Virus-specific CD4(+) T cells are key orchestrators of host responses to viral infection yet, compared with their CD8(+) T cell counterparts, remain poorly characterized at the single cell level. ...Here we use nine MHC II-epitope peptide tetramers to visualize human CD4(+) T cell responses to Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis (IM), a disease associated with large virus-specific CD8(+) T cell responses. We find that, while not approaching virus-specific CD8(+) T cell expansions in magnitude, activated CD4(+) T cells specific for epitopes in the latent antigen EBNA2 and four lytic cycle antigens are detected at high frequencies in acute IM blood. They then fall rapidly to values typical of life-long virus carriage where most tetramer-positive cells display conventional memory markers but some, unexpectedly, revert to a naive-like phenotype. In contrast CD4(+) T cell responses to EBNA1 epitopes are greatly delayed in IM patients, in line with the well-known but hitherto unexplained delay in EBNA1 IgG antibody responses. We present evidence from an in vitro system that may explain these unusual kinetics. Unlike other EBNAs and lytic cycle proteins, EBNA1 is not naturally released from EBV-infected cells as a source of antigen for CD4(+) T cell priming.
While the use of complementary, alternative and integrative medicine (CAIM) is substantial, it continues to exist at the periphery of allopathic medicine. Understanding the attitudes of medical ...students toward CAIM will be useful in understanding future integration of CAIM and allopathic medicine. This study was conducted to develop and evaluate an instrument and assess medical students' attitudes toward CAIM. The Complementary, Alternative and Integrative Medicine Attitudes Questionnaire (CAIMAQ) was developed by a panel of experts in CAIM, allopathic medicine, medical education and survey development. A total of 1770 CAIMAQ surveys (51% of US medical schools participated) were obtained in a national sample of medical students in 2007. Factor analysis of the CAIMAQ revealed five distinct attitudinal domains: desirability of CAIM therapies, progressive patient/physician health care roles, mind-body-spirit connection, principles of allostasis and a holistic understanding of disease. The students held the most positive attitude for the “mind-body-spirit connection” and the least positive for the “desirability of CAIM therapies”. This study provided initial support for the reliability of the CAIMAQ. The survey results indicated that in general students responded more positively to the principles of CAIM than to CAIM treatment. A higher quality of CAIM-related medical education and expanded research into CAIM therapies would facilitate appropriate integration of CAIM into medical curricula. The most significant limitation of this study is a low response rate, and further work is required to assess more representative populations in order to determine whether the relationships found in this study are generalizable.
The rising popularity of complementary and alternative medicine (CAM) in child and adolescent psychiatry raises unique ethical and legal concerns for psychiatrists and other conventional health care ...providers. This article explores these concerns and provides clinical advice for promoting patient health and safety while minimizing the psychiatrist's risk. Although any departure from the conventional standard of care is a potential risk, the risk of malpractice liability for practicing integrative medicine in child and adolescent psychiatry is low. CAM is most safely recommended from a legal standpoint when there is some published evidence of safety and efficacy.
This study examined whether a traditional low-impact mind-body exercise, Tai Chi, affects health-related quality-of-life (HRQOL) and headache impact in an adult population suffering from tension-type ...headaches. Forty-seven participants were randomly assigned to either a 15 week intervention program of Tai Chi instruction or a wait-list control group. HRQOL (SF-36v2) and headache status (HIT-6™) were obtained at baseline and at 5, 10 and 15 weeks post-baseline during the intervention period. Statistically significant (P < 0.05) improvements in favor of the intervention were present for the HIT score and the SF-36 pain, energy/fatigue, social functioning, emotional well-being and mental health summary scores. A 15 week intervention of Tai Chi practice was effective in reducing headache impact and also effective in improving perceptions of some aspects of physical and mental health.
Jordan dramatically strengthened the level of intellectual property protection it provides for pharmaceutical products in consequence of joining the World Trade Organization in 2000 and signing a ...Free Trade Agreement with the United States in 2001. This study assesses the impact of higher levels of intellectual property protection on access to medicines by quantifying the effects on the private retail pharmaceutical market of delayed market entry of generic products. Adjusted for increased sales volume and inflation, from 1999 to 2004 there was a 17% increase in total annual expenditure for medicines in Jordan. When assessing originator medicines that were marketed in both 1999 and 2004, and for which there were generic equivalents, the weighted average price of originator medicines increased while the weighted average price of equivalent generic medicines decreased. Delayed market entry of generics due to enhanced intellectual property protection is estimated to have cost Jordanian private consumers approximately 18 million U.S. dollars in 2004. Jordan should consider amending its current regulatory scheme on data protection and amending the Unfair Competition and Trade Secrets Law of 2000. Jordan should also consider increased spending on public health to offset the adverse impact on consumers of strengthening its intellectual property protection relevant to pharmaceutical products.
In the general population, a high body mass index (BMI; in kg/m2) is associated with increased cardiovascular disease and all-cause mortality. However, the effect of overweight (BMI: 25-30) or ...obesity (BMI: >30) in patients with chronic kidney disease (CKD) undergoing maintenance hemodialysis (MHD) is paradoxically in the opposite direction; ie, a high BMI is associated with improved survival. Although this "reverse epidemiology" of obesity or dialysis-risk-paradox is relatively consistent in MHD patients, studies in CKD patients undergoing peritoneal dialysis have yielded mixed results. Growing confusion has developed among physicians, some of whom are no longer confident about whether to treat obesity in CKD patients. A similar reverse epidemiology of obesity has been described in geriatric populations and in patients with chronic heart failure (CHF). Possible causes of the reverse epidemiology of obesity include a more stable hemodynamic status, alterations in circulating cytokines, unique neurohormonal constellations, endotoxin-lipoprotein interaction, reverse causation, survival bias, time discrepancies among competitive risk factors, and malnutrition-inflammation complex syndrome. Reverse epidemiology may have significant clinical implications in the management of dialysis, CHF, and geriatric patients, ie, populations with extraordinarily high mortality. Exploring the causes and consequences of the reverse epidemiology of obesity in dialysis patients can enhance our insights into similar paradoxes observed for other conventional risk factors, such as blood pressure and serum cholesterol and homocysteine concentrations, and in other populations such as those with CHF, advanced age, cancer, or AIDS. Weight-gaining interventional studies in dialysis patients are urgently needed to ascertain whether they can improve survival and quality of life.
Stochasticity is a core component of ecology, as it underlies key processes that structure and create variability in nature. Despite its fundamental importance in ecological systems, the concept is ...often treated as synonymous with unpredictability in community ecology, and studies tend to focus on single forms of stochasticity rather than taking a more holistic view. This has led to multiple narratives for how stochasticity mediates community dynamics. Here, we present a framework that describes how different forms of stochasticity (notably demographic and environmental stochasticity) combine to provide underlying and predictable structure in diverse communities. This framework builds on the deep ecological understanding of stochastic processes acting at individual and population levels and in modules of a few interacting species. We support our framework with a mathematical model that we use to synthesize key literature, demonstrating that stochasticity is more than simple uncertainty. Rather, stochasticity has profound and predictable effects on community dynamics that are critical for understanding how diversity is maintained. We propose next steps that ecologists might use to explore the role of stochasticity for structuring communities in theoretical and empirical systems, and thereby enhance our understanding of community dynamics
OBJECTIVE:To compare the survival outcomes associated with clinical and pathological response in pancreatic ductal adenocarcinoma (PDAC) patients receiving neoadjuvant chemotherapy (NAC) with ...FOLFIRINOX (FLX) or gemcitabine/nab-paclitaxel (GNP) followed by curative-intent pancreatectomy.
BACKGROUND:Newer multiagent NAC regimens have resulted in improved clinical and pathological responses in PDAC; however, the effects of these responses on survival outcomes remain unknown.
METHODS:Clinicopathological and survival data of PDAC patients treated at 7 academic medical centers were analyzed. Primary outcomes were overall survival (OS), local recurrence-free survival (L-RFS), and metastasis-free survival (MFS) associated with biochemical (CA 19–9 decrease ≥50% vs <50%) and pathological response (complete, pCR; partial, pPR or limited, pLR) following NAC.
RESULTS:Of 274 included patients, 46.4% were borderline resectable, 25.5% locally advanced, and 83.2% had pancreatic head/neck tumors. Vein resection was performed in 34.7% and 30-day mortality was 2.2%. R0 and pCR rates were 82.5% and 6%, respectively. Median, 3-year, and 5-year OS were 32 months, 46.3%, and 30.3%, respectively. OS, L-RFS, and MFS were superior in patients with marked biochemical response (CA 19–9 decrease ≥50% vs <50%; OS42.3 vs 24.3 months, P < 0.001; L-RFS-27.3 vs 14.1 months, P = 0.042; MFS-29.3 vs 13 months, P = 0.047) and pathological response pCR vs pPR vs pLROS- not reached (NR) vs 40.3 vs 26.1 months, P < 0.001; L-RFS-NR vs 24.5 vs 21.4 months, P = 0.044; MFS-NR vs 23.7 vs 20.2 months, P = 0.017. There was no difference in L-RFS, MFS, or OS between patients who received FLX or GNP.
CONCLUSION:This large, multicenter study shows that improved biochemical, pathological, and clinical responses associated with NAC FLX or GNP result in improved OS, L-RFS, and MFS in PDAC. NAC with FLX or GNP has similar survival outcomes.
Understanding the magnitude, nature, and forcing mechanisms of past abrupt changes in Indian Summer Monsoon (ISM) strength is central to characterizing future manifestations in the face of global ...climate change, particularly at centennial time scales. Here we summarize a 6200 year record of oxygen isotopes from Lake Qilu in Yunnan Province, China. The lake is sensitive to changes in precipitation-evaporation balance and precipitates calcite, potentially providing insight into past hydroclimate through oxygen isotope analysis. Beginning at 5200 cal years BP, oxygen isotopes shift to higher values, indicative of a period of aridity and lower lake levels which persist until 3600 cal years BP. Thereafter, lake levels are extraordinarily stable until 1500 cal years BP. At 1500 cal years BP, measurable anthropogenic impacts occur, resulting in the delivery of red, iron-rich catchment soil to the lake and higher oxygen isotope values. These changes are likely the result of land clearance for the expansion of agricultural activities. The Qilu record is remarkably consistent with the record from Xingyun Lake, 10 km to the north, strongly suggesting that regional climate drivers are responsible for the changes after 5200 cal years BP and then the stability from 3600 to 1500 cal years BP. Comparison of both these records with Dongge Cave illustrate the importance of evaporative enrichment in driving higher oxygen isotope values from 5200 to 3600 cal years BP.
•A lacustrine archive of the Indian Summer Monsoon using oxygen isotopes.•Stable lake levels prior to 5200 cal years BP.•Rapid drop in lake level from 5200 to 3600 cal years BP.•Anthropogenic influence after 1500 cal years BP.•Trends very similar to nearby Xingyun Lake.
Background
The ACS‐NSQIP risk calculator predicts perioperative risk. This study tested the calculator's ability to predict risk for outcomes following retroperitoneal sarcoma (RPS) resection.
...Methods
The United States Sarcoma Collaborative database was queried for adults who underwent RPS resection. Estimated risk for outcomes was calculated twice in the risk calculator, once using sarcoma‐specific CPT codes and once using codes indicative of most comorbid organ resection (eg nephrectomy). ROC curves were generated, with area under the curve (AUC) and Brier scores reported to assess discrimination and calibration. An AUC < 0.6 was considered ineffective discrimination. A negative ▲ Brier indicated improved performance relative to baseline outcome rates.
Results
In total, 482 patients were identified with a 42.3% 90‐day complication rate. Discrimination was poor for all outcomes except “all complications” and “renal failure.” Baseline outcome rates were better predictors than calculator estimates except for “discharge to nursing or rehab facility” and “renal failure.” Replacing sarcoma‐specific CPT codes with resection‐specific codes did not improve performance.
Conclusion
The ACS‐NSQIP risk calculator poorly predicted outcomes following RPS resection. Changing sarcoma‐specific CPT to resection‐specific codes did not improve performance. Comorbidities in the calculator may not effectively capture perioperative risk. Future work should evaluate a sarcoma‐specific calculator.
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