Risk of Gastric and Small Intestinal Cancer in Patients With Lynch syndrome - Data From a Large, Community-Based U.S. Population.

INTRODUCTION: Risk of gastric and small intestinal cancer in Lynch syndrome (LS) remains poorly understood. We investigated the risk of gastric and small intestinal cancer in patients with LS in a large, community-based population. METHODS: This retrospective cohort study included all patients diagnosed with LS between 1/1/1997-12/31/2020 at Kaiser Permanente Northern California. Cumulative incidence of gastric cancer and small intestinal cancer was calculated using competing risk methodology. RESULTS: Among 1106 LS patients with a median follow-up of 19.3 years (interquartile range [IQR] 9.4-24.0 years), 11 developed gastric cancer (8 MSH2, 2 MLH1 and 1 PMS2) with the median diagnosis age of 56 years (IQR 42-63 years); 11 developed small intestinal cancer (6 MSH2, 3 MLH1, 1 MSH6 and 1 PMS2) with the median diagnosis age of 57 years (IQR 50-66 years). Cumulative incidence by age 80 years was 7.26% (95% confidence internal [CI], 1.80-18.03%) for men and 3.43% (95% CI, 0.50-11.71%) for women for gastric cancer, and was 7.28% (95% CI, 3.19-13.63%) for men and 2.21% (95% CI, 0.23-9.19%) for women for small intestinal cancer. Pathogenic variants (PV) carriers of MSH2 and MLH1 had the highest risk of gastric and small intestinal cancer. History of Helicobacter pylori (H. pylori) infection was associated with increased risk of gastric cancer (adjusted odds ratio 5.52; 95% CI, 1.72-17.75). DISCUSSION: Patients with LS, particularly MSH2 and MLH1 PV carriers, had significantly increased lifetime risk of gastric and small intestinal cancer. Testing and treatment of H. pylori should be considered for all patients with LS.

Periodic heat waves-induced neuronal etiology in the elderly is mediated by gut-liver-brain axis: a transcriptome profiling approach.

Heat stress exposure in intermittent heat waves and subsequent exposure during war theaters pose a clinical challenge that can lead to multi-organ dysfunction and long-term complications in the elderly. Using an aged mouse model and high-throughput sequencing, this study investigated the molecular dynamics of the liver-brain connection during heat stress exposure. Distinctive gene expression patterns induced by periodic heat stress emerged in both brain and liver tissues. An altered transcriptome profile showed heat stress-induced altered acute phase response pathways, causing neural, hepatic, and systemic inflammation and impaired synaptic plasticity. Results also demonstrated that proinflammatory molecules such as S100B, IL-17, IL-33, and neurological disease signaling pathways were upregulated, while protective pathways like aryl hydrocarbon receptor signaling were downregulated. In parallel, Rantes, IRF7, NOD1/2, TREM1, and hepatic injury signaling pathways were upregulated. Furthermore, current research identified Orosomucoid 2 (ORM2) in the liver as one of the mediators of the liver-brain axis due to heat exposure. In conclusion, the transcriptome profiling in elderly heat-stressed mice revealed a coordinated network of liver-brain axis pathways with increased hepatic ORM2 secretion, possibly due to gut inflammation and dysbiosis. The above secretion of ORM2 may impact the brain through a leaky blood-brain barrier, thus emphasizing intricate multi-organ crosstalk.

Rates of resistance and heteroresistance to newer ß-lactam/ß-lactamase inhibitors for carbapenem-resistant Enterobacterales.

Background: Heteroresistance (HR), the presence of antibiotic-resistant subpopulations within a primary isogenic population, may be a potentially overlooked contributor to newer ß-lactam/ß-lactamase inhibitor (BL/BLI) treatment failure in carbapenem-resistant Enterobacterales (CRE) infections. Objectives: To determine rates of susceptibility and HR to BL/BLIs ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam in clinical CRE isolates. Methods: The first CRE isolate per patient per year from two >500 bed academic hospitals from 1 January 2016 to 31 December 2021, were included. Reference broth microdilution (BMD) was used to determine antibiotic susceptibility, and population analysis profiling (PAP) to determine HR. Carbapenemase production (CP) was determined using the Carba NP assay. Results: Among 327 CRE isolates, 46% were Enterobacter cloacae, 38% Klebsiella pneumoniae and 16% Escherichia coli. By BMD, 87% to 98% of CRE were susceptible to the three antibiotics tested. From 2016 to 2021, there were incremental decreases in the rates of susceptibility to each of the three BL/BLIs. HR was detected in each species-antibiotic combination, with the highest rates of HR (26%) found in K. pneumoniae isolates with imipenem/relebactam. HR or resistance to at least one BL/BLI by PAP was found in 24% of CRE isolates and 65% of these had detectable CP. Conclusion: Twenty-four percent of CRE isolates tested were either resistant or heteroresistant (HR) to newer BL/BLIs, with an overall decrease of ∼10% susceptibility over 6 years. While newer BL/BLIs remain active against most CRE, these findings support the need for ongoing antibiotic stewardship and a better understanding of the clinical implications of HR in CRE.

Infectious Diseases Among People Experiencing Homelessness: A Systematic Review of the Literature in the United States and Canada, 2003-2022.

Homelessness increases the risk of acquiring an infectious disease. We conducted a systematic review of the literature to identify quantitative data related to infectious diseases and homelessness. We searched Google Scholar, PubMed, and SCOPUS for quantitative literature published from January 2003 through December 2022 in English from the United States and Canada. We excluded literature on vaccine-preventable diseases and HIV because these diseases were recently reviewed. Of the 250 articles that met inclusion criteria, more than half were on hepatitis C virus or Mycobacterium tuberculosis. Other articles were on COVID-19, respiratory syncytial virus, Staphylococcus aureus, group A Streptococcus, mpox (formerly monkeypox), 5 sexually transmitted infections, and gastrointestinal or vectorborne pathogens. Most studies showed higher prevalence, incidence, or measures of risk for infectious diseases among people experiencing homelessness as compared with people who are housed or the general population. Although having increased published data that quantify the infectious disease risks of homelessness is encouraging, many pathogens that are known to affect people globally who are not housed have not been evaluated in the United States or Canada. Future studies should focus on additional pathogens and factors leading to a disproportionately high incidence and prevalence of infectious diseases among people experiencing homelessness.

Defining conversion therapy for esophageal squamous cell carcinoma.

A multimodality treatment conference with experts from across East Asia was held to establish a consensus for conversion therapy. An agreement was reached that conversion therapy was defined as surgery or chemoradiotherapy (CRT) aiming at cure after initial treatment for tumors that were initially unresectable due to adjacent organ invasion or distant metastasis.

Drainless thoracoscopic surgery should be avoided in primary spontaneous pneumothorax with pleural adhesion.

OBJECTIVES: Drainless thoracoscopic surgery, defined by omitting chest drain after surgery, has been demonstrated to be feasible in selected patients for pulmonary resection. However, drainless procedure for the treatment of primary spontaneous pneumothorax has raised concerns for its safety and thus has been less often reported. We aimed to share our preliminary experience regarding how to select patients with spontaneous pneumothorax for this procedure. METHODS: A retrospective study recruiting 303 consecutive patients with the diagnosis of spontaneous pneumothorax undergoing thoracoscopic surgery in our centre from August 2016 to June 2020 was done. After careful selection, the chest drain was omitted in selected patients who underwent non-intubated uniportal thoracoscopic surgery. Patients' clinical characteristics and perioperative outcomes were analysed. RESULTS: A total of 34 patients underwent drainless thoracoscopic surgery for the treatment of spontaneous pneumothorax. Pleural adhesion was noted in 9 patients during surgery, and all of them (100%) developed residual pneumothorax, among which intercostal drainage was required in 2 (22.2%) patients and ipsilateral pneumothorax recurred 3 years after surgery in 1 (11.1%) patient. Among the remaining 25 without pleural adhesion, 17 (68.0%) developed minor residual pneumothorax (P = 0.006), which all resolved spontaneously within 1-2 weeks, with no complications or recurrence during postoperative follow-up for at least 2 years. CONCLUSIONS: Drainless thoracoscopic surgery for the treatment of primary spontaneous pneumothorax is feasible but can be risky without careful patient selection. In our experience, the drainless procedure should be avoided in patients with identifiable pleural adhesion noted during surgery.

Diagnostic Utility of Ultrasound Versus Physical Examination in Assessing Knee Effusions: A Systematic Review and Meta-analysis.

Knee effusion can be detected by physical examination, ultrasound and MRI, but the utility of each test is unclear. This study aimed to analyze the diagnostic value of physical examination and ultrasound for knee effusion. A systematic literature search of electronic databases was completed. Bivariate mixed-effects regression modelling was used to estimate sensitivity, specificity and diagnostic odds ratio of physical examination and ultrasound diagnosis of knee effusion. Sensitivity of ultrasound diagnosis of knee effusion was higher than the bulge sign and patellar tap, leading to improved positive and negative predictive values.

A Primed Subpopulation of Bacteria Enables Rapid Expression of the Type 3 Secretion System in Pseudomonas aeruginosa.

Type 3 secretion systems (T3SS) are complex nanomachines that span the cell envelope and play a central role in the biology of Gram-negative pathogens and symbionts. In Pseudomonas aeruginosa, T3SS expression is strongly associated with human disease severity and with mortality in murine acute pneumonia models. Uniform exposure of isogenic cells to T3SS-activating signal results in heterogeneous expression of this critical virulence trait. To understand the function of such diversity, we measured the production of the T3SS master regulator ExsA and the expression of T3SS genes using fluorescent reporters. We found that heterogeneous expression of ExsA in the absence of activating signal generates a "primed" subpopulation of cells that can rapidly induce T3SS gene expression in response to signal. T3SS expression is accompanied by a reproductive trade-off as measured by increased division time of T3SS-expressing cells. Although T3SS-primed cells are a minority of the population, they compose the majority of T3SS-expressing cells for several hours following activation. The primed state therefore allows P. aeruginosa to maximize reproductive fitness while maintaining the capacity to quickly express the T3SS. As T3SS effectors can serve as shared public goods for nonproducing cells, this division of labor benefits the population as a whole. IMPORTANCE The expression of specific virulence traits is strongly associated with Pseudomonas aeruginosa's success in establishing acute infections but is thought to carry a cost for bacteria. Producing multiprotein secretion systems or motility organelles is metabolically expensive and can target a cell for recognition by innate immune system receptors that recognize structural components of the type 3 secretion system (T3SS) or flagellum. These acute virulence factors are also negatively selected when P. aeruginosa establishes chronic infections in the lung. We demonstrate a regulatory mechanism by which only a minority subpopulation of genetically identical P. aeruginosa cells is "primed" to respond to signals that turn on T3SS expression. This phenotypic heterogeneity allows the population to maximize the benefit of rapid T3SS effector production while maintaining a rapidly growing and nonexpressing reservoir of cells that perpetuates this genotype within the population.

Gastroenterology visitation and reminders predict surveillance uptake for patients with adenomas with high-risk features.

Individuals diagnosed with colorectal adenomas with high-risk features during screening colonoscopy have increased risk for the development of subsequent adenomas and colorectal cancer. While US guidelines recommend surveillance colonoscopy at 3 years in this high-risk population, surveillance uptake is suboptimal. To inform future interventions to improve surveillance uptake, we sought to assess surveillance rates and identify facilitators of uptake in a large integrated health system. We utilized a cohort of patients with a diagnosis of ≥ 1 tubular adenoma (TA) with high-risk features (TA ≥ 1 cm, TA with villous features, TA with high-grade dysplasia, or ≥ 3 TA of any size) on colonoscopy between 2013 and 2016. Surveillance colonoscopy completion within 3.5 years of diagnosis of an adenoma with high-risk features was our primary outcome. We evaluated surveillance uptake over time and utilized logistic regression to detect factors associated with completion of surveillance colonoscopy. The final cohort was comprised of 405 patients. 172 (42.5%) patients successfully completed surveillance colonoscopy by 3.5 years. Use of a patient reminder (telephone, electronic message, or letter) for due surveillance (adjusted odds = 1.9; 95%CI = 1.2-2.8) and having ≥ 1 gastroenterology (GI) visit after diagnosis of an adenoma with high-risk features (adjusted odds = 2.6; 95%CI = 1.6-4.2) significantly predicted surveillance colonoscopy completion at 3.5 years. For patients diagnosed with adenomas with high-risk features, surveillance colonoscopy uptake is suboptimal and frequently occurs after the 3-year surveillance recommendation. Patient reminders and visitation with GI after index colonoscopy are associated with timely surveillance completion. Our findings highlight potential health system interventions to increase timely surveillance uptake for patients diagnosed with adenomas with high-risk features.

Salmonella Prostatic Abscess in an Immunocompetent Patient.

Patients returning from travel to a foreign country often present with atypical infections that can present as diagnostic challenges. Although rarely seen in the United States, Salmonella infections are commonly seen in Sub-Saharan Africa. The common clinical manifestations of Salmonella infection include fever and diarrhea; however, about 5% of cases of non-typhi Salmonella progress to bacteremia. Here, we present a case of a unique presentation of Salmonella infection manifesting as a prostatic abscess in an immunocompetent patient.

Healthcare pathway discovery and probabilistic machine learning.

BACKGROUND AND PURPOSE: Healthcare pathways define the execution sequence of clinical activities as patients move through a treatment process, and they are critical for maintaining quality of care. The aim of this study is to combine healthcare pathway discovery with predictive models of individualized recovery times. The pathway discovery has a particular emphasis on producing pathway models that are easy to interpret for clinicians without a sufficient background in process mining. The predictive model takes the stochastic volatility of pathway performance indicators into account. METHOD: This study utilizes the business process-mining software ProM to design a process mining pipeline for healthcare pathway discovery and enrichment using hospital records. The efficacy of combining learned healthcare pathways with probabilistic machine learning models is demonstrated via a case study that applies the proposed process mining pipeline to discover appendicitis pathways from hospital records. Machine learning methodologies based on probabilistic programming are utilized to explore pathway features that influence patient recovery time. RESULTS: The produced appendicitis pathway models are easy for clinical interpretation and provide an unbiased overview of patient movements through the treatment process. Analysis of the discovered pathway model enables reasons for longer than usual treatment times to be explored and deviations from standard treatment pathways to be identified. A probabilistic regression model that estimates patient recovery time based on the information extracted by the process mining pipeline is developed and has the potential to be very useful for hospital scheduling purposes. CONCLUSION: This study establishes the application of the business process modelling tool ProM for the improvement of healthcare pathway mining methods. The proposed pipeline for healthcare pathway discovery has the potential to support the development of probabilistic machine learning models to further relate healthcare pathways to performance indicators such as patient recovery time.

Common Injuries of the Weekend Athlete.

Each year increasing numbers of people participate in a wider variety of athletic endeavors. Unlike previous generations, many patients remain in these activities later into their lives, some well beyond retirement. As the population ages and their activities continue, they are subject to injury of various forms affecting all aspects of their bodies.

Emergency video-assisted thoracic surgery for ruptured pulmonary arteriovenous malformation-related hemothorax in a pregnant woman: a case report.

BACKGROUND: Pulmonary arteriovenous malformations are rare vascular abnormalities that permit direct communication between the pulmonary artery and vein. During pregnancy, pulmonary arteriovenous malformation carries an increased risk of enlargement and rupture, which could lead to life-threatening hemothorax. This is the first case reporting successful thoracoscopic surgery for a pregnant woman with pulmonary arteriovenous malformation rupture-related hemothorax. CASE PRESENTATION: We present a case of a 32-year-old pregnant Asian woman (31 weeks' gestation) whose pulmonary arteriovenous malformation ruptured, leading to right-sided spontaneous tension hemothorax. First, an emergency cesarean section for hypovolemic shock-related fetal distress was performed to save the baby. Immediately afterwards, video-assisted thoracic surgery with the single-incision approach allowed us to successfully obtain hemostasis and eradication of abnormal vasculature by conducting wedge resection of the pulmonary arteriovenous malformation. CONCLUSIONS: Emergency thoracoscopic surgery for a pregnant woman with pulmonary arteriovenous malformation rupture-related hemothorax is safe and feasible. In contrast to transcatheter arterial embolization, video-assisted thoracic surgery could simultaneously achieve hemostasis for prevention of mortality, eradication of abnormal vasculature, and removal of massive thrombi.

A Medial Portal for Hip Arthroscopy in Children With Septic Arthritis: A Safety Study.

BACKGROUND: Prompt open arthrotomy is historically utilized to treat pediatric septic arthritis of the hip, but arthroscopy has been described as a valid alternative to prevent long-term sequelae. Standard hip arthroscopy in adolescents and adults utilizes lateral-based portals, but successful irrigation in infants may necessitate a medial portal due to the smaller joint size. The purpose of this study was to determine the safety of a medial hip portal in children based on its anatomic relation to neurovascular structures. METHODS: A retrospective review of children 6 years of age or below with septic hip arthritis who obtained a preoperative magnetic resonance imaging (MRI) between 2009 and 2015 was performed. Multiple measures were recorded from the MRI to create a 3D cone with the vertex just posterior to the adductor longus at the convergence of the gluteal and inguinal creases-a previously described posteromedial portal-with the cone base being a circle defined as the central joint diameter. The distance to the femoral vessels and nerve were then recorded. An adult cadaver was then utilized to replicate the proposed portal starting point and trajectory to confirm that it could be reproducible in a clinical setting. RESULTS: After applying criteria, 47 MRI were evaluated (21 boys, 26 girls) demonstrating a mean distance to femoral vessels and nerve: at insertion, 18.9 mm (minimum 10.5 mm) and at the hip joint, 11.1 mm (minimum 5.2 mm). Girls and boys did not differ significantly, but there was a significant correlation of both age (r=0.75) and body weight (r=0.84) to the measured distance (P<0.001). Imaging of the cadaver confirmed that the starting point could be replicated. CONCLUSIONS: There is a direct relation to size of the child and the distance from the neurovascular structures to the cannula trajectory, but even the smallest of children have at least 5.5 mm of adductor longus to protect the femoral structures. A medial-based portal that utilizes a medial needle for initial aspiration features a wide margin of safety for children requiring treatment for septic hip arthritis. LEVEL OF EVIDENCE: Level IV.

Inflammation: A Double-Edged Sword in the Response to Pseudomonas aeruginosa Infection.

The Gram-negative opportunistic pathogen Pseudomonas aeruginosa exploits failures of barrier defense and innate immunity to cause acute infections at a range of anatomic sites. We review the defense mechanisms that normally protect against P. aeruginosa pulmonary infection, as well as the bacterial products and activities that trigger their activation. Innate immune recognition of P. aeruginosa is critical for pathogen clearance; nonetheless, inflammation is also associated with pathogen persistence and poor host outcomes. We describe P. aeruginosa adaptations that improve this pathogen's fitness in the inflamed airway, and briefly discuss strategies to manipulate inflammation to benefit the host. Such adjunct therapies may become increasingly important in the treatment of acute and chronic infections caused by this multi-drug-resistant pathogen.

SIDEseq: A Cell Similarity Measure Defined by Shared Identified Differentially Expressed Genes for Single-Cell RNA sequencing Data.

One goal of single-cell RNA sequencing (scRNA seq) is to expose possible heterogeneity within cell populations due to meaningful, biological variation. Examining cell-to-cell heterogeneity, and further, identifying subpopulations of cells based on scRNA seq data has been of common interest in life science research. A key component to successfully identifying cell subpopulations (or clustering cells) is the (dis)similarity measure used to group the cells. In this paper, we introduce a novel measure, named SIDEseq, to assess cell-to-cell similarity using scRNA seq data. SIDEseq first identifies a list of putative differentially expressed (DE) genes for each pair of cells. SIDEseq then integrates the information from all the DE gene lists (corresponding to all pairs of cells) to build a similarity measure between two cells. SIDEseq can be implemented in any clustering algorithm that requires a (dis)similarity matrix. This new measure incorporates information from all cells when evaluating the similarity between any two cells, a characteristic not commonly found in existing (dis)similarity measures. This property is advantageous for two reasons: (a) borrowing information from cells of different subpopulations allows for the investigation of pairwise cell relationships from a global perspective and (b) information from other cells of the same subpopulation could help to ensure a robust relationship assessment. We applied SIDEseq to a newly generated human ovarian cancer scRNA seq dataset, a public human embryo scRNA seq dataset, and several simulated datasets. The clustering results suggest that the SIDEseq measure is capable of uncovering important relationships between cells, and outperforms or at least does as well as several popular (dis)similarity measures when used on these datasets.

LSR/angulin-1 is a tricellular tight junction protein involved in blood-brain barrier formation.

The blood-brain barrier (BBB) is a term used to describe the unique properties of central nervous system (CNS) blood vessels. One important BBB property is the formation of a paracellular barrier made by tight junctions (TJs) between CNS endothelial cells (ECs). Here, we show that Lipolysis-stimulated lipoprotein receptor (LSR), a component of paracellular junctions at points in which three cell membranes meet, is greatly enriched in CNS ECs compared with ECs in other nonneural tissues. We demonstrate that LSR is specifically expressed at tricellular junctions and that its expression correlates with the onset of BBB formation during embryogenesis. We further demonstrate that the BBB does not seal during embryogenesis in Lsr knockout mice with a leakage to small molecules. Finally, in mouse models in which BBB was disrupted, including an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and a middle cerebral artery occlusion (MCAO) model of stroke, LSR was down-regulated, linking loss of LSR and pathological BBB leakage.

Osteopathic emergency medicine programs infrequently publish in high-impact emergency medicine journals.

INTRODUCTION: Both the Accreditation Council for Graduate Medical Education (ACGME) and the American Osteopathic Association (AOA) require core faculty to engage in scholarly work, including publication in peer-reviewed journals. With the ACGME/AOA merger, we sought to evaluate the frequency of publication in high-impact peer-reviewed EM journals from authors affiliated with osteopathic emergency medicine (EM) programs. METHODS: We performed a retrospective literature review using the Journal Citation Report database and identified the top five journals in the category of 'Emergency Medicine' by their 2011 Impact Factor. We examined all publications from each journal for 2011. For each article we recorded article type, authors' names, position of authorship (first, senior or other), the author's degree and affiliated institution. We present the data in raw numbers and percentages. RESULTS: The 2011 EM journals with the highest impact factor were the following: Annals of Emergency Medicine, Resuscitation, Journal of Trauma, Injury, and Academic Emergency Medicine. Of the 9,298 authors published in these journals in 2011; 1,309 (15%) claimed affiliation with U.S.-based EM programs, of which 16 (1%) listed their affiliations with eight different osteopathic EM programs. The 16 authors claimed affiliation with 8 of 46 osteopathic EM programs (17%), while 1,301 authors claimed affiliation with 104 of 148 (70%) U.S.-based allopathic programs. CONCLUSION: Authors from osteopathic EM programs are under-represented in the top EM journals. With the pending ACGME/AOA merger, there is a significant opportunity for improvement in the rate of publication of osteopathic EM programs in top tier EM journals.

The impact of genetic susceptibility to systemic lupus erythematosus on placental malaria in mice.

Severe malaria, including cerebral malaria (CM) and placental malaria (PM), have been recognized to have many of the features of uncontrolled inflammation. We recently showed that in mice genetic susceptibility to the lethal inflammatory autoimmune disease, systemic lupus erythematosus (SLE), conferred resistance to CM. Protection appeared to be mediated by immune mechanisms that allowed SLE-prone mice, prior to the onset of overt SLE symptoms, to better control their inflammatory response to Plasmodium infection. Here we extend these findings to ask does SLE susceptibility have 1) a cost to reproductive fitness and/or 2) an effect on PM in mice? The rates of conception for WT and SLE susceptible (SLE(s)) mice were similar as were the number and viability of fetuses in pregnant WT and SLE(s) mice indicating that SLE susceptibility does not have a reproductive cost. We found that Plasmodium chabaudi AS (Pc) infection disrupted early stages of pregnancy before the placenta was completely formed resulting in massive decidual necrosis 8 days after conception. Pc-infected pregnant SLE(s) mice had significantly more fetuses (∼1.8 fold) but SLE did not significantly affect fetal viability in infected animals. This was despite the fact that Pc-infected pregnant SLE(s) mice had more severe symptoms of malaria as compared to Pc-infected pregnant WT mice. Thus, although SLE susceptibility was not protective in PM in mice it also did not have a negative impact on reproductive fitness.

Testing in mice the hypothesis that melanin is protective in malaria infections.

Malaria has had the largest impact of any infectious disease on shaping the human genome, exerting enormous selective pressure on genes that improve survival in severe malaria infections. Modern humans originated in Africa and lost skin melanization as they migrated to temperate regions of the globe. Although it is well documented that loss of melanization improved cutaneous Vitamin D synthesis, melanin plays an evolutionary ancient role in insect immunity to malaria and in some instances melanin has been implicated to play an immunoregulatory role in vertebrates. Thus, we tested the hypothesis that melanization may be protective in malaria infections using mouse models. Congenic C57BL/6 mice that differed only in the gene encoding tyrosinase, a key enzyme in the synthesis of melanin, showed no difference in the clinical course of infection by Plasmodium yoelii 17XL, that causes severe anemia, Plasmodium berghei ANKA, that causes severe cerebral malaria or Plasmodium chabaudi AS that causes uncomplicated chronic disease. Moreover, neither genetic deficiencies in vitamin D synthesis nor vitamin D supplementation had an effect on survival in cerebral malaria. Taken together, these results indicate that neither melanin nor vitamin D production improve survival in severe malaria.