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Hon Shing Ong,1–3 Mohamed Farook,1 Benjamin Boon Chuan Tan,1 Geraint P Williams,1,2 Marcony R Santhiago,4,5 Jodhbir S Mehta1–3,6 1Department of Corneal and External Diseases, Singapore National Eye Centre, Singapore, Singapore; 2Tissue Engineering and Stem Cell Group, Singapore Eye Research Institute, Singapore, Singapore; 3SingHealth Duke-NUS Ophthalmology and Visual Sciences Academic Clinical Programme, Duke-NUS Graduate Medical School, Singapore, Singapore; 4Department of Ophthalmology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; 5Department of Ophthalmology, University of Sao Paulo, Sao Paulo, Brazil; 6School of Material Science and Engineering, Nanyang Technological University, Singapore, SingaporeCorrespondence: Hon Shing Ong; Jodhbir S MehtaDepartment of Corneal and External Diseases, Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore168751, SingaporeTel +65 6227 7255Email honshing@gmail.com; jodmehta@gmail.comPurpose: A percentage tissue altered (PTA) score of ≥40% has been advocated as an independent indicator of post-operative ectasia risk following laser in-situ keratomileusis (LASIK). This study was performed to test the hypothesis that refractive procedures, such as laser-assisted sub-epithelial keratectomy (LASEK) or small incision lenticule extraction (SMILE), may alter the range of PTA, within which refractive corneal surgery can be safely performed.Setting: Refractive department, tertiary ophthalmic hospital.Design: Retrospective observational study.Methods: Review of case notes was performed for patients who presented for refractive surgeries, other than LASIK. To determine the risk of corneal ectasia for each patient prior to refractive surgery, we estimated what each patient’s PTA would have been if they had undergone LASIK. The Randleman Ectasia Risk Score System (ERSS) was also calculated.Results: 114 eyes (66 patients) were included. 94 eyes underwent SMILE. 20 eyes underwent LASEK. A significant proportion of eyes had PTA ≥40% – SMILE eyes: up to 31.9%, LASEK eyes: up to 60.0% (at presumed LASIK flap of 120 μm). The maximum calculated PTA was up to 47.9% in the SMILE group and up to 51.5% in the LASEK group. Using ERSS, 12.8–16% of SMILE eyes and 15.0–80.0% of LASEK eyes would have been considered to have moderate-to-high ectasia risk. No post-surgical ectasia was observed at 3 years.Conclusion: SMILE and LASEK alter the range of PTA, within which corneal refractive surgery may be performed with a lower risk of developing post-operative corneal ectasia; a safe PTA threshold needs to be determined for these procedures before recommendations for clinical practice can be made.Keywords: percentage tissue altered, ectasia, refractive surgery, laser in situ keratomileusis, laser-assisted sub-epithelial keratectomy, small incision lenticule extraction

An intensive enthopharmaoclogical survey was conducted among siddha, ayurveda, traditional practitioners, and local people along the coastal areas of Cape Comorin to evaluate the potential of flora in the coastal lands to treat diseases and illness. A total of 40 informants, ranging in age from 60 to 90 years of age, were interviewed using an informal questionnaire. Responses to the survey reported 129 medicinal genera in 56 families used for medicinal purposes in the coastal region. Of these plants, 19 were reported as being used for the treatment or control of livestock ailments. The remaining plants were reported as used to treat human ailments, such as skin diseases (8 species), leukorrhea (6 species), inflammation (15 species), diabetes (5 species), jaundice (4 species), rheumatism (9 species), kidney stones (5 species), and wound healing (6 species). The remaining plants were used to treat other ailments, including migraines, intestinal cancer, scabies, body pain, venereal disease, premature ejaculation, liver disease, malarial fever, cough, worms, chicken pox, dandruff, hydrocele, rabies, abscesses, and teeth and gums. A single plant Marsilea quadrifolia L. was reported as a pteridophytic member. [ABSTRACT FROM AUTHOR]

Background: Surgical management of lumbar spondylolisthesis requires neural decompression, stabilization, and alignment restoration. Minimally invasive spine approaches offer a wide variety of advantages for spondylolisthesis management. This intraoperative note describes the treatment of L4-L5 lumbar spondylolisthesis with lateral lumbar interbody fusion (LLIF) and percutaneous pedicle screw fixation (PSF)., Methods: The surgical technique for treating L4-L5 lumbar spondylolisthesis using a minimally invasive approach with LLIF and percutaneous PSF is described. This operative technique is illustrated with figures, and an intraoperative case example of its application is described., Results: LLIF with percutaneous PSF can be a safe, effective, and reliable option for treating lumbar spondylolisthesis when applied with appropriate surgical technique in a selected patient population. This technique is a valuable addition to the range of available spine surgical options., Conclusions: LLIF with percutaneous PSF can be an effective technique for treating lumbar L4-L5 spondylolisthesis., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Thoracic discectomy procedures require early and adequate pain control to alleviate patient discomfort after surgery. The intraoperative placement of a nerve block after intercostal nerve violation can offer early pain management after thoracic discectomy., Methods: The anatomy and technique of placing an intercostal nerve block after retropleural thoracic discectomy are described. Patient data were collected for patients who underwent this technique., Results: This approach is presented with an illustrative figure and a review of relevant anatomical landmarks to describe the technique and ensure its reproducibility. Data for 93 patients (57 [61%] women; 36 [39%] men; mean [SD] age, 54.1 [14.1] years) who underwent the procedure are provided to assess the reliability of this technique., Conclusions: Intercostal nerve blockage offers a valuable addition to postoperative pain management and may be considered as an available pain relief option for patients undergoing thoracic discectomy., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Previous studies have shown that the nucleus could offer structural support to the lens capsule. This study investigated the biomechanical performance of porcine lens with and without nucleus for 4 mm, 4.5 mm, 5 mm, 5.5 mm and 6 mm capsulotomy and its potential impact on the stretch ratio of capsular bag when the anterior capsulotomy edge was stretched. Our simulation results showed higher strain for the capsular bag with nucleus, which is crucial for the porcine lens to tolerate more stretch without failure. This simulation could support future study on the optimization of capsulotomy based on patient specific condition, that is, the geometry of lens.

Post-acute sequelae of COVID-19 (PASC), or Long COVID, is a chronic condition following acute SARS-CoV-2 infection. Symptoms include exertion fatigue, respiratory issues, myalgia, and neurological manifestations such as 'brain fog,' posing concern for their debilitating nature and potential role in other neurological disorders. However, the underlying potential pathogenic mechanisms of the neurological complications of PASC is largely unknown. Herein, we investigated differences in antigen-specific T cell responses from the peripheral blood towards SARS-CoV-2, latent viruses, or neuronal antigens in 14 PASC individuals with neurological manifestations (PASC-N) versus 22 individuals fully recovered from COVID-19. We employed Activation Induced Marker (AIM), ICS and FluoroSpot assays to determine the specificity and magnitude of CD4 + and CD8 + T cell responses towards SARS-CoV-2 (Spike and rest of proteome), latent viruses (CMV, EBV), and several neuronal antigens. Overall, we observed similar antigen-specific T cell frequencies and cytokine effector T cell responses between PASC donors compared to recovered controls for all antigens tested (viral or autoantigen) in both CD4 + and CD8 + T cell compartments. Our findings suggest that PASC-N does not appear to be associated with changes in antigen-specific T cell responses towards a subset of disease-relevant targets, but more studies in a larger cohort are needed to confirm these unaltered responses., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

OBJECTIVE: To determine if adding lumbar neuromuscular control retraining exercises to a 12-week program of strengthening exercises had greater effect for improving disability than 12 weeks of strengthening exercises alone in people with chronic low back pain (LBP). DESIGN: Single-center, participant- and assessor-blinded, comparative effectiveness randomized controlled trial. METHODS: Sixty-nine participants (31 females; 29 males; mean age: 46.5 years) with nonspecific chronic LBP were recruited for a 12-week program involving lumbar extension neuromuscular retraining in addition to resistance exercises (intervention) or 12 weeks of resistance exercises alone (control). The primary outcome measure was the Oswestry Disability Index. Secondary outcome measures included the Numeric Rating Scale, Tampa Scale for Kinesiophobia, Pain Self-Efficacy Questionnaire, and the International Physical Activity Questionnaire. Outcomes were measured at baseline, 6 weeks, and 12 weeks. RESULTS: Forty-three participants (22 control, 21 intervention) completed all outcome measures at 6 and 12 weeks. Fourteen participants were lost to follow-up, and 12 participants discontinued due to COVID-19 restrictions. Both groups demonstrated clinically important changes in disability, pain intensity, and kinesiophobia. The difference between groups with respect to disability was imprecise and not clinically meaningful (mean difference, -4.4; 95% CI: -10.2, 1.4) at 12 weeks. Differences in secondary outcomes at 6 or 12 weeks were also small with wide confidence intervals. CONCLUSIONS : Adding lumbar neuromuscular control retraining to a series of resistance exercises offered no additional benefit over resistance exercises alone over a 12-week period. J Orthop Sports Phys Ther 2024;54(5):1-10. Epub 18 March 2024. doi:10.2519/jospt.2024.12349 .

Background: Osseous spinal metastases from intracranial meningiomas are rare but represent a serious disease progression. A literature review was performed on this topic to understand the clinical course of patients with this disease entity. We also present a case of spinal metastasis in a patient with a World Health Organization grade III meningioma., Methods: The PubMed/MEDLINE database was queried on August 15, 2021, using the keywords (meningioma) AND (metastasis) AND (vertebra∗ OR spin∗). All publications reporting outcomes of patients with meningioma metastatic to the spine were included. Disease characteristics, treatment modality, and outcomes were extracted from each study. Because data availability varied widely between studies, no meta-analysis was performed., Results: A total of 30 articles with 33 cases were included. Outcome data varied greatly in terms of quality and length of follow-up. Of 28 cases with reported outcomes data, 20 resulted in patient mortality ranging from a few weeks to 5 years after spinal metastasis. Mean (standard deviation) survival time was 5.8 (6.4) years following initial diagnosis, but only 1.4 (3.2) years from spinal metastasis. The longest survivor was noted to have no recurrence of disease 4 years after spinal metastasis., Conclusions: Bony spinal metastasis from intracranial meningioma is an extremely rare occurrence. Within the limits of the available literature, outcomes of patients with this disease appear to be poor. However, data reporting is inconsistent, and several articles did not report any outcome data. Further study is needed to better clarify the course and prognosis of this disease., (Copyright © 2023. Published by Elsevier Inc.)

A gold-standard clinical measure of leg muscle strength has not been established. Therefore, the aim of this study was to evaluate clinimetric properties of five clinically feasible measures of lower-limb extensor muscle strength in neurological rehabilitation settings. This was a cross-sectional observational study of 36 participants with leg weakness as a result of a neurological condition/injury. Participants were recruited across a range of walking abilities, from non- to independently ambulant. Each was assessed using each of the following five measures: manual muscle test (MMT), hand-held dynamometry (HHD), seated single leg press one repetition maximum (1RM), functional sit-to-stand (STS) test and seated single leg press measured with a load cell. Each clinical measure was evaluated for its discriminative ability, floor/ceiling effects, test-retest reliability and clinical utility. The load cell and HHD were the most discriminative of the tests and were also resistant to floor/ceiling effects; however, the load cell was superior to the HHD when compared for its clinical utility. The MMT/STS tests received perfect scores for clinical utility, although similar to the 1RM test, they were susceptible to floor and ceiling effects. The load cell leg press test was the only measure of lower limb strength to satisfy all four clinimetric properties. Implications for clinical practice include, firstly, that strength tests available to clinicians vary in their clinimetric properties. Secondly, the functional status of the person will determine selection of the best clinical strength test. And lastly, load cell device technology should be considered for clinical strength assessments., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Social determinants of health (SDH), such as social isolation and loneliness, are often more frequently experienced in brain injury survivors. The paper explores the personal experiences of loneliness among brain injury survivors during lockdown to negate health inequalities and improve rehabilitation for this population in the future. Twenty-four brain injury survivors participated in semi-structured interviews and questionnaires relating to loneliness, resilience and wellbeing. Three themes (the experience of loneliness, loneliness during the pandemic and loneliness after the pandemic) explored survivors' experiences of loneliness generally post-brain injury, but also chronicle how these feelings developed in lockdown and survivors' feelings regarding society returning to 'normal'. Future interventions should focus on reframing survivors' beliefs regarding societal expectations and minimise the pressure they experience to keep up with their peers physically and emotionally. Additionally, we recommend creating accessible peer support options for all brain injury survivors as an important step for alleviating loneliness.

Background: In 2020, routine cataract surgery was halted in most countries due to the COVID-19 pandemic in order to reduce transmission. With a consequent lack of theatre space, we developed a safe cataract pathway in outpatient department clean rooms to minimize patient exposure and time spent in hospital using a sterile laminar air flow device. We describe our initial experiences of restarting elective cataract surgery in the UK outpatient setting, outside of the operating theatre environment., Methods: This was a prospective consecutive study of our clinical practice. A sterile air zone unit, the Toul Meditech Operio Mobile device, was used to create a sterile surgical site in three separate outpatient clean rooms from May 2020 to December 2021 in different geographical locations within Herefordshire, UK. Observations of the time spent in the department and a formal patient satisfaction survey were carried out for the initial 100 patients. All patients were followed up to assess development of post-operative complications., Results: 1269 patients were included in the study. No patients sustained post-operative infection (n = 0/1269, 0%). For the initial 100 patients, the average time spent within the department was 74.3 min (unilateral cases, range 45-115 min) and 93.1 min (bilateral, 55-135 min). Patient satisfaction was high., Conclusion: Initial results demonstrate a safe, efficient and effective cataract surgery pathway with high patient satisfaction by converting outpatient clean rooms into ophthalmic operating theatres using the Toul Meditech Operio Mobile., (© 2022. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Dopaminergic cell loss due to the accumulation of α-syn is a core feature of the pathogenesis of Parkinson disease. Neuroinflammation specifically induced by α-synuclein has been shown to exacerbate neurodegeneration, yet the role of central nervous system (CNS) resident macrophages in this process remains unclear. We found that a specific subset of CNS resident macrophages, border-associated macrophages (BAMs), play an essential role in mediating α-synuclein related neuroinflammation due to their unique role as the antigen presenting cells necessary to initiate a CD4 T cell response whereas the loss of MHCII antigen presentation on microglia had no effect on neuroinflammation. Furthermore, α-synuclein expression led to an expansion in border-associated macrophage numbers and a unique damage-associated activation state. Through a combinatorial approach of single-cell RNA sequencing and depletion experiments, we found that border-associated macrophages played an essential role in immune cell recruitment, infiltration, and antigen presentation. Furthermore, border-associated macrophages were identified in post-mortem PD brain in close proximity to T cells. These results point to a role for border-associated macrophages in mediating the pathogenesis of Parkinson disease through their role in the orchestration of the α-synuclein-mediated neuroinflammatory response., (© 2023. The Author(s).)

Background and Objectives: Parkinson's disease (PD) is associated with a heightened inflammatory state, including activated T cells. However, it is unclear whether these PD T cell responses are antigen specific or more indicative of generalized hyperresponsiveness. Our objective was to measure and compare antigen-specific T cell responses directed towards antigens derived from commonly encountered human pathogens/vaccines in patients with PD and age-matched healthy controls (HC)., Methods: Peripheral blood mononuclear cells (PBMCs) from 20 PD patients and 19 age-matched HCs were screened. Antigen specific T cell responses were measured by flow cytometry using a combination of the activation induced marker (AIM) assay and intracellular cytokine staining., Results: Here we show that both PD patients and HCs show similar T cell activation levels to several antigens derived from commonly encountered human pathogens/vaccines in the general population. Similarly, we also observed no difference between HC and PD in the levels of CD4 and CD8 T cell derived cytokines produced in response to any of the common antigens tested. These antigens encompassed both viral (coronavirus, rhinovirus, respiratory syncytial virus, influenza, cytomegalovirus) and bacterial (pertussis, tetanus) targets., Conclusions: These results suggest the T cell dysfunction observed in PD may not extend itself to abnormal responses to commonly encountered or vaccine-target antigens. Our study supports the notion that the targets of inflammatory T cell responses in PD may be more directed towards autoantigens like α-synuclein (α-syn) rather than common foreign antigens., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Many bidialectal children grow up speaking a variety (e.g., a regional dialect) that differs from the variety in which they subsequently acquire literacy. Previous computational simulations and artificial literacy learning experiments with adults have demonstrated lower accuracy in reading contrastive words for which dialect variants exist compared with noncontrastive words without dialect variants. At the same time, exposure to multiple varieties did not affect learners' ability to phonologically decode untrained words; in fact, longer literacy training resulted in a benefit from dialect exposure as competing variants in the input may have increased reliance on grapheme-phoneme conversion. However, these previous experiments interleaved word learning and reading/spelling training, yet children typically acquire substantial oral language knowledge prior to literacy training. Here we used artificial literacy learning with adults to examine whether the previous findings replicate in an ecologically more valid procedure where word learning precedes literacy training. We also manipulated training conditions to explore interventions thought to be beneficial for literacy acquisition, such as providing explicit social cues for variety use and literacy training in both varieties. Our findings replicated the reduced accuracy for reading contrastive words in those learners who had successfully acquired the dialect variants prior to literacy training. This effect was exacerbated when literacy training also included dialect variation. Crucially, although no benefits from the interventions were found, dialect exposure did not affect reading and spelling of untrained words suggesting that phonological decoding skills can remain unaffected by the existence of multiple word form variants in a learner's lexicon. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Heart failure (HF) is a major challenge worldwide and needs continuous monitoring of patients even after hospital discharge. This case report summarises the data collected and experience gained from the first usage of an automated, point-of-care device (Heartfelt device) in a patient's home in the UK. The device monitors the onset of peripheral oedema and alerts clinicians if an increase in volume outside an expected normal range for the patient is detected. This may provide a reliable method of remotely and automatically monitoring HF patients in the home for those who do not reliably use weighing scales. The device successfully provided data for about 15 months and generated alerts in advance, which supported decisions for the patient's care. The rate of data acquisition was very high and consistent throughout this period. The patient was satisfied with the device and agreed that it helped in her decision to seek medical attention., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Inflammation has increasingly become a focus of study in regards to Parkinson's disease (PD). Moreover, both central and peripheral sources of inflammation have been implicated in the pathogenesis of PD. Central inflammation consisting of activated microglia, astroglia, and T cell responses within the PD central nervous system; and peripheral inflammation referring to activated innate cells and T cell signaling in the enteric nervous system, gastrointestinal tract, and blood. This review will highlight important work that further implicates central and peripheral inflammation in playing a role in PD. We also discuss how these two distant inflammations appear related and how that may be mediated by autoantigenic responses to α-syn.

Despite the prevalence and medical significance of human cytomegalovirus (HCMV) infections, a systematic analysis of the targets of T cell recognition in humans that spans the entire genome and includes recently described potential novel open reading frames (ORFs) is not available. Here, we screened a library of epitopes predicted to bind HLA class II that spans over 350 different HCMV ORFs and includes ∼150 previously described and ∼200 recently described potential novel ORFs by using an ex vivo gamma interferon (IFN-γ) FluoroSpot assay. We identified 235 unique HCMV-specific epitopes derived from 100 ORFs, some previously described as immunodominant and others that were not previously described to be immunogenic. Of those, 41 belong to the set of recently reported novel ORFs, thus providing evidence that at least some of these are actually expressed in vivo in humans. These data reveal that the breadth of the human T cell response to HCMV is much greater than previously thought. The ORFs and epitopes identified will help elucidate how T cell immunity relates to HCMV pathogenesis and instruct ongoing HCMV vaccine research. IMPORTANCE To understand the crucial role of adaptive immunity in controlling cytomegalovirus infection and disease, we systematically analyzed the CMV "ORFeome" to identify new CMV epitopes targeted primarily by CD4 T cells in humans. Our study identified >200 new T cell epitopes derived from both canonical and novel ORFs, highlighting the substantial breadth of the anti-CMV T cell response and providing new targets for vaccine design.

α-Synuclein, a key pathological component of Parkinson's disease, has been implicated in the activation of the innate and adaptive immune system. This immune activation includes microgliosis, increased inflammatory cytokines, and the infiltration of T cells into the CNS. More recently, peripherally circulating CD4 and CD8 T cells derived from individuals with Parkinson's disease have been shown to produce Th1/Th2 cytokines in response to α-synuclein, suggesting there may be a chronic memory T cell response present in Parkinson's disease. To understand the potential effects of these α-syn associated T cell responses we used an α-synuclein overexpression mouse model, T cell-deficient mice, and a combination of immunohistochemistry and flow cytometry. In this study, we found that α-synuclein overexpression in the midbrain of mice leads to the upregulation of the major histocompatibility complex II (MHCII) protein on CNS myeloid cells as well as the infiltration of IFNγ producing CD4 and CD8 T cells into the CNS. Interestingly, genetic deletion of TCRβ or CD4, as well as the use of the immunosuppressive drug fingolimod, were able to reduce the CNS myeloid MHCII response to α-synuclein. Furthermore, we observed that CD4-deficient mice were protected from the dopaminergic cell loss observed due to α-syn overexpression. These results suggest that T cell responses associated with α-synuclein pathology may be damaging to key areas of the CNS in Parkinson's disease and that targeting these T cell responses could be an avenue for disease modifying treatments., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Correlational studies have demonstrated detrimental effects of exposure to a mismatch between a nonstandard dialect at home and a mainstream variety at school on children's literacy skills. However, dialect exposure often is confounded with reduced home literacy, negative teacher expectation, and more limited educational opportunities. To provide proof of concept for a possible causal relationship between variety mismatch and literacy skills, we taught adult learners to read and spell an artificial language with or without dialect variants using an artificial orthography. In 3 experiments, we confirmed earlier findings that reading is more error-prone for contrastive words; that is, words for which different variants exist in the input, especially when learners also acquire the joint meanings of these competing variants. Despite this contrastive deficit, no detriment from variety mismatch emerged for reading and spelling of untrained words, a task equivalent to nonword reading tests routinely administered to young schoolchildren. With longer training, we even found a benefit from variety mismatch on reading and spelling of untrained words. We suggest that such a dialect benefit in literacy learning can arise when competition between different variants leads learners to favor phonologically mediated decoding. Our findings should help to assuage educators' concerns about detrimental effects of linguistic diversity. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Competing Interests: There are no specific funding sources applicable here, and there are no conflicts of interest to report.

Introduction: Mild cognitive impairment is considered a precursor to dementia and significantly impacts upon quality of life. The prevalence of mild cognitive impairment is higher in the post-surgical cardiac population than in the general population, with older age and comorbidities further increasing the risk of cognitive decline. Exercise improves neurogenesis, synaptic plasticity and inflammatory and neurotrophic factor pathways, which may help to augment the effects of cognitive decline. However, the effects of resistance training on cognitive, functional and overall patient-reported recovery have not been investigated in the surgical cardiac population. This study aims to determine the effect of early moderate-intensity resistance training, compared to standard care, on cognitive recovery following cardiac surgery via a median sternotomy. The safety, feasibility and effect on functional recovery will also be examined., Methods: This study will be a prospective, pragmatic, pilot randomised controlled trial comparing a standard care group (low-intensity aerobic exercise) and a moderate-intensity resistance training group. Participants aged 18 years and older with coronary artery and/or valve disease requiring surgical intervention will be recruited pre-operatively and randomised 1:1 to either the resistance training or standard care group post-operatively. The primary outcome, cognitive function, will be assessed using the Alzheimer's Disease Assessment Scale and cognitive subscale. Secondary measures include safety, feasibility, muscular strength, physical function, multiple-domain quality of recovery, dynamic balance and patient satisfaction. Assessments will be conducted at baseline (pre-operatively) and post-operatively at 2 weeks, 8 weeks, 14 weeks and 6 months., Discussion: The results of this pilot study will be used to determine the feasibility of a future large-scale randomised controlled trial that promotes the integration of early resistance training into existing aerobic-based cardiac rehabilitation programs in Australia., Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12617001430325p . Registered on 9 October 2017. Universal Trial Number (UTN): U1111-1203-2131.

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by abnormal accumulation of alpha-synuclein (α-syn) in oligodendrocytes accompanied by inflammation, demyelination, and subsequent synapse and neuronal loss. Little is known about the mechanisms of neurodegeneration in MSA. However, recent work has highlighted the important role of the immune system to the pathophysiology of other synuclein-related diseases such as Parkinson's disease. In this study, we investigated postmortem brain tissue from MSA patients and control subjects for evidence of immune activation in the brain. We found a significant increase of HLA-DR + microglia in the putamen and substantia nigra of MSA patient tissue compared to controls, as well as significant increases in CD3 + , CD4 + , and CD8 + T cells in these same brain regions. To model MSA in vivo, we utilized a viral vector that selectively overexpresses α-syn in oligodendrocytes (Olig001-SYN) with > 95% tropism in the dorsal striatum of mice, resulting in demyelination and neuroinflammation similar to that observed in human MSA. Oligodendrocyte transduction with this vector resulted in a robust inflammatory response, which included increased MHCII expression on central nervous system (CNS) resident microglia, and infiltration of pro-inflammatory monocytes into the CNS. We also observed robust infiltration of CD4 T cells into the CNS and antigen-experienced CD4 T cells in the draining cervical lymph nodes. Importantly, genetic deletion of TCR-β or CD4 T cells attenuated α-syn-induced inflammation and demyelination in vivo. These results suggest that T cell priming and infiltration into the CNS are key mechanisms of disease pathogenesis in MSA, and therapeutics targeting T cells may be disease modifying.

Parkinson's disease (PD) has classically been defined as a movement disorder, in which motor symptoms are explained by the aggregation of alpha-synuclein (α-syn) and subsequent death of dopaminergic neurons of the substantia nigra pars compacta (SNpc). More recently, the multisystem effects of the disease have been investigated, with the immune system being implicated in a number of these processes in the brain, the blood, and the gut. In this review, we highlight the dysfunctional immune system found in both human PD and animal models of the disease, and discuss how genetic risk factors and risk modifiers are associated with pro-inflammatory immune responses. Finally, we emphasize evidence that the immune response drives the pathogenesis and progression of PD, and discuss key questions that remain to be investigated in order to identify immunomodulatory therapies in PD., (© 2020 Elsevier B.V. All rights reserved.)

Objective: Herpes simplex keratitis (HSK) is a sight-threatening disease and a leading cause of infectious corneal blindness. Involving patients in setting the research agenda maximises patient benefit and minimises research waste. With no published patient involvement exercises, patients' priorities in HSK are unclear. The objective of this study is to explore patients' priorities for research in HSK., Methods: A literature review of publications in the year preceding recruitment of patients identified nine domains of research interest. A questionnaire was sent to participants asking them to rank these in order of priority. The ranking results were given a weighted-average score, and a thematic analysis was undertaken for the narrative data., Results: Thirty-seven patients participated in the survey. Top priorities for patients were risk factors for recurrence of infection, diagnostic tests and treatment failure. The narrative data revealed three key clinical needs: difficulties in long-term symptom control, the need for rapid access care in acute infection and the desire for more accessible information., Conclusion: This study highlighted three major issues in our current approach to HSK. First, there may be a misalignment between research efforts and patient priorities. Second, high-quality patient information is not widely available. This may hamper patients' abilities to make informed decisions and contribute towards research. Third, clinical service priorities are of equal importance to patients as research. Researchers and clinicians are encouraged to address both needs in parallel., Competing Interests: Competing interests: None declared.

Background: Phenolic endocrine-disrupting compounds (EDCs) have long been suspected of increasing human breast cancer risk, via aromatase up-regulation; however, the metabolic effects upon aromatase in human breast cells exposed to environmentally relevant concentrations of phenolic compounds, have not been addressed., Objectives: To examine the mechanistic responses of aromatase CYP19A1 mRNA, aromatase activity, estradiol biosynthesis and cellular proliferation, in three human breast cell lines, exposed to seven phenolic compounds, at environmentally relevant concentrations., Methods: MCF-7 and ZR-75-1 breast cancer cells, and HMF3A breast fibroblasts were treated with specific concentrations of p,p'-DDT, methoxychlor, benzophenone-2, bisphenol A, bisphenol S, 4-phenylphenol and n-butylparaben, with and without the presence of aromatase inhibitors and estrogen receptor inhibitors., Results: All test EDCs up-regulated aromatase mRNA, increased aromatase activity, significantly increased the aromatase-induced biosynthesis of the breast carcinogen 17β-estradiol, and increased ERα-positive breast cell proliferation., Conclusion: Inadvertent exposures to 'phenolic' EDCs, increase estradiol biosynthesis, and estrogen-sensitive breast cancer proliferation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Concerns have been growing about the veracity of psychological research. Many findings in psychological science are based on studies with insufficient statistical power and nonrepresentative samples, or may otherwise be limited to specific, ungeneralizable settings or populations. Crowdsourced research, a type of large-scale collaboration in which one or more research projects are conducted across multiple lab sites, offers a pragmatic solution to these and other current methodological challenges. The Psychological Science Accelerator (PSA) is a distributed network of laboratories designed to enable and support crowdsourced research projects. These projects can focus on novel research questions, or attempt to replicate prior research, in large, diverse samples. The PSA's mission is to accelerate the accumulation of reliable and generalizable evidence in psychological science. Here, we describe the background, structure, principles, procedures, benefits, and challenges of the PSA. In contrast to other crowdsourced research networks, the PSA is ongoing (as opposed to time-limited), efficient (in terms of re-using structures and principles for different projects), decentralized, diverse (in terms of participants and researchers), and inclusive (of proposals, contributions, and other relevant input from anyone inside or outside of the network). The PSA and other approaches to crowdsourced psychological science will advance our understanding of mental processes and behaviors by enabling rigorous research and systematically examining its generalizability.

Background: Parkinson's disease (PD) is characterized by intracellular alpha-synuclein (α-syn) inclusions, progressive death of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and activation of the innate and adaptive immune systems. Disruption of immune signaling between the central nervous system (CNS) and periphery, such as through targeting the chemokine receptor type 2 (CCR2) or the major histocompatibility complex II (MHCII), is neuroprotective in rodent models of PD, suggesting a key role for innate and adaptive immunity in disease progression. The purpose of this study was to investigate whether genetic knockout or RNA silencing of the class II transactivator (CIITA), a transcriptional co-activator required for MHCII induction, is effective in reducing the neuroinflammation and neurodegeneration observed in an α-syn mouse model of PD., Methods: In vitro, we utilized microglia cultures from WT or CIITA -/- mice treated with α-syn fibrils to investigate inflammatory iNOS expression and antigen processing via immunocytochemistry (ICC). In vivo, an adeno-associated virus (AAV) was used to overexpress α-syn in WT and CIITA -/- mice as a model for PD. Concurrently with AAV-mediated overexpression of α-syn, WT mice received CIITA-targeted shRNAs packaged in lentiviral constructs. Immunohistochemistry and flow cytometry were used to assess inflammation and peripheral cell infiltration at 4 weeks post transduction, and unbiased stereology was used 6 months post transduction to assess neurodegeneration., Results: Using ICC and DQ-ovalbumin, we show that CIITA -/- microglial cultures failed to upregulate iNOS and MHCII expression, and had decreased antigen processing in response to α-syn fibrils when compared to WT microglia. In vivo, global knock-out of CIITA as well as local knockdown using lentiviral shRNAs targeting CIITA attenuated MHCII expression, peripheral immune cell infiltration, and α-syn-induced neurodegeneration., Conclusion: Our data provide evidence that CIITA is required for α-syn-induced MHCII induction and subsequent infiltration of peripheral immune cells in an α-syn mouse model of PD. Additionally, we demonstrate that CIITA in the CNS drives neuroinflammation and neurodegeneration. These data provide further support that the disruption or modulation of antigen processing and presentation via CIITA is a promising target for therapeutic development in preclinical animal models of PD.

Purpose: To compare the postoperative higher-order-aberrations (HOAs) after hyperopic small incision lenticule extraction (SMILE), hyperopic laser-assisted in situ keratomileusis ( LASIK), and lenticule implantation for correction of hyperopia., Methods: Eighteen monkeys were divided to six groups: +2.00 D and +4.00 D hyperopic SMILE, +2.00 D and +4.00 D hyperopic LASIK ( n = 6 eyes for each), and lenticule implantation with a -2.00 D and -4.00 D lenticule ( n = 3 eyes for each). The corneal HOAs were evaluated preoperatively and 3-month postoperatively., Results: At 3-month postoperatively, the spherical aberrations significantly increased toward negative direction in all +4.00 D groups (all P < 0.05). There was a significant change toward more negative values in the third-order vertical coma in the SMILE +4.00 D and LASIK +4.00 D groups ( P = 0.026 and P = 0.036, respectively). There were also significant changes in the third-order horizontal trefoil ( P = 0.034) and oblique secondary astigmatism ( P = 0.012) in the LASIK +4.00 D group. In the eyes that underwent +4.00 D lenticule implantation, the fourth-order horizontal quatrefoil significantly increased ( P = 0.029). In low hyperopia correction (+2.00 D), treatment with lenticule implantation tended to have less changes in HOAs, compared to the other two groups., Conclusions: In hyperopic SMILE, hyperopic LASIK or lenticule implantation surgery, significant induction of third- and fourth-order HOAs were seen in moderate hyperopia correction but not in low hyperopia correction. In low hyperopia treatment, lenticule implantation might offer a favorable trend in the aspect of HOAs., Translational Relevance: The results provided the knowledge of surgically induced HOAs and understanding of the effects of surgery in different types of hyperopic correction.

Hyperopia is a common refractive error, apparent in 25% of Europeans. Treatments include spectacles, contact lenses, laser interventions and surgery including implantable contact lenses and lens extraction. Laser treatment offers an expedient and reliable means of correcting ametropia. LASIK is well-established however SMILE (small-incision lenticule extraction) or lenticule implantation (derived from myopic laser-correction) are newer options. In this study we compared the outcomes of hyperopic LASIK, SMILE and lenticule re-implantation in a primate model at +2D/+4D treatment. While re-implantation showed the greatest regression, broadly comparable refractive results were seen at 3-months with SMILE and LASIK (<1.4D of intended), but a greater tendency to regression in +2D lenticule reimplantation. Central corneal thickness showed greater variation at +2D treatment, but central thickening during lenticule reimplantation at +4D treatment was seen (-17± 27μm LASIK, -45 ± 18μm SMILE and 28 ± 17μm Re-implantation; p <0.01) with expected paracentral thinning following SMILE. Although in vivo confocal microscopy appeared to show higher reflectivity in all +4D treatment groups, there were minimal and inconsistent changes in inflammatory responses between modalities. SMILE and lenticule re-implantation may represent a safe and viable method for treating hyperopia, but further optimization for lower hyperopic treatments is warranted.

Accumulation of alpha-synuclein (α-syn) in the central nervous system (CNS) is a core feature of Parkinson disease (PD) that leads to activation of the innate immune system, production of inflammatory cytokines and chemokines, and subsequent neurodegeneration. Here, we used heterozygous reporter knock-in mice in which the first exons of the fractalkine receptor (CX3CR1) and of the C-C chemokine receptor type 2 (CCR2) are replaced with fluorescent reporters to study the role of resident microglia (CX3CR1+) and infiltrating peripheral monocytes (CCR2+), respectively, in the CNS. We used an α-syn mouse model induced by viral over-expression of α-syn. We find that in vivo, expression of full-length human α-syn induces robust infiltration of pro-inflammatory CCR2+ peripheral monocytes into the substantia nigra. Genetic deletion of CCR2 prevents α-syn induced monocyte entry, attenuates MHCII expression and blocks the subsequent degeneration of dopaminergic neurons. These results demonstrate that extravasation of pro-inflammatory peripheral monocytes into the CNS plays a key role in neurodegeneration in this model of PD synucleinopathy, and suggest that peripheral monocytes may be a target of neuroprotective therapies for human PD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To explore the optimal lenticule storage conditions that maintain lenticule integrity and clarity., Methods: A total of 99 lenticules obtained from myopic patients undergoing small incision lenticule extraction (SMILE) were divided into four combinations for short-term storage conditions: PBS, Dulbecco's Modified Eagle's Medium (DMEM), Optisol GS, or anhydrous glycerol. Two thirds of the lenticules were further stored for 4 weeks under eight different conditions. Clarity evaluation with transmittance measurements, cell-death assays with terminal deoxynucleotidyl transferase-mediated nick end labeling assay (TUNEL), collagen fibril spacing and necrotic response assessed with transmission electron microscopy (TEM), and immunohistochemistry analysis for human leukocyte antigens (HLAs) and CD45 for immunogenicity, and matrix metalloproteinase (MMP)-2 for keratocyte response, were undertaken at baseline, 48 h (short term), and 4 weeks (long term)., Results: The TUNEL and immunogenicity results were comparable among the groups. The mean percentage of TUNEL-positive cells across all groups was 24.3% ± 11.8% and 62.9% ± 20.7% at the 48 h and 4 week time points, respectively. HLA-ABC+, HLA-DR+, and CD45+ cells were extremely rare, and MMP-2 expression ranged from non-detectable to minimal, under all conditions at all time points. Transmittance at 4 weeks was significantly different among groups with the greatest maintenance of clarity seen in the lenticules stored initially in DMEM at 4 °C for 48 h followed by cryopreservation in serum-free medium or glycerol at 4 °C followed by storage at room temperature. At TEM analysis at 4 weeks, the lenticules cryopreserved in liquid nitrogen, regardless of storage solutions, had significantly narrower inter-fibrillar distance than controls, while glycerol-preserved lenticules, at either room temperature or -80 °C, maintained the inter-fibrillar distance., Conclusions: Clarity, structural integrity, and low immunogenicity under various conditions, at 4 °C or room temperature for short-term storage, offer encouragement for lenticule storage. It can be undertaken without access to s specialized and potentially expensive laboratory setup at least within the first 48 h before transportation to larger facilities for long-term storage.

Purpose: To determine the effects of the Ziemer LDV Z8 liquid interface femtosecond laser platform during capsulotomy under different energy settings in the presence of corneal edema., Methods: Cadaveric porcine eyes (n = 36) employed at less than 6 and greater than 24 post enucleation hours to simulate clear/edematous corneas, underwent capsulotomy with the Ziemer LDV Z8 femtosecond laser (5-mm diameter, energy 90%, 130%, or 150%). Lens capsules were removed for evaluation by scanning electron microscopy and rupture strengths determined by the single column universal testing system. Following ethical approval, 23 patients had lens capsules removed during routine cataract surgery following manual or Z8 capsulotomy and subjected to TUNEL assay., Results: There was no difference in edge morphology or rupture strength (120, 113, and 118 mN at increasing energy, P = 0.42) in the clear cornea. Only 50% of capsulotomies succeeded at 90% energy in an edematous cornea, improving with increased energy (75% completion at 130%, 100% at 150%). Rupture strength in edematous corneas was not significantly different at 112, 133, and 114 mN for 90%, 130%, and 150%, respectively (P = 0.3). In human samples, increased TUNEL-positive cells were seen at 130% energy, but not at 150% (0.0 manual vs. 0.2 [90%] vs. 2.1 [130%] vs. 0.6 [150%], P < 0.05)., Conclusions: Because of the low energy delivered by a femtosecond nanojoule platform, even incremental increases in energy appeared to have minimal effect on lens capsule morphology and strength and negligible influence on cell death. Furthermore, increasing energy appeared to enhance consistency and the ability to complete a capsulotomy in an edematous cornea.

Laser refractive surgeries reshape corneal stroma to correct refractive errors, but unavoidably affect corneal nerves. Slow nerve regeneration and atypical neurite morphology cause desensitization and neuro-epitheliopathy. Following injury, surviving corneal stromal keratocytes (CSKs) are activated to stromal fibroblasts (SFs). How these two different cell types influence nerve regeneration is elusive. Our study evaluated the neuro-regulatory effects of human SFs versus CSKs derived from the same corneal stroma using an in vitro chick dorsal root ganglion model. The neurite growth was assessed by a validated concentric circle intersection count method. Serum-free conditioned media (CM) from SFs promoted neurite growth dose-dependently, compared to that from CSKs. We detected neurotrophic and pro-inflammatory factors (interleukin-8, interleukin-15, monocyte chemoattractant protein-1, eotaxin, RANTES) in SFCM by Bio-Plex Human Cytokine assay. More than 130 proteins in SFCM and 49 in CSKCM were identified by nanoLC-MS/MS. Proteins uniquely present in SFCM had reported neuro-regulatory activities and were predicted to regulate neurogenesis, focal adhesion and wound healing. Conclusively, this was the first study showing a physiological relationship between nerve growth and the metabolically active SFs versus quiescent CSKs from the same cornea source. The dose-dependent effect on neurite growth indicated that nerve regeneration could be influenced by SF density.

Purpose: Unifying terminology for the description of ocular surface disease (OSD) is vital for determining treatment responses and ensuring robust clinical trial outcomes. To date, there are no agreed parameters describing 'activity' and 'damage' phases of disease., Methods: A working group of international experts in OSD, oculoplastics, and uveitis from a range of backgrounds (university, teaching, district general and private hospitals) participated in a modified Delphi consensus-building exercise (October 31, 2011 to March 20, 2015). Two steering group meetings took place in which factors based upon published literature were discussed and supplemented with anonymous web-based questionnaires to refine clinical indices according to 'activity' (reversible changes resulting directly from the inflammatory process) and/or 'damage' (persistent, >6 months duration) changes resulting from previously active disease that are cumulative and irreversible)., Results: The recommended set of clinical parameters for the assessment of OSD encompasses 68 clinical indices and 22 ancillary grading tools (in parenthesis) subdivided by anatomical domain as follows: 4(4) tear-film, eyelid 21(3), 17(3) conjunctiva, 15(10) cornea and 11(2) Anterior Chamber/Sclera. Of these; 17(2) were considered as measures of clinical activity, 27(3) as damage, 1(8) as measures of both activity and damage. Twenty-three clinical descriptors and 9 tools did not reach the threshold for inclusion into the main standard set. These were defined as 'second tier' parameters for use in special clinical settings., Conclusion: These core parameters provide the first description of 'activity' and 'damage' relevant to OSD and provide a platform for the future development of scoring scales for each parameter., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Ocular mucous membrane pemphigoid (OcMMP) is a rare autoimmune disorder resulting in progressive conjunctival fibrosis and ocular surface failure leading to sight loss in up to 50%. This study was designed to optimize an ocular surface sampling technique for identification of novel biomarkers associated with disease activity and/or progressive fibrosis., Methods: Fifty-seven patients with OcMMP underwent detailed examination of conjunctival inflammation and fibrosis using fornix depth measurement. Ocular surface impression cytology (OSIC) to sample superior bulbar conjunctiva combined with flow cytometry (OSIC-flow) profiled infiltrating leukocytes. Profiles were compared with healthy controls (HC) and disease controls (primary Sjögren's syndrome, pSS). Thirty-five OcMMP patients were followed every 3 months for 12 months., Results: Overall neutrophils were elevated in OcMMP eyes when compared to pSS or HC (109 [18%] neutrophils/impression [NPI]; 2 [0.2%]; 6 [0.8%], respectively [P < 0.0001]) and in OcMMP patients with no visible inflammation when compared with HC (44.3 [7.9%]; 5.8 [0.8%]; P < 0.05). At 12 months follow-up, 53% of OcMMP eyes progressed, and this was associated with baseline conjunctival neutrophilia (P = 0.004). As a potential biomarker, a value of 44 NPI had sensitivity, specificity, and positive predictive values of 75%, 70%, and 73%, respectively. Notably, eyes with no visible inflammation and raised conjunctival neutrophils were more likely to progress and have a greater degree of conjunctival shrinkage compared to those without raised neutrophils., Conclusions: These data suggest that OSIC-flow cytometric analyses may facilitate repeated patient sampling. Neutrophils may act as a biomarker for monitoring disease activity, progressive fibrosis, and response to therapy in OcMMP even when the eye appears clinically uninflamed.

The introduction of femtosecond laser assisted cataract surgery (FLACS) is a paradigm changing approach in cataract surgery, the most commonly performed surgical procedure. FLACS has the potential to optimize the creation of an anterior lens capsulotomy, a critical step in accessing the cataractous lens. The merits of using a laser instead of a manual approach include a potentially more circular, consistent, and stronger aperture. In this study we demonstrated for the first time in both a porcine and human experimental setting that with a low energy, high repetition FLACS system, that a circular, smooth and strong capsulotomy was achievable. While there was no demonstrable difference in the resistance to rupture before or after the removal of the nucleus, larger capsulotomies had an increase in tensile strength. The LDV Z8 system appeared to create circular, rupture-resistant and smooth capsulotomies in both porcine and more importantly human globes.