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Abstract Background We systematically reviewed Mendelian randomization (MR) studies and summarized evidence on the potential effects of different antihypertensive drugs on health. Methods We searched PubMed and Embase for MR studies evaluating the effects of antihypertensive drug classes on health outcomes until 22 May 2024. We extracted data on study characteristics and findings, assessed study quality, and compared the evidence with that from randomized controlled trials (RCTs). Results We identified 2643 studies in the search, of which 37 studies were included. These studies explored a wide range of health outcomes including cardiovascular diseases and their risk factors, psychiatric and neurodegenerative diseases, cancer, immune function and infection, and other outcomes. There is strong evidence supporting the protective effects of genetically proxied antihypertensive drugs on cardiovascular diseases. We found strong protective effects of angiotensin-converting enzyme (ACE) inhibitors on diabetes whereas beta-blockers showed adverse effects. ACE inhibitors might increase the risk of psoriasis, schizophrenia, and Alzheimer’s disease but did not affect COVID-19. There is strong evidence that ACE inhibitors and calcium channel blockers (CCBs) are beneficial for kidney and immune function, and CCBs showed a safe profile for disorders of pregnancy. Most studies have high quality. RCT evidence supports the beneficial effects of ACE inhibitors and CCBs on stroke, diabetes, and kidney function. However, there is a lack of reliable RCTs to confirm the associations with other diseases. Conclusions Evidence of the benefits and off-target effects of antihypertensive drugs contribute to clinical decision-making, pharmacovigilance, and the identification of drug repurposing opportunities.

Abstract We assessed the causal relation of four glycemic traits and type 2 diabetes liability with 167 metabolites using Mendelian randomization with various sensitivity analyses and a reverse Mendelian randomization analysis. We extracted instruments for fasting glucose, 2-h glucose, fasting insulin, and glycated hemoglobin from the Meta-Analyses of Glucose and Insulin-related traits Consortium (n = 200,622), and those for type 2 diabetes liability from a meta-analysis of multiple cohorts (148,726 cases, 965,732 controls) in Europeans. Outcome data were from summary statistics of 167 metabolites from the UK Biobank (n = 115,078). Fasting glucose and 2-h glucose were not associated with any metabolite. Higher glycated hemoglobin was associated with higher free cholesterol in small low-density lipoprotein. Type 2 diabetes liability and fasting insulin were inversely associated with apolipoprotein A1, total cholines, lipoprotein subfractions in high-density-lipoprotein and intermediate-density lipoproteins, and positively associated with aromatic amino acids. These findings indicate hyperglycemia-independent patterns and highlight the role of insulin in type 2 diabetes development. Further studies should evaluate these glycemic traits in type 2 diabetes diagnosis and clinical management.

Abstract Background Mental disorders are among the top causes of disease burden worldwide. Existing evidence regarding the repurposing of antihypertensives for mental disorders treatment is conflicting and cannot establish causation. Methods We used Mendelian randomization to assess the effects of angiotensin-converting-enzyme inhibitors (ACEIs), beta blockers (BBs), and calcium channel blockers (CCBs) on risk of bipolar disorder (BD), major depression disorder (MDD), and schizophrenia (SCZ). We used published genetic variants which are in antihypertensive drugs target genes and correspond to systolic blood pressure (SBP) in Europeans and East Asians, and applied them to summary statistics of BD (cases = 41,917; controls = 371,549 in Europeans), MDD (cases = 170,756; controls = 329,443 in Europeans and cases = 15,771; controls = 178,777 in East Asians), and SCZ (cases = 53,386; controls = 77,258 in Europeans and cases = 22,778; controls = 35,362 in East Asians) from the Psychiatric Genomics Consortium. We used inverse variance weighting with MR-Egger, weighted median, weighted mode, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier. We performed gene-specific analysis and utilized various methods to address potential pleiotropy. Results After multiple testing correction, genetically proxied ACEIs were associated with an increased risk of SCZ in Europeans (odds ratio (OR) per 5 mmHg lower in SBP 2.10, 95% CI 1.54 to 2.87) and East Asians (OR per 5 mmHg lower in SBP 2.51, 95% CI 1.38 to 4.58). Genetically proxied BBs were not associated with any mental disorders in both populations. Genetically proxied CCBs showed no benefits on mental disorders. Conclusions Antihypertensive drugs have no protection for mental disorders but potential harm. Their long-term use among hypertensive patients with, or with high susceptibility to, psychiatric illness needs careful evaluation.

Аim: to present the difficulties of surgical treatment of patients with multiple and combined echinococcal lesions. Key points. A 47-year-old patient who lived in Central Asia for up to 29 years of age was diagnosed with multiple echinococcosis of the abdominal cavity (CE1-2): II, Ivb, V, VI, VII segments of the liver, upper and lower poles of the spleen, lesser and greater omentum, small intestine, subphrenic space, area of the hepatoduodenal ligament, gastrocolic ligament. Surgical intervention was performed: atypical resection of liver segments V, VI, VII, subtotal pericystectomy, cholecystectomy, subtotal pericystectomy of cysts of II and IVb liver segments, subtotal pericystectomy of splenic cysts, resection of the greater omentum, echinococcectomy of the lesser omentum, mesentery of the small intestine, hepatoduodenal ligament, gastrocolic ligament, drainage of the abdominal cavity. Pericystectomy was carried out according to the technique of the National Medical Research Center of Surgery named after A. Vishnevsky.Conclusion. Due to the peculiarities of the course of helminthiasis and the pronounced variability of the lesion, it is extremely difficult to develop universal and effective treatment algorithms. The presented clinical observation demonstrates an example of the successful use of special surgical tactics for the treatment of “complex” echinococcosis of the abdominal cavity with good long-term follow-up results.

Aim: the reason for the publication was the rare occurrence, as well as the non-specificity of symptoms of the cystic form of duodenal dystrophy. The listed features of this disease lead to difficulties in its differential diagnosis and the choice of the optimal method of treatment.General statements. The report is devoted to the description of a case of successful treatment of a cystic form of duodenal dystrophy — a chronic inflammation of the pancreatic tissue, ectopic in the wall of the duodenum. A 47-year-old patient was admitted to the clinic with complaints of persistent abdominal pain, periodic vomiting, general weakness, weight loss of 20 kg in three months. With the help of computed tomography, the diagnosis was established, the tumor process was rejected, and chronic pancreatitis was detected in the orthotopic pancreas. Due to the presence of changes in the main pancreas, the patient underwent pancreatoduodenal resection. The features of the operation were pronounced infiltrative changes and pronounced vitreous tissue edema, which made it difficult to mobilize the hepatic flexure of the colon and duodenum.Conclusion. Pancreatoduodenal resection is the optimal surgical intervention for the combination of cystic form of duodenal dystrophy with sub-/decompensated duodenal stenosis.

Aim: to present a clinical case of pancreatic PEComa with liver metastases with an emphasis on morphological features, radiology diagnostic methods and features of treatment tactics, allowing practitioners to get an idea about this rare mesenchymal tumors composed of “perivascular epithelioid cells”, and a review of literature data on pancreatic PEComa, including 32 author's cases.General statements. A 22-year-old woman who was surgically treated for pancreatic head PEComa with infiltration of the duct of Wirsung, common bile duct, duodenal wall, focal invasion into the blood and lymphatic vessels, and perineural space infiltration. Synchronously, metastases were detected in both liver lobes, for which she took Everolimus for 6 years under the control of radiology methods with dose adjustment and frequency of administration. At the A.V. Vishnevsky National Medical Research Center of Surgery, the patient underwent right-sided hemihepatectomy and atypical resection of II-III liver segments.Conclusion. To determine clearer criteria for the diagnosis and differential diagnosis of PEComa, to identify criteria for the malignancy of these tumors, to develop treatment tactics and further dynamic monitoring, a set of statistical data of significant group and randomized clinical trials are needed. Pancreatic PEComas in this group are extremely rare and often have a benign course. The presented clinical case demonstrates the most malignant form of this tumor with localization in the pancreas and liver metastases.

Background: Few studies have examined the role of outdoor air pollution exposure in sarcopenia in Asia. We aimed to investigate the association of outdoor air pollutants exposure with sarcopenia among Chinese adults. Methods: This nationally population-representative study used data from the China Health and Retirement Longitudinal Study (CHARLS) in 2015, 11,700 participants at least 45 years old from 125 Chinese cities were included. Sarcopenia status was identified according to the Asian Working Group for Sarcopenia 2019 (AWGS 2019) criteria. Ambient annual average air pollutants including fine particulate matter (PM2.5), inhalable particles (PM10), coarse particulate matter (PMcoarse), nitrogen dioxide (NO2), sulfur dioxide (SO2), and carbon monoxide (CO) were estimated by satellite models and ground-based measurements. Multinomial logistic regression models were performed to examine the associations of air pollutants exposure with different status of sarcopenia (including possible sarcopenia and sarcopenia). Stratified analyses were utilized to assess the effect modifiers. Results: Among the 11,700 participants (52.6% women), the average age was 61.0 years. Each 10 μg/m3 increment of annual PMcoarse was associated with a higher risk of possible sarcopenia (odds ratio (OR) = 1.08, 95% confidence interval (CI) 1.04–1.11). Stratified analyses showed a positive risk of possible sarcopenia in women after exposure to PM10, PMcoarse, and NO2. Ambient NO2 exposure was positively associated with sarcopenia (OR = 1.13, 95% CI 1.04–1.22) in those aged 65 years and older. However, we have not observed differences by sex, age, residence, smoking, and drinking. Robustness results were found for PMcoarse in the sensitivity analyses. Conclusion: This nationwide study suggested that long-term exposure to outdoor air pollution, especially for PMcoarse, was associated with the risk of sarcopenia among Chinese adults. Our findings provide epidemiological implications for protecting healthy ageing by improving air quality.

Abstract Venous thromboembolism occurs in up to one-third of patients with COVID-19. Venous thromboembolism and COVID-19 may share a common genetic architecture, which has not been clarified. To fill this gap, we leverage summary-level genetic data from the latest COVID‐19 host genetics consortium and UK Biobank and examine the shared genetic etiology and causal relationship between COVID-19 and venous thromboembolism. The cross-trait and co-localization analyses identify 2, 3, and 4 shared loci between venous thromboembolism and severe COVID-19, COVID-19 hospitalization, SARS-CoV-2 infection respectively, which are mapped to ABO, ADAMTS13, FUT2 genes involved in coagulation functions. Enrichment analysis supports shared biological processes between COVID-19 and venous thromboembolism related to coagulation and immunity. Bi-directional Mendelian randomization suggests that venous thromboembolism was associated with higher risk of three COVID-19 traits, and SARS-CoV-2 infection was associated with a higher risk of venous thromboembolism. Our study provides timely evidence for the genetic etiology between COVID-19 and venous thromboembolism (VTE). Our findings contribute to the understanding of COVID-19 and VTE etiology and provide insights into the prevention and comorbidity management of COVID-19.

Background. Biliary cystadenomas and cystadenocarcinomas are rare cystic tumors of the liver. Complicated differential diagnostics for simple cysts often leads to errors in surveillance of patients with these tumors. Cystadenoma and cystadenocarcinoma should be suspected upon detection of single or multilocular cystic neoplasms of the liver with septa and blood flow loci in the cyst wall, especially in middle-aged women. The localization of the tumor is critical. The most common localization is segment IV of the liver. Urgent intraoperative biopsy is required to determine the extent of surgery.Case description. Clinical observations with analysis of the examination and treatment data of two female patients aged 38 and 56 were presented. Both clinical observations illustrate the underestimation of the preoperative examination data that served as a ground for diagnosis of liver cysts with inadequate extent of surgery. In the first case, the resection was incomplete, and, as such, the biliary cystadenoma recurred in the resection area, the capsule of the neoplasm was ruptured and an encysted fluid collection was formed. In the second case, lack of histological examination of the excised neoplasm, due to confidence in its morphological verification as a cyst, resulted in cystadenoma recurrence in the resection zone with metastasis to the contralateral lobe of the liver.Conclusion. Hepatic cystadenomas and cystadenocarcinomas are often misdiagnosed as simple cysts. These tumors should be suspected in central localization of the tumor in the liver, especially in young women. The clinical and instrumental symptomatology and radiological semiotics of the disease require careful evaluation. The recurrence of a cystic lesion in the resection zone in a patient previously operated for a hepatic cyst serves as an additional signal for detecting biliary cystadenoma. Rational strategy for surgical management of cystic liver lesions should include hepatectomy within healthy tissues (both anatomical and atypical) with mandatory intraoperative ultrasound and urgent histological examinations.

Abstract Background l-carnitine is emerging as an item of interest for cardiovascular disease (CVD) prevention and treatment, but controversy exists. To examine the effectiveness and safety of l-carnitine, we assessed how genetically different levels of l-carnitine are associated with CVD risk and its risk factors. Given higher CVD incidence and l-carnitine in men, we also examined sex-specific associations. Methods We used Mendelian randomization to obtain unconfounded estimates. Specifically, we used genetic variants to predict l-carnitine, and obtained their associations with coronary artery disease (CAD), ischemic stroke, heart failure, and atrial fibrillation, as well as CVD risk factors (type 2 diabetes, glucose, HbA1c, insulin, lipid profile, blood pressure and body mass index) in large consortia and established cohorts, as well as sex-specific association in the UK Biobank. We obtained the Wald estimates (genetic association with CVD and its risk factors divided by the genetic association with l-carnitine) and combined them using inverse variance weighting. In sensitivity analysis, we used different analysis methods robust to pleiotropy and replicated using an l-carnitine isoform, acetyl-carnitine. Results Genetically predicted l-carnitine was nominally associated with higher risk of CAD overall (OR 1.07 per standard deviation (SD) increase in l-carnitine, 95% CI 1.02 to 1.11) and in men (OR 1.09, 95% CI 1.02 to 1.16) but had a null association in women (OR 1.00, 95% CI 0.92 to 1.09). These associations were also robust to different methods and evident for acetyl-carnitine. Conclusions Our findings do not support a beneficial association of l-carnitine with CVD and its risk factors but suggest potential harm. l-carnitine may also exert a sex-specific role in CAD. Consideration of the possible sex disparity and exploration of the underlying pathways would be worthwhile.

Abstract Background Kidney dysfunction occurs in severe COVID-19, and is a predictor of COVID-19 mortality. Whether kidney dysfunction causes severe COVID-19, and hence is a target of intervention, or whether it is a symptom, is unclear because conventional observational studies are open to confounding. To obtain unconfounded estimates, we used Mendelian randomization to examine the role of kidney function in severe COVID-19. Methods We used genome-wide significant, uncorrelated genetic variants to predict kidney function, in terms of estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR), and then assessed whether people with genetically instrumented higher eGFR or lower UACR, an indication of better kidney function, had a lower risk of severe COVID-19 (8779 cases, 1,001,875 controls), using the largest available cohorts with extensive genotyping. For comprehensiveness, we also examined their role in COVID-19 hospitalization (24,274 cases, 2,061,529 controls) and all COVID-19 (1,12,612 cases, 2,474,079 controls). Results Genetically instrumented higher eGFR was associated with lower risk of severe COVID-19 (odds ratio (OR) 0.90, 95% confidence interval (CI) 0.83, 0.98) but not related to COVID-19 hospitalization or infection. Genetically instrumented UACR was not related to COVID-19. Conclusions Kidney function appears to be one of the key targets for severe COVID-19 treatment. Use of available medications to improve kidney function, such as antihypertensives, might be beneficial for COVID-19 treatment, with relevance to drug repositioning.

Abstract Men are more vulnerable to ischemic heart disease (IHD) than women, possibly due to testosterone. Correspondingly, sex hormone binding globulin (SHBG) which lowers circulating testosterone might protect men against IHD. SHBG may also affect IHD independent of testosterone, which has not previously been examined. To assess the sex-specific role of SHBG in IHD, in univariable Mendelian randomization (MR), we used sex-specific, genome-wide significant genetic variants to predict SHBG, and examined their association with IHD in the UK Biobank. We also replicated using genetic instruments from Japanese men and applied to Biobank Japan. To assess the role of SHGB independent of testosterone in men, we used multivariable MR controlling for testosterone. Genetically predicted SHBG was associated with lower IHD risk in men [odds ratio (OR) 0.78 per standard deviation, 95% confidence interval (CI) 0.70 to 0.87], and the association was less clear in women. The estimates were similar in Japanese. The inverse association remained after controlling for testosterone in men (OR 0.79, 95% CI 0.71 to 0.88). SHBG might lower the risk of IHD in men, with a role independent of testosterone. Exploring intervention strategies that increase SHBG is important for targeting IHD treatments.

Abstract Life expectancy in the developed West is currently stagnated and remains shorter in men than women. Well-established evolutionary biology theory suggests lifespan trades-off against reproductive success, possibly sex-specifically. We examined whether a key driver of reproductive success, testosterone, affected survival using a Mendelian randomization longevity study in the UK Biobank to obtain unbiased estimates, along with control exposures. We applied published genetic instruments for testosterone to obtain inverse variance weighted estimates of associations with survival to (i.e., age at) recruitment, in 167,020 men and 194,174 women. We similarly obtained estimates for a positive control (smoking initiation), and a negative control (absorbate), a marker of vitamin C metabolism. Testosterone was associated with poorer survival (0.10 years younger at recruitment per effect size of testosterone, 95% confidence interval (CI) 0.004 to 0.20). As expected, smoking initiation was also associated with poorer survival (0.37 years younger, 95% CI 0.25 to 0.50), but not absorbate (0.01 years younger, 95% CI − 0.09 to 0.11). Several aspects of a healthy lifestyle (low animal fat diet) and several widely used medications (statins, metformin, dexamethasone and possibly aspirin) may modulate testosterone. Explicitly designing interventions sex-specifically based on these insights might help address stagnating life expectancy and sexual disparities.

Abstract APOE genotypes are associated with ischemic heart disease (IHD), several other cardiovascular diseases and dementia. Previous studies have not comprehensively considered all genotypes, especially ε2ε2, nor associations by age and sex, although IHD incidence differs by sex. In the UK Biobank, including 391,992 white British participants, we compared effects of APOE genotypes on IHD and its risk factors. Compared to the ε3ε3 genotype, ε2ε2 was not clearly associated with IHD but was associated with lower plasma apolipoprotein B (apoB). The ε2ε3 genotype conferred lower IHD risk, systolic blood pressure (SBP), pulse pressure and plasma apoB than ε3ε3. ε3ε4 and ε4ε4 conferred higher IHD risk, higher pulse pressure and plasma apoB, but lower glycated haemoglobin (HbA1c) than ε3ε3. The associations by age and sex were fairly similar, except ε2ε2 compared to ε3ε3 was marginally positively associated with IHD in the younger age group and nominally inversely associated with SBP in men. ε3ε4 compared to ε3ε3 was nominally positively associated with SBP in women. APOE genotypes affect IHD risk increasingly from ε2ε3, ε3ε3, ε3ε4 to ε4ε4, with similar patterns for pulse pressure and plasma apoB, but not for diabetes. Associations with blood pressure differed by sex. Greater understanding of products of APOE and their effects might generate targets of intervention.

Abstract Background Angiotensin-converting enzyme (ACE) inhibitors and/or in combination with calcium channel blockers (CCBs) are generally recommended as the first-line antihypertensive therapy for people with hypertension and kidney dysfunction. Evidence from large randomized controlled trials comprehensively comparing renal effects of different classes of antihypertensive drugs is lacking. Methods We used a Mendelian randomization study to obtain unconfounded associations of genetic proxies for antihypertensives with kidney function. Specifically, we used published genetic variants in genes regulating target proteins of these drugs and then applied to a meta-analysis of the largest available genome-wide association studies of kidney function (estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), and albuminuria). Inverse variance weighting was used as the main analysis and to combine estimates from different sources. Results Genetically predicted ACE inhibition was associated with higher eGFR (effect size 0.06, 95% confidence interval (CI) 0.008, 0.11), while genetic proxies for beta-blockers were associated with lower eGFR (− 0.02, 95% CI − 0.04, − 0.004) when meta-analyzing the UK Biobank and CKDGen. Genetic proxies for CCBs were associated with lower UACR (− 0.15, 95% CI − 0.28, − 0.02) and lower risk of albuminuria (odds ratio 0.58, 95% CI 0.37, 0.90) in CKDGen. The associations were robust to using different analysis methods and different genetic instruments. Conclusions Our findings suggest the reno-protective associations of genetically proxied ACE inhibitors and CCBs, while genetic proxies for beta-blockers may be related to lower eGFR. Understanding the underlying mechanisms would be valuable, with implications for drug development and repositioning of treatments for kidney disease.

Abstract Background Observational studies suggest poorer glycemic traits and type 2 diabetes associated with coronavirus disease 2019 (COVID-19) risk although these findings could be confounded by socioeconomic position. We conducted a two-sample Mendelian randomization to clarify their role in COVID-19 risk and specific COVID-19 phenotypes (hospitalized and severe cases). Method We identified genetic instruments for fasting glucose (n = 133,010), 2 h glucose (n = 42,854), glycated hemoglobin (n = 123,665), and type 2 diabetes (74,124 cases and 824,006 controls) from genome wide association studies and applied them to COVID-19 Host Genetics Initiative summary statistics (17,965 COVID-19 cases and 1,370,547 population controls). We used inverse variance weighting to obtain the causal estimates of glycemic traits and genetic predisposition to type 2 diabetes in COVID-19 risk. Sensitivity analyses included MR-Egger and weighted median method. Results We found genetic predisposition to type 2 diabetes was not associated with any COVID-19 phenotype (OR: 1.00 per unit increase in log odds of having diabetes, 95%CI 0.97 to 1.04 for overall COVID-19; OR: 1.02, 95%CI 0.95 to 1.09 for hospitalized COVID-19; and OR: 1.00, 95%CI 0.93 to 1.08 for severe COVID-19). There were no strong evidence for an association of glycemic traits in COVID-19 phenotypes, apart from a potential inverse association for fasting glucose albeit with wide confidence interval. Conclusion We provide some genetic evidence that poorer glycemic traits and predisposition to type 2 diabetes unlikely increase the risk of COVID-19. Although our study did not indicate glycemic traits increase severity of COVID-19, additional studies are needed to verify our findings.

The aging process causes profound restructuring of the host immune system, typically associated with declining host protection against cancer and infection. In the case of T cells, aging leads to the accumulation of a diverse set of T-cell aging-associated phenotypes (TASP), some of which have been implicated in driving tissue inflammation in autoimmune diseases. T cell aging as a risk determinant for autoimmunity is exemplified in two classical autoimmune conditions: rheumatoid arthritis (RA), a disease predominantly affecting postmenopausal women, and giant cell arteritis (GCA), an inflammatory vasculopathy exclusively occurring during the 6th–9th decade of life. Pathogenic T cells in RA emerge as a consequence of premature immune aging. They have shortening and fragility of telomeric DNA ends and instability of mitochondrial DNA. As a result, they produce a distinct profile of metabolites, disproportionally expand their endoplasmic reticulum (ER) membranes and release excess amounts of pro-inflammatory effector cytokines. Characteristically, they are tissue invasive, activate the inflammasome and die a pyroptotic death. Patients with GCA expand pathogenic CD4+ T cells due to aberrant expression of the co-stimulatory receptor NOTCH1 and the failure of the PD-1/PD-L1 immune checkpoint. In addition, GCA patients lose anti-inflammatory Treg cells, promoting tissue-destructive granulomatous vasculitis. In summary, emerging data identify T cell aging as a risk factor for autoimmune disease and directly link TASPs to the breakdown of T cell tolerance and T-cell-induced tissue inflammation.

Abstract Background Chronic kidney disease (CKD) has an apparent sex disparity, with a more rapid progress in men than in women. Whether the well-established sex-specific evolutionary biology trade-off between reproduction and longevity might inform CKD has not previously been considered. Relevant evidence from randomized controlled trials (RCTs) is not available. Methods We used a bi-directional Mendelian randomization study to obtain unconfounded estimates using the UK Biobank. Single nucleotide polymorphisms (SNPs) that strongly (p value

Abstract Background The role of n-6 polyunsaturated fatty acids (PUFAs) in ischemic heart disease (IHD) is controversial, and dietary guidelines vary. Observationally, lower saturated fat intake and higher intake of vegetable oils rich in linoleic acid (LA), the main n-6 PUFA, is associated with lower IHD and diabetes; however, randomized controlled trials have not fully corroborated these benefits. We assessed how genetically predicted LA affected IHD and its risk factors, including diabetes, lipids, and blood pressure. We also assessed the role of LA in reticulocyte count, the red blood cell precursor, which has recently been identified as a possible causal factor in IHD. Methods Two-sample instrumental variable analysis with genetic instruments, i.e., Mendelian randomization, was used to obtain unconfounded estimates using genetic variants strongly (p value

Background: Mendelian randomization (MR) provides unconfounded estimates. MR is open to selection bias when the underlying sample is selected on surviving to recruitment on the genetically instrumented exposure and competing risk of the outcome. Few methods to address this bias exist.Methods: We show that this selection bias can sometimes be addressed by adjusting for common causes of survival and outcome. We use multivariable MR to obtain a corrected MR estimate for statins on stroke. Statins affect survival, and stroke typically occurs later in life than ischemic heart disease (IHD), making estimates for stroke open to bias from competing risk.Results: In univariable MR in the UK Biobank, genetically instrumented statins did not protect against stroke [odds ratio (OR) 1.33, 95% confidence interval (CI) 0.80–2.20] but did in multivariable MR (OR 0.81, 95% CI 0.68–0.98) adjusted for major causes of survival and stroke [blood pressure, body mass index (BMI), and smoking initiation] with a multivariable Q-statistic indicating absence of selection bias. However, the MR estimate for statins on stroke using MEGASTROKE remained positive and the Q statistic indicated pleiotropy.Conclusion: MR studies of harmful exposures on late-onset diseases with shared etiology need to be conceptualized within a mechanistic understanding so as to identify any potential bias due to survival to recruitment on both genetically instrumented exposure and competing risk of the outcome, which may then be investigated using multivariable MR or estimated analytically and results interpreted accordingly.

Background: Arachidonic acid (AA), a major long-chain n-6 polyunsaturated fatty acid in animal foods, has been linked to inflammation, coagulation, and testosterone, which might relate to atherosclerotic cardiovascular diseases (ASCVD). We assessed the associations of genetically predicted plasma phospholipid AA with ASCVD and other CVD overall and by sex using Mendelian randomization (MR). Methods: We conducted two-sample MR, applying eight genetic variants, independent of a highly pleiotropic variant (rs174547), strongly (p

Finding a focal liver lesion during screening may not uncommonly lead to a misinterpretation of the results of radiological diagnostics. Based on the consolidation of our wide experience (more than 1000 cases) of surgical treatment of patients with various focal liver diseases, we analyzed the main causes of diagnostic pitfalls and, as a consequence, errors in the treatment of these patients. The most typical objective and subjective diagnostic pitfalls that may lead to a wrong treatment strategy are discussed with clinical cases taken as examples. The objective factors are related to the rarity of disease, absence of pathognomonic semiotics, as well as limitations in the resolution power of imaging methods. In addition, a misinterpretation of results of ultrasound examination, magnetic resonance imaging and multiaxial computed tomography may be explained by identical properties of images in different tumors related to similar physical and chemical properties of a lesion. The subjective factors are related to a wrong interpretation of clinical and instrumental assessment data, or insufficient evaluation needed in an individual patient. The number of diagnostic and treatment errors could be decreased by a multidisciplinary approach taking into account the opinions of various profile experts.

Abstract To clarify the role of thyroid function in ischemic heart disease (IHD) we assessed IHD risk and risk factors according to genetically predicted thyroid stimulating hormone (TSH), free thyroxine (FT4) and thyroid peroxidase antibody (TPOAb) positivity. Separate-sample instrumental variable analysis with genetic instruments (Mendelian randomization) was used in an extensively genotyped case (n = 64,374)-control (n = 130,681) study, CARDIoGRAMplusC4D. Associations with lipids, diabetes and adiposity were assessed using the Global Lipids Genetics Consortium Results (n = 196,475), the DIAbetes Genetics Replication And Meta-analysis case (n = 34,380)-control (n = 114,981) study, and the Genetic Investigation of ANthropometric Traits (body mass index in 152,893 men and 171,977 women, waist-hip ratio in 93,480 men and 116,741 women). Genetically predicted thyroid function was not associated with IHD (odds ratio (OR) per standard deviation for TSH 1.05, 95% confidence interval (CI) 0.97 to 1.12; for FT4 1.01, 95% CI 0.91 to 1.12; for TPOAb positivity 1.10, 95% CI 0.83 to 1.46) or after Bonferroni correction with risk factors, except for an inverse association of FT4 with low-density lipoprotein-cholesterol. The associations were generally robust to sensitivity analyses using a weighted median method and MR Egger. This novel study provides little indication that TSH, FT4 or TPOAb positivity affects IHD, despite potential effects on its risk factors.

Cholangiocellular carcinoma (CCA) is a rare disease. In average it is 3% of all malignant tumors of the gastrointestinal tract. Intrahepatic type (iCCA) represents from 5 to 10% of the CCA. The chronic inflammation plays an important role in pathogenesis of CCA, against the background of what there is an activation of various cellular signaling pathways leading to disruption of cell proliferation of cholangiocytes. The majority of patients with iCCA develop symptoms only at an advanced stage of disease. Surgical treatment at an early stage is curative in improving the prognosis of these patients. Certainly, knowledge of changes at the molecular genetic level in patients with iCCA will improve the methods of examination of these patients, that elevate the diagnosis and treatment results.

The article presents analysis of scientific literature of the last 15 years about complications after orthotopic liver transplantation, depending on the severity of the initial status of recipient and expression of metabolic and functional disorders. Factors affecting the development of vascular complications (arterial and venous thrombosis), biliary complications (cholestasis, cholangitis), immune response (acute rejection), and also surgical and infectious complications and functional insufficiency of the graft are analyzed in this review. The necessity to improve monitoring in the immediate post transplant period is considered.

Angiotensin-converting enzyme (ACE) inhibitors are widely used to reduce blood pressure. Here, we examined if an ACE is important for the antibacterial effectiveness of neutrophils. ACE knockout mice or mice treated with an ACE inhibitor were more susceptible to bacterial infection by methicillin-resistant Staphylococcus aureus (MRSA). In contrast, mice overexpressing ACE in neutrophils (NeuACE mice) have increased resistance to MRSA and better in vitro killing of MRSA, Pseudomonas aeruginosa, and Klebsiella pneumoniae. ACE overexpression increased neutrophil production of reactive oxygen species (ROS) following MRSA challenge, an effect independent of the angiotensin II AT1 receptor. Specifically, as compared with wild-type (WT) mice, there was a marked increase of superoxide generation (>twofold, P < .0005) in NeuACE neutrophils following infection, whereas ACE knockout neutrophils decreased superoxide production. Analysis of membrane p47-phox and p67-phox indicates that ACE increases reduced NAD phosphate oxidase activity but does not increase expression of these subunits. Increased ROS generation mediates the enhanced bacterial resistance of NeuACE mice because the enhanced resistance is lost with DPI (an inhibitor of ROS production by flavoenzymes) inhibition. NeuACE granulocytes also have increased neutrophil extracellular trap formation and interleukin-1β release in response to MRSA. In a mouse model of chemotherapy-induced neutrophil depletion, transfusion of ACE-overexpressing neutrophils was superior to WT neutrophils in treating MRSA infection. These data indicate a previously unknown function of ACE in neutrophil antibacterial defenses and suggest caution in the treatment of certain individuals with ACE inhibitors. ACE overexpression in neutrophils may be useful in boosting the immune response to antibiotic-resistant bacterial infection. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common global dementia and is universally fatal. Most late-stage AD disease-modifying therapies are intravenous and target amyloid beta (Aβ), with only modest effects on disease progression: there remains a high unmet need for convenient, safe, and effective therapeutics. Senescent cells (SC) and the senescence-associated secretory phenotype (SASP) drive AD pathology and increase with AD severity. Preclinical senolytic studies have shown improvements in neuroinflammation, tau, Aβ, and CNS damage; most were conducted in transgenic rodent models with uncertain human translational relevance. In this study, aged cynomolgus monkeys had significant elevation of biomarkers of senescence, SASP, and neurological damage. Intermittent treatment with the senolytic navitoclax induced modest reversible thrombocytopenia; no serious drug-related toxicity was noted. Navitoclax reduced several senescence and SASP biomarkers, with CSF concentrations sufficient for senolysis. Finally, navitoclax reduced TSPO-PET frontal cortex binding and showed trends of improvement in CSF biomarkers of neuroinflammation, neuronal damage, and synaptic dysfunction. Overall, navitoclax administration was safe and well tolerated in aged monkeys, inducing trends of biomarker changes relevant to human neurodegenerative disease., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Edward Greenberg, MD reports financial support was provided by AbbVie Inc. Edward Greenberg MD reports a relationship with AbbVie Inc that includes: employment, equity or stocks, and funding grants. EFG, MV, AS, DRR, YZ, JQW, DWW, EA, MH, CH, RD, MT, KO, WA, LD, HK, JSS, YH, KM, VZ, SY, JM, YF, AV, SW, MD, SJF, and HF are employees of AbbVie and may hold stock. KD was an employee of AbbVie at the time of the study and may hold stock. The design, study conduct, and all funding for this research was provided by AbbVie, the maker of navitoclax (ABT-263). AbbVie participated in the interpretation of data, review, and approval of the publication. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Infectious disease dynamics are driven by the complex interplay of epidemiological, ecological, and evolutionary processes. Accurately modeling these interactions is crucial for understanding pathogen spread and informing public health strategies. However, existing simulators often fail to capture the dynamic interplay between these processes, resulting in oversimplified models that do not fully reflect real-world complexities in which the pathogen's genetic evolution dynamically influences disease transmission. We introduce the epidemiological-ecological-evolutionary simulator (e3SIM), an open-source framework that concurrently models the transmission dynamics and molecular evolution of pathogens within a host population while integrating environmental factors. Using an agent-based, discrete-generation, forward-in-time approach, e3SIM incorporates compartmental models, host-population contact networks, and quantitative-trait models for pathogens. This integration allows for realistic simulations of disease spread and pathogen evolution. Key features include a modular and scalable design, flexibility in modeling various epidemiological and population-genetic complexities, incorporation of time-varying environmental factors, and a user-friendly graphical interface. We demonstrate e3SIM's capabilities through simulations of realistic outbreak scenarios with SARS-CoV-2 and Mycobacterium tuberculosis , illustrating its flexibility for studying the genomic epidemiology of diverse pathogen types.

Recurrent excitatory connections in hippocampal regions CA3 and CA2 are thought to play a key role in the generation of sharp-wave ripples (SWRs), electrophysiological oscillations tightly linked with learning and memory consolidation. However, it remains unknown how defined populations of inhibitory interneurons regulate these events during behavior. Here, we use large-scale, three-dimensional calcium imaging and retrospective molecular identification in the mouse hippocampus to characterize molecularly identified CA3 and CA2 interneuron activity during SWR-associated memory consolidation and spatial navigation. We describe subtype- and region-specific responses during behaviorally distinct brain states and find that SWRs are preceded by decreased cholecystokinin-expressing interneuron activity and followed by increased parvalbumin-expressing basket cell activity. The magnitude of these dynamics correlates with both SWR duration and behavior during hippocampal-dependent learning. Together these results assign subtype- and region-specific roles for inhibitory circuits in coordinating operations and learning-related plasticity in hippocampal recurrent circuits., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objectives: Although the World Health Organization recommends 'frequent' screening of sexually transmitted infections (STI) for people who use pre-exposure prophylaxis for HIV, there is no evidence for optimal frequency., Methods: We searched five databases and used random-effects meta-analysis to calculate pooled estimates of STI test positivity. We narratively synthesized data on secondary outcomes, including adherence to recommended STI screening frequency and changes in STI epidemiology., Results: Of 7477 studies, we included 38 for the meta-analysis and 11 for secondary outcomes. With 2-3 monthly STI screening, the pooled positivity was 0.20 (95% confidence interval [CI]: 0.15-0.25) for chlamydia, 0.17 (95% CI: 0.12-0.22) for gonorrhea, and 0.07 (95% CI: 0.05-0.08) for syphilis. For chlamydia and gonorrhea, the positivity was approximately 50% and 75% lower, respectively, in studies that screened 4-6 monthly vs 2-3 monthly. There was no significant difference in the positivity for syphilis in studies that screened 4-6 monthly compared to 2-3 monthly. Adherence of clients to recommended screening frequency varied significantly (39-94%) depending on population and country. Modeling studies suggest more frequent STI screening could reduce incidence., Conclusion: Although more frequent STI screening could reduce delayed diagnoses and incidence, there remain significant knowledge gaps regarding the optimal STI screening frequency., Competing Interests: Declaration of Competing Interest None of the authors has any competing interests to declare. Some of the authors are present or former staff members of the World Health Organization. The authors alone are responsible for the views expressed in this publication, and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: This study aimed to evaluate the time interval to menarche after gonadotropin-releasing hormone agonist (GnRHa) treatment in females with central precocious puberty (CPP) and to identify factors contributing to timing of menarche., Methods: We retrospectively reviewed medical records of 39 females with CPP who reached menarche after GnRHa treatment (leuprolide or histrelin). CPP diagnostic criteria were breast development at &lt;8 years old, measurable pubertal luteinizing hormone and/or estradiol concentrations, and bone age advancement. Indications to treat were advanced bone age and psychosocial concerns. Descriptive summaries were reported as frequency and proportion for categorical variables and mean and standard deviation for continuous measures. Linear regression models were developed to evaluate the associations of clinical factors with the time interval to menarche., Results: Mean age was 9.4±1.6 years at treatment onset, and treatment duration was 2.2±1.4 years. Menarche occurred at 12.6±1.1 years, which was 1.04±0.5 years after treatment discontinuation. This was negatively associated with Tanner stage of breast development and bone age at treatment onset and change in bone age during treatment. No association was seen between time interval to menarche and treatment duration, medication, or body mass index., Conclusion: We found the average time interval to menarche after GnRHa treatment in our population of female patients with CPP to be 1.04±0.5 years; this is in agreement with other reports. Tanner stage of breast development, bone age at treatment onset, and change in bone age were negatively associated with time interval to menarche. These data provide clinical correlates that assist providers during anticipatory guidance of patients with CPP after GnRHa treatment.

Cotranslational folding depends on the folding speed and stability of the nascent protein. It remains difficult, however, to predict which proteins cotranslationally fold. Here, we simulate evolution of model proteins to investigate how native structure influences evolution of cotranslational folding. We developed a model that connects protein folding during and after translation to cellular fitness. Model proteins evolved improved folding speed and stability, with proteins adopting one of two strategies for folding quickly. Low contact order proteins evolve to fold cotranslationally. Such proteins adopt native conformations early on during the translation process, with each subsequently translated residue establishing additional native contacts. On the other hand, high contact order proteins tend not to be stable in their native conformations until the full chain is nearly extruded. We also simulated evolution of slowly translating codons, finding that slower translation speeds at certain positions enhances cotranslational folding. Finally, we investigated real protein structures using a previously published data set that identified evolutionarily conserved rare codons in Escherichia coli genes and associated such codons with cotranslational folding intermediates. We found that protein substructures preceding conserved rare codons tend to have lower contact orders, in line with our finding that lower contact order proteins are more likely to fold cotranslationally. Our work shows how evolutionary selection pressure can cause proteins with local contact topologies to evolve cotranslational folding., (Copyright © 2020 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

CD137 (TNFRSF9, 4-1BB) agonist antibodies (mAb) have demonstrated potent antitumor activity with memory response while causing hepatotoxicity in mouse models. In clinical trials, the degrees of liver toxicity of anti-CD137 vary from grade 4 transaminitis (urelumab) to nonexistent (utomilumab). To exploit the antitumor potential of CD137 signaling, we identified a new class of CD137 agonist mAbs with strong antitumor potency without significant transaminitis in vivo compared with CD137 agonists previously reported. These mAbs are cross-reactive to mouse and cynomolgus monkey and showed cross-linking-dependent T-cell costimulation activity in vitro Antitumor efficacy was maintained in Fc gamma receptor (FcγR) III-deficient mice but diminished in FcγRIIB-deficient mice, suggesting the critical role for FcγRIIB to provide cross-linking in vivo Interestingly, a single dose of an affinity-reduced variant was sufficient to control tumor growth, but a higher affinity variant did not improve efficacy. These observations suggest that binding epitope and FcγR interaction, but not necessarily high affinity, are important for antitumor efficacy and reduced liver toxicity of CD137 mAb. Our study suggests the possibility of CD137 agonist therapy with improved safety profile in humans., (©2020 American Association for Cancer Research.)

Compared to individuals in lower positions of power, higher-power individuals are theorized to be less motivated to attend to social cues. In support of this theory, previous research has consistently documented negative correlations between social class and emotion perception. Prior studies, however, were limited by the size and diversity of the participant samples as well as the systematicity with which social class and emotion perception were operationalized. Here, we examine the generalizability of prior research across 10,000+ total participants. In an initial modest sample, (n = 179), Study 1 partially replicated past results: emotion identification correlated negativity with subjective social class (β = -0.15, 95% CI = [-0.28,-0.02]) and one of two objective social class measures (participant education β = -0.15, 95% CI = [-0.03,-0.01]). Studies 2-4 followed up on Study 1's mixed results for objective social class in three much larger samples. These results diverged from past literature. In Study 2, complex emotion identification correlated non-significantly with participant education (β = 0.02, p = 0.25; 95% CI = [-0.01, 0.05], n = 2,726), positively with childhood family income (β = 0.03, 95% CI = [0.01,0.06], n = 4,312), and positively with parental education (β = 0.06, 95% CI = [0.04,0.09], n = 4,225). In Study 3, basic emotion identification correlated positively with participant education (β = 0.05, 95% CI = [0.02, 0.09]), n = 2,564). In Study 4, basic emotion discrimination correlated positively with participant education (β = 0.09, 95% CI = [0.05,0.13], n = 2,079), positively with parental education (β = 0.06, 95% CI = [0.02,0.09], n = 3,225), and non-significantly with childhood family income (β = 0.2, 95% CI = [0.01,0.07], n = 3,272). Results remained similar when restricting analyses to U.S.-based participants. Taken together, these findings suggest that previously reported negative correlations between emotion perception and social class may generalize poorly past select samples and/or subjective measures of social class. Data from the three large web-based samples used in Studies 2-4 are available at osf.io/jf7r3 as normative datasets and to support future investigations of these and other research questions., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To investigate the temperature dependence of the resonance frequency of lipid-dissolved xenon (LDX) and to assess the accuracy of LDX-based MR thermometry., Methods: The chemical shift temperature dependence of water protons, methylene protons, and LDX was measured from samples containing tissues with varying fat contents using a high-resolution NMR spectrometer. LDX results were then used to acquire relative and absolute temperature maps in vivo and the results were compared with PRF-based MR thermometry., Results: The temperature dependence of proton resonance frequency (PRF) is strongly affected by the specific distribution of water and fat. A redistribution of water and fat compartments can reduce the apparent temperature dependence of the water chemical shift from -0.01 ppm/°C to -0.006 ppm, whereas the LDX chemical shift shows a consistent temperature dependence of -0.21 ppm/°C. The use of the methylene protons resonance frequency as internal reference improves the accuracy of LDX-based MR thermometry, but degrades that of PRF-based MR thermometry, as microscopic susceptibility gradients affected lipid and water spins differently., Conclusion: The LDX resonance frequency, with its higher temperature dependence, provides more accurate and precise temperature measurements, both in vitro and in vivo. More importantly, the resonance frequency of nearby methylene protons can be used to extract absolute temperature information. Magn Reson Med 78:1070-1079, 2017. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

Objective: It was previously demonstrated that daclizumab therapy normalizes cellular cerebrospinal fluid (CSF) abnormalities typical of multiple sclerosis (MS) in the majority of treated patients. However, CSF cells represent only the mobile portion of intrathecal immune responses. Therefore, we asked whether daclizumab also reverses compartmentalized inflammation and if not, whether residual inflammation correlates with clinical response to the drug., Methods: Forty MS patients treated with an intravenous or subcutaneous injection of daclizumab were followed for up to 16 years in two open-label clinical trials. MRI contrast-enhancing lesions (CELs), clinical scales, and CSF biomarkers quantified residual disease., Results: Rapid decreases in CELs, sustained throughout the observation period, were observed with daclizumab treatment. Daclizumab therapy induced modest but statistically significant ( P < 0.0001) decreases in CSF levels of T-cell activation marker CD27 and IgG index. Interleukin 2 (IL-2) CSF levels increased from baseline levels during treatment, consistent with reduced IL-2 consumption by T cells, as a consequence of daclizumab's saturation of high-affinity IL-2 receptors. CSF levels of IL-12p40, chitinase-3-like protein-1 (CHI3L1), chemokine C-X-C motif ligand 13, and neurofilament light chain (NFL) were also significantly reduced by daclizumab. Among them, inhibition of CHI3L1 correlated with inhibition of NFL and with lack of disease progression., Interpretation: These observations confirm daclizumab's direct pharmacodynamics effects on immune cells within central nervous system tissues and identify inhibition of CSF biomarkers of myeloid lineage as a stronger determinant of reduction in clinical MS activity than inhibition of biomarkers of adaptive immunity.

Enavatuzumab is a humanized IgG1 anti-TWEAK receptor monoclonal antibody that was evaluated in a phase I clinical study for the treatment of solid malignancies. The current study was to determine whether and how myeloid effector cells were involved in postulated mechanisms for its potent antitumor activity in xenograft models. The initial evidence for a role of effector cells was obtained in a subset of tumor xenograft mouse models whose response to enavatuzumab relied on the binding of Fc of the antibody to Fc γ receptor. The involvement of effector cells was further confirmed by immunohistochemistry, which revealed strong infiltration of CD45 + effector cells into tumor xenografts in responding models, but minimal infiltration in nonresponders. Consistent with the xenograft studies, human effector cells preferentially migrated toward in vivo -responsive tumor cells treated by enavatuzumab in vitro , with the majority of migratory cells being monocytes. Conditioned media from enavatuzumab-treated tumor cells contained elevated levels of chemokines, which might be responsible for enavatuzumab-triggered effector cell migration. These preclinical studies demonstrate that enavatuzumab can exert its potent antitumor activity by actively recruiting and activating myeloid effectors to kill tumor cells. Enavatuzumab-induced chemokines warrant further evaluation in clinical studies as potential biomarkers for such activity.

Background: Prescriptive analytics is a concept combining statistical and computer sciences to prescribe an optimal course of action, based on predictions of possible future events. In this simulation study we investigate using prescriptive analytics to recommend optimal in-brace corrections for braced Adolescent Idiopathic Scoliosis (AIS) patients. The objectives were to estimate the efficacy of these recommendations, ultimately working toward improved brace design protocols., Methods: Data was obtained for 90 AIS patients who had finished brace treatment at our center (60 full-time and 30 nighttime braces). Rates of ≥6 degree progression were 53% for daytime and 30% for nighttime braces. A modeling technique previously developed by our group was used to predict these patients' likely treatment outcomes given a range of in-brace corrections - the model was blinded to the true outcomes during this process. Each patient's 'recommended' correction was identified as the least aggressive correction resulting in a desirable predicted outcome. The efficacy of these recommendations was estimated using a technique called "clinical trial simulation" (CTS). This technique used a statistical model to predict progression rate under the model-recommended treatment, and compared it to the true progression rate, observed retrospectively, under the actual treatment. Significance was calculated using a permutation test., Results: Model-recommended corrections ranged from 20%-58% for daytime and 65%-130% for nighttime braces, roughly corresponding with previous literature. Interestingly, in 37% of cases the recommended correction was less than that which had actually been applied, suggesting some opportunity for less aggressive (more comfortable) braces without compromising treatment outcome. The CTS estimated 26% fewer progressive cases using the model-recommended in-brace correction, over the actual correction observed retrospectively in the charts (p=0.05). The patients whose correction decreased under the model's recommendation did not show an increased progression rate., Conclusions: Optimal correction may be less than the maximum achievable correction. The preliminary results suggest that considering model-generated recommendations during brace fitting could improve outcomes. Future work will expand the system to recommend wear-times as well as corrections, improving its clinical relevance. We envision this pilot demonstration to promote development of model-based decision support in scoliosis treatment, and prompt discussion on its future role.

Objective: Parenteral nutrition has been associated with metabolic and infectious complications in intensive care unit patients. The underlying mechanism for the high risk of complications is not known but may relate to the proinflammatory effects of soybean oil-based lipid emulsions, the only Food and Drug Administration-approved lipid formulation for clinical use., Design: Prospective, double-blind, randomized, controlled trial., Setting: Medical-surgical intensive care units from a major urban teaching hospital and a tertiary referral university hospital., Patients: Adult medical-surgical intensive care unit patients., Intervention: Parenteral nutrition containing soybean oil-based (Intralipid) or olive oil-based (ClinOleic) lipid emulsions., Measurements: Differences in hospital clinical outcomes (nosocomial infections and noninfectious complications), hospital length of stay, glycemic control, inflammatory and oxidative stress markers, and granulocyte and monocyte functions between study groups., Results: A total of 100 patients were randomized to either soybean oil-based parenteral nutrition or olive oil-based parenteral nutrition for up to 28 days. A total of 49 patients received soybean oil-based parenteral nutrition (age 51 ± 15 yrs, body mass index 27 ± 6 kg/m2, and Acute Physiology and Chronic Health Evaluation II score 15.5 ± 7 [±SD]), and a total of 51 patients received olive oil-based lipid emulsion in parenteral nutrition (age 46 ± 19 yrs, body mass index 27 ± 8 kg/m2, and Acute Physiology and Chronic Health Evaluation II score 15.1 ± 6 [±SD]) for a mean duration of 12.9 ± 8 days. The mean hospital blood glucose concentration during parenteral nutrition was 129 ± 14 mg/dL, without differences between groups. Patients treated with soybean oil-based and olive oil-based parenteral nutrition had a similar length of stay (47 ± 47 days and 41 ± 36 days, p = .49), mortality (16.3% and 9.8%, p = .38), nosocomial infections (43% vs. 57%, p = .16), and acute renal failure (26% vs. 18%, p = .34). In addition, there were no differences in inflammatory and oxidative stress markers or in granulocyte and monocyte functions between groups., Conclusion: The administration of parenteral nutrition containing soybean oil-based and olive oil-based lipid emulsion resulted in similar rates of infectious and noninfectious complications and no differences in glycemic control, inflammatory and oxidative stress markers, and immune function in critically ill adults.

Understanding intraspecific geographic variation in animal signals poses a challenging evolutionary problem. Studies addressing geographic variation typically focus on signals used in mate-choice, however, geographic variation in intrasexual signals involved in competition is also known to occur. In Polistes dominulus paper wasps, females have black facial spots that signal dominance: individuals wasps with more complex 'broken' facial patterns are better fighters and are avoided by rivals. Recent work suggests there is dramatic geographic variation in these visual signals of quality, though this variation has not been explicitly described or quantified. Here, we analyze variation in P. dominulus signals across six populations and explore how environmental conditions may account for this variation. Overall, we found substantial variation in facial pattern brokenness across populations and castes. Workers have less broken facial patterns than gynes and queens, which have similar facial patterns. Strepsipteran parasitism, body size and temperature are all correlated with the facial pattern variation, suggesting that developmental plasticity likely plays a key role in this variation. First, the extent of parasitism varies across populations and parasitized individuals have lower facial pattern brokenness than unparasitized individuals. Second, there is substantial variation in body size across populations and a weak but significant relationship between facial pattern brokenness and body size. Wasps from populations with smaller body size (e.g. Italy) tend to have less broken facial patterns than wasps from populations with larger body size (e.g. New York, USA). Third, there is an apparent association between facial patterns and climate, with wasp from cooler locations tending to have higher facial pattern brokenness than wasps from warmer locations. Additional experimental work testing the causes and consequences of facial pattern variation will be important, as geographic variation in signals has important consequences for the evolution of communication systems and social behavior.

We present the application of THz plasmonics in imaging dielectric objects embedded in metal-filled media. By exploiting the time domain information from the transmitted pulse, signatures of the objects were observed. To enhance the low quality images acquired through THz time domain spectroscopy, a super-resolution image processing technique was applied. It is shown that pulse arrival time and phase magnitude information compared to the integrated instantaneous power of the transmitted pulse provides more detailed images of the embedded object.

PET was used in a cross-linguistic study to determine whether neural mechanisms subserving pitch perception differ as a function of linguistic relevance. We compared tone perception in 12 native Mandarin speakers, who use tonal patterns to distinguish lexical meaning, with that of 12 native speakers of a nontone language, English. Subjects were scanned under two conditions: a silent resting baseline and a tonal task involving discrimination of pitch patterns in Mandarin words. Both groups showed common regions of CBF increase, but only Mandarin speakers showed additional activation in frontal, parietal, and parieto-occipital regions of the left hemisphere; this latter finding indicates that language experience may influence brain circuitry in the processing of auditory cues. In contrast, only the English group showed activity in the right inferior frontal cortex, consistent with a right-hemispheric role in pitch perception., (Copyright 2001 Academic Press.)

Positron emission tomography (PET) was used to investigate cerebral organization in seven subjects who had Mandarin Chinese as their native language (L1), and learned English (L2) later in life. When activation from word repetition was subtracted from verb generation in L1 and L2, CBF increases were observed for both languages in left inferior frontal, dorsolateral frontal, temporal and parietal cortices, and right cerebellum. Direct comparison of the difference between verb generation and word repetition in L1 and L2 revealed no significant differences. Within-subject analysis of verb generation minus word repetition yielded CBF increases in left frontal cortex for all individuals for L1 and L2, and a comparison of differences yielded no spatial separation in frontal peaks. We argue for shared neural substrates even for such contrasting languages as Mandarin and English.

Objective: To study the chemical constituents of essential oil from the root and rhizome of Valeriana alternifolia., Method: The essential oil was extracted by steam distillation. The components were separated and identified by gas chromatography-mass spectrometry and elucidated on the standard mass spectral data and the percentages were determined by gas chromatographic area normalization method., Result: Twenty-eight constituents were identified, which make up 64.05% of the oil., Conclusion: Bornyl acetate is the main constituent, and other constituents include borneol, terpinyl acetate, alpha-curcumene, camphene, isovaleric acid, trans-beta-farnesene, beta-bisabolene, etc.