Retinal vascular reactivity in carriers of X-linked inherited retinal disease - a study using optical coherence tomography angiography.

Purpose: Female carriers of X-linked inherited retinal diseases (IRDs) can show highly variable phenotypes and disease progression. Vascular reactivity, a potential disease biomarker, has not been investigated in female IRD carriers. In this study, functional optical coherence tomography angiography (OCT-A) was used to dynamically assess the retinal microvasculature of X-linked IRD carriers. Methods: Genetically confirmed female carriers of IRDs (choroideremia or X-linked retinitis pigmentosa), and healthy women were recruited. Macular angiograms (3x3mm, Zeiss Plex Elite 9000) were obtained in 36 eyes of 15 X-linked IRD female carriers and 21 age-matched control women. Two tests were applied to test vascular reactivity: (i) mild hypoxia and (ii) handgrip test, to induce a vasodilatory or vasoconstrictive response, respectively. Changes to vessel density (VD) and vessel length density (VLD) were independently evaluated during each of the tests for both the superficial and deep capillary plexuses. Results: In the control group, the superficial and deep VD decreased during the handgrip test (p<0.001 and p=0.037, respectively). Mean superficial VLD also decreased during the handgrip test (p=0.025), while the deep plexus did not change significantly (p=0.108). During hypoxia, VD and VLD increased in the deep plexus (p=0.027 and p=0.052, respectively) but not in the superficial plexus. In carriers, the physiologic vascular responses seen in controls were not observed in either plexus during either test, with no difference in VD or VLD noted (all p>0.05). Conclusions: Functional OCT-A is a useful tool to assess dynamic retinal microvascular changes. Subclinical impairment of the physiological vascular responses seen in carriers of X-linked IRDs may serve as a valuable clinical biomarker.

Gene and cell therapy for age-related macular degeneration: A review.

Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss among the elderly in Western communities, with an estimated global prevalence of 10 - 20% in people older than 65 years. AMD leads to central vision loss due to degeneration of the photoreceptors, retinal pigment epithelium and the choriocapillaris. Beckman's classification for AMD, based upon color fundus photographs, divides the disease into early, intermediate, and late forms. The late, vision-threatening stage includes both neovascular AMD and geographic atrophy. Despite its high prevalence and impact on patients' quality of life, treatment options for AMD are limited. While neovascular AMD can be medically managed with anti-VEGF intravitreal injections, until very recently there has been no approved treatment options for atrophic AMD; however, in February 2023 the first treatment for geographic atrophy - pegcetacoplan - was approved by the US FDA. We describe the current landscape of potential gene and cell therapeutic strategies for late-stage AMD, with an emphasis on the therapeutic options that might become available in the next few years.

Protective Role of NS1-Specific Antibodies in the Immune Response to Dengue Virus through Antibody-Dependent Cellular Cytotoxicity.

BACKGROUND: Dengue virus (DENV) non-structural protein 1 (NS1) has multiple functions within infected cells, on the cell surface, and in secreted form, and is highly immunogenic. Immunity from previous DENV infections is known to exert both positive and negative effects on subsequent DENV infections, but the contribution of NS1-specific antibodies to these effects is incompletely understood. METHODS: We investigated the functions of NS1-specific antibodies and their significance in DENV infection. We analyzed plasma samples collected in a prospective cohort study prior to symptomatic or subclinical secondary DENV infection. We measured binding to purified recombinant NS1 protein and to NS1-expressing CEM cells, antibody-mediated NK cell activation by plate-bound NS1 protein, and antibody-dependent cellular cytotoxicity (ADCC) of NS1-expressing target cells. RESULTS: We found that antibody responses to NS1 were highly serotype-cross-reactive and that subjects who experienced subclinical DENV infection had significantly higher antibody responses to NS1 in pre-infection plasma than subjects who experienced symptomatic infection. We observed strong positive correlations between antibody binding and NK activation. CONCLUSIONS: These findings demonstrate the involvement of NS1-specific antibodies in ADCC and provide evidence for a protective effect of NS1-specific antibodies in secondary DENV infection.

Dinosaur trackways from the Upper Cretaceous Nichkesai Formation near Mayluu Suu City, Southern Tien Shan Mountains, north-western Kyrgyzstan.

Trackways provide essential data on the biogeographic distribution, locomotion and behaviour of dinosaurs. Cretaceous dinosaur trackways are abundant in the Americas, Europe, North Africa and East Asia, but are less well documented in Central Asia despite extensive exposure of Cretaceous terrestrial sedimentary rocks in the region. Here we report the presence of bipedal, tridactyl dinosaur trackways near the city of Mayluu Suu, Jalal Abad Oblast, north-western Kyrgyzstan, the first discovery of dinosaur trace fossils within the country. The trackways are situated on a steep slope uncovered by a landslide around the year 2000 in a highly landslide-affected area. Photogrammetry is used to digitally analyse and conserve the trace fossils. We infer a shoreface setting for the trackways based on the locality sedimentology, discuss the identity of the track makers and highlight the potential for future trackway discovery in the area. This discovery contributes vital data to an otherwise sparse record on the spatio-temporal distribution of dinosaurs in Kyrgyzstan, and to the dinosaur trackway record of Central Asia.

Organizing Pneumonia and Ulcerative Colitis: A Relationship To Remember.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterised by relapsing and remitting mucosal inflammation of the colon. Despite primarily affecting the gastrointestinal tract, UC has various extraintestinal manifestations that often affect other organs and systems. Although pulmonary involvement is uncommon, organising pneumonia (OP), which affects the lung parenchyma, is one of the potential extraintestinal manifestations of UC. We report a case of OP in a 35-year-old male with a longstanding history of UC, well-medicated with sulfasalazine (SSZ). He presented to the emergency department (ED) with complaints of fatigue, coughing, myalgia, thoracalgia and dyspnoea. A chest X-ray showed parenchymal infiltrates and computed tomography revealed bilateral consolidation. Under a preliminary diagnosis of atypical pneumonia, he was treated with an empirical broad-spectrum antimicrobial agent, which did not lead to any clinical, laboratory or imaging improvement. Furthermore, the diagnostic work-up excluded any malignancy or infectious cause. A probable diagnostic hypothesis was OP as an extraintestinal manifestation of UC or as an adverse effect of SSZ therapy. Hence, SSZ was discontinued, and he was successfully treated with corticosteroids, exhibiting significant improvements and recovering completely during the follow-up period. Despite lung involvement in UC being rare, we present this case to emphasise the importance of a thorough differential diagnosis when treating acute respiratory illness in patients with UC, including extraintestinal manifestations of UC, especially OP, even during a period of remission. We also emphasise the importance of early initiation of corticosteroid therapy to prevent major complications and promote recovery.

PREDICTION OF MACULAR HOLE SIZE PROGRESSION BASED ON BASELINE OPTICAL COHERENCE TOMOGRAPHY FINDINGS.

PURPOSE: To quantify the rate of idiopathic macular hole progression from presentation and identify factors that may influence stratification and urgency for surgical listing based on the initial optical coherence tomography scans. METHODS: The minimal linear diameter (MLD), base diameter (BD), and hole height on nasal and temporal sides of idiopathic macular hole were measured on spectral domain optical coherence tomographies, on initial presentation and just before surgery. Mean hole height, hole height asymmetry (absolute difference between nasal and temporal height), MLD/BD, and MLD change per day (MLD/day) were calculated for each patient. Multivariable linear regression analysis with MLD/day as the dependent variable was performed to identify significant risk factors for MLD progression. Minimal linear diameter was grouped to quintiles: 1: ≤290 µ m, 2: >290 µ m and ≤385 µ m, 3: >385 µ m and ≤490 µ m, 4: >490 µ m and ≤623 µ m, and 5: >623 µ m. RESULTS: In 161 eyes (157 patients), we report significant associations with MLD/day: 1) MLD/BD ( P = 0.039) (i.e., wide BD relative to MLD lead to faster progression of MLD), 2) hole height asymmetry ( P = 0.006) (larger absolute difference between nasal and temporal hole height lead to faster progression), and 3) days between scans ( P < 0.001) (longer duration between scans had reduced MLD/day, indicating more rapid increase initially then plateaux), and relative to MLD Quintile 1, MLD Quintile 3 ( P = 0.002) and MLD Quintile 4 ( P = 0,008), and MLD Quintile 5 ( P < 0.001) all lead to a reduced MLD/day rate on multivariable regression. CONCLUSION: In addition to finding that the previously reported initial smaller MLD is a risk factor for rapid MLD progression, we report two novel findings, large hole height asymmetry and a low MLD/BD (wide base relative to MLD), that represent significant risk factors. These factors should be taken into consideration on presentation to stratify timing of surgery.

Retrieving A retained Heavy Silicone Oil Bubble: Two Novel Surgical Techniques.

PURPOSE: To describe two surgical techniques for rescuing a retained heavy silicone oil bubble in the posterior pole: 1) light pipe method and 2) perfluorocarbon liquid method. METHODS: The surgical techniques are described in detail, along with an illustrative video for each. RESULTS: A short 25-gauge metallic cannula and active suction pump are used for standard heavy silicone oil removal. Both surgical approaches are practical and effective options to complete the removal of heavy silicone oil when a bubble sinks to the posterior pole. CONCLUSION: Both the light pipe and perfluorocarbon methods are suitable to remove retained heavy silicone oil and thus avoid the need for further incisions and the risks associated with the use of larger gauge instrumentation.

Seafood consumers engagement in reducing environmental impacts from packaging.

Packaging is essential to protect food, inform consumers, and avoid food waste, yet it can also contribute to the environmental footprint of products. Recycling waste treatment potentially provides more environmental benefits than other options (e.g., landfill), but only 66 % of packaging waste goes to recycling in the European Union. However, the prevention of packaging production with greater reuse, while extending the lifetime or improving packaging design should be firstly encouraged. This highlights the need to assess the willingness of consumers in reducing the environmental impact of seafood products from packaging. An online questionnaire was conducted in three countries (Portugal, Spain, and Ireland), composed of four sections: (i) seafood consumption, (ii) waste separation to be sent recycling, (iii) willingness to purchase seafood products with packaging designed to reduce environmental impact, and (iv) sociodemographic characteristics. Findings revealed that respondents from Spain and Portugal reported a slightly higher frequency of waste sent to recycle compared to Ireland. Irish respondents appear to have more difficulties about the type of plastic materials that can be sent to recycling due to Irish waste management capabilities; whereas Spanish and Portuguese respondents were not fully aware that packaging does not need to be washed prior to recycling. The most popular alternatives to improve the sustainability of seafood packaging were the use of reusable packaging, compostable packaging material, glass jars for canned seafood instead of cans, and intelligent packaging. Most respondents were willing to pay more for seafood products that use more sustainable packaging (62 % for Spain, 68 % for Ireland, 70 % for Portugal) and half of the respondents intimated that they avoid seafood products due to excessive packaging. With more detailed information on the waste management of packaging, seafood consumers could actively contribute with their attitudes where commensurate changes can improve environmental assessment of seafood.

Supported or unsupported three-center two-electron bonds? A criterion based on Interference Energy Analysis.

The classification of three-center two-electron (3c2e) bonds into supported (closed) or unsupported (open) was proposed by Lipscomb in his work on boranes and extended to transition metal complexes by Bau and co-workers. The species in which the interactions of the terminal atoms are negligible are called "unsupported bonds." Examples of chemical species that are said to exhibit such bonds are Li2H+, Na2H+, B2H7 -, Al2(CH3)7 -, and [(µ2-H)Cr2(CO)10]- although the general criterion for distinguishing these types of bonds is somewhat qualitative. Besides providing a unifying view of the nature of the chemical bond, in terms of quantum interference among electronic states, the Generalized Product Function Energy Partitioning method through the Interference Energy Analysis (IEA) is also potentially capable of providing a rigorous ground to the concept of supported bonds by looking at the specific interference energies between the orbital pairs associated with the bond. The IEA was performed in the species Li2H+, Na2H+, B2H7 -, C2H7 -, Al2H7 -, and [(µ2-H)Cr2(CO)10]-, as well as along the reaction path Li2H+ → Li2 + + H. The results shown that in all studied A-B-C bonds, the A-C interactions are as important as the A-B/B-C ones, leading to the conclusion that all studied 3c2e bonds are "supported," in the sense that the A-C interaction is not negligible. The particularity of those species in preferring linear geometry is completely explained by quasi-classical effects, more specifically, by minimization of the electron-electron and nucleus-nucleus repulsions.

Cor Pulmonale Secondary to Severe Pulmonary Hypertension As the First Manifestation of Graves' Disease.

Pulmonary hypertension (PH), especially if severe, carries a significant morbidity and mortality. Herein we describe a case of an 88-year-old woman with severe heart failure and several hospitalizations that year for the same reason, rapid re-admission after discharge and loss of walking ability. Transthoracic echocardiography (TTE) revealed severe pulmonary hypertension (PASP=69 mmHg) and right ventricular dysfunction without left structural or functional dysfunction. Pulmonary thromboembolism, relevant pulmonary pathology was excluded, and an extended autoimmune study was also negative. Thyroid disorders were investigated, a Graves' disease with thyrotoxicosis was diagnosed and promptly treated with thiamazole, also known as methimazole. There was a rapid improvement in the clinical and hemodynamic status of the patient, stabilization of the right heart failure (HF), resolution of the volume overload and a TTE showed improvement with moderate PH (PASP=55 mmHg). This case shows a reversible cause of PH and highlights how treatment of Graves' disease can reduce pulmonary artery pressure and contribute to symptomatic relief and better quality of life.

Three-centre two-electron bonds from the quantum interference perspective.

The nature of the three-center two-electron (3c2e) chemical bond is investigated by the Interference Energy Analysis (IEA) method and using a SC(2, 3) (spin coupled wave function with two electrons and three orbitals) approach for describing 3c2e bonds. In this approach, each center involved in the bonding contributes with a one-electron state for the interference process. The species H3+, Li3+, LiH2+, C3H5+, C3H3+, R2CBeCR2 (R = H, CH3), C7H11+ and CH5+ are considered in the study. The results show that 3c2e bonds have the same features of a 2c2e bond: the stability of the chemical systems exhibiting 3c2e bonds derives from quantum interference among electronic states. Other (quasi-classical) factors are always overall destabilizing, mostly because of the nuclear repulsion. The interference energy of a 3c2e bond is about three times higher than that of a 2c2e bond involving atoms of the same elements. In particular, concerning Li3+ and C3H3+ we found no evidence that the 'aromatic' character attributed to those species imparts any special features to their chemical structures, compared to other 3c2e bonds. Therefore, these species exhibit multicenter bonds, essentially equivalent to the other studied cases.

The 2021 Portuguese Society of Ophthalmology joint guidelines with Paediatric Rheumatology on the screening, monitoring and medical treatment of juvenile idiopathic arthritis-associated uveitis.

AIM: To develop the first Ophthalmology joint guidelines with Paediatric Rheumatology with recommendations on the screening, monitoring and medical treatment of juvenile idiopathic arthritis-associated uveitis (JIA-U), endorsed by the Portuguese Society of Ophthalmology (SPO). METHODS: A systematic literature review was conducted to include publications up to July 14th 2020, with no language restrictions, in order to include all the international position papers/guidelines concerning the medical management of JIA-U and randomised clinical trials assessing the efficacy and safety of medical treatment in this field. We searched through MEDLINE (PubMed), Scopus, Web of Science and Cochrane Library. The Delphi modified technique to generate consensus was used. Preliminary evidence statements were subject to an anonymous agreement assessment and discussion process using an online survey, followed by further discussion and update at a national meeting. A draft of the manuscript with all recommendations was then circulated among all participants and suggestions were incorporated. The final version was again circulated before publication. RESULTS: Twenty-six recommendations were developed focusing on the following topics: general management (3), screening and follow-up of uveitis (4), treatment (17) and health education in JIA-U among patients and families (2). CONCLUSION: These guidelines were designed to support the shared medical management of patients with JIA-U and emphasize the need for a multidisciplinary approach between Ophthalmology and Paediatric Rheumatology regarding the comprehensive care of JIA-U. We acknowledge that updating these recommendations will be warranted in the future, as more evidence becomes available. KEY-WORDS: juvenile idiopathic arthritis, uveitis, biological treatment, conventional immunosuppressive treatment, multidisciplinary management, guidelines, consensus, review, Delphi Technique.

Photodynamic disinfection of SARS-CoV-2 clinical samples using a methylene blue formulation.

The amplitude of the coronavirus disease 2019 (COVID-19) pandemic motivated global efforts to find therapeutics that avert severe forms of this illness. The urgency of the medical needs privileged repositioning of approved medicines. Methylene blue (MB) has been in clinical use for a century and proved especially useful as a photosensitizer for photodynamic disinfection (PDI). We describe the use of MB to photo-inactivate SARS-CoV-2 in samples collected from COVID-19 patients. One minute of treatment can reduce the percentage inhibition of amplification by 99.99% under conditions of low cytotoxicity. We employed a pseudotyped lentiviral vector (LVs) encoding the luciferase reporter gene and exhibiting the S protein of SARS-CoV-2 at its surface, to infect human ACE2-expressing HEK293T cells. Pre-treatment of LVs with MB-PDI prevented infection at low micromolar MB concentrations and 1 min of illumination. These results reveal the potential of MB-PDI to reduce viral loads in the nasal cavity and oropharynx in the early stages of COVID-19, which may be employed to curb the transmission and severity of the disease.

Disseminated cutaneous Actinomyces bovis infection in an immunocompromised host: case report and review of the literature.

BACKGROUND: Actinomycosis is an uncommon endogenous bacterial infection caused by Actinomyces species, characterized by the development of abscesses, tissue fibrosis, and fistulisation. It remains a diagnostic challenge, due to its similarities with diverse aetiologies' presentation, such as neoplasms, tuberculosis, or fungal infections. Actinomyces bovis is a microorganism rarely reported as a cause of human disease. Cutaneous involvement is sporadic. In this case, Actinomyces bovis was responsible for disseminated cutaneous disease in an immunosuppressed patient. CASE PRESENTATION: We report the case of a 69-year-old female with multiple skin masses, under immunosuppressive therapy due to ulcerative colitis. Imaging exams were compatible with multiple cutaneous abscesses in the cervicofacial region and limbs. Actinomyces bovis was isolated in culture after abscess drainage. Antimicrobial therapy with parenteral penicillin G and oral amoxicillin was administered for 6 months, with complete resolution of cutaneous lesions and no relapse of the infection. CONCLUSIONS: Considering actinomycosis as a possible diagnosis in the presence of subacute/chronic recurrent mass-like cutaneous lesions, especially in the setting of immunosuppression, may reduce the burden associated with delayed diagnosis and incorrect treatment and provide better outcomes and improvement of patient's quality of life.

Broadening risk factor or disease definition as a driver for overdiagnosis: A narrative review.

Medical overuse-defined as the provision of health services for which potential harms exceed potential benefits-constitutes a paradigm of low-value care and is seen as a threat to the quality of care. Value in healthcare implies a precise definition of disease. However, defining a disease may not be straightforward since clinical data do not show discrete boundaries, calling for some clinical judgment. And, if in time a redefinition of disease is needed, it is important to recognize that it can induce overdiagnosis, the identification of medical conditions that would, otherwise, never cause any significant symptoms or lead to clinical harm. A classic example is the impact of recommendations from professional societies in the late 1990s, lowering the threshold for abnormal total cholesterol from 240 mg/dl to 200 mg/dl. Due to these changes in risk factor definition, literally overnight there were 42 million new cases eligible for treatment in the United States. The same happened with hypertension-using either the 2019 NICE guidelines or the 2018 ESC/ECC guidelines criteria for arterial hypertension, the proportion of people overdiagnosed with hypertension was calculated to be between 14% and 33%. In this review, we will start by discussing resource overuse. We then present the basis for disease definition and its conceptual problems. Finally, we will discuss the impact of changing risk factor/disease definitions in the prevalence of disease and its consequences in overdiagnosis and overtreatment (a problem particularly relevant when definitions are widened to include earlier or milder disease).

Early Pars Plana Vitrectomy in Acute Endophthalmitis: The Manchester Series.

BACKGROUND AND OBJECTIVE: Current literature lacks good-quality evidence regarding the outcomes of early pars plana vitrectomy (PPV) for acute exogenous endophthalmitis. The aim for this study was to analyze and discuss the outcomes of PPV for endophthalmitis in a UK tertiary hospital. PATIENTS AND METHODS: This study was a retrospective case series. The clinical records of consecutive patients who had PPV for acute exogenous endophthalmitis were reviewed. Demographic data, etiology, timing of onset, timing of PPV, intraand postoperative complications, baseline and final best-corrected visual acuity (BCVA), therapeutic regimens, and microbiology details were collected. Primary efficacy and safety outcome measures were BCVA improvement of two or more logMAR lines and intra- or postoperative complications, respectively. RESULTS: Forty-one patients with a median age of 76 (interquartile range, 64 to 82) years were studied. The most common etiology was intravitreal injection (41%), followed by phacoemulsification (34%). Median interval to PPV was 1.0 (interquartile range, 1.0 to 3.0) days. In a multivariate model controlling for age, baseline BCVA, microbiology positivity, and etiology (post-intravitreal injection), PPV after 24 hours was seven times more likely to achieve significant BCVA improvement (odds ratio, 7.47; 95% confidence interval, 1.12 to 49.66; P = .038). PPV within 24 hours of presentation was associated with more intraoperative complications. CONCLUSIONS: Favorable outcomes may be achieved with current antibiotic regimens and PPV for endophthalmitis. The series suggests that an early surgical intervention may be associated with poorer functional outcomes. Tap and inject at presentation, followed by a semi-urgent PPV as required, seems to be a sensible approach. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:96-102.].

Caffeine Intoxication: Unregulated, Over-the-Counter Sale of Potentially Deadly Supplements.

Caffeine is an integral part of beverages, food, and medications. Severe intoxication of caffeine is rare, and reports are even scarcer. However, over-the-counter, unregulated sale of performance-enhancing compounds, such as caffeine, turns high-dose consumption into a real concern. Severe intoxication may be fatal, usually by malignant cardiac arrhythmia. We report a case of a 23-year-old university student who accidentally consumed about 100 times the amount present in an expresso of anhydrous caffeine.