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Background and Aim: Parasitic infections are a public health problem worldwide, including in Thailand. An epidemiological survey for helminthiasis based on stool examination uses the Kato–Katz method as recommended by the World Health Organization. Limitations of this method include the need for fresh stool, time requirement, and lack of quality control. The aim of this study was to enhance the efficiency of the Kato–Katz technique using formalin and glycerol solutions and to implement specimen preparation in fieldwork. Materials and Methods: For the Kato–Katz method, stool samples were divided into formalin-fixed and unfixed groups at various time points and processes. Fresh echinostome eggs were added to each stool group. Incubation with glycerol increased the clearing process. Each group was observed and photographed using a light microscope. Parasite eggs were imaged and compared using the standard Kato–Katz method. Results: Visualization of echinostome eggs from formalin-fixed stool slides was significantly better than that from unfixed stool slides (p < 0.01). Stool samples fixed for 7 days retained normal echinostome eggs morphology. Incubation with glycerol for 1 h resulted in increased Kato–Katz performance by digesting the stool content and enhancing egg observation. Moreover, the results of the Kato–Katz method using fixed and fixed stool plus glycerol for natural helminth infection showed good quality of Opisthorchis viverrini and Taenia egg visualization and normal morphology with a clear background of slides. Conclusion: Formalin-fixed stool could be more suitable than fresh stool for the Kato–Katz method.

Background and Aim: Captive animals are susceptible to parasitic diseases due to the stress and confinement they experience. In addition, they can serve as reservoirs of zoonotic parasites that have the potential to infect humans. To investigate this possibility, we estimated the prevalence of gastrointestinal (GI) parasites in captive mammals at Khon Kaen Zoo, Thailand. Materials and Methods: One hundred and forty-seven individual mammals (37 primates, 43 carnivores, 62 herbivores, and 5 rodents) were examined for parasitic infections by fecal examination daily for 3 consecutive days using the formalin-ethyl acetate concentration technique (FECT) and the agar plate culture method. Results: According to FECT, the overall prevalence of GI parasites was 62.6% (92/147). Within animal groups, the numbers were as follows: 67.6% (25/37) in primates, 23.3% (10/43) in carnivores, 85.5% (53/62) in herbivores, and 80.0% (4/5) in rodents. Using the agar plate culture method, 21.43% (27/126) were positive for Strongyloides spp. and hookworm infections. The GI parasites identified belonged to three categories: protozoa (including Entamoeba histolytica species complex, Entamoeba coli, Giardia spp., coccidia, and ciliated protozoa), trematodes (minute intestinal flukes and rumen flukes), and nematodes (strongyle/hookworm, Strongyloides spp., Ascarididae, and Trichuris spp.). Conclusion: The findings of this study indicate the prevalence of several GI parasites in zoo animals with the potential for transmission to humans, given the animals’ close proximity to both visitors and animal caretakers.

Abstract Background Detection of parasite-specific IgG in urine is a sensitive method for diagnosis of strongyloidiasis and gives similar accuracy to serum IgG. However, there are no data concerning detection of IgG subclass in urine. To further explore the utility of diagnosis from urine samples, we evaluated the diagnostic performance of IgG4 in urine compared with parasitological and other immunological methods. Methods The urine and sera included proven strongyloidiasis (group 1, n = 93), other parasitic infections (group 2, n = 40) and parasite negatives (group 3, n = 93). The performance of Strongyloides-specific IgG4 in urine for diagnosis of strongyloidiasis using fecal examinations as the reference standard was assessed. Results With fecal examination as a gold standard, Strongyloides-specific IgG4 in urine had 91.4% sensitivity and 93.2% specificity while serum IgG4 had 93.6% sensitivity and 91.0% specificity. IgG4 in both urine and serum had almost perfect diagnostic agreements with fecal examination (Cohen's kappa coefficient was > 0.8). Cross-reactivity to Opisthorchis viverrini and Taenia spp. of IgG4 in urine were 7.5% and 12.5% in serum. Concurrent analyses of total IgG in urine and serum showed that the sensitivities (97.9–100%) and specificities (88.7–91.0%) were similar (P > 0.05). The sensitivity for parasitological examination by the formalin-ethyl acetate concentration technique (FECT) was 49.5% and that for agar plate culture technique (APC) it was 92.6%. Conclusion Our findings showed that specific IgG4 detection in urine yielded similar diagnostic performance to the same biomarkers in serum. This suggests that accurate diagnosis of strongyloidiasis can be performed using urine samples and IgG4 is a valid choice of diagnostic marker. Further assessment is required to assess the utility of urine IgG4 for measuring the response treatment in strongyloidiasis. Graphical Abstract

Background and Aim: The risk factors for cholangiocarcinoma (CCA) are opisthorchiasis and the intake of a combination of nitroso compounds through the consumption of traditionally fermented fish, which is very popular in areas where liver flukes are endemic. The incidence of CCA remains high because this cultural habit of rural people has been altered. Therefore, decreasing nitrate and nitrite concentrations in fermented fish are an alternative approach to reducing the risk of CCA. Thus, this study aimed to reduce nitrate and nitrite concentrations in fermented foods by heating and investigated its effect on CCA development in a hamster model. Materials and Methods: We used Association of Official Analytical Chemists method 973.31 to measure the nitrate and nitrite concentrations in both fermented fish (pla-ra [PR]) and pickled fish (pla-som [PS]) before and after boiling for 5 and 30 min, respectively. The same samples were fed to Opisthorchis viverrini (OV)-infected or -uninfected hamsters for 3 months. Thereafter, the hamsters’ liver and blood were collected for analysis. Results: The levels of nitrates and nitrites in PS and PR significantly decreased following boiling for 5 and 30 min. The OV-PR and OV-PS groups showed dramatically increased numbers of inflammatory cells, fibrosis surrounding the bile duct, and focal fibrotic areas. However, after boiling the fermented dishes for 5 and 30 min, the extent of inflammatory cell infiltration and intensity of fibrosis in these groups were decreased. Conclusion: Our findings suggest that boiling reduces nitrate and nitrite toxicity in fermented dishes, as evidenced by reduced hepatic inflammation. However, regardless of heating, kidney tissues are adversely affected when fermented meals are consumed daily.

Chylothorax refers to chyle within the pleural space, which frequently arises from an interruption in the thoracic duct or because of reduced lymphatic drainage. Pleural fluid that is white/milky in appearance, with a triglyceride concentration of greater than 110 mg/dL, strongly supports the diagnosis of chylothorax. Chylothorax is nearly always exudative. Transudative chylothorax is extremely rare and typically presents due to a secondary cause, such as liver cirrhosis, nephrotic syndrome, or congestive heart failure. We present a case of chylothorax that occurs in the setting of lung adenocarcinoma. A 65-year-old African American man with a past medical history of metastatic right lung adenocarcinoma presented with dyspnea and palpitations. He denied fever, orthopnea, and paroxysmal nocturnal dyspnea. Therapeutic drainage of the left pleural effusion resulted in 650 mL of milky-white fluid. Pleural fluid analysis demonstrated a triglyceride concentration of 520 mg/dL, a pleural/serum protein ratio of 0.41, a pleural/serum lactate dehydrogenase (LDH) ratio of 0.26, a total pleural LDH of 127 IU/L, and a cholesterol level of 58 mg/dL. This effusion can be classified as transudative as per Light’s criteria and exudative as per Heffner’s and pleural cholesterol criteria. A subsequent pleural fluid cytology found malignant cells consistent with lung adenocarcinoma. Malignancy is the most common cause of nontraumatic, exudative chylothorax. Light’s criteria misinterpret about 25% of transudative effusions as exudative. Therefore, to minimize this error, a combination of the 3-criterial consideration is ideal.

Background and Aim: The brown dog tick, Rhipicephalus sanguineus sensu lato, is the most common tick found on domestic dogs in Southeast Asia, including Thailand. Canine tick-borne pathogens are a public health concern worldwide. Tick-borne diseases are diagnosed by identifying pathogens based on the morphological or molecular analyses of dog blood samples. However, the collection of ticks, a non-invasive procedure, is easier than drawing blood. This study aimed to demonstrate the usefulness of collecting brown dog ticks for the diagnosis of tick-borne diseases and for estimating the prevalence of tick-borne pathogens among companion dogs in Khon Kaen, Northeast Thailand. Materials and Methods: Seventy brown dog ticks from 70 companion dogs in Khon Kaen Province, Thailand, were evaluated for molecular evidence of tick-borne pathogens, including Babesia spp., Ehrlichia canis, and Hepatozoon canis. Ticks were collected from dogs at a private animal hospital based on the presence of at least one of the three inclusion criteria: fever, anorexia, or lethargy. Molecular diagnosis was performed using conventional polymerase chain reaction for the detection of pathogens. Results: Of the 70 ticks collected from 70 sick dogs, 55 (78.57%) were positive for tick-borne pathogens. The most common infection was a single infection with H. canis (65.71%) followed by Babesia spp. (31.43%) and E. canis (30.00%). Coinfection was observed in 14 ticks (20.00%), and coinfection with Babesia spp. and E. canis was the most prevalent double infection (n = 6). The prevalence of coinfection was identical for H. canis mixed with Babesia spp. and H. canis mixed with E. canis (n = 4). Conclusion: The present study showed that tick-borne pathogens are highly prevalent among companion dogs in Khon Kaen Province. Therefore, we encourage an increase in tick control or the reduction and prevention of tick-borne diseases in this region. Furthermore, this study revealed that ticks are valuable samples for the molecular detection of tick-borne pathogens.

Abstract Background Control and elimination of the liver fluke (Opisthorchis viverrini) is a primary preventive strategy against cholangiocarcinoma in Southeast Asia. A sensitive parasitological diagnostic method is required to facilitate a surveillance and control program. In this study, we evaluated the performance of Mini Parasep® SF stool concentrator kit (stool kit) compared with Kato-Katz (KK) and the quantitative formalin-ethyl acetate concentration technique (FECT) for detection of O. viverrini and co-endemic parasitic infections. Methods A cross-sectional survey for parasitic infection in residents aged > 15 years in a community in Kalasin province, Northeast Thailand, was conducted in 2018. Fecal samples were collected and screened by KK method, and a subset of samples was further examined by the stool kit and FECT methods. The results were analyzed for prevalence of parasitic infections in addition to the diagnostic performance of the methods for qualitative and quantitative detection of helminthiases. Results The initial survey of parasitic infection determined by the KK method (n = 567) showed the prevalence of O. viverrini was 32.63%, followed by Taenia 2.65%, echinostomes 1.76%, hookworms 1.41%, Trichuris trichiura 0.53% and Strongyloides stercoralis 0.53%. Within a subset of samples tested with multiple diagnostics (n = 150), the detection rates of O. viverrini by the stool kit, FECT and KK methods were 27.3%, 30.7% and 28.7%, respectively. The diagnostic sensitivity for opisthorchiasis was similar for FECT (75.5%), KK(66.0%) and the stool kit (67.3%). For other parasitic infections, FECT and stool kit methods performed better than KK, particularly in detecting minute intestinal flukes (MIF), S. stercoralis and coinfections. When measuring the intensity of O. viverrini infection (fecal egg counts), the stool kit results showed a significant positive correlation with KK and FECT (P

Background and Aim: Canine demodicosis is a skin disease that is a major global health problem in dogs. Ivermectin is a drug of choice for treatment, but it may cause toxicity in dogs carrying multidrug resistance mutation-1 gene mutations. Hence, alternative herbal medicines are used instead of the drug, such as Dipterocarpus alatus oil (YN oil), Rhinacanthus nasutus leaf (WC), and Garcinia mangostana pericarps (MG) extracts. This study aimed to determine the efficacy of D. alatus oil, R. nasutus leaf, and G. mangostana pericarp extracts on canine demodicosis in vivo. Materials and Methods: Twenty-five mixed-breed dogs with localized demodicosis were examined. Dogs were diagnosed with demodicosis through deep skin scraping and screened with the inclusion criteria. Five dogs of each group were treated in five treatment groups (ivermectin, YN oil, YN oil+WC, YN oil+MG, and YN oil+WC+MG) for 1 month. The individual dogs were clinically evaluated, and the dermatological lesions were monitored daily for 60 days. Results: Dermatological lesion improvement was predominantly observed in the group of dogs treated with YN oil+WC. This was evidenced by the disappearance of the hyperpigmentation and lichenification on day 28 post-treatment and alopecia on day 56 post-treatment. Moreover, no allergic or clinical signs were observed during treatment. Conclusion: YN oil+WC is an alternative herbal medicine that could be used for the treatment of localized canine demodicosis.

Fly is one of the vectors of foodborne pathogenic vectors and causes myiasis in humans and animals. To prevent the contamination of food and myiasis, various chemical products are commonly used. However, eco-friendly is now a trend all over the world so natural products are the alternative ways to reduce the chemical residue in the environment. The present study was screened the 12 natural products in 4 groups; the essential oil plants, the alkaloid plants, the cyanogenic plant, and the inorganic compounds which use a simple extraction on the fly repelling and larvicide. The fly repelling efficacy with 2 criteria consist of the time of the first swarm and percent repelling (PR) in the first 15 min. The larvicidal efficacy was determined by the mortality rate within 24 h. The Kaffir lime peels aqueous crude extract exhibited the best result on fly repelling from both criteria with no significant difference. The bamboo shoots aqueous crude extract gave the best result on larvicide with significantly different from other groups (P < 0.001) which was faster than the positive control group (Coumaphos & Propoxur). Moreover, the high mortality rate reached 73.33 ± 15.28% within 24 h, higher than the positive control group. The present study indicates the power of common natural products on fly repellent and larvicide that may apply for fly repellant to reduce the food contamination especially fresh materials and prevention or treatment of animal and human myiasis in rural areas

Background and Aim: Haemonchus contortus is one of the major trichostrongyloid nematodes affecting small ruminant production worldwide, especially in tropical and subtropical regions. Adult H. contortus suck the blood from the host abomasum leading to anemia and often death in heavily infected animals. The mainstay of parasitic control is an anthelmintic drug, but long-term drug use may cause drug resistance. The aim of this study was to examine benzimidazole resistance in H. contortus of goats from different regions in Thailand by detecting the frequency of the F200Y polymorphism in the β-tubulin isotype 1 gene. Materials and Methods: A total of 121 H. contortus adults were obtained from 31 naturally infected out of 37 slaughtered goats from city abattoirs in five regions of Thailand. The frequency of the F200Y polymorphism in the β-tubulin isotype 1 gene was detected following the allele-specific polymerase chain reaction protocol. Results: The overall genotype frequencies in Thailand were homozygous resistant (RR: 24%), heterozygous (SR: 44.6%), and homozygous susceptible (SS: 31.4%). The allele frequencies were resistant allele (R: 46%) and susceptible allele (S: 54%). The R allele frequency and the RR genotype varied from 30% to 65% and 0% to 43.9%, respectively. The frequency of R alleles was significantly higher in the southern region (0.65) as compared to northern (0.30, p=0.001), western (0.38, p=0.04), and central regions (0.30, p=0.03). The RR genotype was also significantly higher in the southern region (43.9%) versus the northern (0 %, p=0.001), western (11.8%, p=0.012), and central regions (17.4%, p=0.001). Conclusion: This is the first study of the detection of single-nucleotide polymorphisms in codon 200 of the β-tubulin isotype 1 gene of H. contortus from goats in Thailand. These findings are essential and imply that an integrated approach is needed for issues such as drug treatment, farm management, prevention, and control strategies. This is of interest to farmers, veterinarians, and the department of livestock.

The Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) manifests as impaired executive control, linguistic processing, visual spatial function, and affect regulation. The CCAS has been described in the spinocerebellar ataxias (SCAs), but its prevalence is unknown. We analyzed results of the CCAS/Schmahmann Scale (CCAS-S), developed to detect and quantify CCAS, in two natural history studies of 309 individuals Symptomatic for SCA1, SCA2, SCA3, SCA6, SCA7, or SCA8, 26 individuals Pre-symptomatic for SCA1 or SCA3, and 37 Controls. We compared total raw scores, domain scores, and total fail scores between Symptomatic, Pre-symptomatic, and Control cohorts, and between SCA types. We calculated scale sensitivity and selectivity based on CCAS category designation among Symptomatic individuals and Controls, and correlated CCAS-S performance against age and education, and in Symptomatic patients, against genetic repeat length, onset age, disease duration, motor ataxia, depression, and fatigue. Definite CCAS was identified in 46% of the Symptomatic group. False positive rate among Controls was 5.4%. Symptomatic individuals had poorer global CCAS-S performance than Controls, accounting for age and education. The domains of semantic fluency, phonemic fluency, and category switching that tap executive function and linguistic processing consistently separated Symptomatic individuals from Controls. CCAS-S scores correlated most closely with motor ataxia. Controls were similar to Pre-symptomatic individuals whose nearness to symptom onset was unknown. The use of the CCAS-S identifies a high CCAS prevalence in a large cohort of SCA patients, underscoring the utility of the scale and the notion that the CCAS is the third cornerstone of clinical ataxiology.

In southern Thailand, the increasingly growing population of stray dogs is a concern to public health and environmental safety because of the lack of medical attention and control. More importantly, these animals are considered reservoirs for many zoonotic pathogens. The objective of this study was to molecularly detect canine vector-borne pathogens, and to perform genetic characterization of Babesia gibsoni present in stray dogs from southern Thailand. Blood samples were collected from 174 stray dogs in two provinces (Songkhla and Narathiwat) in southern Thailand. PCR analyses were executed using specific primers based on the Babesia spp. 18S rRNA gene, Babesia gibsoni Internal transcribed spacer 1 (ITS1) region, Ehrlichia canis citrate synthase (gltA) gene, Hepatozoon spp. 18S rRNA gene and Anaplasma platys heat shock protein (groEL) gene. The most common canine vector-borne pathogen found infecting stray dogs in this study was Hepatozoon canis (24.7%) followed by A. platys (14.9%), Babesia vogeli (8.0%), B. gibsoni (6.3%), and E. canis (1.72%). Concurrent infection with more than one pathogen occurred in 72 cases. Phylogenetic analysis based on the ITS1 region and 18S rRNA gene revealed that the B. gibsoni isolates from this study shared a large proportion of their identities with each other and with other reported B. gibsoni genotypes from Asia. This study highlights the molecular detection of B. gibsoni in dogs in Thailand for the first time and presents the genetic characterization by sequencing the ITS1 region and 18S rRNA gene of B. gibsoni from Thailand. Follow-up studies are needed to elucidate the origin, distribution, and vectors of B. gibsoni parasites circulating in dogs in Thailand, as well as to determine to what extent dogs are important reservoir hosts for zoonotic canine vector-borne disease infection in the studied area.

Abstract Background The food environment has been implicated as an underlying contributor to the global obesity epidemic. However, few studies have evaluated the relationship between the food environment, dietary intake, and overweight/obesity in low- and middle-income countries (LMICs). The aim of this study was to assess the association of full service and fast food restaurant density with dietary intake and overweight/obesity in Delhi, India. Methods Data are from a cross-sectional, population-based study conducted in Delhi. Using multilevel cluster random sampling, 5364 participants were selected from 134 census enumeration blocks (CEBs). Geographic information system data were available for 131 CEBs (n = 5264) from a field survey conducted using hand-held global positioning system devices. The number of full service and fast food restaurants within a 1-km buffer of CEBs was recorded by trained staff using ArcGIS software, and participants were assigned to tertiles of full service and fast food restaurant density based on their resident CEB. Height and weight were measured using standardized procedures and overweight/obesity was defined as a BMI ≥25 kg/m2. Results The most common full service and fast food restaurants were Indian savory restaurants (57.2%) and Indian sweet shops (25.8%). Only 14.1% of full service and fast food restaurants were Western style. After adjustment for age, household income, education, and tobacco and alcohol use, participants in the highest tertile of full service and fast food restaurant density were less likely to consume fruit and more likely to consume refined grains compared to participants in the lowest tertile (both p

Purpose: With the rapid advancement of generative artificial intelligence (AI), it is important to consider how young people are making sense of these tools in their everyday lives. Drawing on critical postdigital approaches to learning and literacy, this study aims to center the experiences and perspectives of young people who encounter and experiment with generative AI in their daily writing practices. Design/methodology/approach: This critical case study of one digital platform -- Character.ai -- brings together an adolescent and adult authorship team to inquire about the intertwining of young people's playful and critical perspectives when writing on/with digital platforms. Drawing on critical walkthrough methodology (Light et al., 2018), the authors engage digital methods to study how the creative and "fun" uses of AI in youths' writing lives are situated in broader platform ecologies. Findings: The findings suggest experimentation and pleasure are key aspects of young people's engagement with generative AI. The authors demonstrate how one platform works to capitalize on these dimensions, even as youth users engage critically and artfully with the platform and develop their digital writing practices. Practical implications: This study highlights how playful experimentation with generative AI can engage young people both in pleasurable digital writing and in exploration and contemplation of platforms dynamics and structures that shape their and others' literate activities. Educators can consider young people's creative uses of these evolving technologies as potential opportunities to develop a critical awareness of how commercial platforms seek to benefit from their users. Originality/value: This study contributes to the development of a critical and humanist research agenda around generative AI by centering the experiences, perspectives and practices of young people who are underrepresented in the burgeoning research devoted to AI and literacies.

Spinocerebellar ataxias (SCAs) are progressive neurodegenerative disorders, but there is no metric that predicts disease severity over time. We hypothesized that by developing a new metric, the Severity Factor (S-Factor) using immutable disease parameters, it would be possible to capture disease severity independent of clinical rating scales. Extracting data from the CRC-SCA and READISCA natural history studies, we calculated the S-Factor for 438 participants with symptomatic SCA1, SCA2, SCA3, or SCA6, as follows: ((length of CAG repeat expansion - maximum normal repeat length) /maximum normal repeat length) × (current age - age at disease onset) × 10). Within each SCA type, the S-Factor at the first Scale for the Assessment and Rating of Ataxia (SARA) visit (baseline) was correlated against scores on SARA and other motor and cognitive assessments. In 281 participants with longitudinal data, the slope of the S-Factor over time was correlated against slopes of scores on SARA and other motor rating scales. At baseline, the S-Factor showed moderate-to-strong correlations with SARA and other motor rating scales at the group level, but not with cognitive performance. Longitudinally the S-Factor slope showed no consistent association with the slope of performance on motor scales. Approximately 30% of SARA slopes reflected a trend of non-progression in motor symptoms. The S-Factor is an observer-independent metric of disease burden in SCAs. It may be useful at the group level to compare cohorts at baseline in clinical studies. Derivation and examination of the S-factor highlighted challenges in the use of clinical rating scales in this population.

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BackgroundMany loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance.MethodsWe carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy.ResultsWe found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10-8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34; P = 1.47 × 10-8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro.ConclusionsThe locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association.ImpactThis finding provides insight into genetic markers associated with EOC outcome and potential treatment options.See related commentary by Peres and Monteiro, p. 1604.

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10-6). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.

PurposeThe known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes.MethodsWe sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics.ResultsThe ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive.ConclusionsWe have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.

Abstract: Accumulating evidence suggests a relationship between endometrial cancer and epithelial ovarian cancer. For example, endometrial cancer and epithelial ovarian cancer share epidemiological risk factors and molecular features observed across histotypes are held in common (e.g. serous, endometrioid and clear cell). Independent genome-wide association studies (GWAS) for endometrial cancer and epithelial ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. Using GWAS summary statistics, we explored the shared genetic etiology between endometrial cancer and epithelial ovarian cancer. Genetic correlation analysis using LD Score regression revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e. inverse-variance meta-analysis, co-localization, and M-values), and performed analyses by stratified by subtype. We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10−9). In addition, four novel regions at 7p22.2, 7q22.1, 9p12 and 11q13.3 were identified at a sub-genome wide threshold (P < 5 × 10−7). Integration with promoter-associated HiChIP chromatin loops from immortalized endometrium and epithelial ovarian cell lines, and expression quantitative trait loci (eQTL) data highlighted candidate target genes for further investigation.

Abstract: Purpose: The known EOC susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. Methods: We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases verses controls were further examined in an independent set of 14,146 EOC cases and 28,661 controls from the ovarian cancer association consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. Results: The odds ratios (OR) associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 – 5.68; P = 0.00068), 1.99 for POLK (95% CI 1.15 – 3.43; P = 0.014), and 4.07 for SLX4 (95% CI 1.34-12.4; P = 0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 −1.00, P=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. Conclusions: We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

Researchers have demonstrated mixed associations between acculturative stress and prosocial behaviors (actions intended to benefit others) among Latino/a adolescents and emerging adults. The current study aimed to examine the relations between acculturative stress and Latino/a young adults' prosocial behaviors via familism values and emotion reappraisal. Participants were 1,527 Latino/a college students (M age = 20.35 years, SD = 3.88; 75.2% women) from universities across the United States. The results demonstrated direct and indirect links between acculturative stress and prosocial behaviors. Specifically, acculturative stress was positively related to familism values, which in turn were positively associated with multiple forms of prosocial behaviors. Additionally, emotion reappraisal was positively associated with specific forms of prosocial behaviors. There was also evidence that familism and emotion reappraisals moderated the associations between acculturative stress and specific forms of prosocial behaviors. Discussion focuses on the interplay of culture-related and emotion-regulation processes associated with Latino/a young adults' positive social outcomes.

Nearly one-third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop a psychotic disorder during life, most of them by early adulthood. Importantly, a full-blown psychotic episode is usually preceded by subthreshold symptoms. In the current study, 760 participants (aged 6-55 years) with a confirmed hemizygous 22q11.2 microdeletion have been recruited through 10 medical sites worldwide, as part of an international research consortium. Of them, 692 were nonpsychotic and with complete measurement data. Subthreshold psychotic symptoms were assessed using the Structured Interview for Prodromal Syndromes (SIPS). Nearly one-third of participants met criteria for positive subthreshold psychotic symptoms (32.8%), less than 1% qualified for acute positive subthreshold symptoms, and almost a quarter met criteria for negative/disorganized subthreshold symptoms (21.7%). Adolescents and young adults (13-25 years) showed the highest rates of subthreshold psychotic symptoms. Additionally, higher rates of anxiety disorders and attention deficit/hyperactivity disorder (ADHD) were found among the study participants with subthreshold psychotic symptoms compared to those without. Full-scale IQ, verbal IQ, and global functioning (GAF) scores were negatively associated with participants' subthreshold psychotic symptoms. This study represents the most comprehensive analysis reported to date on subthreshold psychosis in 22q11.2DS. Novel findings include age-related changes in subthreshold psychotic symptoms and evidence that cognitive deficits are associated with subthreshold psychosis in this population. Future studies should longitudinally follow these symptoms to detect whether and how early identification and treatment of these manifestations can improve long-term outcomes in those that eventually develop a psychotic disorder.

BackgroundThe programmed death-1/programmed death-ligand-1 (PD-1/PD-L1) immune regulatory axis has emerged as a promising new target for cancer therapeutics, with lasting responses seen in the treatment of metastatic renal and lung carcinomas, as well as melanomas. As tumor surface expression of PD-L1 has been found to correlate with objective responses to anti-PD-L1 immunotherapies, we investigated the expression of PD-L1 in human cervical tumors and provide an adopted scoring system for the systematic evaluation of PD-L1 staining.MethodsImmunohistochemical staining for PD-L1 expression was performed on a tissue microarray of 101 normal and neoplastic cervical tissues. Neoplastic cores were divided into three groups: squamous cell carcinoma, adenosquamous carcinoma, and endocervical adenocarcinoma. PD-L1 expression was scored based on an adopted scoring system accounting to percentage and intensity of positivity, and results provided alongside available clinical and demographic data.ResultsOverall, PD-L1 was positive in 32 of 93 (34.4%) cervical carcinomas. Subcategorically, PD-L1 was positive in 28 of 74 (37.8%) squamous cell carcinomas, two of seven (28.6%) adenosquamous carcinomas, and two of 12 (16.7%) endocervical adenocarcinomas. It was negative in six benign cervical tissues.ConclusionsThis study shows a significant expression of PD-L1 in 34.4% of cervical carcinomas and no expression of PD-L1 in benign cervical tissues. These findings suggest a role for further investigation of anti-PD-L1/PD-1 immunotherapies in the treatment of PD-L1-positive cervical tumors. In addition, our adopted scoring system will facilitate more systematic correlations between tumor reactivity and response to treatment.

Opisthorchis viverrini is a major public health concern in Southeast Asia. Various reports have suggested that this parasite may represent a species complex, with genetic structure in the region perhaps being dictated by geographical factors and different species of intermediate hosts. We used four microsatellite loci to analyze O. viverrini adult worms originating from six species of cyprinid fish in Thailand and Lao PDR. Two distinct O. viverrini populations were observed. In Ban Phai, Thailand, only one subgroup occurred, hosted by two different fish species. Both subgroups occurred in fish from That Luang, Lao PDR, but were represented to very different degrees among the fish hosts there. Our data suggest that, although geographical separation is more important than fish host specificity in influencing genetic structure, it is possible that two species of Opisthorchis, with little interbreeding, are present near Vientiane in Lao PDR.

Endosomal sorting complexes required for transport III (ESCRT-III) proteins have been implicated in sealing the nuclear envelope in mammals, spindle pole body dynamics in fission yeast, and surveillance of defective nuclear pore complexes in budding yeast. Here, we report that Lem2p (LEM2), a member of the LEM (Lap2-Emerin-Man1) family of inner nuclear membrane proteins, and the ESCRT-II/ESCRT-III hybrid protein Cmp7p (CHMP7), work together to recruit additional ESCRT-III proteins to holes in the nuclear membrane. In Schizosaccharomyces pombe, deletion of the ATPase vps4 leads to severe defects in nuclear morphology and integrity. These phenotypes are suppressed by loss-of-function mutations that arise spontaneously in lem2 or cmp7, implying that these proteins may function upstream in the same pathway. Building on these genetic interactions, we explored the role of LEM2 during nuclear envelope reformation in human cells. We found that CHMP7 and LEM2 enrich at the same region of the chromatin disk periphery during this window of cell division and that CHMP7 can bind directly to the C-terminal domain of LEM2 in vitro. We further found that, during nuclear envelope formation, recruitment of the ESCRT factors CHMP7, CHMP2A, and IST1/CHMP8 all depend on LEM2 in human cells. We conclude that Lem2p/LEM2 is a conserved nuclear site-specific adaptor that recruits Cmp7p/CHMP7 and downstream ESCRT factors to the nuclear envelope.