ELAPOR1 induces the classical/progenitor subtype and contributes to reduced disease aggressiveness through metabolic reprogramming in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with distinct molecular subtypes described as classical/progenitor and basal-like/squamous PDAC. We hypothesized that integrative transcriptome and metabolome approaches can identify candidate genes whose inactivation contributes to the development of the aggressive basal-like/squamous subtype. Using our integrated approach, we identified endosome-lysosome associated apoptosis and autophagy regulator 1 (ELAPOR1/KIAA1324) as a candidate tumor suppressor in both our NCI-UMD-German cohort and additional validation cohorts. Diminished ELAPOR1 expression was linked to high histological grade, advanced disease stage, the basal-like/squamous subtype, and reduced patient survival in PDAC. In vitro experiments demonstrated that ELAPOR1 transgene expression not only inhibited the migration and invasion of PDAC cells but also induced gene expression characteristics associated with the classical/progenitor subtype. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program associated with both upregulated ELAPOR1 and the classical/progenitor subtype, encompassing upregulated lipogenesis and downregulated amino acid metabolism. 1-Methylnicotinamide, a known oncometabolite derived from S-adenosylmethionine, was inversely associated with ELAPOR1 expression and promoted migration and invasion of PDAC cells in vitro. Taken together, our data suggest that enhanced ELAPOR1 expression promotes transcriptome and metabolome characteristics that are indicative of the classical/progenitor subtype, whereas its reduction associates with basal-like/squamous tumors with increased disease aggressiveness in PDAC patients. These findings position ELAPOR1 as a promising candidate for diagnostic and therapeutic targeting in PDAC.

MIF/NR3C2 Axis Regulates Glucose Metabolism Reprogramming in Pancreatic Cancer through MAPK-ERK and AP-1 Pathways.

Inflammation and aberrant cellular metabolism are widely recognized as hallmarks of cancer. In pancreatic ductal adenocarcinoma (PDAC), inflammatory signaling and metabolic reprogramming are tightly interwoven, playing pivotal roles in the pathogenesis and progression of the disease. However, the regulatory functions of inflammatory mediators in metabolic reprogramming in pancreatic cancer have not been fully explored. Earlier, we demonstrated that pro-inflammatory mediator macrophage migration inhibitory factor (MIF) enhances disease progression by inhibiting its downstream transcriptional factor nuclear receptor subfamily 3 group C member 2 (NR3C2). Here, we provide evidence that MIF and NR3C2 interactively regulate metabolic reprogramming, resulting in MIF-induced cancer growth and progression in PDAC. MIF positively correlates with the HK1 (hexokinase 1), HK2 (hexokinase 2), and LDHA (lactate dehydrogenase) expression and increased pyruvate and lactate production in PDAC patients. Additionally, MIF augments glucose uptake and lactate efflux by upregulating HK1, HK2 and LDHA expression in pancreatic cancer cells in vitro and in mouse models of PDAC. Conversely, a reduction in HK1, HK2, LDHA expression is observed in tumors with high NR3C2 expression in PDAC patients. NR3C2 suppresses HK1, HK2, and LDHA expression, thereby inhibiting glucose uptake and lactate efflux in pancreatic cancer. Mechanistically, MIF-mediated regulation of glycolytic metabolism involves the activation of MAPK-ERK signaling pathway, whereas NR3C2 interacts with the activator protein 1 (AP-1) to regulate glycolysis. Our findings reveal an interactive role of the MIF/NR3C2 axis in regulating glucose metabolism supporting tumor growth and progression and may be a potential target for designing novel approaches for improving disease outcome.

Changes in Use of Hepatitis C Direct-Acting Antivirals After Access Restrictions Were Eased by State Medicaid Programs.

Importance: Direct-acting antivirals (DAAs) are safe and highly effective for curing hepatitis C virus (HCV) infection, but their high cost led certain state Medicaid programs to impose coverage restrictions. Since 2015, many of these restrictions have been lifted voluntarily in response to advocacy or because of litigation. Objective: To estimate how the prescribing of DAAs to Medicaid patients changed after states eased access restrictions. Design, Setting, and Participants: This modified difference-in-differences analysis of 39 state Medicaid programs included Medicaid beneficiaries who were prescribed a DAA from January 1, 2015, to December 31, 2019. DAA coverage restrictions were measured based on a series of cross-sectional assessments performed from 2014 through 2022 by the US National Viral Hepatitis Roundtable and the Center for Health Law and Policy Innovation. Exposure: Calendar quarter when states eased or eliminated 3 types of DAA coverage restrictions: limiting treatment to patients with severe liver disease, restricting use among patients with active substance use, and requiring prescriptions to be written by or in consultation with specialists. States with none of these restrictions at baseline were excluded. Main Outcomes and Measures: Quarterly number of HCV DAA treatment courses per 100 000 Medicaid beneficiaries. Results: Of 39 states, 7 (18%) eliminated coverage restrictions, 25 (64%) eased restrictions, and 7 (18%) maintained the same restrictions from 2015 to 2019. During this period, the average quarterly use of DAAs increased from 669 to 3601 treatment courses per 100 000 Medicaid beneficiaries. After states eased or eliminated restrictions, the use of DAAs increased by 966 (95% CI, 409-1523) treatment courses per 100 000 Medicaid beneficiaries each quarter compared with states that did not ease or eliminate restrictions. Conclusions and Relevance: The results of this study suggest that there was greater use of DAAs after states relaxed coverage restrictions related to liver disease severity, sobriety, or prescriber specialty. Further reductions or elimination of these rules may improve access to a highly effective public health intervention for patients with HCV.

Availability and Cost of Expensive and Common Generic Prescription Drugs: A Cross-sectional Analysis of Direct-to-Consumer Pharmacies.

BACKGROUND: Direct-to-consumer (DTC) pharmacies sell generic prescription drugs, often at lower prices than traditional retail pharmacies; however, not all drugs are available, and prices vary. OBJECTIVE: To determine the availability and cost of generic drugs at DTC pharmacies. DESIGN: Cross-sectional study. SETTING: Five national DTC pharmacies in April and May 2023. PARTICIPANTS: Each qualifying form of 100 generic drugs with the highest cost-per-patient (expensive) and the 50 generic drugs with the highest number of patients (common) in Medicare Part D in 2020 MAIN MEASURES: Availability of these drugs and the lowest DTC pharmacy price for a standardized drug strength and supply (e.g., 30 pills), compared to GoodRx retail pharmacy prices. KEY RESULTS: Of the 118 expensive generic dosage forms, 94 (80%) were available at 1 or more DTC pharmacies; out of 52 common generic dosage forms, 51 (98%) were available (p < 0.001). Of the 88 expensive generics available in comparable quantities and strengths across pharmacies, 42 (47%) had the lowest cost at Amazon, 23 (26%) at Mark Cuban Cost Plus Drug Company, 13 (14%) at Health Warehouse, and 12 (13%) at Costco; for 51 common generic formulations, 16 (31%) had the lowest cost at Costco, 14 (27%) at Amazon, 10 (20%) at Walmart, 6 (12%) at Health Warehouse, and 5 (10%) at Mark Cuban Cost Plus Drug Company. For the 77 expensive generics with available GoodRx retail pharmacy prices, the median cost savings at DTC pharmacies were $231 (95% CI, $129-$792) or 76% (IQR, 53-91%); for 51 common generics, savings were $19 (95% CI, $10-$34) or 75% (IQR, 67-83%). CONCLUSIONS: Many of the most expensive generic drugs are unavailable at direct-to-consumer pharmacies. Meanwhile, less expensive, commonly used generics are widely available, but drug prices vary by pharmacy and savings are modest, requiring patients to shop around for the lowest cost.

LMO3 is a suppressor of the basal-like/squamous subtype and reduces disease aggressiveness of pancreatic cancer through glycerol 3-phosphate metabolism.

Pancreatic ductal adenocarcinoma (PDAC) encompasses diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, each exhibiting distinct characteristics, with the latter known for its aggressiveness. We employed an integrative approach combining transcriptome and metabolome analyses to pinpoint potential genes contributing to the basal-like/squamous subtype differentiation. Applying this approach to our NCI-UMD-German and a validation cohort, we identified LIM Domain Only 3 (LMO3), a transcription co-factor, as a candidate suppressor of the basal-like/squamous subtype. Reduced LMO3 expression was significantly associated with higher pathological grade, advanced disease stage, induction of the basal-like/squamous subtype, and decreased survival among PDAC patients. In vitro experiments demonstrated that LMO3 transgene expression inhibited PDAC cell proliferation and migration/invasion, concurrently downregulating the basal-like/squamous gene signature. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program linked to elevated LMO3 and the classical/progenitor subtype, characterized by enhanced lipogenesis and suppressed amino acid metabolism. Notably, glycerol 3-phosphate (G3P) levels positively correlated with LMO3 expression and associated with improved patient survival. Furthermore, glycerol-3-phosphate dehydrogenase 1 (GPD1), a crucial enzyme in G3P synthesis, showed upregulation in LMO3-high and classical/progenitor PDAC, suggesting its potential role in mitigating disease aggressiveness. Collectively, our findings suggest that heightened LMO3 expression reduces transcriptome and metabolome characteristics indicative of basal-like/squamous tumors with decreased disease aggressiveness in PDAC patients. The observations describe LMO3 as a candidate for diagnostic and therapeutic targeting in PDAC.

Dairy farmers' knowledge, awareness and practices regarding bovine lameness in Malaysian dairy farms.

Given the data paucity on dairy farmers' perspectives regarding bovine lameness and hoof diseases, particularly in South East Asian countries, this study was conducted to assess the knowledge, attitude and practices toward lameness and hoof health among dairy cattle farmers in Malaysia. An online-based and face-to-face survey was conducted among 114 dairy farmers from four states in Peninsular Malaysia. Data were analysed using descriptive statistics, principal component analysis and an independent sample t-test. Overall, farmers demonstrated satisfactory knowledge and attitude regarding lameness and its impact on dairy cattle welfare and production. Lameness was ranked the second most important health issue in dairy farms after mastitis. Notably, 90% reported the presence of at least one lame cow on their farms, and 55% stated lameness as the reason for culling their cows. While sole ulcer was the hoof lesion mostly identified by farmers, 75% of them underestimated lameness prevalence on their farms and rarely implemented management strategies such as preventive hoof trimming and footbath. Farmers' educational qualification influenced their understanding of the impact of lameness on dairy cattle production. Despite reflecting satisfactory knowledge and attitude towards lameness in dairy cows, farmers in this study need to improve their current management practices to address lameness problem in their herds. Educating farmers on the importance of early detection and prompt treatment, and preventive measures are crucial for lameness control and improving hoof health in these dairy farms.

A Rare Case of Traumatic Colonic Intramural Hematoma in Saudi Arabia.

Colonic intramural hematomas are rarely encountered clinically. They are most commonly caused by blunt trauma to the abdomen. Diagnosis is usually reached by a combination of a detailed history, physical examination, and radiological investigations. A 14-year-old female patient presented to the emergency department complaining of abdominal pain with a history of a go-karting accident. Upon physical examination, the patient was tachycardic and hypertensive, with right-side abdominal tenderness and fullness. After going through routine radiological investigations, a computed tomography scan showed a large intramural hematoma of the ascending colon measuring around 7.7 x 8.4 x 2 cm. The patient was admitted for conservative management. Throughout her admission, serial examinations were performed, which showed improvement in the patient's condition and the size of the hematoma. The patient was discharged in a stable condition after showing good recovery. Following up with the patient a month later, she was in good condition with no active complaints, and an ultrasound was done that revealed complete resolution. To our understanding, this report of colonic intramural hematoma caused by the unusual etiology of the go-karting accident, which was successfully managed conservatively, adds significantly to the literature.

Retraction: Epiploic Appendagitis Clinically Masquerading as an Acute Diverticulitis.

[This retracts the article DOI: 10.7759/cureus.20188.].

Association between changes in prices and out-of-pocket costs for brand-name clinician-administered drugs.

OBJECTIVE: To determine whether annual changes in prices for clinician-administered drugs are associated with changes in patient out-of-pocket costs. DATA SOURCES AND STUDY SETTING: National commercial claims database, 2009 to 2018. STUDY DESIGN: In a serial, cross-sectional study, we calculated the annual percent change in manufacturer list prices and net prices after rebates. We used two-part generalized linear models to assess the relationship between annual changes in price with (1) the percentage of individuals incurring any out-of-pocket costs and (2) the percent change in median non-zero out-of-pocket costs. DATA COLLECTION/EXTRACTION METHODS: We created annual cohorts of privately insured individuals who used one of 52 brand-name clinician-administered drugs. PRINCIPAL FINDINGS: List prices increased 4.4%/yr (interquartile range [IQR], 1.1% to 6.0%) and net prices 3.3%/yr (IQR, 0.3% to 5.5%). The median percentage of patients with any out-of-pocket costs increased from 38% in 2009 to 48% in 2018, and median non-zero annual out-of-pocket costs increased by 9.6%/yr (IQR, 4.1% to 15.4%). There was no association between changes in prices and out-of-pocket costs for individual drugs. CONCLUSIONS: From 2009 to 2018, prices and out-of-pocket costs for brand-name clinician-administered drugs increased, but these were not directly related for individual drugs. This may be due to changes to insurance benefit design and private insurer drug reimbursement rates.

Erdafitinib in BCG-treated high-risk non-muscle-invasive bladder cancer.

BACKGROUND: Treatment options are limited for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) with disease recurrence after bacillus Calmette-Guérin (BCG) treatment and who are ineligible for/refuse radical cystectomy. FGFR alterations are commonly detected in NMIBC. We evaluated the activity of oral erdafitinib, a selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, versus intravesical chemotherapy in patients with high-risk NMIBC and select FGFR3/2 alterations following recurrence after BCG treatment. PATIENTS AND METHODS: Patients aged ≥18 years with recurrent, BCG-treated, papillary-only high-risk NMIBC (high-grade Ta/T1) and select FGFR alterations refusing or ineligible for radical cystectomy were randomized to 6 mg daily oral erdafitinib or investigator's choice of intravesical chemotherapy (mitomycin C or gemcitabine). The primary endpoint was recurrence-free survival (RFS). The key secondary endpoint was safety. RESULTS: Study enrollment was discontinued due to slow accrual. Seventy-three patients were randomized 2 : 1 to erdafitinib (n = 49) and chemotherapy (n = 24). Median follow-up for RFS was 13.4 months for both groups. Median RFS was not reached for erdafitinib [95% confidence interval (CI) 16.9 months-not estimable] and was 11.6 months (95% CI 6.4-20.1 months) for chemotherapy, with an estimated hazard ratio of 0.28 (95% CI 0.1-0.6; nominal P value = 0.0008). In this population, safety results were generally consistent with known profiles for erdafitinib and chemotherapy. CONCLUSIONS: Erdafitinib prolonged RFS compared with intravesical chemotherapy in patients with papillary-only, high-risk NMIBC harboring FGFR alterations who had disease recurrence after BCG therapy and refused or were ineligible for radical cystectomy.

Identifying therapeutic alternatives in Medicare drug price negotiation: The case of etanercept.

As the Centers for Medicare & Medicaid Services (CMS) navigates the process of negotiating drug prices, it plans to compare the cost, safety, and effectiveness of each drug with its therapeutic alternatives. How CMS selects therapeutic alternatives is a consequential decision, and there remains uncertainty about their methodology. To understand the challenges CMS will face in selecting therapeutic alternatives, we developed a methodology that leverages clinical guidelines by US medical professional associations to identify potential therapeutic alternatives for etanercept, one of the first 10 drugs selected for Medicare price negotiation. For each of etanercept's 5 US Food and Drug Administration-approved indications, we identified all drugs with the same mechanism of action as etanercept and considered drugs with different mechanisms if they were recommended in place of etanercept at the same treatment stage, or if there was no strong comparative safety or effectiveness evidence that the drug differed from etanercept. We identified 22 potential therapeutic alternatives to etanercept, including 4 drugs with the same mechanism, 10 biologics with different mechanisms, and 8 small-molecule drugs. We faced several challenges in selecting therapeutic alternatives using clinical guidelines, such as how to reconcile strong recommendations that were based on weak evidence and how to consider combination therapies. This exercise demonstrates the complex considerations that CMS will face as it negotiates drug prices based on therapies' cost, safety, and effectiveness relative to therapeutic alternatives.

Effects of Se nanoparticles supplementation on growth performance, hematological parameters and nutrient digestibility of Labeo rohita fingerling fed sunflower meal based diet / Efeitos da suplementação de nanopartículas de Se no desempenho de crescimento, parâmetros hematológicos e digestibilidade de nutrientes da dieta baseada em farinha de girassol alimentada com alevinos de Labeo rohita

Abstract The aim of the present study is to assess the effects of selenium nanoparticles on the growth, hematology and nutrients digestibility of Labeorohita fingerlings. Fingerlings were fed with seven isocaloric sunflower meal-based diet supplemented with different concentrations of nanoparticles naming T1 to T7 (0, 0.5, 1, 1.5, 2, 2.5, and 3 mg/kg), with 5% wet body weight while chromic oxide was used as an indigestible marker. After experimentation for 90 days T3 treated group (1mg/kg -1Se-nano level) showed the best result in hematological parameters (WBC's 7.97 ×103mm-3, RBC's 2.98 ×106 mm-3 and Platelet count 67), nutrient digestibility (crude protein: 74%, ether extract: 76%, gross energy: 70%) and growth performance (weight gain 13.24 g, weight gain% 198, feed conversion ratio 1.5, survival rate 100%) as compared to the other treatment groups. Specific growth rates were found significantly higher in T5 than in other groups. The present study indicated positive effect of 1 mg/kg Se-nanoparticles on growth advancement, hematological parameters, and nutrients digestibility of L. rohita fingerlings.

Resumo O objetivo do presente estudo é avaliar os efeitos das nanopartículas de selênio no crescimento, hematologia e digestibilidade dos nutrientes de alevinos de Labeo rohita. Os alevinos foram alimentados com sete dietas isocalóricas à base de farinha de girassol suplementada com diferentes concentrações de nanopartículas, nomeando T1 a T7 (0, 0,5, 1, 1,5, 2, 2,5 e 3 mg / kg), com 5% do peso corporal úmido enquanto o óxido crômico foi usado como um marcador indigesto. Após a experimentação por 90 dias, o grupo tratado com T3 (nível 1mg / kg -1Se-nano) mostrou o melhor resultado em parâmetros hematológicos (WBC's 7,97 × 103mm-3, RBC's 2,98 × 106mm-3 e contagem de plaquetas 67), digestibilidade dos nutrientes (proteína bruta: 74%, extrato de éter: 76%, energia bruta: 70%) e desempenho de crescimento (ganho de peso 13,24 g, ganho de peso % 198, taxa de conversão alimentar 1,5, taxa de sobrevivência 100%) em comparação com os outros grupos de tratamento. As taxas de crescimento específicas foram encontradas significativamente mais altas em T5 do que em outros grupos. O presente estudo indicou efeito positivo de 1 mg / kg de nanopartículas de Se no avanço do crescimento, parâmetros hematológicos e digestibilidade de nutrientes de alevinos de L. rohita.

Effect of biosal®, deltamethrin and lambda-cyhalothrin on the activity of GOT, GPT and total protein contents in two fodder pests Hermolaus modestus and Hermolaus ocimumi / Efeito do biosal®, deltametrina e lambda-cialotrina na atividade do GOT, GPT e conteúdo de proteína total em duas pragas forrageiras Hermolaus modestus e Hermolaus ocimumi

Abstract The assessment of the comparative effect of biosal (phytopesticide), deltamethrin, and lambda-cyhalothrin (pyrethroids) were made against two fodder pests, Hermolaus modestus and Hermolaus ocimumi by filter paper impregnation method. The activity of total protein contents, GPT (glutamic-pyruvic transaminase) and GOT (glutamic oxaloacetate transaminase) were affected in Hermolaus modestus and Hermolaus ocimumi against biosal, deltamethrin, and lambda cyhalothrin. The activity of total protein contents in H. modestus was 31.053%, 4.607%, and 24.575%, against biosal, deltamethrin, and lambda-cyhalothrin, respectively. The activity of total protein contents was observed as 24.202%, 15.25%, and 56.036% against deltamethrin, lambda-cyhalothrin, and biosal, respectively in H. ocimumi. The activity of GOT was observed as 98.675% for biosal 33.95% for deltamethrin and 83.619% for lambda-cyhalothrin in H. modestus. The GOT activity was estimated in H. ocimumi as 78.831%, 47.645%, and 71.287% against biosal, deltamethrin, and lambda-cyhalothrin, respectively. The efficacy of GPT enzyme against biosal, deltamethrin, and lambda-cyhalothrin was calculated as 89.26%, 73.07%, and 47.58%, respectively in H. modestus. The H. ocimumi showed GPT activity as 77.58% for biosal, 68.84% for deltamethrin, and 52.67% for lambda-cyhalothrin, respectively.

Resumo A avaliação do efeito comparativo do biosal (fitopesticida), deltametrina e lambda-cialotrina (piretróides) foi feita contra duas pragas forrageiras, Hermolaus modestus e Hermolaus ocimumi, pelo método de impregnação com papel de filtro. A atividade do conteúdo de proteína total, GPT (transaminase glutâmico-pirúvica) e GOT (oxaloacetato transaminase glutâmico) foram afetados em Hermolaus modestus e Hermolaus ocimumi contra biosal, deltametrina e lambda cialotrina. A atividade do conteúdo de proteína total em H. modestus foi 31.053%, 4.607% e 24.575%, contra biosal, deltametrina e lambda-cialotrina, respectivamente. A atividade do conteúdo de proteína total foi observada como 24.202%, 15.25% e 56,036% contra deltametrina, lambda-cialotrina e biosal, respectivamente em H. ocimumi. A atividade do GOT foi observada em 98.675% para o biosal, 33,95% para a deltametrina e 83.619% para a lambda-cialotrina em H. modestus. A atividade do GOT foi estimada em H. ocimumi como 78.831%, 47.645% e 71.287% contra biosal, deltametrina e lambda-cialotrina, respectivamente. A eficácia da enzima GPT contra biosal, deltametrina e lambda-cialotrina foi calculada como 89.26%, 73.07% e 47.58%, respectivamente em H. modestus. A H. ocimumi apresentou atividade GPT de 77.58% para biosal, 68.84% para deltametrina e 52.67% para lambda-cialotrina, respectivamente.

Association of blood groups/Rh and diabetes mellitus in Karachi city, Pakistan / Associação de grupos sanguíneos/Rh e diabetes mellitus na cidade de Karchi, Paquistão

Abstract The main purpose of this study was to find out a possible association between ABO blood groups or Rh and diabetes mellitus (DM) in the local population of eight (8) different towns of Karachi, Pakistan. For this purpose a survey was carried out in Karachi to have a practical observation of these towns during the period of 9 months from June 2019 to Feb. 2020. Out of eighteen (18) towns of Karachi, samples (N= 584) were collected from only eight (8) Towns of Karachi and gave a code-number to each town. Diabetic group sample was (n1=432) & pre-diabetes sample was (n2 =152). A standard Abbot Company Glucometer for Random Blood Sugar (RBS) and Fasting Blood Sugar (FBS) tests, standard blood anti sera were used for ABO/Rh blood type. Health assessment techniques were performed ethically by taking informed consent from all registered subjects. Finally data was analyzed by SPSS version 20.0. In our current study, the comparison of ABO blood groups frequencies between diabetic and pre-diabetic individuals were carried out. The percentage values of blood Group-B as given as: (32% in DM vs. 31% in pre-diabetics), followed by blood Group-O as: (18% in DM vs. 11% in pre-diabetics). Contrary to Group-"B" & "O", blood Group-A and Group-AB were distribution percentage higher pre-diabetic as compared to DM patients, as given as: Group-A (32% in pre-diabetics vs. 26% in DM) & Group-AB (26% in pre-diabetics vs. 24% in diabetic's patients). In addition, percentage distribution of Rh system was also calculated, in which Rh+ve Group was high and more common in DM patients as compared to pre-diabetics; numerically given as: Rh+ve Group (80% in DM vs. 72% in pre-diabetics). Different views and dimensions of the research topic were studied through literature support, some have found no any association and some established a positive association still some were not clear in making a solid conclusion. It is concluded that DM has a positive correlation with ABO blood groups, and people with Group-B have increased susceptibility to DM disease.

Resumo O objetivo principal deste estudo foi descobrir uma possível associação entre grupos sanguíneos ABO ou Rh e diabetes mellitus (DM) na população local de oito (8) diferentes cidades de Karachi, Paquistão. Para tanto, foi realizado um levantamento em Karachi para observação prática dessas cidades durante o período de 9 meses de junho de 2019 a fevereiro de 2020.De dezoito (18) cidades de Karachi, as amostras (N = 584) foram coletadas de apenas oito (8) cidades de Karachi e deram um número-código para cada cidade. A amostra do grupo de diabéticos foi (n1 = 432) e a amostra de pré-diabetes foi (n2 = 152). Um glicômetro padrão da Abbot Company para testes de açúcar no sangue aleatório (RBS) e açúcar no sangue em jejum (FBS), antissoros de sangue padrão foram usados ​​para o tipo de sangue ABO / Rh. As técnicas de avaliação de saúde foram realizadas de forma ética, tomando o consentimento informado de todos os indivíduos registrados. Finalmente, os dados foram analisados ​​pelo SPSS versão 20.0.No presente estudo, foi realizada a comparação das frequências dos grupos sanguíneos ABO entre diabéticos e pré-diabéticos. Os valores percentuais do sangue do Grupo-B são dados como: (32% em DM vs. 31% em pré-diabéticos), seguido pelo sangue do Grupo-O como: (18% em DM vs. 11% em pré-diabéticos). Ao contrário dos Grupos "B" e "O", sangue do Grupo-A e Grupo-AB tiveram distribuição percentual maior de pré-diabéticos em comparação com pacientes com DM, dado como: Grupo-A (32% em pré-diabéticos vs. 26% em DM) e Grupo AB (26% em pré-diabéticos vs. 24% em pacientes diabéticos). Além disso, também foi calculada a distribuição percentual do sistema Rh, no qual o Grupo Rh + ve foi elevado e mais comum em pacientes com DM em comparação aos pré-diabéticos; dados numericamente como: Grupo Rh + ve (80% em DM vs. 72% em pré-diabéticos). Diferentes visões e dimensões do tema de pesquisa foram estudadas com o suporte da literatura, alguns não encontraram nenhuma associação e alguns estabeleceram uma associação positiva, embora alguns não estivessem claros em fazer uma conclusão sólida. Conclui-se que o DM tem correlação positiva com os grupos sanguíneos ABO, e as pessoas com o Grupo B têm maior suscetibilidade à doença DM.

Genomic characterization of Puccinia triticina using molecular marker technology / Caracterização genômica de Puccinia triticina usando tecnologia de marcadores moleculares

Leaf rust, caused by Puccinia triticina, is the most common rust disease of wheat. The fungus is an obligate parasite capable of producing infectious urediniospores. To study the genetic structure of the leaf rust population 20 RAPD primers were evaluated on 15 isolates samples collected in Pakistan. A total of 105 RAPD fragments were amplified with an average of 7 fragments per primer. The number of amplified fragments varied from 1 to 12. GL Decamer L-07 and GL Decamer L-01 amplified the highest number of bands (twelve) and primer GL Decamer A-03 amplified the lowest number of bands i.e one. Results showed that almost all investigated isolates were genetically different that confirms high genetic diversity within the leaf rust population. Rust spores can follow the migration pattern in short and long distances to neighbor areas. Results indicated that the greatest variability was revealed by 74.9% of genetic differentiation within leaf rust populations. These results suggested that each population was not completely identical and high gene flow has occurred among the leaf rust population of different areas. The highest differentiation and genetic distance among the Pakistani leaf rust populations were detected between the leaf rust population in NARC isolate (NARC-4) and AARI-11and the highest similarity was observed between NARC isolates (NARC-4) and (NARC-5). The present study showed the leaf rust population in Pakistan is highly dynamic and variable.

A ferrugem da folha, causada por Puccinia triticina, é a ferrugem mais comum do trigo. O fungo é um parasita obrigatório, capaz de produzir urediniósporos infecciosos. Para estudar a estrutura genética da população de ferrugem da folha, 20 primers RAPD foram avaliados em 15 amostras de isolados coletadas no Paquistão. Um total de 105 fragmentos RAPD foram amplificados com uma média de 7 fragmentos por primer. O número de fragmentos amplificados variou de 1 a 12. GL Decamer L-07 e GL Decamer L-01 amplificaram o maior número de bandas (doze), e o primer GL Decamer A-03 amplificou o menor número de bandas, ou seja, um. Os resultados mostraram que quase todos os isolados investigados eram geneticamente diferentes, o que confirma a alta diversidade genética na população de ferrugem da folha. Os esporos de ferrugem podem seguir o padrão de migração em distâncias curtas e longas para áreas vizinhas. Os resultados indicaram que a maior variabilidade foi revelada por 74,9% da diferenciação genética nas populações de ferrugem. Esses resultados sugeriram que cada população não era completamente idêntica e um alto fluxo gênico ocorreu entre a população de ferrugem da folha de diferentes áreas. A maior diferenciação e distância genética entre as populações de ferrugem da folha do Paquistão foram detectadas entre a população de ferrugem da folha no isolado NARC (NARC-4) e AARI-11 e a maior similaridade foi observada entre os isolados NARC (NARC-4) e (NARC-5). O presente estudo mostrou que a população de ferrugem da folha no Paquistão é altamente dinâmica e variável.

Trainee-Led Intervention to Motivate Resident Physician Voter Registration.

This quality improvement study describes a trainee-led intervention to improve resident physician voter registration for national elections.

Administrative action on drug pricing: Lessons and opportunities for the Center for Medicare and Medicaid Innovation.

BACKGROUND: In October 2022, the Biden administration issued an executive order to the Center for Medicare and Medicaid Innovation (CMMI) to develop new health care payment and delivery models to lower prescription drug costs and promote access to innovative therapies. In response, the agency proposed 3 novel drug payment models for testing. OBJECTIVE: To understand the impact that CMMI demonstration projects can have on the prescription drug market. METHODS: We examined each of the models listed on the CMMI website and searched the Federal Register and news articles for additional models that contained interventions related to patient out-of-pocket drug costs, Medicare drug spending, or Medicaid drug spending. We excluded models with indirect effects on drug costs (for example, bundled payments). We comprehensively reviewed all previous cases in which CMMI has attempted models addressing prescription drug costs and spending and evaluated the circumstances, impact, and lessons learned that may aid policymakers in the design and implementation of new models. RESULTS: We identified 9 CMMI models containing direct interventions related to drug costs. Among prior models addressing drug prices, nearly half (44%, 4/9) were not implemented because of their scope, voluntary nature, and procedural challenges. No implemented models met the CMMI standard for expansion, although key elements of the Senior Savings model limiting monthly insulin costs to $35 were later incorporated into the Inflation Reduction Act. CONCLUSIONS: In future CMMI implementation efforts, we suggest maximizing voluntary collaboration when selection bias concerns are minimal, using mandatory models when not, ensuring that the geographic scope is not overly ambitious, and adhering closely to statutory authority and established administrative procedure to minimize legal challenges and maximize model demonstration utility.

Effects of tumor derived exosomes on T cells markers expression / Efeitos de exossomos derivados de tumor na expressão de marcadores de células T

Exosomes are 30-120nm bio particles transferred from donor to recipient cells leading to modification in their regulatory mechanisms depending upon the coded message in the form of loaded biomolecule. Cancer cells derived exosomes the true representatives of the parent cells have been found to modify the tumor surrounding/distinct regions and participate in metastasis, angiogenesis and immune suppression. Tis study was aimed to study the effects of tumor mice derived exosomes on the normal mice spleen isolated T cells by using co-culture experiments and flow cytometer analysis. We mainly focused on some of the T cells population and cytokines including IFN-γ, FOXP3+ regulatory T (Treg) cells and KI67 (proliferation marker). Overall results indicated random changes in different set of experiments, where the cancer derived exosomes reduced the IFN-γ expression in both CD4 and CD8 T cells, similarly the Treg cells were also found decreased in the presence of cancer exosomes. No significant changes were observed on the Ki67 marker expression. Such studies are helpful in understanding the role of cancer exosomes in immune cells suppression in tumor microenvironment. Cancer exosomes will need to be validated in vivo and in vitro on a molecular scale in detail for clinical applications.

Os exossomos são biopartículas de 30-120 nm transferidas de células doadoras para células receptoras, levando à modificação em seus mecanismos reguladores, dependendo da mensagem codificada na forma de biomolécula carregada. Verificou-se que exossomos derivados de células cancerosas ­ os verdadeiros representantes das células-mãe ­ modificam as regiões circundantes / distintas do tumor e participam da metástase, angiogênese e imunossupressão. Este estudo teve como objetivo estudar os efeitos de exossomos derivados de camundongos com tumor nas células T isoladas de baço de camundongos normais, usando experimentos de cocultura e análise de citômetro de fluxo. Concentrou-se, principalmente, em algumas populações de células T e citocinas, incluindo IFN-γ, células T reguladoras FOXP3 + (Treg) e KI67 (marcador de proliferação). Os resultados gerais indicaram mudanças aleatórias em diferentes conjuntos de experimentos, em que os exossomos derivados de câncer reduziram a expressão de IFN-γ em células T CD4 e CD8, da mesma forma que as células Treg também foram encontradas diminuídas na presença de exossomos de câncer. Nenhuma mudança significativa foi observada na expressão do marcador Ki67. Esses dados são úteis para a compreensão do papel dos exossomos do câncer na supressão de células do sistema imunológico no microambiente tumoral. Exossomos de câncer precisarão ser validados in vivo e in vitro em escala molecular com detalhes para aplicações clínicas.

Evaluation of different Starch Binders on physical quality of fish feed pellets / Avaliação de diferentes aglutinantes de amido na qualidade física de rações para peixes

Binders are the products that are used to bind, glue or hold the various feed ingredients together in order to maintain pellet integrity. For aqua-culturists, feed manufacturing is an expensive exercise due to the high cost of ingredients along with traditional artificial binders. The use of grain starches as aqua feed binders have advantages which include availability of that binder, nutritional contribution, and minimization of feed cost. A research trial was conducted to test physical properties such as palatability, water stability, dustiness, friability, settling velocity and floatation time of locally available starch i.e. wheat gluten, pea starch and guar gum and to assist their incorporation in on-farm aqua feed. Results revealed that among these three starch, the starch from pea source was proved superior over other two (wheat gluten and guar gum) as all physical quality parameters (dustiness, water stability and friability) revealed better performance of pea starch except pelletability in which guar gum performed best. Although not a single diet proved best in case of flotation time (Tf) and settling velocity (Vset) at varying lengths (6mm, 9mm and 12 mm). This finding indicates the significance of suitable binders for optimal water pollution and sustainable aquaculture. The use of these binders i.e. wheat gluten, pea starch and guar gum in fish feed pellets may also reduce dependence on synthetic binders and minimizes cost.

Aglutinantes são produtos usados para unir, colar ou manter juntos os vários ingredientes da ração, a fim de conservar a integridade do pellet. Para os aquicultores, a fabricação de ração é uma atividade difícil e cara por causa do alto preço dos aglutinantes artificiais tradicionais. O uso de amidos de grãos como aglutinantes de rações aquáticas tem vantagens que incluem acessibilidade, disponibilidade, contribuição nutricional e minimização do custo da ração. Um ensaio de pesquisa foi conduzido para testar propriedades físicas, como palatabilidade, estabilidade em água, pulverulência, friabilidade, velocidade de sedimentação e tempo de flutuação de amido disponível localmente, ou seja, glúten de trigo, amido de ervilha e goma de guar, e para auxiliar sua incorporação em rações aquáticas. Os resultados revelaram que, entre esses três amidos, o amido de ervilha se mostrou superior aos outros dois (glúten de trigo e goma de guar), pois todos os parâmetros de qualidade física (pulverulência, estabilidade da água e friabilidade) obtiveram melhor desempenho, exceto peletabilidade, em que a goma de guar se destacou. Nenhuma dieta se mostrou melhor no caso de tempo de flotação (Tf) e velocidade de sedimentação em comprimentos variados (6 mm, 9 mm e 12 mm). Essa descoberta indica a importância de aglutinantes adequados para a poluição ótima da água e a aquicultura sustentável. O uso desses aglutinantes, ou seja, glúten de trigo, amido de ervilha e goma de guar, em pellets de ração para peixes também pode reduzir a dependência de aglutinantes sintéticos e minimizar o custo.

Genetic variations among the isolates of Bipolaris Maydis based on phenotypic and molecular markers

Abstract Maydis leaf blight, caused by Bipolaris maydis, is an important disease of maize crop in Khyber Pakhtunkhwa (KP) Pakistan. Fifteen isolates of the pathogen, collected across KP, were studied for variability based on phenotypic and molecular markers. Significant variability among the isolates was observed when assessed using phenotypic traits such as radial growth, spore concentration, fungicide sensitivity and virulence. The isolates were classified into six culture groups based on colour, texture and margins of the colony. Conidial morphology was also variable. These were either straight or slightly curved and light to dark brown in colour. Fungicide test showed significant variation in the degree of sensitivity against Carbendazim. Isolate Bm8 exhibited maximum radial growth on carbendazim spiked plates. Conversely, isolate Bm15 showed the lowest radial growth. Variations in virulence pattern of the isolates were evident when a susceptible maize variety Azam was inoculated with spores of B. maydis. Genetic variability amongst the isolates was also estimated by RAPD as well as sequencing of ITS region. The RAPD dendrogram grouped all the isolates into two major clusters. Average genetic distance ranged from 0.6% to 100%, indicating a diverse genetic gap among the isolates. Maximum genetic distance was found between isolates Bm9 and Bm10 as well as Bm2 and Bm8. Conversely, isolates Bm13 and Bm15 were at minimum genetic distance. Phylogenetic dendrogram based on sequencing of ITS region grouped all the isolates into a single major cluster. The clusters in both the dendrogram neither correlate to the geographical distribution nor to the morphological characteristics.

Resumo A ferrugem das folhas de maydis, causada por Bipolaris maydis, é uma doença importante da cultura do milho em Khyber Pakhtunkhwa (KP), Paquistão. Quinze isolados do patógeno, coletados em KP, foram estudados quanto à variabilidade com base em marcadores fenotípicos e moleculares. Variabilidade significativa entre os isolados foi observada quando avaliada por meio de características fenotípicas, como crescimento radial, concentração de esporos, sensibilidade a fungicida e virulência. Os isolados foram classificados em seis grupos de cultura com base na cor, textura e margens da colônia. A morfologia dos conídios também foi variável. Estes eram retos ou ligeiramente curvos e de cor marrom-claro a escuro. O teste de fungicida mostrou variação significativa no grau de sensibilidade ao carbendazim. O isolado Bm8 exibiu crescimento radial máximo em placas com adição de carbendazim. Por outro lado, o isolado Bm15 apresentou o menor crescimento radial. As variações no padrão de virulência dos isolados foram evidentes quando uma variedade de milho suscetível Azam foi inoculada com esporos de B. maydis. A variabilidade genética entre os isolados também foi estimada por RAPD, bem como sequenciamento da região ITS. O dendrograma RAPD agrupou todos os isolados em dois grupos principais. A distância genética média variou de 0,6% a 100%, indicando uma lacuna genética diversa entre os isolados. A distância genética máxima foi encontrada entre os isolados Bm9 e Bm10 e também entre Bm2 e Bm8. Por outro lado, os isolados Bm13 e Bm15 estavam a uma distância genética mínima. O dendrograma filogenético baseado no sequenciamento da região ITS agrupou todos os isolados em um único aglomerado principal. Os agrupamentos em ambos os dendrogramas não se correlacionam com a distribuição geográfica nem com as características morfológicas.