IgM in human immunity to Plasmodium falciparum malaria.

Most studies on human immunity to malaria have focused on the roles of immunoglobulin G (IgG), whereas the roles of IgM remain undefined. Analyzing multiple human cohorts to assess the dynamics of malaria-specific IgM during experimentally induced and naturally acquired malaria, we identified IgM activity against blood-stage parasites. We found that merozoite-specific IgM appears rapidly in Plasmodium falciparum infection and is prominent during malaria in children and adults with lifetime exposure, together with IgG. Unexpectedly, IgM persisted for extended periods of time; we found no difference in decay of merozoite-specific IgM over time compared to that of IgG. IgM blocked merozoite invasion of red blood cells in a complement-dependent manner. IgM was also associated with significantly reduced risk of clinical malaria in a longitudinal cohort of children. These findings suggest that merozoite-specific IgM is an important functional and long-lived antibody response targeting blood-stage malaria parasites that contributes to malaria immunity.

Whole-body lymphangioscintigraphy and SPECT/CT in children with lymphatic complications after surgery for complex congenital heart disease.

The number of patients surviving repair of complex congenital heart disease (CCHD) has increased due to improved surgical techniques, post operative management and outpatient care. Likewise, this growing patient population has demonstrated an increasing number and complexity of complications involving the lymphatic system. To evaluate the peripheral and central lymphatic system, whole-body lymphangioscintigraphy (LAS) is considered as the initial imaging evaluation of choice. To date, very few publications exist on the value of lymphatic imaging techniques in infants and small children with lymphatic complications following surgery for congenital heart disease. A retrospective review of medical records from 2008 to 2018 was performed for pediatric patients referred for lymphatic complications after CCHD surgery at an academic medical center. LAS and SPECT/CT was performed using intradermal bipedal injections of Tc 99m labeled filtered sulfur colloid, and in some patients also bilateral hand injections, followed by dynamic imaging and whole- body planar imaging typically up to 180 minutes post injection. Clinical decision making and outcomes were recorded. LAS and SPECT/CT were performed without complication in pediatric patients with prior surgery for CCHD. LAS successfully localized various lymphatic abnormalities such as lymphatic obstruction, reflux, and leaks, which were further delineated by SPECT/CT. LAS findings directed further evaluation with more definitive studies, management and prognosis. Five of the ten patients had follow up outcome data - 2 years and up to 10 years. LAS and SPECT/CT are safe and effective techniques for the initial evaluation of lymphatic abnormalities in pediatric patients with CCHD. LAS, particularly with further 3D localization by SPECT/CT, provides functional imaging of peripheral and central lymphatic flow and thus provides guidance for medical therapy, non operative interventional management, and surgical therapy for these diverse, debilitating, and often life threatening disorders.

Succinate dehydrogenase mutations: paraganglioma imaging and at-risk population screening.

Paragangliomas are rare vascular tumours of the autonomic nervous system. They can be classified as sympathetic or parasympathetic. Sympathetic paragangliomas, which include phaeochromocytomas, tend to be functional and symptomatic. Parasympathetic paragangliomas are usually non-functional and may present with mass effect. Forty percent of paragangliomas are linked to genetic syndromes, most commonly due to mutations of the succinate dehydrogenase (SDH) enzyme complex and are collectively known as paraganglioma syndromes, of which five are described. Genetic testing is recommended for all patients, and their first-degree relatives, diagnosed with paragangliomas. When SDH mutations are discovered, biochemical screening and imaging surveillance is indicated. There is currently no consensus on imaging surveillance protocols. Most advocate full-body imaging, but the choice of technique and frequency varies. If paragangliomas are demonstrated, functional imaging to look for synchronous tumours or metastases is indicated. 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron-emission tomography (PET)-computed tomography (CT) is the technique of choice for metastatic evaluation, but [123I]-metaiodobenzylguanidine or [111In]-DTPA-octreotide scintigraphy are also utilised. Current research into emerging positron-emitting radiolabelled somatostatin analogues have yielded promising results, which is likely to be reflected in future guidelines. As genetic testing becomes increasingly prevalent, the need to answer the remaining questions regarding surveillance imaging is paramount.

Proposal for Prevention or Alleviation of Protein/Lymph-Losing Enteropathy (PLE/LLE) After Fontan Circulation Treatment of Univentricular Hearts: Restoration of Lymph Balance With a "Lymphatic Right-to-Left Shunt."

In Fontan circulations created for univentricular hearts, systemic venous return is diverted to the lungs before returning to the heart. The Total Cavopulmonary Connection (TCPC) is often the preferred surgical procedure whereby a 4-way anastomosis is created with inflow from the superior vena cava (SVC) and inferior vena cava (IVC) and outflow to the right and left branches of the pulmonary artery. In this arrangement, the systemic venous pressure must be elevated sufficiently to perfuse the lungs passively without the normal boost of the right ventricle. Hence, unlike surgical corrections for other congenital heart conditions, the systemic venous pressures in a Fontan circuit must be elevated to make the circulation work. It is proposed here that the incidence of PLE/LLE is directly related to elevated venous and lymphatic pressures, which cause leakage of proteins/lymph into the gastrointestinal tract (GIT) and expulsion from the body. It is commonly held that elevated venous pressures are relatively better tolerated in the upper body, but much less so in the heptatosplanchnic circulation and the lower body. It is also well established that elevated venous pressure increases lymph formation, most of which is produced in the hepatosplanchnic region (liver and intestine). It is further argued here that the increase in lymph filling pressure arising from the higher lymph flow, in association with the backpressure exerted by elevated venous pressure at the main drainage point into the venous system, results in a substantial increase in pressure in the thoracic duct. This pressure is transmitted back to the intestinal lymphatics, causing dilatation with lacteal rupture and protein or bulk lymph leakage into the intestine. We propose in this paper a new approach, based on experimental evidence, to prevent and/or alleviate this condition by draining or redirecting the thoracic duct (or, alternatively, a more localized intestinal lymphatic vessel) into one of the pulmonary veins or the left atrium, which are typically at near-normal pressure in a Fontan circulation. This "lymphatic-venous right-to-left" shunt maneuver would significantly reduce the venous backpressure on the lymphatics as well as improve lymph circulation, resulting in a decrease in the intestinal lymphatic pressure and thereby prevent or alleviate protein/lymph loss, i.e. lymph balance would be restored. Moreover, the greatly facilitated lymphatic flow would encourage further capillary filtration to relieve excessive venous pressure in the hepatosplanchnic region and protect the liver and kidneys. This paper is intended as a discussion document for elicitation of comments on the soundness and viability of this proposal as well as on technical challenges and steps to explore and advance it.

Unmet clinical needs in the management of advanced melanoma: findings from a survey of oncologists.

Advanced melanoma is a life-threatening cancer with limited life expectancy. The recent introduction of new targeted systemic therapies has provided clinicians with the means to potentially extend survival for the first time. However, the chance of cure remains very low and treatment-induced toxicity is well described. This qualitative study was undertaken to evaluate clinicians' assessment regarding the key concerns in managing advanced melanoma following the introduction of these new treatments. Three hundred and forty-three oncologists were surveyed online between August and November 2012 (in 11 countries) and March and April 2013 (in an additional country). Analysis of free-text responses identified 23 clinical issues of concern across all countries. Of these, the most common clinical concerns were drug toxicity and tolerability, followed by limited treatment effectiveness and limited treatment options. These results suggest that despite the promise of the two new agents in the field, clinicians are still concerned about the limitations of current treatment options, recognising that there remains a significant unmet need in the treatment of advanced melanoma.

Treatment patterns in advanced melanoma: findings from a survey of European oncologists.

With the emergence of new therapies, established patterns of treating advanced melanoma are changing. The aim of this study was to understand how advanced melanoma is treated in clinical practice in Europe following the introduction of ipilimumab and vemurafenib. An online survey was conducted between August and November 2012 with 150 oncologists and dermatologists, from France, Germany, Italy, Spain and the U.K.; respondents reported treating the majority of patients with one or two lines of therapy. For BRAF mutant melanoma, the most frequently used first-line treatments were vemurafenib and dacarbazine. For BRAF wild-type melanoma, the most frequently used first-line treatment was dacarbazine. There was no single preferred agent for the second-line treatment of BRAF mutant or BRAF wild-type disease. Most sequencing from first- to second-line was from conventional dacarbazine to newer agents such as ipilimumab and vemurafenib. The treatment of advanced melanoma is rapidly evolving due to the introduction of new agents. This study presents an early insight into access to the new agents, ipilimumab and vemurafenib, and clinical practice in several European countries.

A study protocol for a randomised open-label clinical trial of artesunate-mefloquine versus chloroquine in patients with non-severe Plasmodium knowlesi malaria in Sabah, Malaysia (ACT KNOW trial).

INTRODUCTION: Malaria due to Plasmodium knowlesi is reported throughout South-East Asia, and is the commonest cause of it in Malaysia. P. knowlesi replicates every 24 h and can cause severe disease and death. Current 2010 WHO Malaria Treatment Guidelines have no recommendations for the optimal treatment of non-severe knowlesi malaria. Artemisinin-combination therapies (ACT) and chloroquine have each been successfully used to treat knowlesi malaria; however, the rapidity of parasite clearance has not been prospectively compared. Malaysia's national policy for malaria pre-elimination involves mandatory hospital admission for confirmed malaria cases with discharge only after two negative blood films; use of a more rapidly acting antimalarial agent would have health cost benefits. P. knowlesi is commonly microscopically misreported as P. malariae, P. falciparum or P. vivax, with a high proportion of the latter two species being chloroquine-resistant in Malaysia. A unified ACT-treatment protocol would provide effective blood stage malaria treatment for all Plasmodium species. METHODS AND ANALYSIS: ACT KNOW, the first randomised controlled trial ever performed in knowlesi malaria, is a two-arm open-label trial with enrolments over a 2-year period at three district sites in Sabah, powered to show a difference in proportion of patients negative for malaria by microscopy at 24 h between treatment arms (clinicaltrials.gov #NCT01708876). Enrolments started in December 2012, with completion expected by September 2014. A total sample size of 228 is required to give 90% power (α 0.05) to determine the primary end point using intention-to-treat analysis. Secondary end points include parasite clearance time, rates of recurrent infection/treatment failure to day 42, gametocyte carriage throughout follow-up and rates of anaemia at day 28, as determined by survival analysis. ETHICS AND DISSEMINATION: This study has been approved by relevant institutional ethics committees in Malaysia and Australia. Results will be disseminated to inform knowlesi malaria treatment policy in this region through peer-reviewed publications and academic presentations. TRIAL REGISTRATION NUMBER: NCT01708876.

Factors that are associated with the risk of acquiring Plasmodium knowlesi malaria in Sabah, Malaysia: a case-control study protocol.

INTRODUCTION: Plasmodium knowlesi has long been present in Malaysia, and is now an emerging cause of zoonotic human malaria. Cases have been confirmed throughout South-East Asia where the ranges of its natural macaque hosts and Anopheles leucosphyrus group vectors overlap. The majority of cases are from Eastern Malaysia, with increasing total public health notifications despite a concurrent reduction in Plasmodium falciparum and P. vivax malaria. The public health implications are concerning given P. knowlesi has the highest risk of severe and fatal disease of all Plasmodium spp in Malaysia. Current patterns of risk and disease vary based on vector type and competence, with individual exposure risks related to forest and forest-edge activities still poorly defined. Clustering of cases has not yet been systematically evaluated despite reports of peri-domestic transmission and known vector competence for human-to-human transmission. METHODS AND ANALYSIS: A population-based case-control study will be conducted over a 2-year period at two adjacent districts in north-west Sabah, Malaysia. Confirmed malaria cases presenting to the district hospital sites meeting relevant inclusion criteria will be requested to enrol. Three community controls matched to the same village as the case will be selected randomly. Study procedures will include blood sampling and administration of household and individual questionnaires to evaluate potential exposure risks associated with acquisition of P. knowlesi malaria. Secondary outcomes will include differences in exposure variables between P. knowlesi and other Plasmodium spp, risk of severe P. knowlesi malaria, and evaluation of P. knowlesi case clustering. Primary analysis will be per protocol, with adjusted ORs for exposure risks between cases and controls calculated using conditional multiple logistic regression models. ETHICS: This study has been approved by the human research ethics committees of Malaysia, the Menzies School of Health Research, Australia, and the London School of Hygiene and Tropical Medicine, UK.

Successful treatment of plastic bronchitis with low fat diet and subsequent thoracic duct ligation in child with fontan physiology.

Plastic bronchitis is a rare condition characterized by the formation and expectoration of long, branching bronchial casts that develop in the tracheobronchial tree and cause airway obstruction. Plastic bronchitis has become increasingly recognized as a feared complication of the Fontan operation with a mortality of up to 50%. We report an 11 year old boy who developed severe plastic bronchitis following Fontan repair and the successful long-term control of cast formation utilizing a low-fat diet and subsequent thoracic duct ligation.

A systematic review of treatment guidelines for metastatic colorectal cancer.

AIM: A systematic review of treatment guidelines for metastatic colorectal cancer (mCRC) was performed to assess recommendations for monoclonal antibody therapy in these guidelines. METHOD: Relevant papers were identified through electronic searches of MEDLINE, MEDLINE In Process, EMBASE and the Cochrane Library; through manual searches of reference lists; and by searching the Internet. RESULTS: A total of 57 relevant guidelines were identified, 32 through electronic database searches and 25 through the website searches. The majority of guidelines were published between 2004 and 2010. The country publishing the most guidelines was the USA (12), followed by the UK (10), Canada (eight), France (eight), Germany (three), Australia (two), Spain (two) and Italy (one). In addition, eight European and three international guidelines were identified. As monoclonal antibody therapy for mCRC was not introduced until 2004, no firm recommendations for monoclonal antibody therapy were made in guidelines published between 2004 and 2006. Recommendations for monoclonal antibody therapy first appeared in 2007 and evolved as more data became available. The most recent international, European and US guidelines recommend combination chemotherapy with the addition of a monoclonal antibody for the first-line treatment of mCRC. Second-line treatment depends on the first-line regimen used. For chemoresistant mCRC, cetuximab or panitumumab are recommended as monotherapy in patients with wild-type KRAS tumours. CONCLUSION: The study indicates that recent treatment guidelines have recognized the role of monoclonal antibodies in the management of mCRC, and that treatment guidelines should be updated in a timely manner to reflect the most recently available data.

Health-related quality of life in patients with metastatic colorectal cancer treated with panitumumab in first- or second-line treatment.

BACKGROUND: Panitumumab in combination with chemotherapy was evaluated in two pivotal clinical trials in first- and second-line treatment of metastatic colorectal cancer (mCRC), respectively. This analysis compared the health-related quality of life (HRQoL) of patients with or without panitumumab in the two trials. METHODS: Patients with mCRC were randomised to FOLFOX (first-line trial) or FOLFIRI (second-line trial)±panitumumab. The EuroQoL 5-Dimensions Health State Index (EQ-5D HSI) and Visual Analogue Scale (EQ-5D VAS) were assessed at baseline and monthly follow-up until disease progression. Patients with wild-type KRAS mCRC with baseline and post-baseline HRQoL scores were included. Difference in change from baseline between treatment groups was evaluated using linear mixed and pattern-mixture models. RESULTS: In the first-line trial, 576 patients with wild-type KRAS mCRC (284 panitumumab+FOLFOX4 and 292 FOLFOX4 alone) were included in the HRQoL analyses. In the second-line trial, 530 patients with wild-type KRAS mCRC were included in these analyses (263 panitumumab+FOLFIRI and 267 FOLFIRI alone). There was no significant difference in the change in EQ-5D HSI and VAS scores between treatment groups in either trial. CONCLUSION: The addition of panitumumab to FOLFOX4 or FOLFIRI in first- or second-line treatment of wild-type KRAS mCRC significantly improved progression-free survival without compromising HRQoL.

A Q-TWiST analysis comparing panitumumab plus best supportive care (BSC) with BSC alone in patients with wild-type KRAS metastatic colorectal cancer.

BACKGROUND: Panitumumab+best supportive care (BSC) significantly improved progression-free survival (PFS) vs BSC alone in patients with chemo-refractory wild-type KRAS metastatic colorectal cancer (mCRC). We applied the quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) analysis to provide an integrated measure of clinical benefit, with the objective of comparing quality-adjusted survival between the two arms. As the trial design allowed patients on BSC alone to receive panitumumab after disease progression, which confounded overall survival (OS), the focus of this analysis was on PFS. METHODS: For each treatment group, the time spent in the toxicity (grade 3 or 4 adverse events; TOX), time without symptoms of disease or toxicity (TWiST), and relapse (after disease progression; REL) states were estimated by the product-limit method, and adjusted using utility weights derived from patient-reported EuroQoL 5-dimensions measures. Sensitivity analyses were performed in which utility weights (varying from 0 to 1) were applied to time in the TOX and REL health states. RESULTS: There was a significant difference between groups favouring panitumumab+BSC in quality-adjusted PFS (12.3 weeks vs 5.8 weeks, respectively, P<0.0001) and quality-adjusted OS (P=0.0303). CONCLUSION: In patients with chemo-refractory wild-type KRAS mCRC, panitumumab+BSC significantly improved quality-adjusted survival compared with BSC alone.

Eating local: influences of habitat on the diet of little brown bats (Myotis lucifugus).

We employ molecular methods to profile the diet of the little brown bat, Myotis lucifugus, and describe spatial and temporal changes in diet over their maternity season. We identified 61 prey species of insects and 5 species of arachnid. The largest proportion of prey (∼32%) were identified as species of the mass-emerging Ephemeroptera (mayfly) genus Caenis. Bats roosting in agricultural settings had lower dietary richness than those occupying a roost located on a forest fragment in a conservation area. We detected temporal fluctuations in diet over the maternity season. Dipteran (fly) species dominated the diet early in the season, replaced later by species of mayfly. Because our methodology provides species-level identification of prey, we were able to isolate environmental indicator species in the diet and draw conclusions about the location and type of their foraging habitat and the health of these aquatic systems. The species detected suggested that the bats use variable habitats; members of one agricultural roost foraged on insects originating in rivers or streams while those in another agricultural roost and the forest roost fed on insects from pond or lake environments. All source water for prey was of fair to good quality, though no species detected are intolerant of pollution thus the habitat cannot be classified as pristine. Our study outlines a model system to investigate the abiotic and biotic interactions between habitat factors through this simple food chain to the top predator.

Two pulses of diversification across the Isthmus of Tehuantepec in a montane Mexican bird fauna.

Understanding the evolutionary history of the species in a particular region provides insights into how that fauna was formed. Of particular interest to biogeographers is examining the impact a geographical barrier had in generating temporal genetic diversity among codistributed species. We examined the impact a major New World barrier, the Isthmus of Tehuantepec (IT) in southern Mexico, had on a regional bird fauna. Specifically, genetic data from 10 montane-forest bird taxa were analysed using approximate Bayesian computation (ABC) to test the hypothesis of simultaneous intraspecific diversification at the IT. Because effective population size (N(e)) has the greatest impact on coalescent times, thereby affecting tests of divergence among codistributed taxa, we chose priors for both current and ancestral N(e) using empirical estimates of theta. The ABC method detected two discrete diversification events. Subsequent analysis with the number of diversification events constrained to two suggests that four taxa diverged in an older event, with the remaining six diverging more recently. Application of a range of mutation rates from 2.0 to 5.0% Myr(-1) places both events within the Pleistocene or Late Pliocene, suggesting that fluctuations in montane habitat induced by climate cycles and a late Pliocene seaway may have fractured this montane bird fauna. The results presented here suggest this avian fauna responded in a relatively concerted fashion over the last several million years.

Clinical and economic impact of infusion reactions in patients with colorectal cancer treated with cetuximab.

BACKGROUND: Systemic agents in cancer treatment were often associated with possible infusion reactions (IRs). This study estimated the incidence of IRs requiring medical intervention and assessed the clinical and economic impacts of IRs in patients with colorectal cancer (CRC) treated with cetuximab. PATIENTS AND METHODS: Details on patients with CRC receiving cetuximab in 2004-2006 were extracted from a large USA administrative claims database. IRs were identified based on the occurrence of outpatient treatment, emergency room (ER) visit, and/or hospitalization for hypersensitivity and allergic reactions. Multivariate regressions were used to examine potential risk factors and quantify the economic impact of IRs. RESULTS: A total of 1122 CRC patients receiving cetuximab were identified. The incidence of IRs requiring medical intervention was 8.4%. Sixty-eight percent of the patients had treatment disruptions and 34% discontinued cetuximab treatment. Mean adjusted costs were $13,863 for cetuximab administrations with an IR requiring ER visit or hospitalization and $6280 for those with an IR requiring outpatient treatment, compared with $4555 for those without an IR. CONCLUSIONS: The incidence rate of cetuximab-related IRs requiring medical intervention in clinical practice was found to be higher than rates reported in the product label and clinical trials. The clinical and economic impacts of these IRs are substantial.

The hospital burden of disease associated with bone metastases and skeletal-related events in patients with breast cancer, lung cancer, or prostate cancer in Spain.

Metastatic bone disease (MBD) is the most common cause of cancer pain and of serious skeletal-related events (SREs) reducing quality of life. Management of MBD involves a multimodal approach aimed at delaying the first SRE and reducing subsequent SREs. The objective of the study was to characterise the hospital burden of disease associated with MBD and SREs following breast, lung and prostate cancer in Spain. Patients admitted into a participating hospital, between 1 January 2003 and 31 December 2003, with one of the required cancers were identified and selected for inclusion into the study. The index admission to hospital, incidence of patients admitted and hospital length of stay were analysed. There were 28,162 patients identified with breast, lung and prostate cancer. The 3 year incidence rates of hospital admission due to MBD were 95 per 1000 for breast cancer, 156 per 1000 for lung cancer and 163 per 1000 for prostate cancer. For patients admitted following an SRE, the incidence rates were 211 per 1000 for breast cancer, 260 per 1000 for lung cancer and 150 per 1000 for prostate cancer. This study has shown that cancer patients consume progressively more hospital resources as MBD and subsequent SREs develop.

Association between androgen-deprivation therapy and incidence of diabetes among males with prostate cancer.

OBJECTIVES: Previous research has documented an increase in metabolic syndrome among patients who use androgen-deprivation therapy (ADT). Given that metabolic syndrome is related to diabetes, this research examined whether use of ADT was associated with an increase in the incidence of diabetes. METHODS: A retrospective, claims database was used to compare men diagnosed with prostate cancer who received ADT (N = 1231) with men diagnosed with prostate cancer who did not receive ADT (N = 7250). Unjustified comparisons among the cohorts were examined using chi-square statistics for categorical variables and t-statistics for continuous variables. A multivariate logistic regression was estimated to examine the association between receipt of ADT and the incidence of diabetes, while controlling for a wide range of factors that also potentially affect the probability of being newly diagnosed with diabetes. RESULTS: Descriptive statistics revealed that the patients who initiated ADT were significantly older (P <0.01), in poorer health (P <0.01), and more likely to have a prior diagnosis of hypertension (P = 0.04). Results from the multivariate regression indicate that for men diagnosed with prostate cancer, demographic characteristics, comorbid conditions, prior statin use, and receipt of ADT all affect the probability of incident diabetes. While controlling for other factors, the estimated relative risk of incident diabetes associated with the receipt of ADT was 1.36 (P = 0.01). CONCLUSIONS: Results from this study suggest that among prostate cancer patients, those initiating ADT are more likely to develop incident diabetes within 1 year. This finding supports previous research that established the relationship between ADT and metabolic syndrome.