Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy.

We study a patient with the human papilloma virus (HPV)-2-driven "tree-man" phenotype and two relatives with unusually severe HPV4-driven warts. The giant horns form an HPV-2-driven multifocal benign epithelial tumor overexpressing viral oncogenes in the epidermis basal layer. The patients are unexpectedly homozygous for a private CD28 variant. They have no detectable CD28 on their T cells, with the exception of a small contingent of revertant memory CD4+ T cells. T cell development is barely affected, and T cells respond to CD3 and CD2, but not CD28, costimulation. Although the patients do not display HPV-2- and HPV-4-reactive CD4+ T cells in vitro, they make antibodies specific for both viruses in vivo. CD28-deficient mice are susceptible to cutaneous infections with the mouse papillomavirus MmuPV1. The control of HPV-2 and HPV-4 in keratinocytes is dependent on the T cell CD28 co-activation pathway. Surprisingly, human CD28-dependent T cell responses are largely redundant for protective immunity.

Global View of Domain-Specific O-Linked Mannose Glycosylation in Glycoengineered Cells.

Protein O-linked mannose (O-Man) glycosylation is an evolutionary conserved posttranslational modification that fulfills important biological roles during embryonic development. Three nonredundant enzyme families, POMT1/POMT2, TMTC1-4, and TMEM260, selectively coordinate the initiation of protein O-Man glycosylation on distinct classes of transmembrane proteins, including α-dystroglycan, cadherins, and plexin receptors. However, a systematic investigation of their substrate specificities is lacking, in part due to the ubiquitous expression of O-Man glycosyltransferases in cells, which precludes analysis of pathway-specific O-Man glycosylation on a proteome-wide scale. Here, we apply a targeted workflow for membrane glycoproteomics across five human cell lines to extensively map O-Man substrates and genetically deconstruct O-Man initiation by individual and combinatorial knockout of O-Man glycosyltransferase genes. We established a human cell library for the analysis of substrate specificities of individual O-Man initiation pathways by quantitative glycoproteomics. Our results identify 180 O-Man glycoproteins, demonstrate new protein targets for the POMT1/POMT2 pathway, and show that TMTC1-4 and TMEM260 pathways widely target distinct Ig-like protein domains of plasma membrane proteins involved in cell-cell and cell-extracellular matrix interactions. The identification of O-Man on Ig-like folds adds further knowledge on the emerging concept of domain-specific O-Man glycosylation which opens for functional studies of O-Man-glycosylated adhesion molecules and receptors.

Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder.

Free oligosaccharides (fOSs) are soluble oligosaccharide species generated during N-glycosylation of proteins. Although little is known about fOS metabolism, the recent identification of NGLY1 deficiency, a congenital disorder of deglycosylation (CDDG) caused by loss of function of an enzyme involved in fOS metabolism, has elicited increased interest in fOS processing. The catabolism of fOSs has been linked to the activity of a specific cytosolic mannosidase, MAN2C1, which cleaves α1,2-, α1,3-, and α1,6-mannose residues. In this study, we report the clinical, biochemical, and molecular features of six individuals, including two fetuses, with bi-allelic pathogenic variants in MAN2C1; the individuals are from four different families. These individuals exhibit dysmorphic facial features, congenital anomalies such as tongue hamartoma, variable degrees of intellectual disability, and brain anomalies including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis. Complementation experiments with isogenic MAN2C1-KO HAP1 cells confirm the pathogenicity of three of the identified MAN2C1 variants. We further demonstrate that MAN2C1 variants lead to accumulation and delay in the processing of fOSs in proband-derived cells. These results emphasize the involvement of MAN2C1 in human neurodevelopmental disease and the importance of fOS catabolism.

Brain-specific glycosylation enzyme GnT-IX maintains levels of protein tyrosine phosphatase receptor PTPRZ, thereby mediating glioma growth.

Gliomas are the most prevalent primary tumor of the central nervous system. Despite advances in imaging technologies, neurosurgical techniques, and radiotherapy, a cure for high-grade glioma remains elusive. Several groups have reported that protein tyrosine phosphatase receptor type Z (PTPRZ) is highly expressed in glioblastoma, and that targeting PTPRZ attenuates tumor growth in mice. PTPRZ is modified with diverse glycan, including the PTPRZ-unique human natural killer-1 capped O-mannosyl core M2 glycans. However, the regulation and function of these unique glycans are unclear. Using CRISPR genome-editing technology, we first demonstrated that disruption of the PTPRZ gene in human glioma LN-229 cells resulted in profoundly reduced tumor growth in xenografted mice, confirming the potential of PTPRZ as a therapeutic target for glioma. Furthermore, multiple glycan analyses revealed that PTPRZ derived from glioma patients and from xenografted glioma expressed abundant levels of human natural killer-1-capped O-Man glycans via extrinsic signals. Finally, since deficiency of O-Man core M2 branching enzyme N-acetylglucosaminyltransferase IX (GnT-IX) was reported to reduce PTPRZ protein levels, we disrupted the GnT-IX gene in LN-229 cells and found a significant reduction of glioma growth both in vitro and in the xenograft model. These results suggest that the PTPR glycosylation enzyme GnT-IX may represent a promising therapeutic target for glioma.

Establishment and application of a quadruplex real-time RT-qPCR assay for differentiation of TGEV, PEDV, PDCoV, and PoRVA.

Porcine viral diarrhea is a common ailment in clinical settings, causing significant economic losses to the swine industry. Notable culprits behind porcine viral diarrhea encompass transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), porcine deltacoronavirus (PDCoV), and porcine rotavirus-A (PoRVA). Co-infections involving the viruses are a common occurrence in clinical settings, thereby amplifying the complexities associated with differential diagnosis. As a consequence, it is therefore necessary to develop a method that can detect and differentiate all four porcine diarrhea viruses (TGEV, PEDV, PDCoV, and PoRVA) with a high sensitivity and specificity. Presently, polymerase chain reaction (PCR) is the go-to method for pathogen detection. In comparison to conventional PCR, TaqMan real-time PCR offers heightened sensitivity, superior specificity, and enhanced accuracy. This study aimed to develop a quadruplex real-time RT-qPCR assay, utilizing TaqMan probes, for the distinctive detection of TGEV, PEDV, PDCoV, and PoRVA. The quadruplex real-time RT-qPCR assay, as devised in this study, exhibited the capacity to avoid the detection of unrelated pathogens and demonstrated commendable specificity, sensitivity, repeatability, and reproducibility, boasting a limit of detection (LOD) of 27 copies/µL. In a comparative analysis involving 5483 clinical samples, the results from the commercial RT-qPCR kit and the quadruplex RT-qPCR for TGEV, PEDV, PDCoV, and PoRVA detection were entirely consistent. Following sample collection from October to March in Guangxi Zhuang Autonomous Region, we assessed the prevalence of TGEV, PEDV, PDCoV, and PoRVA in piglet diarrhea samples, revealing positive detection rates of 0.2 % (11/5483), 8.82 % (485/5483), 1.22 % (67/5483), and 4.94 % (271/5483), respectively. The co-infection rates of PEDV/PoRVA, PEDV/PDCoV, TGEV/PED/PoRVA, and PDCoV/PoRVA were 0.39 %, 0.11 %, 0.01 %, and 0.03 %, respectively, with no detection of other co-infections, as determined by the quadruplex real-time RT-qPCR. This research not only established a valuable tool for the simultaneous differentiation of TGEV, PEDV, PDCoV, and PoRVA in practical applications but also provided crucial insights into the prevalence of these viral pathogens causing diarrhea in Guangxi.

An unusual diagnosis of alpha-mannosidosis with ocular anomalies: Behind the scenes of a hidden copy number variation.

Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder caused by biallelic mutations in the MAN2B1 gene and characterized by a wide clinical heterogeneity. Diagnosis for this multisystemic disorder is confirmed by the presence of either a deficiency in the lysosomal enzyme acid alpha-mannosidase or biallelic mutations in the MAN2B1 gene. This diagnosis confirmation is crucial for both clinical management and genetic counseling purposes. Here we describe a late diagnosis of alpha-mannosidosis in a patient presenting with syndromic intellectual disability, and a rare retinopathy, where reverse phenotyping played a pivotal role in interpreting the exome sequencing result. While a first missense variant was classified as a variant of uncertain significance, the phenotype-guided analysis helped us detect and interpret an in-trans apparent alu-element insertion, which appeared to be a copy number variant (CNV) not identified by the CNV caller. A biochemical analysis showing abnormal excretion of urinary mannosyloligosaccharide and an enzyme assay permitted the re-classification of the missense variant to likely pathogenic, establishing the diagnosis of alpha-mannosidosis. This work emphasizes the importance of reverse phenotyping in the context of exome sequencing.

Synthetic vitreous fibers (SVFs): adverse outcome pathways (AOPs) and considerations for next generation new approach methods (NAMs).

Fiber dimension, durability/dissolution, and biopersistence are critical factors for the risk of fibrogenesis and carcinogenesis. In the modern era, to reduce, refine, and replace animals in toxicology research, the application of in vitro test methods is paramount for hazard evaluation and designing synthetic vitreous fibers (SVFs) for safe use. The objectives of this review are to: (1) summarize the international frameworks and acceptability criteria for implementation of new approach methods (NAMs), (2) evaluate the adverse outcome pathways (AOPs), key events (KEs), and key event relationships (KERs) for fiber-induced fibrogenesis and carcinogenesis in accordance with Organization for Economic Co-operation and Development (OECD) guidelines, (3) consider existing and emerging technologies for in silico and in vitro toxicity testing for the respiratory system and the ability to predict effects in vivo, (4) outline a recommended testing strategy for evaluating the hazard and safety of novel SVFs, and (5) reflect on methods needs for in vitro in vivo correlation (IVIVC) and predictive approaches for safety assessment of new SVFs. AOP frameworks following the conceptual model of the OECD were developed through an evaluation of available molecular and cellular initiating events, which lead to KEs and KERs in the development of fiber-induced fibrogenesis and carcinogenesis. AOP framework development included consideration of fiber physicochemical properties, respiratory deposition and clearance patterns, biosolubility, and biopersistence, as well as cellular, organ, and organism responses. Available data support that fiber AOPs begin with fiber physicochemical characteristics which influence fiber exposure and biosolubility and subsequent key initiating events are dependent on fiber biopersistence and reactivity. Key cellular events of pathogenic fibers include oxidative stress, chronic inflammation, and epithelial/fibroblast proliferation and differentiation, which ultimately lead to hyperplasia, metaplasia, and fibrosis/tumor formation. Available in vitro models (e.g. single-, multi-cellular, organ system) provide promising NAMs tools to evaluate these intermediate KEs. However, data on SVFs demonstrate that in vitro biosolubility is a reasonable predictor for downstream events of in vivo biopersistence and biological effects. In vitro SVF fiber dissolution rates >100 ng/cm2/hr (glass fibers in pH 7 and stone fibers in pH 4.5) and in vivo SVF fiber clearance half-life less than 40 or 50 days were not associated with fibrosis or tumors in animals. Long (fiber lengths >20 µm) biodurable and biopersistent fibers exceeding these fiber dissolution and clearance thresholds may pose a risk of fibrosis and cancer. In vitro fiber dissolution assays provide a promising avenue and potentially powerful tool to predict in vivo SVF fiber biopersistence, hazard, and health risk. NAMs for fibers (including SVFs) may involve a multi-factor in vitro approach leveraging in vitro dissolution data in complement with cellular- and tissue- based in vitro assays to predict health risk.

Eliminating Intracellular MRSA via Mannosylated Lipid-Coated Calcium Phosphate Nanoparticles.

Methicillin-resistant Staphylococcus aureus (MRSA) within cells proves exceptionally challenging to eradicate using conventional antimicrobials, resulting in recurring infections and heightened resistance. Herein, we reported an innovative mannosylated lipid-coated photodynamic/photothermal calcium phosphate nanoparticle (MAN-LCaP@ICG) for eradicating intracellular MRSA. The MAN-LCaP functioned as the vehicle for drug delivery, exhibiting preferential uptake by macrophages and facilitating the transport of ICG to intracellular pathogens. The MAN units integrated into MAN-LCaP@ICG could promote binding with MAN residuals on macrophage cells, as evidenced by cellular uptake assays using fluorescence microscopy and flow cytometry. Following its targeted accumulation, MAN-LCaP@ICG could enter into the cytoplasm and efficiently eradicate intracellular MRSA by a combination of the lysosome escape capability of CaP and the photodynamic and photothermal therapeutic effects of ICG. Furthermore, MAN-LCaP@ICG could kill MRSA more effectively than LCaP@ICG without MAN units or free ICG in a mouse peritoneal infection model. Therefore, MAN-LCaP@ICG provided a promising direction for human clinical application in combating intracellular infections.

Administration of oxathridine, a first-in-class histamine-3 receptor partial agonist in healthy male volunteers: Central nervous system depression and pseudo-hallucinations.

AIMS: To characterise the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of oxathridine, a first-in-class histamine-3 receptor partialagonist, in healthy male volunteers. METHODS: A randomised, double-blind, placebo-controlled study including the NeuroCart, consisting of a battery of drug sensitive neurophysiological tests, was performed. Oxathridine was administered orally as an aqueous solution. After dosing, safety and NeuroCart tests (adaptive tracking [AT], body sway [BS], saccadic peak velocity [SPV], smooth pursuit [SP] eye movements, VAS according to Bond and Lader, VAS according to Bowdle [VAS B&L, Bowdle], pharmaco-electroencephalogram [pEEG], Sustained Attention to Response Task [SART]) were performed at set times. RESULTS: Forty volunteers completed the study. Given doses were: 0.5, 2.5, 5, 0.25 and 1.5 mg. At 5 mg, unacceptable and unanticipated adverse events (AEs) of (orthostatic) hypotension and pseudo-hallucinations were reported. Statistically significant effects ([CI]; p-value) of 2.5 mg and 5 mg oxathridine were observed on AT ([-8.28, -1.60]; p = 0.0048), ([-8.10, -1.51]; p = 0.00530), BS ([0.6, 80.2]; p = 0.0455), ([5.9, 93.1]; p = 0.0205) and SPV ([-59.0, -15.9]; p = 0.0011), ([-43.9, -1.09]; p = 0.0399), respectively. Oxathridine 5 mg significantly increased all three VAS Bowdle subscale scores; VAS external ([0.183, 0.476]; p = <.0001), VAS internal ([0.127, 0.370]; p = 0.0001) and VAS feeling high ([0.263, 0.887]; p = 0.0006). CONCLUSION: NeuroCart tests indicated central nervous system (CNS) depressant effects. Oxathridine also unexpectedly caused pseudohallucinations. Although this led to the decision to stop further development of oxathridine, these observations suggest that the H3R system could be an interesting new target for the development of novel antipsychotics.

Long-term mental health cost of the Great Chinese Famine.

The Great Chinese Famine (1959-1961) claimed tens of millions of lives. This study aims to causally examine the long-term mental health cost it imposed on those who survived. To estimate the nationwide total mental health cost, we use a novel dataset to measure the famine intensity of every prefecture-level region, match it to a nationally representative survey, and then identify the long-term effects of the famine on the depression of rural residents then in the early years of their lives. Difference-in-differences estimates reveal that a one-standard-deviation rise in the experienced famine intensity increased a standard measure of depression by about 0.039 and 0.064 if the individual experienced the famine at ages 0-2 and 3-5, respectively. This translates into roughly 7.99 million cases of severe depressive symptoms caused by the famine, which is likely an undercount. Examining the mechanisms behind the large effects, we find that important roles were played by starvation experience and childhood maltreatment, as well as the primary mediators including other health outcomes, economic status, and social relationship. Our findings shed light on how large-scale food security failures impact the mental well-being of the survivors.

Older Gay Men's Sexual Experiences as Boys with Men: An Empirical and Narrative Analysis.

A dominant view among researchers is that boys' sexual interactions with adult men are traumatizing. In contrast, many gay men recall childhood sexual experiences with adult males as positive. The current study tested for both of these outcomes by examining recalled boyhood sexual experiences of older gay men. Interviews were conducted in the 1970-1980s, and thus, before the public view became popular that child-adult sexual interactions must be traumatizing. Quantitative analyses suggested that gay men with boyhood sexual experiences with adult males (n = 7, mostly aged 11-16 at first experience with men aged 20s to 50s) were as well adjusted as those without these experiences (n = 10), and these experiences were usually viewed positively (71%). Narrative analyses indicated that adjustment problems in adulthood were not related to these early sexual experiences but to other factors such as parental abusiveness, societal intolerance, internalized homophobia, or social isolation.

Ethnoprimatology reveals new extended distribution of critically endangered banded langur Presbytis femoralis (Martin, 1838) in Pahang, Malaysia: Insights from indigenous traditional knowledge and molecular analysis.

The banded langur (Presbytis femoralis) is a critically endangered primate, which within Malaysia has not been known to extend significantly outside the state of Johor. Traditionally, distribution studies on this highly threatened primate have relied on conventional methods such as DNA identification, live counting, and camera trapping. However, ethnoprimatology offers an alternative approach to data collection, involving the active participation of indigenous and local communities possessing valuable knowledge and experience with local primate species. This study employed an integrated approach incorporating ethnoprimatology by utilizing pooled local expert opinion, local surveys, interviews, and fecal DNA analysis, resulting in a novel distribution range for the banded langur. The combination of expert opinions revealed this species' most optimistic distribution scenario across Johor and Pahang, inhabiting various ecosystems, including lowland forests, peat swamps, and human-modified landscapes. Further interviews and surveys conducted within the Orang Asli community in Tasik Chini and Tasek Bera have provided additional support for the revised distribution, documenting occurrences of banded langur utilization in indigenous practices, such as food consumption, cultural beliefs, medicinal applications, and craftsmanship. Phylogenetic analysis demonstrated genetic differentiation between populations in Johor and Pahang, with the populations in the southern part of Peninsular Malaysia likely serving as ancestral sources for other populations. Consequently, this study not only elucidated the updated distribution of banded langur through DNA records and direct observations but also established the efficacy of ethnoprimatology as a precursory tool for uncovering the present distribution patterns of other primate species in Malaysia.

Impacts of mining disasters on the ambulatory care of the Brazilian national health system: the cases of Mariana and Brumadinho/Brazil.

BACKGROUND: Disasters are events that bring with them effects that contribute to the disruption of the normality of a population and thus highlight the vulnerabilities of the health system. In Mariana and Brumadinho, the collapse of the dam of ore tailings brought with it several impacts that were felt in the short term and will be felt in the medium and long term. And that by being intensely intertwined with issues of economic and productive nature, has as its meaning an uninterrupted result of its activities. METHODS: Through the DATASUS database, two specific variables were chosen to perform the analysis: the approved amount and the approved value. For this research, a methodological device, the segmented regression line, was used to observe the influences that the disasters that occurred in Mariana and Brumadinho had on the ambulatory health systems. RESULTS: The results of the segmented regression line show that, with Mariana, the amount approved continued to grow throughout the period, which shows that there was no change because of the disaster. There was a reduction in spending. In Brumadinho, regarding the amount approved, there was an upward trend in the disaster's month, which did not change immediately afterwards, and regarding expenditure, the growth pattern was maintained in all three periods. Corroborating this data, the relative and absolute base elements show an increase in the amount approved and in the number of services provided at various posts compared with Minas Gerais. CONCLUSIONS: Based on the findings, it was possible to understand that although disasters exert an influence that may have some effect on the health system, the lack of significance sometimes cannot be interpreted as a lack of impact on the disaster. The segmented regression line outlines some effects that are not conclusive but indicative of a numerical interpretation and a trend interpretation.

Evaluating the Efficacy of ChatGPT as a Patient Education Tool in Prostate Cancer: Multimetric Assessment.

BACKGROUND: Artificial intelligence (AI) chatbots, such as ChatGPT, have made significant progress. These chatbots, particularly popular among health care professionals and patients, are transforming patient education and disease experience with personalized information. Accurate, timely patient education is crucial for informed decision-making, especially regarding prostate-specific antigen screening and treatment options. However, the accuracy and reliability of AI chatbots' medical information must be rigorously evaluated. Studies testing ChatGPT's knowledge of prostate cancer are emerging, but there is a need for ongoing evaluation to ensure the quality and safety of information provided to patients. OBJECTIVE: This study aims to evaluate the quality, accuracy, and readability of ChatGPT-4's responses to common prostate cancer questions posed by patients. METHODS: Overall, 8 questions were formulated with an inductive approach based on information topics in peer-reviewed literature and Google Trends data. Adapted versions of the Patient Education Materials Assessment Tool for AI (PEMAT-AI), Global Quality Score, and DISCERN-AI tools were used by 4 independent reviewers to assess the quality of the AI responses. The 8 AI outputs were judged by 7 expert urologists, using an assessment framework developed to assess accuracy, safety, appropriateness, actionability, and effectiveness. The AI responses' readability was assessed using established algorithms (Flesch Reading Ease score, Gunning Fog Index, Flesch-Kincaid Grade Level, The Coleman-Liau Index, and Simple Measure of Gobbledygook [SMOG] Index). A brief tool (Reference Assessment AI [REF-AI]) was developed to analyze the references provided by AI outputs, assessing for reference hallucination, relevance, and quality of references. RESULTS: The PEMAT-AI understandability score was very good (mean 79.44%, SD 10.44%), the DISCERN-AI rating was scored as "good" quality (mean 13.88, SD 0.93), and the Global Quality Score was high (mean 4.46/5, SD 0.50). Natural Language Assessment Tool for AI had pooled mean accuracy of 3.96 (SD 0.91), safety of 4.32 (SD 0.86), appropriateness of 4.45 (SD 0.81), actionability of 4.05 (SD 1.15), and effectiveness of 4.09 (SD 0.98). The readability algorithm consensus was "difficult to read" (Flesch Reading Ease score mean 45.97, SD 8.69; Gunning Fog Index mean 14.55, SD 4.79), averaging an 11th-grade reading level, equivalent to 15- to 17-year-olds (Flesch-Kincaid Grade Level mean 12.12, SD 4.34; The Coleman-Liau Index mean 12.75, SD 1.98; SMOG Index mean 11.06, SD 3.20). REF-AI identified 2 reference hallucinations, while the majority (28/30, 93%) of references appropriately supplemented the text. Most references (26/30, 86%) were from reputable government organizations, while a handful were direct citations from scientific literature. CONCLUSIONS: Our analysis found that ChatGPT-4 provides generally good responses to common prostate cancer queries, making it a potentially valuable tool for patient education in prostate cancer care. Objective quality assessment tools indicated that the natural language processing outputs were generally reliable and appropriate, but there is room for improvement.

Endometrial cancer and endometrial changes in transgender men: Insights from Japanese individuals on testosterone.

AIM: Endometrial changes in Japanese transgender men (TGM) on testosterone use remain elucidated. This study aims to present TGM with endometrial cancer and insights from a literature review of similar cases. Furthermore, we investigated the correlation between endometrial cancer and severe obesity in TGM who underwent gender-affirming surgery. METHODS: Between July 2020 and April 2023, two groups were assessed: 2 TGM with endometrial cancer and 43 TGM without cancer who underwent gender-affirming surgery. A literature review for TGM with endometrial cancer was conducted. Clinical data were retrospectively collected, and histopathological evaluation of female genital organs was performed. RESULTS: Two TGM with endometrial cancer and an additional four similar cases were identified through a literature search. These TGM had severe obesity (body mass index [BMI] ≥30 kg/m2) and long-term testosterone use, indicating a possible link between endometrial cancer and these factors. Subsequently, we investigated the 43 TGM without cancer. We revealed 30% with obesity (BMI ≥25), only three cases of severe obesity (BMI ≥30), and a significant correlation between testosterone use duration and BMI in TGM without cancer. Histological examination revealed focal proliferative endometrium in 51% of cases and polycystic ovarian changes in 77%. CONCLUSIONS: Our observations suggest a potential link between severe obesity, prolonged testosterone use, and endometrial cancer in transgender men. Histological changes in the female genital tract highlighted frequent focal proliferative endometrium, even under testosterone therapy. Further research should focus on larger, multi-institutional studies to confirm these findings and establish endometrial cancer screening for Japanese TGM.

Physiology and Execution of Swallowing Maneuvers in 3D Videos: Integrating the Technology into Patient Care.

Educational technologies have proven to be an effective way to guide and educate patients, allowing them to increase awareness of their dysphagia condition and how treatment will help them. In this sense, this study aimed to develop and validate the content and appearance of 3D iconographic videos, which addressed the physiological demonstration and execution of protective and facilitating swallowing maneuvers, as well as verifying the feasibility of its use in teleconsultation, having adults and elderly people with oropharyngeal dysphagia as the main target audience. The development of the 3D videos was elaborated based on a guiding scientific script, constructed from an integrative literature review. After the development of the 3D videos by the digital designer, a committee of 12 expert judges evaluated the material produced to validate the content and appearance where a minimum agreement index of 0.8 among the judges was considered satisfactory. Subsequently with the validated material, the proof of concept was conducted together with the target population of 10 dysphagic patients through individual teleconsultation via Google Meet platform. After the teleconsultation, patients responded to a Google Forms questionnaire, analyzing the videos presented. From the integrative literature review, 29 studies that contained relevant information about the physiological effects caused by swallowing maneuvers were selected. Based on this information, the scientific script was created, allowing a detailed description of the physiological events that occurred during swallowing while executing the maneuvers. With the finished script, 3D videos of swallowing maneuvers were produced. After developing the material, the committee of expert judges validated the content and appearance. The twelve items that had an agreement index below 0.8 were adjusted. Once the adjustments were completed, the videos were analyzed again, obtaining approval from the judges, and ensuring the validation of content and appearance of the material developed. A proof of concept was conducted on ten dysphagic patients. The maneuver applied was chosen according to the patient's physiological changes, causing only 4 of the 9 maneuvers to be tested, as the patients did not demonstrate changes in swallowing that would justify the use of the other maneuvers. After this, patients answered a form in which all items covered received positive evaluations, related to both ease of understanding and learning. This study allowed the development of the 3D videos with a didactic demonstration of the physiology and execution of protective and facilitating swallowing maneuvers, in addition to having its content and appearance validity assured through analysis by the committee of expert judges.

Exploring the Implementation of UNESCO's MAB Program in South Africa: A Case Study of the Cape Winelands Biosphere Reserve.

The Man and the Biosphere Program (MAB) responds to challenges of the Anthropocene through an explicit social-ecological approach. Implemented as a world network of biosphere reserves, MAB aims to increase [eco]system sustainability and resilience globally, via individual model sites for learning and sustainable development. This research provides an in-depth case study of MAB implementation in South Africa using the Cape Winelands Biosphere Reserve (CWBR), established in 2007 when a key MAB guiding policy, the Madrid Action Plan came into effect. The study utilized semi-structured in-depth interviews with strategic and operational management, and document analysis. The CWBR prioritizes their role as a landscape coordinator, a driver of socio-economic development and site in which humans derive benefits from healthy natural environments. The CWBR have adopted a non-profit organization cooperative governance model in support of this vision, fulfilling the socio-economic development function primarily through successful international partnerships. Challenges faced include a perceived lack of sufficient government support, limited stakeholder awareness and insufficient resources for project implementation. Over reliance on the pillar of their model, the chief executive officer in the current governance form, is an instrument in their effectiveness, yet carries significant risk. These are learnings useful for other biosphere reserves translating an international designation for a local context.

Land use, land cover changes and expansion of artificial reservoirs in Eastern Thailand: implications for agriculture and vegetation drought reduction.

Eastern Thailand and Rayong province face perennial drought and water scarcity due to natural characteristics of climate and geology. Therefore, increasing water surface by man-made reservoirs is one of the priorities in the regional development plan to provide water adequately for industrial purposes, domestic consumption, and agriculture. The large reservoir constructions may induce land use, land cover changes (LULCC), yet it also is expected to alleviate the drought harshness in the region. By delineating Landsat satellite images and spatial analysis, this study revealed the LULCC in Rayong from 1990 to 2020. The most prominent LULCC was surface water expansion, about 10.9% per year, yet the increase was the most substantial in the first decade rather than the last two decades. Vegetation expansion was observed, contributing to an increase in forests/plantations and intensified agriculture by 39.19% and 25.54%, respectively. The LULCC corresponded to a 3.64% increase in ecosystem service values (ESV), implying positive benefits from the LULCC. Vegetation drought conditions monitored by the vegetation health index (VHI) exhibited an improvement trend, especially in the eastern basins. The development of artificial reservoirs was proven to stimulate the expansion of intensive agriculture and vegetation drought mitigation with spatial heterogeneity, spreading mainly across areas of the basins rather than remote areas. The research findings inform the efficiency of the reservoirs and irrigation systems regarding the beneficial effects on drought mitigation and water scarcity for agricultural cultivation. They also provide spatial information on areas still hindered by water problems that should be addressed in future strategies.

Factors associated with sexual dysfunction in patients with bipolar disorder.

OBJECTIVES: The aims of our study were to assess the sexual function in men with bipolar disorder type 1 in remission and to determine the various sociodemographic, clinical and therapeutic factors associated with sexual dysfunction. METHODS: We conducted a cross-sectional study over an 18-month period (January 2020-June 2021) in which we included men followed up for bipolar disorder type 1 in the euthymic phase strictly defined by a score <8 on the Young Mania Rating Scale and a score ≤7 on the Hamilton Depression Rating Scale. Sexual function was assessed using the Arizona Sexual Experiences Scale (Asex) in its Arabic-validated version. RESULTS: Sixty patients were included in the study. The mean age was 42.5 (SD=11.1) years. Among the patients, 68% had sexual dysfunction according to the total score of the Asex scale. According to univariate analysis, several factors were significantly associated with sexual dysfunction in patients with bipolar disorder type 1: age (P=0.001), total number of hospitalizations for thymic relapse (P=0.015), total number of depressive episodes (P=0.006) and depressive dominant polarity (P=0.046). The factors identified as modifying sexuality according to the total score of the Asex scale by multivariate analysis were age at first antipsychotic prescription: P=0.01; ORa=1.109; 95% CI [1.021-1.206] and number of hospitalizations for thymic relapse: P=0.015; ORa=1.259; 95% CI [1.046-1.546]. CONCLUSION: Studies assessing factors associated with sexual dysfunction in patients with bipolar disorder type 1 in euthymia were mostly concerned with the effects of psychotropic drugs on sexual function, with factors inherent in bipolar illness itself not widely addressed in the literature. According to the results of our study, sexual dysfunction in patients with bipolar disorder in the euthymic phase is frequent and significantly associated with clinical factors inherent in the bipolar illness itself and its course.

Stiff-person syndrome.

Stiff-person syndrome (SPS) is an autoimmune disease associated mainly with antibodies to glutamic acid decarboxylase (GAD) or to glycine, characterised by intermittent painful spasms, stiffness and rigidity of the proximal and truncal muscles. Neuro-ophthalmological and gastrointestinal symptoms also occur. The symptoms are caused by neuronal excitability due to impaired inhibitory (gamma amino butyric acid [GABA] and glycine) neurotransmission. SPS is part of a larger spectrum of GAD antibody-spectrum disorders, which overlaps with autoimmune epilepsy, cerebellar ataxia, myoclonus, progressive encephalomyelitis, rigidity and myoclonus (PERM) and limbic encephalitis. PERM is often caused by antibodies against the glycine receptor. Some SPS cases are paraneoplastic. Diagnostic delay is often associated with irreversible disability, and therefore, clinicians need a high degree of clinical suspicion to make an earlier diagnosis. This review updates the various clinical presentations that should raise suspicion of SPS and its related conditions and includes a diagnostic algorithm and various treatment strategies including immunotherapy and GABA-ergic drugs.