The neural basis of swap errors in working memory.

When making decisions in a cluttered world, humans and other animals often have to hold multiple items in memory at once-such as the different items on a shopping list. Psychophysical experiments in humans and other animals have shown remembered stimuli can sometimes become confused, with participants reporting chimeric stimuli composed of features from different stimuli. In particular, subjects will often make "swap errors" where they misattribute a feature from one object as belonging to another object. While swap errors have been described behaviorally and theoretical explanations have been proposed, their neural mechanisms are unknown. Here, we elucidate these neural mechanisms by analyzing neural population recordings from monkeys performing two multistimulus working memory tasks. In these tasks, monkeys were cued to report the color of an item that either was previously shown at a corresponding location or will be shown at the corresponding location. Animals made swap errors in both tasks. In the neural data, we find evidence that the neural correlates of swap errors emerged when correctly remembered information is selected from working memory. This led to a representation of the distractor color as if it were the target color, underlying the eventual swap error. We did not find consistent evidence that swap errors arose from misinterpretation of the cue or errors during encoding or storage in working memory. These results provide evidence that swap errors emerge during selection of correctly remembered information from working memory, and highlight this selection as a crucial-yet surprisingly brittle-neural process.

Redundant representations are required to disambiguate simultaneously presented complex stimuli.

A pedestrian crossing a street during rush hour often looks and listens for potential danger. When they hear several different horns, they localize the cars that are honking and decide whether or not they need to modify their motor plan. How does the pedestrian use this auditory information to pick out the corresponding cars in visual space? The integration of distributed representations like these is called the assignment problem, and it must be solved to integrate distinct representations across but also within sensory modalities. Here, we identify and analyze a solution to the assignment problem: the representation of one or more common stimulus features in pairs of relevant brain regions-for example, estimates of the spatial position of cars are represented in both the visual and auditory systems. We characterize how the reliability of this solution depends on different features of the stimulus set (e.g., the size of the set and the complexity of the stimuli) and the details of the split representations (e.g., the precision of each stimulus representation and the amount of overlapping information). Next, we implement this solution in a biologically plausible receptive field code and show how constraints on the number of neurons and spikes used by the code force the brain to navigate a tradeoff between local and catastrophic errors. We show that, when many spikes and neurons are available, representing stimuli from a single sensory modality can be done more reliably across multiple brain regions, despite the risk of assignment errors. Finally, we show that a feedforward neural network can learn the optimal solution to the assignment problem, even when it receives inputs in two distinct representational formats. We also discuss relevant results on assignment errors from the human working memory literature and show that several key predictions of our theory already have support.

Sickle cell allele HBB-rs334(T) is associated with decreased risk of childhood Burkitt lymphoma in East Africa.

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that significantly contributes to childhood cancer burden in sub-Saharan Africa. Plasmodium falciparum, which causes malaria, is geographically associated with BL, but the evidence remains insufficient for causal inference. Inference could be strengthened by demonstrating that mendelian genes known to protect against malaria-such as the sickle cell trait variant, HBB-rs334(T)-also protect against BL. We investigated this hypothesis among 800 BL cases and 3845 controls in four East African countries using genome-scan data to detect polymorphisms in 22 genes known to affect malaria risk. We fit generalized linear mixed models to estimate odds ratios (OR) and 95% confidence intervals (95% CI), controlling for age, sex, country, and ancestry. The ORs of the loci with BL and P. falciparum infection among controls were correlated (Spearman's ρ = 0.37, p = .039). HBB-rs334(T) was associated with lower P. falciparum infection risk among controls (OR = 0.752, 95% CI 0.628-0.9; p = .00189) and BL risk (OR = 0.687, 95% CI 0.533-0.885; p = .0037). ABO-rs8176703(T) was associated with decreased risk of BL (OR = 0.591, 95% CI 0.379-0.992; p = .00271), but not of P. falciparum infection. Our results increase support for the etiological correlation between P. falciparum and BL risk.

Liposomal Bupivacaine Transversus Abdominis Plane Blocks in Laparoscopic Colorectal Resections: A Single-Institution Randomized Controlled Trial.

BACKGROUND: Transversus abdominis plane blocks improve postoperative pain after colon and rectal resections, but the benefits of liposomal bupivacaine use for these blocks have not been clearly demonstrated. OBJECTIVE: This study aimed to determine whether using liposomal bupivacaine in transversus abdominis plane blocks improves postoperative pain and reduces opioid use after colorectal surgery compared to standard bupivacaine. DESIGN: This study was a single-blinded, single-institution, prospective randomized controlled trial comparing liposomal bupivacaine to standard bupivacaine in transversus abdominis plane blocks in patients undergoing elective colon and rectal resections. SETTINGS: This study was conducted at a single-institution academic medical center with 6 staff colorectal surgeons and 2 colorectal surgery fellows. PATIENTS: Ninety-six patients aged 18 to 85 years were assessed for eligibility; 76 were included and randomly assigned to 2 groups of 38 patients. INTERVENTIONS: Patients in the experimental group received liposomal bupivacaine transversus abdominis plane blocks, whereas the control group received standard bupivacaine blocks. MAIN OUTCOME MEASURES: The primary outcome was maximum pain score on postoperative day 2. Secondary outcomes included daily maximum and average pain scores in the 3 days after surgery, as well as daily morphine milligram equivalent use and length of hospital stay. RESULTS: Patients receiving liposomal bupivacaine blocks had lower maximum pain scores on the day of surgery (mean, 6.5 vs 7.7; p = 0.008). No other difference was found between groups with respect to maximum or average pain scores at any time point postoperatively, nor was there any difference in morphine milligram equivalents used or length of stay (median, 3.1 d). LIMITATIONS: This was a single-institution study with only patients blinded to group assignment. CONCLUSIONS: Liposomal bupivacaine use in transversus abdominis plane blocks for patients undergoing laparoscopic colorectal resections does not seem to improve postoperative pain, nor does it reduce narcotic use or decrease length of stay. Given its cost, use of liposomal bupivacaine in transversus abdominis plane blocks is not justified for colon and rectal resections. See Video Abstract at http://links.lww.com/DCR/B979 . CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Identifier: NCT04781075. BLOQUEOS TAP DE BUPIVACANA LIPOSOMAL EN RESECCIONES COLORRECTALES LAPAROSCPICAS UN ENSAYO CONTROLADO ALEATORIO DE UNA SOLA INSTITUCIN: ANTECEDENTES:Los bloqueos del plano transverso del abdomen, mejoran el dolor posoperatorio después de las resecciones de colon y recto, pero los beneficios del uso de bupivacaína liposomal para estos bloqueos, no se han demostrado claramente.OBJETIVO:Investigar la eficacia de la inyección con tejido adiposo autólogo recién recolectado en fístulas anales criptoglandulares complejas.DISEÑO:Ensayo controlado, aleatorio, prospectivo, simple ciego, de una sola institución, que compara la bupivacaína liposomal con la bupivacaína estándar en bloqueos del plano transverso del abdomen, en pacientes sometidos a resecciones electivas de colon y recto. Identificador de ClinicalTrials.gov : NCT04781075.ENTORNO CLINICO:Centro médico académico de una sola institución con seis cirujanos de plantilla y becarios de cirugía colorrectal.PACIENTES:Se evaluó la elegibilidad de 96 pacientes de 18 a 85 años; 76 fueron incluidos y aleatorizados en dos grupos de 38 pacientes.INTERVENCIONES:Los pacientes del grupo experimental recibieron bloqueos del plano transverso del abdomen con bupivacaína liposomal, mientras que el grupo de control recibió bloqueos de bupivacaína estándar.PRINCIPALES MEDIDAS DE VALORACION:El resultado primario fue la puntuación máxima de dolor en el segundo día posoperatorio. Los resultados secundarios incluyeron las puntuaciones máximas y medias diarias de dolor en los 3 días posteriores a la cirugía, así como el uso diario equivalente en miligramos de morfina y la duración de la estancia hospitalaria.RESULTADOS:Los pacientes que recibieron bloqueos de bupivacaína liposomal, tuvieron puntuaciones máximas de dolor más bajas, el día de la cirugía (media 6,5 frente a 7,7, p = 0,008). No hubo ninguna otra diferencia entre los grupos con respecto a las puntuaciones de dolor máximas o promedio en cualquier momento después de la operación, ni hubo ninguna diferencia en los equivalentes de miligramos de morfina utilizados o la duración de la estancia (mediana de 3,1 días).LIMITACIONES:Estudio de una sola institución con cegamiento de un solo paciente.CONCLUSIONES:El uso de bupivacaína liposomal en bloqueos del plano transverso del abdomen, para pacientes sometidos a resecciones colorrectales laparoscópicas, no parece mejorar el dolor posoperatorio, ni reduce el uso de narcóticos ni la duración de la estancia hospitalaria. Dado su costo, el uso de bupivacaína liposomal en bloqueos TAP no está justificado para resecciones de colon y recto. Consulte Video Resumen en http://links.lww.com/DCR/B797 . Traducción Dr. Fidel Ruiz Healy.

Genetic and Pharmacological Disruption of Interleukin-1α Leads to Augmented Murine Aortic Aneurysm.

BACKGROUND: Interleukin-1 (IL-1) signaling has an established role as a cytokine signaling pathway important for progression of abdominal aortic aneurysms (AAAs). While the IL-1ß ligand and IL-1R1 have been previously investigated, the role of the IL-1α ligand in AAAs remains unknown. In this study, we sought to examine the role of IL-1α in AAAs using genetic and pharmacologic approaches. METHODS: Eight-week-old wild-type (WT) or IL-1α knock-out (KO) male and female mice (n = 10-16/group) underwent experimental AAA and were harvested 14 days following surgery to assess AAA size and characteristics. In separate studies, 8-week-old WT mice were treated with an inhibitor to IL-1α during AAA formation and harvested 14 days following surgery. Finally, WT and IL-1α KO mice were administered Anakinra, an IL-R1 inhibitor, during AAA formation to determine the effect of inhibiting IL-1R1 when IL-1α is knocked out. RESULTS: Male and female IL-1α KO mice had larger AAAs compared to WT AAAs (male: 153% vs. 89.2%, P = 0.0001; female: 86.6% vs. 63.5%, P = 0.02). IL-1α KO mice had greater elastin breakage (P = 0.01), increased levels of macrophage staining (P = 0.0045), and greater pro-metallo proteinase 2 (P = 0.02). Pharmacologic inhibition of WT male mice with an IL-1α neutralizing antibody resulted in larger AAAs (133.1% vs. 77.0%, P < 0.001). Finally, treatment of IL-1α KO male mice with Anakinra decreased AAA formation compared with vehicle control AAAs (Anakinra + IL-1α KO: 47.7% vs. WT: 147.1%; P = 0.0001). CONCLUSIONS: IL-1α disruption using either genetic or pharmacologic approaches worsens AAAs.

Nonlinear mixed selectivity supports reliable neural computation.

Neuronal activity in the brain is variable, yet both perception and behavior are generally reliable. How does the brain achieve this? Here, we show that the conjunctive coding of multiple stimulus features, commonly known as nonlinear mixed selectivity, may be used by the brain to support reliable information transmission using unreliable neurons. Nonlinearly mixed feature representations have been observed throughout primary sensory, decision-making, and motor brain areas. In these areas, different features are almost always nonlinearly mixed to some degree, rather than represented separately or with only additive (linear) mixing, which we refer to as pure selectivity. Mixed selectivity has been previously shown to support flexible linear decoding for complex behavioral tasks. Here, we show that it has another important benefit: in many cases, it makes orders of magnitude fewer decoding errors than pure selectivity even when both forms of selectivity use the same number of spikes. This benefit holds for sensory, motor, and more abstract, cognitive representations. Further, we show experimental evidence that mixed selectivity exists in the brain even when it does not enable behaviorally useful linear decoding. This suggests that nonlinear mixed selectivity may be a general coding scheme exploited by the brain for reliable and efficient neural computation.

Understanding the holistic experiences of living with a kidney transplant: an interpretative phenomenological study (protocol).

BACKGROUND: Currently very little is known about the perceptions and experiences of kidney transplant recipients from a qualitative perspective. As highlighted by the European Kidney Health Alliance recommendations, providing holistic care to kidney patients is important however this is currently an unmet care need in renal disease. It is imperative to understand patient experiences to ensure that they are included in key strategies and future renal service planning. Ignoring these important patient views means that there is a significant risk of inappropriate renal service provision and lack of adequate support impacting on overall health. METHOD: A purposive sampling strategy will recruit individuals currently living with a kidney transplant, 6 months to 5 years post-transplant. A maximum of 30 patients will be recruited between two Regional Nephrology units within the United Kingdom via clinical gatekeepers. In-depth interviews will be undertaken with participants living with a kidney transplant across the two sites. Interviews will be digitally-recorded, transcribed verbatim and subjected to interpretative phenomenological analysis. DISCUSSION: Renal healthcare professionals need to understand more than the biological impact of receiving a kidney transplant. Understanding the holistic and multi-domain experiences that these patients experience will help healthcare professionals to recognize the needs of this group and ensure more responsive care.

A novel swine model of abdominal aortic aneurysm.

OBJECTIVE: Few large-animal models exist for the study of aortic aneurysms. ß-Aminopropionitrile (BAPN) is a compound known to cause aortic aneurysms by inhibiting lysyl oxidase, a collagen cross-linking enzyme. It is hypothesized that BAPN plus aneurysm induction surgery would result in significant aneurysm formation in swine with biologic properties similar to human disease. METHODS: Initial experiments were performed in uncastrated male swine not treated with BAPN (surgery alone). Subsequently, uncastrated male swine were fed BAPN (0.15 g/kg) for 7 days before undergoing surgery; the infrarenal aorta was circumferentially dissected and measured, balloon dilated, and perfused with elastase (500 units) and type I collagenase (8000 units), with extraluminal elastase application. In the BAPN groups, daily BAPN feedings continued until swine harvest at postoperative days 7, 14, and 28. RESULTS: Swine undergoing surgery alone (n = 12) had significantly less dilation at 28 days compared with BAPN + surgery swine (51.9% ± 29.2% [0%-100%] vs 113.5% ± 30.2% [52.9%-146.2%]; P < .0003). Mean aortic dilation in animals undergoing treatment with surgery and BAPN was 86.9% ± 47.4% (range, 55.6%-157.1%), 105.4% ± 58.1% (50%-133.3%), and 113.5% ± 30.2% (52.9%-146.2%) at 7, 14, and 28 days, respectively. In the BAPN + surgery group, significant elastolysis was present at all time points, whereas aortic wall collagen content was not significantly different. Smooth muscle cells were significantly depleted at 14 and 28 days, and M1 macrophages were increased at 14 and 28 days (P < .05, all). Matrix metalloproteinase 2 was elevated at 7 days (P < .05). Multiple proinflammatory cytokines were elevated within the aortic wall of BAPN + surgery swine. CONCLUSIONS: BAPN plus surgery resulted in significantly larger aortic aneurysms than surgery alone and was critical to aneurysm formation in this novel swine model. Hallmarks of human disease, such as elastin fragmentation, smooth muscle cell depletion, macrophage infiltration, matrix metalloproteinase activation, and proinflammatory cytokine expression, were observed in BAPN-treated swine. This model better parallels many of the characteristics of human AAAs and may be suitable for prehuman drug trials.

Kaposi Sarcoma-Associated Herpesvirus in a Rural Ugandan Cohort, 1992-2008.

Background: The prevalence and titers of antibodies against Kaposi sarcoma-associated herpesvirus (KSHV) in rural Africa are not completely understood, nor are their trends over time in populations in which human immunodeficiency virus (HIV) is also endemic. We examined prevalence, titers, temporal trends, and determinants of anti-KSHV antibodies in each of 3 time periods (1990-1991, 1999-2000, and 2007-2008) within a long-standing, rural population-based cohort in southwestern Uganda. Methods: For each period, we measured antibodies to the K8.1 and ORF73 KSHV antigens in approximately 3000 people of all ages (1:1 sex ratio). Results: In all periods, KSHV prevalence increased rapidly through childhood to approximately 90% by age 15 years, plateauing at approximately 95% thereafter. Similarly, antibody titers, particularly against the lytic antigen K8.1, were among the highest seen and increased significantly with age, suggesting sustained viral replication in this population. Male sex was also independently associated with higher prevalence, whereas HIV coinfection was not. A modest reduction in prevalence among children was noted in the most recent period. Conclusions: KSHV seroprevalence and antibodies titers in this rural Ugandan population are the highest yet reported, perhaps reflecting frequent viral reactivation and persistently elevated transmission.

Erythropoiesis-stimulating agents significantly delay the onset of a regular transfusion need in nontransfused patients with lower-risk myelodysplastic syndrome.

BACKGROUND: The EUMDS registry is an unique prospective, longitudinal observational registry enrolling newly diagnosed patients with lower-risk myelodysplastic syndrome (MDS) from 17 European countries from both university hospitals and smaller regional hospitals. OBJECTIVE: The aim of this study was to describe the usage and clinical impact of erythropoiesis-stimulating agents (ESAs) in 1696 patients enrolled between 2008 and 2014. METHODS: The effects of ESAs on outcomes were assessed using proportional hazards models weighting observations by propensity to receive ESA treatment within a subset of anaemic patients with or without a regular transfusion need. RESULTS: ESA treatment (median duration of 27.5 months, range 0-77 months) was administered to 773 patients (45.6%). Outcomes were assessed in 897 patients (484 ESA treated and 413 untreated). ESA treatment was associated with a nonsignificant survival benefit (HR 0.82, 95% CI: 0.65-1.04, P = 0.09); this benefit was larger amongst patients without prior transfusions (P = 0.07). Amongst 539 patients for whom response to ESA treatment could be defined, median time to first post-ESA treatment transfusion was 6.1 months (IQR: 4.3-15.9 months) in those transfused before ESA treatment compared to 23.3 months (IQR: 7.0-47.8 months) in patients without prior transfusions (HR 2.4, 95% CI: 1.7-3.3, P < 0.0001). Responding patients had a better prognosis in terms of a lower risk of death (HR 0.65, 95% CI: 0.45-0.893, P = 0.018), whereas there was no significant effect on the risk of progression to acute myeloid leukaemia (HR 0.71, 95% CI: 0.39-1.29, P = 0.27). CONCLUSION: Appropriate use of ESAs can significantly delay the onset of a regular transfusion need in patients with lower-risk MDS.

What Is the Risk of Anastomotic Leak After Repeat Intestinal Resection in Patients With Crohn's Disease?

BACKGROUND: Approximately half of Crohn's patients require intestinal resection, and many need repeat resections. OBJECTIVE: The purpose of this study was to evaluate the increased risk of clinical anastomotic leak in patients with a history of previous intestinal resection undergoing repeat resection with anastomosis for Crohn's disease. DESIGN: This was a retrospective analysis of prospectively collected departmental data with 100% capture. SETTINGS: The study was conducted at the department of colorectal surgery in a tertiary care teaching hospital between July 2007 and March 2016. PATIENTS: A cohort of consecutive patients with Crohn's disease who were treated with intestinal resection and anastomosis, excluding patients with proximal fecal diversion, were included. The cohort was divided into 2 groups, those with no previous resection compared with those with previous resection. MAIN OUTCOME MEASURES: Clinical anastomotic leak within 30 days of surgery was measured. RESULTS: Of the 206 patients who met criteria, 83 patients had previous intestinal resection (40%). The 2 groups were similar in terms of patient factors, immune-suppressing medication use, and procedural factors. Overall, 20 clinical anastomotic leaks were identified (10% leak rate). There were 6 leaks (5%) detected in patients with no previous intestinal resection and 14 leaks (17%) detected in patients with a history of previous intestinal resection (p < 0.005). The OR of anastomotic leak in patients with Crohn's disease with previous resection compared with no previous resection was 3.5 (95% CI, 1.3-9.4). Patients with 1 previous resection (n = 53) had a leak rate of 13%, whereas patients with ≥2 previous resections (n = 30) had a leak rate of 23%. The number of previous resections correlated with increasing risk for clinical anastomotic leak (correlation coefficient = 0.998). LIMITATIONS: This was a retrospective study with limited data to perform a multivariate analysis. CONCLUSIONS: Repeat intestinal resection in patients with Crohn's disease is associated with an increased rate of anastomotic leakage when compared with initial resection despite similar patient, medication, and procedural factors. See Video Abstract at http://links.lww.com/DCR/A459.

Long-term safety assessment in children who received hydrolyzed protein formulas with Lactobacillus rhamnosus GG: a 5-year follow-up.

Extensively hydrolyzed (EH) formula with Lactobacillus rhamnosus GG (LGG) was demonstrated to alleviate cow's milk allergy (CMA) symptoms and promote faster acquisition of tolerance to cow's milk protein. We previously demonstrated that partially hydrolyzed (PH) and EH formulas with LGG supported normal growth in healthy-term infants through 120 days of age. The objective of the current study was to evaluate growth, development, and specific adverse events through 5 years of age in participants from that cohort who continued receiving study formula. Infants who completed a double-blind, randomized growth and tolerance study were eligible to continue receiving the assigned study formula through 1 year of age (control: EH casein formula, EHF, or one of two investigational formulas: EH casein formula with LGG (EHF-LGG) or a PH formula with LGG (PHF-LGG)) and participate in follow-up through 5 years of age. Anthropometric measures, behavior development, and specific adverse events were recorded. No significant differences in achieved weight and height or behavioral development outcomes at 3 or 5 years of age were observed among study groups. Few statistically significant differences in the incidence of specific infection-related events through years 3 or 5 were observed among study groups, none of which were considered clinically relevant. CONCLUSION: Extensively and partially hydrolyzed formulas with LGG were associated with normal growth and development and long-term safety through 5 years of age. What is Known: • Infants with cow's milk allergy often experience allergic manifestations that can lead to poor nutrition status and poor growth. • Providing partially hydrolyzed (PH) and EH formulas with or without LGG in infants can support normal growth in healthy-term infants. What is New: • This study provides long-term safety data for the first 5 years of life on the use of extensively and partially hydrolyzed formulas with LGG when fed through 1 year of age. • Extensively and partially hydrolyzed formulas with LGG are associated with normal growth, development, and long-term safety through 5 years of age.

Characterization of Pancreaticojejunal Anastomotic Healing in a Porcine Survival Model.

INTRODUCTION: Anastomotic leak after pancreaticoduodenectomy is the most important cause of postoperative morbidity and mortality. Histological studies of bowel anastomoses have provided valuable insights regarding causes of anastomotic failure. However, this crucial information is lacking for pancreatico-enteric anastomoses. METHODS: Pancreaticoduodenectomy was performed in a porcine model. Animals were survived up to 10 days and then the pancreatico-enteral anastomosis specimen was resected en bloc. Anastomotic bursting pressure was measured and histological sections of the anastomoses were examined. RESULTS: Six out of 8 animals had excellent healing of the anastomoses. One animal developed a clinically significant leak at the pancreaticoduodenal anastomosis (12.5%) and one animal had a subclinical duodeno-duodenal leak discovered on necropsy (12.5%). Both anastomoses that failed had a collagen-to-tissue ratio less than 40%. In contrast, none of the anastomoses with a ratio greater than 40% showed any evidence of disruption. CONCLUSION: Our results indicate that quantitative measurement of collagen deposition at the pancreatic anastomosis provides objective assessment of healing of the pancreatic anastomosis. A survival porcine model of pancreaticoduodenectomy results in a similar leak rate to published data on pancreaticoduodenectomy in humans and will be useful for future studies assessing novel pharmacologic or technical interventions aimed at improving outcomes.

Total pancreatectomy for pancreatic ductal adenocarcinoma: review of the National Cancer Data Base.

BACKGROUND: Total pancreatectomy is infrequently performed for pancreatic cancer. Perceived operative mortality and questionable survival benefit deter many surgeons. Clinical outcomes, described in single-center series, remain largely unknown. METHODS: The National Cancer Database was queried for cases of pancreatic ductal adenocarcinoma undergoing total pancreatectomy (1998-2011). Univariate survival analyses were performed for 21 variables: demographic (8), tumor characteristics (5), surgery outcomes (6), and adjuvant therapy (2). The Log-rank test of differences in Kaplan-Meier survival curves was used for categorical variables. Variables with p < 0.05 were included in a multivariate analysis. Cox proportional hazards regression was used to analyze continuous variables and multivariate models. RESULTS: 2582 patients with staging and survival data made up the study population. 30-day mortality was 5.5%. Median overall survival was 15 months, with 1, 3, and 5-year survival rates of 60%, 22%, and 13%, respectively. Age, facility type, tumor size and grade, lymph node positivity, margin positivity, and adjuvant therapy significantly impacted survival in multivariate analysis. CONCLUSION: Although total pancreatectomy is a reasonable option for selected patients with pancreatic ductal adenocarcinoma, survival of the entire group is limited. Operative mortality is improved from prior reports. Greater survival benefits were seen in younger patients with smaller, node negative tumors resected with negative margins in academic research centers.

Impact of lymph node status in patients with intrahepatic cholangiocarcinoma treated by major hepatectomy: a review of the National Cancer Database.

INTRODUCTION: Routine lymphadenectomy in the surgical treatment of intrahepatic cholangiocarcinoma (ICC) is not routinely performed. We aim to define predictive indicators of survival in patients with positive lymph nodes. METHODS: The National Cancer Data Base (NCDB) was queried for patients who underwent major hepatectomy for ICC between 1998 and 2011. Clinical and pathologic data were assessed using uni- and multi-variate analyses. A sub-analysis was performed on the 160 patients with positive lymph nodes. RESULTS: Of 849 patients with lymph node data, 57% had at least one lymph node examined. Median survival for lymph node negative patients was 37 months versus 15 months for lymph node positive patients. In lymph node positive patients, poorer survival was associated with not receiving chemotherapy (HR 1.83, p = 0.003), tumor size > 5 cm (p = 0.029), and older age (p < 0.0001). Lymph node positive patients age less than 45 had a median survival of 27 months. CONCLUSIONS: Overall survival in patients with lymph node metastases from ICC is poor. Adjuvant therapy was associated with a longer survival in lymph node positive patients, although prospective data are needed. Routine lymphadenectomy should be strongly considered to provide prognostic information and guidance for adjuvant therapy.

Trends in Kaposi's sarcoma-associated Herpesvirus antibodies prior to the development of HIV-associated Kaposi's sarcoma: a nested case-control study.

HIV-associated Kaposi's sarcoma (KS) is a public health challenge in sub-Saharan Africa since both the causative agent, Kaposi's sarcoma associated-herpesvirus (KSHV), and the major risk factor, HIV, are prevalent. In a nested case-control study within a long-standing clinical cohort in rural Uganda, we used stored sera to examine the evolution of antibody titres against the KSHV antigens K8.1 and latency-associated nuclear antigen (LANA) among 30 HIV-infected subjects who subsequently developed HIV-related KS (cases) and among 108 matched HIV/KSHV coinfected controls who did not develop KS. Throughout the 6 years prior to diagnosis, antibody titres to K8.1 and LANA were significantly higher among cases than controls (p < 0.0001), and titres increased prior to diagnosis in the cases. K8.1 titres differed more between KS cases and controls, compared to LANA titres. These differences in titre between cases and controls suggest a role for lytic viral replication in the pathogenesis of HIV-related KS in this setting.

Neoadjuvant radiation therapy and its impact on complications after pancreaticoduodenectomy for pancreatic cancer: analysis of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP).

OBJECTIVES: This study investigated the impact of neoadjuvant radiation therapy (XRT) on postoperative outcomes following pancreaticoduodenectomy for pancreatic cancer. METHODS: The American College of Surgeons National Quality Improvement Program database was queried for the period 2005-2010 to assess complication rates following pancreaticoduodenectomy for pancreatic cancer. Two groups of patients were identified, comprising those who received neoadjuvant XRT and those who did not (control group). RESULTS: A total of 4416 patients were identified, including 200 in the XRT group and 4216 in the control group. There were differences in patient characteristics between the groups, including in age, hypertension and bilirubin level. Despite the fact that weight loss was more common, median operative time was longer (423 min versus 368 min; P < 0.001), and vascular reconstruction was more commonly required (20.5% versus 8.4%; P < 0.001) in the XRT group. In addition, the XRT group had a shorter median hospital stay than the control group (9 days versus 10 days; P = 0.005). Mortality (3.0% versus 2.7%; P = 0.818) and morbidity (40.5% versus 37.6%; P = 0.404) rates were not influenced by neoadjuvant XRT. Blood transfusion rates were increased in the XRT group (13.0% versus 7.4%; P = 0.003). Severe complications were influenced by age >70 years, American Society of Anesthesiologists (ASA) class >2, preoperative sepsis, dyspnoea, weight loss, impaired functional status, peripheral vascular disease and operative time of >8 h. CONCLUSIONS: Neoadjuvant XRT is not associated with an increase in complications after pancreaticoduodenectomy.

Human leukocyte antigen-DQA1*04:01 and rs2040406 variants are associated with elevated risk of childhood Burkitt lymphoma.

Burkitt lymphoma (BL) is responsible for many childhood cancers in sub-Saharan Africa, where it is linked to recurrent or chronic infection by Epstein-Barr virus or Plasmodium falciparum. However, whether human leukocyte antigen (HLA) polymorphisms, which regulate immune response, are associated with BL has not been well investigated, which limits our understanding of BL etiology. Here we investigate this association among 4,645 children aged 0-15 years, 800 with BL, enrolled in Uganda, Tanzania, Kenya, and Malawi. HLA alleles are imputed with accuracy >90% for HLA class I and 85-89% for class II alleles. BL risk is elevated with HLA-DQA1*04:01 (adjusted odds ratio [OR] = 1.61, 95% confidence interval [CI] = 1.32-1.97, P = 3.71 × 10-6), with rs2040406(G) in HLA-DQA1 region (OR = 1.43, 95% CI = 1.26-1.63, P = 4.62 × 10-8), and with amino acid Gln at position 53 versus other variants in HLA-DQA1 (OR = 1.36, P = 2.06 × 10-6). The associations with HLA-DQA1*04:01 (OR = 1.29, P = 0.03) and rs2040406(G) (OR = 1.68, P = 0.019) persist in mutually adjusted models. The higher risk rs2040406(G) variant for BL is associated with decreased HLA-DQB1 expression in eQTLs in EBV transformed lymphocytes. Our results support the role of HLA variation in the etiology of BL and suggest that a promising area of research might be understanding the link between HLA variation and EBV control.

Establishing a Canadian registry of patients with amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating cause of progressive weakness, respiratory failure and death. To date there is no effective therapy to meaningfully extend survival but continuously emerging targets and putative treatments are studied in clinical trials. Canadian epidemiological data on ALS is scarce and the socioeconomic impact of ALS on Canadian society is unclear. The Canadian Neuromuscular Disease Registry (CNDR) is a national clinic-based registry of patients with neuromuscular diseases with the goal of facilitating the design and execution of clinical research. METHODS: We conducted a national stakeholder survey to assess interest for a Canadian ALS registry and an assessment of expected case ascertainment. A dataset derivation meeting was held to establish the registry medical dataset. RESULTS: We report the results of the national stakeholder survey, case ascertainment assessment, and the derived dataset that have resulted in the current implementation of a Canadian registry of patients with ALS. CONCLUSIONS: The development of this long sought-after resource is a significant step forward for the Canadian ALS patient and research communities that will result in more efficient clinical trial recruitment and advancements in our understanding of ALS in Canada.

A microdeletion in cytochrome c oxidase (COX) subunit III associated with COX deficiency and recurrent myoglobinuria.

We have identified a 15-bp microdeletion in a highly conserved region of the mitochondrially encoded gene for cytochrome c oxidase (COX) subunit III in a patient with severe isolated COX deficiency and recurrent myoglobinuria. The mutant mitochondrial DNA (mtDNA) comprised 92% of the mtDNA in muscle and 0.7% in leukocytes. Immunoblots and immunocytochemistry suggested a lack of assembly or instability of the complex. Microdissected muscle fibres revealed significantly higher portions of mutant mtDNA in COX-negative than in COX-positive fibres. This represents the first case of isolated COX deficiency to be defined at the molecular level.