asymmetric lacrimal gland enlargement (78% versus 13%), lack of frontal (0% versus 12%) or infraorbital nerve enlargement (0% versus 36%) were associated with OAL (all P < 0.05). Pre-treatment serum IgG4 level or extra-orbital IgG4-RD involvement was similar among patients with or without malignancies., Conclusion: In this biopsy-proven IgG4-ROD cohort, 7% developed OAL which was 10 times higher than the general population. Patients with asymmetric lacrimal gland enlargement or without trigeminal nerves involvement radiologically were associated with OAL.

Introduction: Cryptococcus neoformans is a basidiomycete fungus that can cause meningoencephalitis, especially in immunocompromised patients. Cryptococcus grows in many different media, although little attention has been paid to the role of growth conditions on the cryptococcal cell wall or on virulence., Objective: The purpose of this study was to determine how different media influenced the amount of chitin and chitosan in the cell wall, which in turn impacted the cell wall architecture and host response., Methods: Yeast extract, peptone, and dextrose (YPD) and yeast nitrogen base (YNB) are two commonly used media for growing Cryptococcus before use in in vitro or in vivo experiments. As a result, C. neoformans was grown in either YPD or YNB, which were either left unbuffered or buffered to pH 7 with MOPS. These cells were then labeled with cell wall-specific fluorescent probes to determine the amounts of various cell wall components. In addition, these cells were employed in animal virulence studies using the murine inhalation model of infection., Results: We observed that the growth of wild-type C. neoformans KN99 significantly changes the pH of unbuffered media during growth. It raises the pH to 8.0 when grown in unbuffered YPD but lowers the pH to 2.0 when grown in unbuffered YNB (YNB-U). Importantly, the composition of the cell wall was substantially impacted by growth in different media. Cells grown in YNB-U exhibited a 90% reduction in chitosan, the deacetylated form of chitin, compared with cells grown in YPD. The decrease in pH and chitosan in the YNB-U-grown cells was associated with a significant increase in some pathogen-associated molecular patterns on the surface of cells compared with cells grown in YPD or YNB, pH 7. This altered cell wall architecture resulted in a significant reduction in virulence when tested using a murine model of infection. Furthermore, when heat-killed cells were used as the inoculum, KN99 cells grown in YNB-U caused an aberrant hyper-inflammatory response in the lungs, resulting in rapid animal death. In contrast, heat-killed KN99 cells grown in YNB, pH 7, caused little to no inflammatory response in the host lung, but, when used as a vaccine, they conferred a robust protective response against a subsequent challenge infection with the virulent KN99 cells., Conclusion: These findings emphasize the importance of culture media and pH during growth in shaping the content and organization of the C. neoformans cell wall, as well as their impact on fungal virulence and the host response., Competing Interests: Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Stroke is the second leading cause of death worldwide. In Hong Kong, the proportion of deaths caused by cerebrovascular disease accounted for approximately 6.8% of total deaths. Although integrative medicine approaches are widely adapted by patients, there is a lack of guideline to support the corresponding clinical practice for stroke management and rehabilitation. Therefore, we design this framework for the development of an integrative medicine clinical practice guideline (CPG) for stroke., Methods: The framework follows the instructions of World Health Organization (WHO) handbook for guideline development, Guideline International Network (GIN), Appraisal of Guidelines for Research and Evaluation Instrument (AGREE II), and Reporting Items for Practice Guidelines in Healthcare (RIGHT). Three stages with ten steps are conducted., Conclusion: Clinical practice guidelines are essential to provide optimal recommendations for patients' prognosis. With proper methodology, this framework will facilitate the formation of clinical practice guideline for stroke through synthesizing evidences in the scope of integrative medicine., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022. Published by Elsevier GmbH.)

Objective: To investigate the efficacy of Integrative medicine (IM), compare with Western medicine (WM), in the treatment of rheumatoid arthritis (RA) in a cohort study. Methods: This is a cohort study with recruitment of RA patients from 10 hospitals in China. The primary outcome was change in disease activity score 28 (DAS28) during 4 follow-up visits. Generalized estimating equation (GEE) models that controlled for variables were used to investigate a time trend and assess group differences in the primary outcome and secondary outcomes after propensity score matching (PSM). Results: A total of 3195 patients with RA received IM (n = 1379, 43.2%) or WM (n = 1816, 56.8%). Following 1:1 propensity score matching, 1,331 eligible patients prescribed IM were compared to 1,331 matched patients prescribed WM. The GEE analysis with PSM showed that the IM was more beneficial to significantly decrease the levels of VAS, PGA and PhGA (VAS: odds ratio (OR), 0.76; 95% CI, 0.63-0.92; p = 0.004; PGA: OR, 0.76; 95% CI, 0.64-0.92; p = 0.007; and PhGA: OR, 0.77; 95% CI, 0.64, 0.93; p = 0.004), and reduce DAS28 (OR, 0.84; 95% CI, 0.73-0.98; p = 0.030) in the per-protocol population. Conclusion: This study suggests that compare to WM, IM has advantages in improving RA-related outcomes. However, the statistical significance might not reveal significant clinical difference. Further studies should be focused on specific treatment strategies and/or disease stages., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhong, Wang, Lam, Zhu, Du, Cao, Jiang, Zhang, Shen, Su, Xue, Mao, Fang, Gao, Hu, Peng, Gu, Wei, Huang, Lyu, Liu and He.)

Procedural skills training in a developing country is challenging, but can improve the quality of care for patients with an important regional health problem. A structured, brief, teach-the-teacher-based training course supports physicians in developing countries to acquire skills needed to perform a complex procedure independently. A case of a patient diagnosed with esophageal cancer is presented and 10 tips are given for training procedural skills in a developing country.

The review aims to evaluate the uses of conventional laser therapy and intravitreal injection of various anti-VEGF in terms of efficacy and side effects for the treatment of retinopathy of prematurity. A literature search of the publication, concerning conventional laser treatment and intravitreal injection of anti-VEGF for ROP. A total of 40 articles were reviewed after curation by the authors for relevance. Intravitreal anti-VEGF showed better ocular efficacy in zone I ROP while laser therapy had a lower recurrence rate in zone II. Comparing the two mainstay anti-VEGF agents, bevacizumab showed lower ROP recurrence rate than ranibizumab. Anti-VEGF has a higher chance in developing persistent peripheral avascularisation compared to conventional laser therapy, but a lower chance of developing high myopia. Ranibizumab has a lower systemic absorption than bevacizumab, despite having no difference in the incidence of persistent peripheral avascularisation. In conclusion, it is advised that intravitreal anti-VEGF should be used as the first-line treatment for zone I ROP while laser therapy should be the mainstay for zone II ROP owing to the different pathogenetic mechanisms. In patients with recurrence after initial anti-VEGF injection, that given ranibizumab may opt to repeat the injection while that given bevacizumab should consider supplement laser ablative treatment., (© 2022. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Recent advances in the research of the mammalian target of the rapamycin (mTOR) signalling pathway demonstrated that mTOR is a robust therapeutic target for ocular degenerative diseases, including age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma. Although the exact mechanisms of individual ocular degenerative diseases are unclear, they share several common pathological processes, increased and prolonged oxidative stress in particular, which leads to functional and morphological impairment in photoreceptors, retinal ganglion cells (RGCs), or retinal pigment epithelium (RPE). mTOR not only modulates oxidative stress but is also affected by reactive oxygen species (ROS) activation. It is essential to understand the complicated relationship between the mTOR pathway and oxidative stress before its application in the treatment of retinal degeneration. Indeed, the substantial role of mTOR-mediated autophagy in the pathogenies of ocular degenerative diseases should be noted. In reviewing the latest studies, this article summarised the application of rapamycin, an mTOR signalling pathway inhibitor, in different retinal disease models, providing insight into the mechanism of rapamycin in the treatment of retinal neurodegeneration under oxidative stress. Besides basic research, this review also summarised and updated the results of the latest clinical trials of rapamycin in ocular neurodegenerative diseases. In combining the current basic and clinical research results, we provided a more complete picture of mTOR as a potential therapeutic target for ocular neurodegenerative diseases., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Background: Functional dyspepsia (FD) is one of the most common functional gastrointestinal disorders. Based on the various symptoms present in patients with functional dyspepsia postprandial distress syndrome (FD-PDS), routine agents such as acid suppressants, prokinetic drugs, and centrally acting drugs, offer limited treatment choices with potential side effects. As a preliminary clinical trial showed that the marketed product Zhizhu Kuanzhong Capsule (ZZKZ) can improve symptoms in FD-PDS patients, our study aims to provide further evidence on the clinical efficacy and safety of ZZKZ in the treatment of patients with FD-PDS., Methods: In this multicenter, randomized, patient- and investigator-blinded, placebo-controlled, parallel-group clinical trial, we will recruit patients with FD-PDS from 18 hospitals in China and Australia. The trial will enroll patients with FD-PDS based on the Rome IV diagnostic criteria. A total of 480 eligible patients will be randomized 1:1 into either ZZKZ or placebo group with 8 weeks of treatment and 4 weeks of follow-up. The primary endpoint will be measured by a self-rated Visual Analogue Score (VAS) for the degree of discomfort with both symptoms of postprandial fullness and early satiation, recorded once a day and 7 days a week. The primary analysis will aim to compare the response rate for FD-PDS VAS score between the groups before and after 8 weeks of treatment with an alpha level of 0.05 (2-sided)., Discussion: This trial aims to strengthen the evidence for the efficacy and safety of ZZKZ, a marketed product, in treating FD-PDS. Compared to the previous clinical trial that targeted FD-PDS, this trial will have an 8-week double-blind treatment period to investigate the effect of long-term mediation through comparison with the placebo group., Trial Registration: ClinicalTrials.gov NCT03825692 . Registered on 28 January 2019., (© 2022. The Author(s).)

Retinal pigment epithelium (RPE) degeneration plays an important role in a group of retinal disorders such as retinal degeneration (RD) and age-related macular degeneration (AMD). The mechanism of RPE cell death is not yet fully elucidated. Ferroptosis, a novel regulated cell death pathway, participates in cancer and several neurodegenerative diseases. Glutathione peroxidase 4 (GPx-4) and ferroptosis suppressor protein 1 (FSP1) have been proposed to be two main regulators of ferroptosis in these diseases; yet, their roles in RPE degeneration remain elusive. Here, we report that both FSP1-CoQ 10 -NADH and GSH-GPx-4 pathways inhibit retinal ferroptosis in sodium iodate (SIO)-induced retinal degeneration pathologies in human primary RPE cells (HRPEpiC), ARPE-19 cell line, and mice. GSH-GPx-4 signaling was compromised after a toxic injury caused by SIO, which was aggravated by silencing GPx-4, and ferroptosis inhibitors robustly protected RPE cells from the challenge. Interestingly, while inhibition of FSP1 caused RPE cell death, which was aggravated by SIO exposure, overexpression of FSP1 effectively protected RPE cells from SIO-induced injury, accompanied by a significant down-regulation of CoQ 10 /NADH and lipid peroxidation. Most importantly, in vivo results showed that Ferrostatin-1 not only remarkably alleviated SIO-induced RPE cell loss, photoreceptor death, and retinal dysfunction but also significantly ameliorated the compromised GSH-GPx-4 and FSP1-CoQ 10 -NADH signaling in RPE cells isolated from SIO-induced RPE degeneration. These data describe a distinct role for ferroptosis in controlling RPE cell death in vitro and in vivo and may provide a new avenue for identifying treatment targets for RPE degeneration., (© 2022. The Author(s).)

Purpose: This case represents the longest follow-up period and youngest patient treated for multiple GRTs in the same eye associated with physical abuse., Observations: A 4-week-old otherwise healthy male presented with a constellation of unexplained injuries. Examination of the left eye revealed a mild lens opacity and a shallow retinal detachment with two giant retinal tears (GRTs) and no retinal hemorrhages. Examination of the right eye was unremarkable. Extensive investigations were negative for any underlying medical conditions. The constellation of injuries was felt to be due to physical abuse. The giant retinal tears were treated successfully with lens sparing pars plana vitrectomy. After long-term follow-up of 5 years, there was no cataract progression or development of glaucoma., Conclusions and Importance: Clinicians should suspect child abuse in any pediatric patient with GRTs, with or without retinal hemorrhages, to ensure they are connected with the appropriate children's safeguarding society as soon as possible., Competing Interests: The following authors have financial disclosures: KM: Research Funding - Bayer; Advisory Board - Santen Canada Inc and Novartis. WCL: Research Funding - Alcon, Bayer; Consulting - Bayer, Novartis; Lecture Fees - Bayer, Novartis. The following authors have no financial disclosures: STS, ASD, SS, CV., (© 2022 The Authors.)

Purpose: To compare the efficacy of topical nepafenac 0.1% versus intravitreal triamcinolone acetonide (IVTA) at the conclusion of vitrectomy surgery versus no adjuvant therapy (NAT) in improving macular morphology post-operatively in patients undergoing vitrectomy for epiretinal membrane (ERM), as measured by optical coherence tomography (OCT) imaging and best-corrected visual acuity (BCVA)., Methods: Design: Prospective randomized clinical trial Setting: Multi-centre 80 patients scheduled to undergo vitrectomy surgery for idiopathic ERM were randomized to receive either IVTA (4 mg/0.1 cc) at the end of surgery, topical nepafenac sodium 0.1% TID for 1 month post-operation or no adjuvant treatment (NAT). Optical coherence tomography (OCT) imaging, best-corrected visual acuity and intraocular pressure (IOP) were measured before surgery, and 1 and 2 months post-operation., Results: Although all three groups showed reduction in macular thickness post-operation, the NAT group showed the most improvement, with a reduction of 136.18 ± 29.84 μm at two months. There was no statistically significant difference in macular thickness between the groups at each time point, p = 0.158. The NAT group also had the best recovery in BCVA with an improvement of 0.207 logMAR (10.35 letters) at two months post-operation. There was no statistically significant difference in BCVA between the groups, p = 0.606. There was statistically significant difference in the IOP between the three groups, p = 0.04 only at 1-month visit. The IVTA group had the highest rise in average IOP at both 1 and 2 months post-operation (2.72 and 1.58 mmHg, respectively)., Conclusion: Our study data suggest there was no advantage in the use of topical nepafenac or IVTA for post-vitrectomy ERM surgery., (© 2021 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Aim: Sex differences are well documented in schizophrenia, but have been much less studied in at-risk mental state (ARMS) for psychosis. We aimed to examine sex differences in symptomatology, cognition, social and role functioning in individuals with ARMS, with specific focus on clarifying relationships between sex, negative symptoms and functioning., Methods: One hundred and seventy-seven Chinese participants aged 15-40 years with ARMS were recruited from a specialized early intervention service in Hong Kong. ARMS status was verified by Comprehensive Assessment of At-Risk Mental State. Assessments encompassing symptom profiles, a brief battery of cognitive tests and social and role functioning were conducted. Brief Negative Symptom Scale was adapted to measure negative symptoms at the level of five core domains., Results: Males with ARMS exhibited significantly poorer social functioning and more severe asociality of negative symptoms than female counterparts. Mediation analysis revealed that sex difference in social functioning became statistically insignificant when asocality was included in the model, indicating that asociality mediated the relationship between sex and social functioning. No sex differences were observed in other core domains of negative symptoms, other symptom dimensions, cognitive measures and role functioning., Conclusions: This study suggests that sex differences in ARMS may be less pronounced that those observed in established psychotic disorders. Our findings of differential pattern of asociality between sexes and its mediating role on sex difference in social functioning underscore the importance in investigating negative symptoms at a separable domain-level. Further research is required to identify sex-specific predictors of longitudinal outcomes in at-risk populations., (© 2021 John Wiley & Sons Australia, Ltd.)

Purpose: To investigate the toxicity of the low-molecular-weight components (LMWCs) in ophthalmic silicone oils (SilOils) on retinal cell lines., Methods: The toxicity of six types of LMWCs were studied and compared with conventional SilOil 1000 cSt. In vitro cytotoxic tests of LMWCs, in both liquid and emulsified forms, on three retinal cell lines (Müller cells (rMC-1), photoreceptor cells (661W) and retinal pigment epithelial cells (ARPE-19)) were conducted using a transwell cell culturing system. The morphology and viability of cells were assessed by light microscopy and Cell Counting Kit-8 (CCK-8) assay at different time points (6, 24 and 72 h). The ARPE-19 apoptotic pathway was investigated by Mitochondrial Membrane Potential/Annexin V Apoptosis Kit at different time points (6, 24 and 72 h)., Results: Apart from dodecamethylpentasiloxane (L5), all liquid LMWCs showed varying degrees of acute cytotoxicity on retinal cell lines within 72 h. Emulsified LMWCs showed comparable cytotoxicity with liquid LMWCs on retinal cell lines. Cyclic LMWCs, octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) had significantly higher cytotoxicity when compared with their linear counterparts decamethyltetrasiloxane (L4) and L5 with similar molecular formula. Using ARPE-19 cells as an example, we showed that LMWCs induce the apoptosis of retinal cells., Conclusions: Most LMWCs, in both liquid and emulsified forms, can induce acute cytotoxicity. In addition, cyclic LMWCs are suspected to have higher cytotoxicity than their linear counterparts. Therefore, LMWCs are suspected to be the main cause of the long-term toxicity of ophthalmic SilOil, due to their toxicity and propensity to cause ophthalmic SilOil to emulsify. The amount of LMWCs should be considered as the paramount parameter when referring to the quality of SilOil.

The public specialty ophthalmic clinics in Hong Kong, under the Hospital Authority, receive tens of thousands of referrals each year. Triaging these referrals incurs a significant workload for practitioners and the other clinical duties. It is well-established that Hong Kong is currently facing a shortage of healthcare workers. Thus a more efficient system in triaging will not only free up resources for better use but also improve the satisfaction of both practitioners and patients. Machine learning (ML) has been shown to improve the efficiency of various medical workflows, including triaging, by both reducing the workload and increasing accuracy in some cases. Despite a myriad of studies on medical artificial intelligence, there is no specific framework for a triaging algorithm in ophthalmology clinics. This study proposes a general framework for developing, deploying and evaluating an ML-based triaging algorithm in a clinical setting. Through literature review, this study identifies good practices in various facets of developing such a network and protocols for maintenance and evaluation of the impact concerning clinical utility and external validity out of the laboratory. We hope this framework, albeit not exhaustive, can act as a foundation to accelerate future pilot studies and deployments., (© 2021. The Author(s).)

Background: Irritable bowel syndrome (IBS) is a common gastrointestinal functional disease. Adults with IBS may experience abdominal pain, change of bowel habits, and abnormal stool form without organic disease. IBS can seriously affect their work productivity and quality of life, especially diarrhea-predominant irritable bowel syndrome (IBS-D). The Chinese medicine JCM-16021 has been shown to be potentially effective in improving the symptoms of IBS-D based on a small scale clinical trial. Hence, a large scale clinical study is designed to further evaluate the efficacy and safety of the Chinese medicine JCM-16021 for IBS-D with traditional Chinese medicine (TCM) pattern of Liver Stagnation and Spleen Deficiency (LSSD)., Methods: This study is a multi-center, randomized, double-blind, placebo-controlled clinical trial. 392 eligible participants will be enrolled with 2-week run-in, 8-week treatment and 8-week follow-up. After run-in period, participants will be randomized to receive either the Chinese medicine JCM-16021 or placebo for 8 weeks, and will have post-treatment follow up for another 8 weeks. The primary outcome is the improvement rate on the global assessment of improvement (GAI) at week 10. The secondary outcomes consist of changes of IBS-D symptoms, TCM pattern improvement, IBS-Quality of Life (IBS-QoL), IBS-Symptom Severity Score (IBS-SSS), safety, etc. RESULTS: A standard protocol has been developed for the study. The protocol will provided a detailed procedure to conduct a clinical trial and verify if the Chinese medicine JCM-16021 would significantly improve the overall symptoms of IBS-D with LSSD pattern of TCM by relieving abdominal pain, reducing stool frequency, improving the stool consistency and improving quality of life. The consolidated evidence from the study can shed light on the treatment of IBS-D with Chinese medicine., Conclusion: The protocol will provide details for investigators about the study following SPIRIT Statement. High-quality evidence on the efficacy and safety of Chinese medicine JCM-16021 for IBS-D will be provided through strict compliance with the protocol., Trial Registration: ClinicalTrial.gov identifier: NCT03457324. Registered 8 February 2018, https://clinicaltrials.gov/ct2/show/NCT03457324?term=NCT03457324&draw=2&rank=1., (© 2021. The Author(s).)

Chitosan, a deacetylated form of chitin, is required for the virulence of Cryptococcus neoformans . There are three chitin deacetylase genes (CDA) that are essential for chitosan production, and deletion of all three genes results in the absence of chitosan, loss of virulence, and induction of a protective host response when used as a vaccine. Cda1 plays a major role in deacetylating chitin during pulmonary infection of CBA/J mice. Inoculation with the cda 1Δ strain did not lead to a lethal infection. However, the infection was not cleared. The persistence of the fungus in the host suggests that chitin is still being deacetylated by Cda2 and/or Cda3. To test this hypothesis, we subjected strains deleted of two CDA genes to fungal virulence in CBA/J, C57BL/6 and BALB/c and found that cda 1Δ cda 2Δ was avirulent in all mouse lines, as evidenced by its complete clearance. Consistent with the major role of Cda1 in CBA/J, we found that cda 2Δ cda 3Δ was as virulent as its wild-type progenitor KN99. On the other hand, cda 1Δ cda 3Δ displayed virulence comparable to that of cda 1Δ. The virulence of each mutant correlates with the amount of chitosan produced when grown under host-mimicking culture conditions. In addition, the avirulence of cda 1Δ cda 2Δ was followed by the induction of a protective immune response in C57BL/6 and CBA/J mice, when a live or heat-killed form of the mutant was used as a vaccine respectively. Taken together, these data imply that, in C. neoformans , coordinated activity of both Cda1 and Cda2 is essential for mediating fungal virulence., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Retinoblastoma is one of the most severe ocular diseases, of which current chemotherapy is limited to the repetitive intravitreal injections of chemotherapeutics. Systemic drug administration is a less invasive route; however, it is also less efficient for ocular drug delivery because of the existence of blood-retinal barrier and systemic side effects. Here, a photoresponsive drug release system is reported, which is self-assembled from photocleavable trigonal small molecules, to achieve light-triggered intraocular drug accumulation. After intravenous injection of drug-loaded nanocarriers, green light can trigger the disassembly of the nanocarriers in retinal blood vessels, which leads to intraocular drug release and accumulation to suppress retinoblastoma growth. This proof-of-concept study would advance the development of light-triggered drug release systems for the intravenous treatment of eye diseases., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background: Acupuncture has been an alternative approach for pain management, but trial evidence is conflicting., Methods: Eighty-six patients with knee osteoarthritis were randomly assigned in a 1:1 ratio from June 14, 2017, to January 20, 2019, to receive either superficial needling acupuncture treatment or sham acupuncture for 10 sessions over a 4-week treatment period, followed by a 6-week follow-up period. The primary outcome was the change of pain intensity at week 4 measured using a 100-mm visual analogue scale. Secondary outcomes included the Western Ontario and McMaster Universities Osteoarthritis Index and 36-Item Short Form Health Survey., Results: At the end of the 4-week treatment period, mean changes in the visual analogue scale were -30.8 (95% confidence interval [CI], -38.2 to -23.0; p <.001) in the acupuncture group and -26.7 (95% CI, -34.4 to -18.8; P <.001) in the sham group. The difference between the acupuncture group and the sham group was -4.1 (95% CI, -14.4 to 6.2; P = 0.431). At week 10, the difference between the groups was -2.2 (95% CI, -13.1 to 8.8; P =0.699). There was no statistically significant difference in Western Ontario and McMaster Universities Osteoarthritis Index subscores (pain, stiffness, and physical function) and 36-Item Short Form Health Survey-related outcomes across groups from weeks 2 to 10. The incidence of treatment-related adverse events was 4.4% in the acupuncture group and 0.8% in the sham acupuncture group. All adverse events were classified as mild., Conclusion: Acupuncture for 4 weeks is not superior to non-penetrating sham acupuncture. The current study cannot confirm that superficial acupuncture has efficacy for the treatment of knee osteoarthritis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To assess the reporting quality of randomized controlled trials (RCTs) with multicenter design, particularly whether necessary information related to multicenter characteristics was adequately reported., Study Design and Setting: Through a search of 4 international electronic databases, we identified multicenter RCTs published in English from 1975 to 2019. Reporting quality was assessed by the CONSORT (Consolidated Standards of Reporting Trials) checklist (37 items) and by a self-designed multicenter-specific checklist (27 items covering multicenter design, implement and analysis). The scores of trials published in three time periods (1975-1995; 1996-2009; and 2010-2019) were also compared., Results: A total of 2,844 multicenter RCTs were included. For the CONSORT checklist, the mean (standard deviation) reporting score was 24.1 (5.5), 12 items were assessed as excellent (>90%), 12 items as good (50%-90%), and 13 items as poor (<50%). For the multicenter checklist, the reporting score was 3.9 (2.2), only 3 items were excellent or good, and the remaining 24 items were poor. Time period comparison showed that reporting quality improved over time, especially after the CONSORT 2010 issued., Conclusion: Although CONSORT appears to have enhanced the reporting quality of multicenter RCTs, further improvement is needed. A "CONSORT extension for multicenter trials" should be developed., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Retinitis pigmentosa (RP) is a leading cause of inherited retinal degeneration, with more than 60 gene mutations. Despite the genetic heterogenicity, photoreceptor cell damage remains the hallmark of RP pathology. As a result, RP patients usually suffer from reduced night vision, loss of peripheral vision, decreased visual acuity, and impaired color perception. Although photoreceptor cell death is the primary outcome of RP, the underlying mechanisms are not completely elucidated. Ferroptosis is a novel programmed cell death, with characteristic iron overload and lipid peroxidation. Recent studies, using in vitro and in vivo RP models, discovered the involvement of ferroptosis-associated cell death, suggesting a possible new mechanism for RP pathogenesis. In this review, we discuss the association between ferroptosis and photoreceptor cell damage, and its implication in the pathogenesis of RP. We propose that ferroptotic cell death not only opens up a new research area in RP, but may also serve as a novel therapeutic target for RP.

Purpose: To compare ultra-wide-field colour fundus imaging (UWFI) to dilated fundus examination (DFE) for the screening of sickle cell retinopathy (SCR)., Design: This study is a prospective, blinded, multicentre case series., Participants: This study included two groups: an adult group (n=268 eyes) and a paediatric group (n=168 eyes). Sickle cell disease (SCD) types included haemoglobin S homozygous (HbSS), haemoglobin S and C (HbSC) and Hb S with β-thalassaemia (HbSß-Thal)., Methods: Participants underwent DFE and UWFI. Each eye received three independent grades (1-4), documented by three graders: clinical grader, image grader 1 and image grader 2. Three clinically relevant diagnostic thresholds were determined. Based on these thresholds, the sensitivity, specificity, positive predictive value and negative predictive value for all three graders were calculated relative to each other as reference tests., Results: HbSC was associated with the most advanced SCR grades. When compared to the clinical grader, image grader 1 and image grader 2 consistently detected more SCR and higher SCR grades in both adult and paediatric groups. In both groups, image grader 1 and image grader 2 identified twice as many cases of capillary occlusion/anastomosis than clinical grader. To detect the presence of any proliferative SCR, image grader 1 and image grader 2 had a sensitivity of 82%, 71% in the paediatrics group and 90% and 72% in the adult group. The clinical grader sensitivity was 52% in the paediatrics group and 53% in the adult group., Conclusion: The UWFI is a sensitive tool to screen for SCR. It is superior to DFE in detecting capillary occlusion or anastomosis., Competing Interests: Competing interests: The fundus camera (Optos—Daytona) that was used in the paediatric group of this study was provided on loan from Optos to conduct this research. Authors have no other relevant financial disclosures to this project., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: Psychiatric comorbidity frequently occurs with at-risk mental state (ARMS) for psychosis. Its relationships with psychopathology, cognition and functioning, however, remain to be further clarified. We aimed to examine prevalence and correlates of psychiatric comorbidity, and its associations with psychosocial functioning and subjective quality-of-life (QoL) in a representative sample of Chinese ARMS individuals., Methods: One hundred ten help-seeking participants aged 15 to 40 years with ARMS were recruited from a specialized early psychosis service in Hong Kong. ARMS status was verified by comprehensive assessment of at-risk mental state (CAARMS). Comorbid Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition non-psychotic psychiatric disorders at baseline were ascertained using diagnostic interview and medical record review. Assessments encompassing symptom profiles, psychosocial functioning, subjective QoL and a brief cognitive battery were conducted., Results: Forty-nine (44.5%) ARMS participants were diagnosed as having comorbid non-psychotic psychiatric disorders at baseline, primarily depressive and anxiety disorders. Binary multiple logistic regression analysis revealed that female gender, more severe depressive symptoms, higher suicidality and poorer global cognitive functioning were independently associated with comorbid diagnosis status. ARMS participants with psychiatric comorbidity displayed significantly more limited extended social networks and poorer subjective QoL than those without psychiatric comorbidity., Conclusion: Comorbid disorders were frequently observed in Chinese ARMS individuals, and were linked to poorer cognition and higher suicide risk. Our findings underscore a potential critical role of psychiatric comorbidity in determining social functioning and subjective QoL in at-risk individuals. Further longitudinal research is required to clarify trajectories of comorbid disorder status and its prospective impact on clinical and functional outcomes in ARMS populations., (© 2020 John Wiley & Sons Australia, Ltd.)

Silicone oil (SO) has been used as a long-term tamponade agent in the treatment of complicated vitreoretinal diseases for about half a century, during which time many advances in surgical techniques and technologies have been made. This review summarizes the chemical and physical properties of SO, its indications and complications, including particularly emulsification. The mechanisms and risk factors for emulsification are discussed, as well as novel strategies for its effective removal. Finally, the review focuses on new improved formulations of SO, including research into slow-release pharmacological agents within SO and provides an overview of alternatives to SO for the purpose of long-term tamponade that are being developed., (© 2020 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Ethnopharmacological Relevance: Chinese Medicine plays a symbolic role among traditional medicines. As Chinese Medicine products are widely used around the globe, regulations for Chinese Medicine products are often used as models for the efficient regulation of natural products that are safe, and high-quality. Aim of the Study: We aimed to compare the regulatory registration requirements for Proprietary Chinese Medicines in Hong Kong and Canada. Materials and Methods: We compared registration requirements for Proprietary Chinese Medicine in Hong Kong and Canada based on publicly available information provided by the respective Regulators. A marketed product, Zhizhu Kuanzhong Capsule (SFDA approval number Z20020003; NPN approval number 80104354), was used as a case study to demonstrate the similarities and differences of the requirements in both Hong Kong and Canada. Results: There were similarities and differences between the two regulatory systems in terms of the quality, safety and efficacy requirements. Despite the superficial appearance of similar categories and groups/classes, Hong Kong requires significantly more primary test data compared to Canada's reliance on attestation to manufacturing according the standards outlined in approved reference pharmacopeias/texts. Conclusion: Improved understand of the similarity and differences will enable applicants to plan appropriate strategies for gaining product approval. Exploring ways to harmonize the regulatory process has the potential to benefit manufacturers, regulators, and patients by increasing efficiency and decreasing costs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhong, Lam, Lu, Tang, Lyu, Bian and Boon.)

Endoscopy provides unique optical properties to circumvent anterior segment opacities and visualize difficult-to-access anatomical regions, including retroirideal, retrolental, ciliary body, and anterior retinal structures. We summarize the basic principles and utilization of endoscopic vitreoretinal surgery, along with recent technological advances in the field base on a structured literature search in Pubmed, Embase, and Google Scholar database up to February, 2020. Endoscopy has been used in the management of retinal detachment, ischemic retinopathies with neovascular glaucoma, severe ocular trauma, endophthalmitis, lens-related disorders in the posterior segment, pediatric vitreoretinal diseases, and implantation of retinal prostheses. Ongoing development of endoscopic technology aims to provide higher resolution images with endoscopes of smaller diameter. New surgical techniques supported by the adoption of endoscopy are available to manage challenging surgical scenarios. Endoscopy can be a useful adjunct to microscope wide-angle viewing systems in the management of complex vitreoretinal diseases., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Retinopathy of prematurity (ROP), the most common cause of childhood blindness, is a hypoxia-induced eye disease characterized by retinal neovascularization. In the normal retina, a well-organized vascular network provides oxygen and nutrients as energy sources to maintain a normal visual function; however, it is disrupted when pathological angiogenesis is induced in ROP patients. Under hypoxia, inadequate oxygen and energy supply lead to oxidative stress and stimulate neovasculature formation as well as affecting the function of photoreceptors. In order to meet the metabolic needs in the developing retina, protection against abnormal vascular formation is one way to manage ROP. Although current treatments provide beneficial effects in reducing the severity of ROP, these invasive therapies may also induce life-long consequences such as systemic structural and functional complications as well as neurodevelopment disruption in the developing infants. Nutritional supplements for the newborns are a novel concept for restoring energy supply by protecting the retinal vasculature and may lead to better ROP management. Nutraceuticals are provided in a non-invasive manner without the developmental side effects associated with current treatments. These nutraceuticals have been investigated through various in vitro and in vivo methods and are indicated to protect retinal vasculature. Here, we reviewed and discussed how the use of these nutraceuticals may be beneficial in ROP prevention and management.

Background: Moxibustion is a common intervention of Chinese medicine (CM). Systematic reviews (SRs) on moxibustion are increasing. Although the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement provides guidelines for SRs, the quality of moxibustion-related SRs is still not satisfactory. In particular, descriptions of the interventions and the rationale for using moxibustion are insufficient. To address these inadequacies, the working group developed this PRISMA extension for reporting SRs of moxibustion (PRISMA-M 2020)., Methods: A group of CM clinical professionals, methodologists of SRs, reporting guideline developers, and journal editors developed this PRISMA-M 2020 through a comprehensive process that includes registration, literature review, consensus meetings, Delphi exercises for soliciting comments, and revision, resulting in this final draft., Results: Seven of the 27 PRISMA checklist items, namely title (1), rationale (3), eligibility criteria (6), data item (11), additional analyses (16), study characteristics (18), and additional analysis (23), were extended, with specific reference to the application of moxibustion. Illustrative examples and explanations for each item are provided., Conclusion: The PRISMA-M 2020 will help improve the reporting quality of SRs with moxibustion., Systematic Review Registration: We have registered it on the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) network, particularly under the item of PRISMA-TCM: http://www.equator-network.org/library/reporting-guidelines-under-development/reporting-guidelines-under-development-for-systematic-reviews/#65 .