Eosinophils, basophils and myeloid-derived suppressor cells in chronic Loa loa infection and its treatment in an endemic setting.

BACKGROUND: Chronic infection by Loa loa remains an unsolved immunological paradox. Despite harboring subcutaneously migrating adult worms and often high densities of microfilariae, most patients experience only relatively mild symptoms, yet microfilaricidal treatment can trigger life-threatening inflammation. Here, we investigated innate cell populations hypothesized to play a role in these two faces of the disease, in an endemic population in Gabon. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed numbers and activation of eosinophils and basophils, as well as myeloid-derived suppressor cell (MDSC) subsets and associated circulating cytokine levels by flow cytometry in sex- and age-matched L. loa-uninfected (LL-), -amicrofilaraemic (MF-) and -microfilaraemic (MF+) individuals (n = 42), as well as microfilaraemic individuals treated with albendazole (n = 26). The percentage of eosinophils was lower in LL- (3.0%) than in the combined L. loa-infected population, but was similar in MF+ (13.1%) and MF- (12.3%). Upon treatment of MF+, eosinophilia increased from day 0 (17.2%) to day 14 (24.8%) and had decreased below baseline at day 168 (6.3%). Expression of the eosinophil activation marker CD123 followed the same pattern as the percentage of eosinophils, while the inverse was observed for CD193 and to some extent CD125. Circulating IL-5 levels after treatment followed the same pattern as eosinophil dynamics. Basophil numbers did not differ between infection states but increased after treatment of MF+. We did not observe differences in MDSC numbers between infection states or upon treatment. CONCLUSIONS/SIGNIFICANCE: We demonstrate that both chronic infection and treatment of L. loa microfilaraemia are associated with eosinophil circulation and distinct phenotypical activation markers that might contribute to inflammatory pathways in this setting. In this first ever investigation into MDSC in L. loa infection, we found no evidence for their increased presence in chronic loiasis, suggesting that immunomodulation by L. loa is induced through other pathways.

Detection of thermotolerant coliforms and SARS-CoV-2 RNA in sewage and recreational waters in the Ecuadorian coast: A call for improving water quality regulation.

Wastewater surveillance represents an alternative approach to regulating contamination and the early detection of infectious agents and outbreaks of diseases of public health importance. This study evaluated domestic wastewater effects on recreational waters in estuarine and seawater bodies in Guayas and Santa Elena provinces in Ecuador, South America. Fecal indicator bacteria (thermotolerant coliforms) served as key indicators for evaluation. Physical, chemical, and microbiological quality markers following the Ecuadorian environmental quality standard and the discharge of effluents to the water resource were analyzed. Samples were collected from 44 coastal sites and 2 oxidation lagoons during the dry and rainy seasons of 2020 and 2021, respectively. SARS-CoV-2 RNA was detected in samples with higher E. coli concentrations using reverse transcription quantitative PCR to detect the genes N and ORF1ab. All samples analyzed for SARS-CoV-2 showed Ct ˂ 40 for at least one gene. Four samples showed at least 20 genome copies of gene N per reaction. These were at an artisanal fishing port, an estuarine area (Palmar), a recreational bay, and an oxidation lagoon. A moderate correlation was found between SARS-CoV-2 RNA, thermotolerant coliform and E. coli (p-value ≤ 0.0037), and a strong and positive correlation between thermotolerant coliform and E. coli. (p-value ≤ 0.00001), highlighting the utility of these established parameters as a proxy of the virus. Significant differences were found in the concentrations of thermotolerant coliforms between seasons (p-value = 0.016) and sites (p-value = 0.005). The highest levels of coliforms were found in the dry season (63000 MPN/100 mL) in Anconcito and during the rainy season (14000 MPN/100 mL) at Esterillo in Playas County. It is recommended that the decentralized autonomous governments of the surveyed provinces in Ecuador implement urgent corrective actions and establish medium-term mechanisms to minimize a potential contamination route. Additional parameters must be included in the monitoring, such as Enterococcus and intestinal parasites, due to their public health implications. In the oxidation lagoons, maintenance actions must be carried out, including the dissolution of sediments, an increase in water retention times, and in situ treatment of the sludge, to improve the system's performance.

PCR-based detection for the quarantine fungus Colletotrichum kahawae, a biosecurity threat to the coffee (Coffea arabica) industry worldwide.

Coffee berry disease (CBD) is caused by Colletotrichum kahawae, a quarantine fungus still absent from most coffee-producing countries. Given the potential adverse effects on coffee berry production, it is a severe worldwide threat to farmers and industry. Current biosecurity management focuses on exclusion by applying quarantine measures, including certification of coffee plants and their products. However, methods for detecting C. kahawae by the NPPO (National Plant Protection Organization) laboratories still need approval. This research aims to functionally demonstrate, standardize, and validate a method for detecting and discriminating C. kahawae from other Colletotrichum species that may be present in coffee plant samples. The method proposes to use an end-point PCR marker for the mating type gene (MAT1-2-1) and a confirmatory test with a qPCR marker developed on the glutamine synthetase (GS) gene. The C. kahawae amplicons for the Cen-CkM10 marker exhibited specific melting temperature (Tm) values that could be readily differentiated from other tested species, including their relatives. Given the fungus's quarantine status, specificity was tested using artificial mixtures of DNA of C. kahawae with other Colletotrichum species and coffee plant DNA. The described method will enable NPPOs in coffee producing and exporting countries, especially Colombia, to prevent this pathogen's entry, establishment, and spread.

Evaluation of the concomitant use of prophylactic treatments in patients with migraine under anti-calcitonin gene-related peptide therapies: The PREVENAC study.

BACKGROUND AND PURPOSE: Anti-calcitonin gene-related peptide (CGRP) therapies are recent preventive therapies approved for both episodic and chronic migraine. One of the measures of effectiveness is the withdrawal of other preventive treatments. The objective of this study is to quantify the impact of anti-CGRP drugs in concomitant preventive treatment in patients with migraine. METHODS: This was an observational, retrospective, multicenter cohort study with patients from nine national headache units. Patients with migraine undergoing treatment for at least 6 months with anti-CGRP antibodies, who were initially associated with some preventive treatment (oral and/or onabotulinumtoxinA) were included. Demographic and clinical variables were collected, as well as variables related to headache. Differences according to withdrawal or nonwithdrawal were evaluated. RESULTS: A total of 408 patients were included, 86.52% women, 48.79 (SD = 1.46) years old. Preventive treatment was withdrawn in 43.87% (179/408), 20.83% partially and 23.04% totally. In 27.45% (112/408), it was maintained exclusively due to comorbidity and in 28.6% (117/408) due to partial efficacy. The most frequent time of withdrawal was between 3 and 5 months after the start of treatment. The baseline characteristics associated with nonwithdrawal were comorbidities: insomnia, hypertension and obesity, chronic migraine, and medication overuse. In the multivariate analysis, the absence of high blood pressure, a greater number of preventive treatments at the start, and a lower number of migraine days/month after anti-CGRP treatment were independently associated with withdrawal of the treatment (p < 0.05). CONCLUSIONS: Anti-CGRP antibodies allow the withdrawal of associated preventive treatment in a significant percentage of patients, which supports its effectiveness in real-life conditions.

Staged treatment of bicondylar tibial plateau fractures: influence of frame configuration and quality of reduction on outcomes.

PURPOSE: Despite evolving treatment, the surgical management of high-energy tibial plateau fractures (TPF) remains challenging, associating high rates of complications. In recent decades, staged management has emerged as an encouraging option. The main goal of our study was to evaluate the influence of bridging external fixation (EF) frame configuration and the resultant quality of reduction (QOR) on outcomes after staged-treatment of bicondylar TPF. METHODS: A retrospective review was conducted of patients with bicondylar TPF treated at our level-I trauma center using a staged-treatment protocol from January 2010 to January 2020. Data on baseline characteristics, injuries, treatments, and clinical/radiological results were collected. The QOR was evaluated on CT images after EF and on plain films after ORIF. RESULTS: Sixty-eight patients were eligible for analysis. By our criteria, QOR was good in 57.4% and 70.6% after EF and ORIF, respectively. A squared EF configuration was associated with superior EF QOR (p = 0.032), while better EF QOR was linked to improved ORIF QOR (p = 0.016). No relationship between ORIF delay and ORIF QOR was identified. Postoperative complications were documented in 19 patients. Average ROM at one-year follow-up was 114.9 ± 12.6°, and non-influenced by anterior femoral pin placement. CONCLUSIONS: Staged management of bicondylar TPF resulted in a reasonable rate of complications. A direct relationship between QORs obtained with EF and after ORIF was found. Squared frames were associated with faster and better reductions, regardless of the surgeon's background. Considering our results, we advocate for the wider use of squared EF configurations in these patients.

Open reduction and polyaxial plating for stemmed knee periprosthetic fractures: A case series.

INTRODUCTION: Stemmed total knee arthroplasty (STKA) periprosthetic fractures (PPFs) are an emerging problem affecting frail patients. Their surgical fixation is challenging, due to intramedullary involvement and poor bone stock. Polyaxial locking plating has yielded good results in implant-related femur fractures. We hypothesized that this treatment would provide similar results for STKA PPFs. METHODS: Retrospective analysis of consecutive patients with a femoral PPF or inter-implant fracture around a knee revision stem who had undergone open reduction and periprosthetic-specific polyaxial plate fixation. RESULTS: We found 14 cases of mean age 85.4 years. Cerclages were used in 80% of cases. Fixation of a mean 8.6 cortices around the revision stem was achieved, with an overall screw density of 1:2 or 1:3. Four patients lost their ability to walk, while four experienced postoperative local complications. Bone healing was achieved in all except one who died during hospitalization. The 13 remaining survived the first year of follow-up. CONCLUSION: STKA PPFs are an emerging and challenging problem affecting frail patients. Treatment using polyaxial locking plates provides stable fixation allowing early mobilization despite high complication rates.

COVID-19 mortality and risk factors in patients with cancer in Ecuador: A retrospective, non-randomized, controlled study.

The 2019 coronavirus disease (COVID-19) pandemic has affected different human populations since March 2020 and challenged healthcare systems, especially in chronic non-communicable diseases such as cancer. The present study aimed to evaluate the mortality, risk factors, and symptoms of cancer patients and control subjects, diagnosed with COVID-19 and admitted to intensive care unit (ICU). This retrospective, observational, non-randomized, controlled study of patients admitted to ICU was conducted between March and August 2020 in an Ecuadorian oncology center. Patient information collected from electronic medical records included sociodemographic information, clinical history, symptoms, laboratory test results, COVID-19 treatment, and discharge status. For patients with neoplasia, diagnosis, type, and status of cancer, as well as antineoplastic treatment received over the past month was also recorded. Descriptive statistics and multiple logistic regression were used to analyze the data. Statistical analysis was performed with SPSS (version 22.0) and R (version 4.1.3). In total, 79 adult COVID-19 patients were studied (40 with cancer and 39 controls). The total mean time until COVID-19 symptoms onset was 6.2 ±â€…3.5 days (5.3 ±â€…3.2 days in the cancer group vs 7.2 ±â€…3.6 days in the control group; P = .016) but no difference was observed in reported symptoms. All patients received an antibiotic treatment, but only 70% of the cancer group had antivirals (P < .001). Cancer patients had lower hemoglobin levels than controls (10.7 ±â€…2.8 vs 13.3 ±â€…1.7 g/dL; P < .001). In terms of mortality, not statistically significance difference was reported between groups. The study showed that high ferritin (Absolute Odds Ratio of 3.9; 95% CI 1.1-14.6) and mechanical ventilation (Absolute Odds Ratio of 4.9; 95% CI 1.3-18.6) were independent COVID-19 mortality risk factors. COVID-19 infection did not represent an increased risk of mortality in cancer patients, but elevated ferritin levels and the need for mechanical ventilation were identified as mortality risk factors.

Non-prosthetic implant-related femur fractures in post-polio patients.

The overall societal impact of poliomyelitis worldwide is decreasing, rendering it almost absent in most developed countries. However, even there, patients are still seen who contracted it in endemic areas or developed polio before vaccinations became widely available. Post-polio syndrome (PPS) causes skeletal and neurological changes that increase affected individuals' likelihood of fractures, including fractures requiring complex surgical treatment. The existence of previous internal fixation creates a particularly difficult challenge. We present here the surgical management of four post-polio patients who suffered non-prosthetic implant-related femoral fractures. Injuries occurred at earlier ages than implant-related fractures in non-polio patients and three of the four fractures occurred around plates, a phenomenon which is usually rare. The treatment of implant-related fractures in patients with post-polio syndrome poses significant technical challenges, often creating problematic functional sequelae for patients and high costs for healthcare systems.

A PfSPZ vaccine immunization regimen equally protective against homologous and heterologous controlled human malaria infection.

Immunization with radiation-attenuated Plasmodium falciparum (Pf) sporozoites (SPZ) in PfSPZ Vaccine, has provided better vaccine efficacy (VE) against controlled human malaria infection (CHMI) with the same parasites as in the vaccine (homologous) than with genetically distant parasites (heterologous). We sought to identify an immunization regimen that provided similar VE against CHMI with homologous and heterologous Pf for at least 9 weeks in malaria-naïve adults. Such a regimen was identified in part 1 (optimization), an open label study, and confirmed in part 2 (verification), a randomized, double-blind, placebo-controlled study in which VE was assessed by cross-over repeat CHMI with homologous (PfNF54) and heterologous (Pf7G8) PfSPZ at 3 and 9-10 weeks. VE was calculated using Bayesian generalized linear regression. In part 1, vaccination with 9 × 105 PfSPZ on days 1, 8, and 29 protected 5/5 (100%) subjects against homologous CHMI at 3 weeks after the last immunization. In part 2, the same 3-dose regimen protected 5/6 subjects (83%) against heterologous CHMI at both 3 and 9-10 weeks after the last immunization. Overall VE was 78% (95% predictive interval: 57-92%), and against heterologous and homologous was 79% (95% PI: 54-95%) and 77% (95% PI: 50-95%) respectively. PfSPZ Vaccine was safe and well tolerated. A 4-week, 3-dose regimen of PfSPZ Vaccine provided similar VE for 9-10 weeks against homologous and heterologous CHMI. The trial is registered with ClinicalTrials.gov, NCT02704533.

Fractures after cephalomedullary nailing of the femur : Systematization of surgical fixation based on the analysis of a single-center retrospective cohort.

PURPOSES: Femoral implant related fractures (IRF) are a growing pathology in an increasingly elderly and frail population. A series of IRF after cephalomedullary nail (CMN) fixation of a femoral fracture is analyzed and an algorithm described to guide the management of such fractures. METHODS: All eligible patients operated on for IRF fixation after CMN were reviewed regarding their demographics, comorbidities, injury pattern, and treatment. Primary outcomes were mortality and local complications. Secondary outcomes were time to consolidation, time to weight-bearing initiation, length of hospitalization, and discharge destination. RESULTS: The incidence of IRF requiring fixation was 1.3% after 3401 CMN implantation procedures. Elderly women with comorbidities and plate fixation predominated. One-year mortality was 18.6%, being higher for patients presenting with infection and those unable to walk at the end of follow-up. Local complications occurred in 25.6%. Median time to weight-bearing was 9.1 weeks, but longer for patients with plate fixation or complications. Patients presenting with an infection and those discharged to nursing facilities had more comorbidity. CONCLUSIONS: Following an algorithm presented here, patients were treated either with nail exchange or lateral locking plate fixation, permitting straightforward evaluations and acceptable results in a very high-risk population.

Influx of kynurenine into the brain is involved in the reduction of ethanol consumption induced by Ro 61-8048 after chronic intermittent ethanol in mice.

BACKGROUND AND PURPOSE: The kynurenine pathway has been proposed as a target for modulating drug abuse. We previously demonstrated that inhibition of kynurenine 3-monooxygenase (KMO), using Ro 61-8048, reduces ethanol consumption in a binge drinking model. Here, we investigate the effect of the kynurenine pathway modulation in ethanol-dependent mice. EXPERIMENTAL APPROACH: Adult male and female mice were subjected to a Chronic Intermittent Ethanol (CIE) paradigm. On the last day of CIE, mice were treated with Ro 61-8048, Ro 61-8048 + PNU-120596, a positive allosteric modulator of α7nAChR, and Ro 61-8048 + L-leucine or probenecid, which blocks the influx or efflux of kynurenine from the brain, respectively. Ethanol, water consumption and preference were measured and kynurenine levels in plasma and limbic forebrain were determined. KEY RESULTS: Ro 61-8048 decreases consumption and preference for ethanol in both sexes exposed to the CIE model, an effect that was prevented by PNU-120596. The Ro 61-8048-induced decrease in ethanol consumption depends on the influx of kynurenine into the brain. CONCLUSION AND IMPLICATIONS: Inhibition of KMO reduces ethanol consumption and preference in both male and female mice subjected to CIE model by a mechanism involving α7nAChR. Moreover, this centrally-mediated effect depends on the influx of peripheral kynurenine to the brain and can be prolonged by blocking the efflux of kynurenine from the brain. Here, for the first time, we demonstrate that the modulation of the kynurenine pathway is an effective strategy for the treatment of ethanol dependence in both sexes.

Challenges and outcomes in the treatment of floating knees. A case series of ipsilateral femur and tibia fractures around the knee.

BACKGROUND: Ipsilateral femur and tibia fractures around the knee (floating knee) are rare injuries that threaten both limb viability and patient life. A correct surgical strategy is essential to reduce complications and sequelae. The aim of this study was to evaluate characteristics and results of treatment in patients with a floating knee treated at a single trauma center. MATERIAL AND METHODS: This is a retrospective and non-consecutive case series of 18 floating knees occurred in 17 patients. All patients were operated in a single third-level public and university hospital from December 2010 to December 2018. Data on demographics, injuries, treatment and follow-up were collected. A general health questionnaire (SF-12) and a knee functional questionnaire (KOOS-PS) were used to display results. RESULTS: We identified 13 men and 4 women, aged between 16 and 52. Mean follow-up period was 16.49 months. High-energy trauma following a traffic collision was the most frequent mechanism. Mean Injury Severity Score (ISS) was 39.05, and a damage control strategy was used in 15 (83.33%) injuries. Extra-articular fractures (Fraser I) largely predominated, resulting in double intramedullary nailing in 72.22% of cases. Eleven injuries (61.11%) presented with an open fracture. Complications appeared in 6 (33.33%) injuries, being 3 infections. Mean score for the SF-12 was 35.59 for the physical dimension and 50.44 for mental dimension. Mean score for the KOOS-PS was 43.64. CONCLUSION: Floating knee injuries usually occur in polytrauma contexts. Visceral involvement and exposed fractures are common, so the most appropriate strategy is usually a staged treatment. Complications and sequelae are frequent.

Immunosuppression in Malaria: Do Plasmodium falciparum Parasites Hijack the Host?

Malaria reflects not only a state of immune activation, but also a state of general immune defect or immunosuppression, of complex etiology that can last longer than the actual episode. Inhabitants of malaria-endemic regions with lifelong exposure to the parasite show an exhausted or immune regulatory profile compared to non- or minimally exposed subjects. Several studies and experiments to identify and characterize the cause of this malaria-related immunosuppression have shown that malaria suppresses humoral and cellular responses to both homologous (Plasmodium) and heterologous antigens (e.g., vaccines). However, neither the underlying mechanisms nor the relative involvement of different types of immune cells in immunosuppression during malaria is well understood. Moreover, the implication of the parasite during the different stages of the modulation of immunity has not been addressed in detail. There is growing evidence of a role of immune regulators and cellular components in malaria that may lead to immunosuppression that needs further research. In this review, we summarize the current evidence on how malaria parasites may directly and indirectly induce immunosuppression and investigate the potential role of specific cell types, effector molecules and other immunoregulatory factors.

Longitudinal monitoring of laboratory markers characterizes hospitalized and ambulatory COVID-19 patients.

Early detection of severe forms of COVID-19 is absolutely essential for timely triage of patients. We longitudinally followed-up two well-characterized patient groups, hospitalized moderate to severe (n = 26), and ambulatory mild COVID-19 patients (n = 16) at home quarantine. Human D-dimer, C-reactive protein (CRP), ferritin, cardiac troponin I, interleukin-6 (IL-6) levels were measured on day 1, day 7, day 14 and day 28. All hospitalized patients were SARS-CoV-2 positive on admission, while all ambulatory patients were SARS-CoV-2 positive at recruitment. Hospitalized patients had higher D-dimer, CRP and ferritin, cardiac troponin I and IL-6 levels than ambulatory patients (p < 0.001, p < 0.001, p = 0.016, p = 0.035, p = 0.002 respectively). Hospitalized patients experienced significant decreases in CRP, ferritin and IL-6 levels from admission to recovery (p < 0.001, p = 0.025, and p = 0.001 respectively). Cardiac troponin I levels were high during the acute phase in both hospitalized and ambulatory patients, indicating a potential myocardial injury. In summary, D-dimer, CRP, ferritin, cardiac troponin I, IL-6 are predictive laboratory markers and can largely determine the clinical course of COVID-19, in particular the prognosis of critically ill COVID-19 patients.

Heterologous protection against malaria by a simple chemoattenuated PfSPZ vaccine regimen in a randomized trial.

Immunization with Plasmodium falciparum (Pf) sporozoites under chemoprophylaxis (PfSPZ-CVac) is the most efficacious approach to malaria vaccination. Implementation is hampered by a complex chemoprophylaxis regimen and missing evidence for efficacy against heterologous infection. We report the results of a double-blinded, randomized, placebo-controlled trial of a simplified, condensed immunization regimen in malaria-naive volunteers (EudraCT-Nr: 2018-004523-36). Participants are immunized by direct venous inoculation of 1.1 × 105 aseptic, purified, cryopreserved PfSPZ (PfSPZ Challenge) of the PfNF54 strain or normal saline (placebo) on days 1, 6 and 29, with simultaneous oral administration of 10 mg/kg chloroquine base. Primary endpoints are vaccine efficacy tested by controlled human malaria infection (CHMI) using the highly divergent, heterologous strain Pf7G8 and safety. Twelve weeks following immunization, 10/13 participants in the vaccine group are sterilely protected against heterologous CHMI, while (5/5) participants receiving placebo develop parasitemia (risk difference: 77%, p = 0.004, Boschloo's test). Immunization is well tolerated with self-limiting grade 1-2 headaches, pyrexia and fatigue that diminish with each vaccination. Immunization induces 18-fold higher anti-Pf circumsporozoite protein (PfCSP) antibody levels in protected than in unprotected vaccinees (p = 0.028). In addition anti-PfMSP2 antibodies are strongly protection-associated by protein microarray assessment. This PfSPZ-CVac regimen is highly efficacious, simple, safe, well tolerated and highly immunogenic.

Expansion of Functional Myeloid-Derived Suppressor Cells in Controlled Human Malaria Infection.

Malaria can cause life-threatening complications which are often associated with inflammatory reactions. More subtle, but also contributing to the burden of disease are chronic, often subclinical infections, which result in conditions like anemia and immunologic hyporesponsiveness. Although very frequent, such infections are difficult to study in endemic regions because of interaction with concurrent infections and immune responses. In particular, knowledge about mechanisms of malaria-induced immunosuppression is scarce. We measured circulating immune cells by cytometry in healthy, malaria-naïve, adult volunteers undergoing controlled human malaria infection (CHMI) with a focus on potentially immunosuppressive cells. Infectious Plasmodium falciparum (Pf) sporozoites (SPZ) (PfSPZ Challenge) were inoculated during two independent studies to assess malaria vaccine efficacy. Volunteers were followed daily until parasites were detected in the circulation by RT-qPCR. This allowed us to analyze immune responses during pre-patency and at very low parasite densities in malaria-naïve healthy adults. We observed a consistent increase in circulating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in volunteers who developed P. falciparum blood stage parasitemia. The increase was independent of preceding vaccination with a pre-erythrocytic malaria vaccine. PMN-MDSC were functional, they suppressed CD4+ and CD8+ T cell proliferation as shown by ex-vivo co-cultivation with stimulated T cells. PMN-MDSC reduced T cell proliferation upon stimulation by about 50%. Interestingly, high circulating PMN-MDSC numbers were associated with lymphocytopenia. The number of circulating regulatory T cells (Treg) and monocytic MDSC (M-MDSC) showed no significant parasitemia-dependent variation. These results highlight PMN-MDSC in the peripheral circulation as an early indicator of infection during malaria. They suppress CD4+ and CD8+ T cell proliferation in vitro. Their contribution to immunosuppression in vivo in subclinical and uncomplicated malaria will be the subject of further research. Pre-emptive antimalarial pre-treatment of vaccinees to reverse malaria-associated PMN-MDSC immunosuppression could improve vaccine response in exposed individuals.

First-in-human, Randomized, Double-blind Clinical Trial of Differentially Adjuvanted PAMVAC, A Vaccine Candidate to Prevent Pregnancy-associated Malaria.

BACKGROUND: Malaria in pregnancy has major impacts on mother and child health. To complement existing interventions, such as intermittent preventive treatment and use of impregnated bed nets, we developed a malaria vaccine candidate with the aim of reducing sequestration of asexual "blood-stage" parasites in the placenta, the major virulence mechanism. METHODS: The vaccine candidate PAMVAC is based on a recombinant fragment of VAR2CSA, the Plasmodium falciparum protein responsible for binding to the placenta via chondroitin sulfate A (CSA). Healthy, adult malaria-naive volunteers were immunized with 3 intramuscular injections of 20 µg (n = 9) or 50 µg (n = 27) PAMVAC, adjuvanted with Alhydrogel or glucopyranosyl lipid adjuvant in stable emulsion (GLA-SE) or in a liposomal formulation with QS21 (GLA-LSQ). Allocation was random and double blind. The vaccine was given every 4 weeks. Volunteers were observed for 6 months following last immunization. RESULTS: All PAMVAC formulations were safe and well tolerated. A total of 262 adverse events (AEs) occurred, 94 (10 grade 2 and 2 grade 3) at least possibly related to the vaccine. No serious AEs occurred. Distribution and severity of AEs were similar in all arms. PAMVAC was immunogenic in all participants. PAMVAC-specific antibody levels were highest with PAMVAC-GLA-SE. The antibodies inhibited binding of VAR2CSA expressing P. falciparum-infected erythrocytes to CSA in a standardized functional assay. CONCLUSIONS: PAMVAC formulated with Alhydrogel or GLA-based adjuvants was safe, well tolerated, and induced functionally active antibodies. Next, PAMVAC will be assessed in women before first pregnancies in an endemic area. CLINICAL TRIALS REGISTRATION: EudraCT 2015-001827-21; ClinicalTrials.gov NCT02647489.

DSM265 for Plasmodium falciparum chemoprophylaxis: a randomised, double blinded, phase 1 trial with controlled human malaria infection.

BACKGROUND: A drug for causal (ie, pre-erythrocytic) prophylaxis of Plasmodium falciparum malaria with prolonged activity would substantially advance malaria control. DSM265 is an experimental antimalarial that selectively inhibits the parasite dihydroorotate dehydrogenase. DSM265 shows in vitro activity against liver and blood stages of P falciparum. We assessed the prophylactic activity of DSM265 against controlled human malaria infection (CHMI). METHODS: At the Institute of Tropical Medicine, Eberhard Karls University (Tübingen, Germany), healthy, malaria-naive adults were allocated to receive 400 mg DSM265 or placebo either 1 day (cohort 1A) or 7 days (cohort 2) before CHMI by direct venous inoculation (DVI) of 3200 aseptic, purified, cryopreserved P falciparum sporozoites (PfSPZ Challenge; Sanaria Inc, Rockville, MD, USA). An additional group received daily atovaquone-proguanil (250-100 mg) for 9 days, starting 1 day before CHMI (cohort 1B). Allocation to DSM265, atovaquone-proguanil, or placebo was randomised by an interactive web response system. Allocation to cohort 1A and 1B was open-label, within cohorts 1A and 2, allocation to DSM265 and placebo was double-blinded. All treatments were given orally. Volunteers were treated with an antimalarial on day 28, or when parasitaemic, as detected by thick blood smear (TBS) microscopy. The primary efficacy endpoint was time-to-parasitaemia, assessed by TBS. All participants receiving at least one dose of chemoprophylaxis or placebo were considered for safety, those receiving PfSPZ Challenge for efficacy analyses. Log-rank test was used to compare time-to-parasitemia between interventions. The trial was registered with ClinicalTrials.gov, number NCT02450578. FINDINGS: 22 participants were enrolled between Oct 23, 2015, and Jan 18, 2016. Five participants received 400 mg DSM265 and two participants received placebo 1 day before CHMI (cohort 1A), six participants received daily atovaquone-proguanil 1 day before CHMI (cohort 1B), and six participants received 400 mg DSM265 and two participants received placebo 7 days before CHMI (cohort 2). Five of five participants receiving DSM265 1 day before CHMI and six of six in the atovaquone-proguanil cohort were protected, whereas placebo recipients (two of two) developed malaria on days 11 and 14. When given 7 days before CHMI, three of six volunteers receiving DSM265 became TBS positive on days 11, 13, and 24. The remaining three DSM265-treated, TBS-negative participants of cohort 2 developed transient submicroscopic parasitaemia. Both participants receiving placebo 7 days before CHMI became TBS positive on day 11. The only possible DSM265-related adverse event was a moderate transient elevation in serum bilirubin in one participant. INTERPRETATION: A single dose of 400 mg DSM265 was well tolerated and had causal prophylactic activity when given 1 day before CHMI. Future trials are needed to investigate further the use of DSM265 for the prophylaxis of malaria. FUNDING: Global Health Innovative Technology Fund, Wellcome Trust, Bill & Melinda Gates Foundation through Medicines for Malaria Venture, and the German Center for Infection Research.

Sterile protection against human malaria by chemoattenuated PfSPZ vaccine.

A highly protective malaria vaccine would greatly facilitate the prevention and elimination of malaria and containment of drug-resistant parasites. A high level (more than 90%) of protection against malaria in humans has previously been achieved only by immunization with radiation-attenuated Plasmodium falciparum (Pf) sporozoites (PfSPZ) inoculated by mosquitoes; by intravenous injection of aseptic, purified, radiation-attenuated, cryopreserved PfSPZ ('PfSPZ Vaccine'); or by infectious PfSPZ inoculated by mosquitoes to volunteers taking chloroquine or mefloquine (chemoprophylaxis with sporozoites). We assessed immunization by direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated PfSPZ ('PfSPZ Challenge') to malaria-naive, healthy adult volunteers taking chloroquine for antimalarial chemoprophylaxis (vaccine approach denoted as PfSPZ-CVac). Three doses of 5.12 × 104 PfSPZ of PfSPZ Challenge at 28-day intervals were well tolerated and safe, and prevented infection in 9 out of 9 (100%) volunteers who underwent controlled human malaria infection ten weeks after the last dose (group III). Protective efficacy was dependent on dose and regimen. Immunization with 3.2 × 103 (group I) or 1.28 × 104 (group II) PfSPZ protected 3 out of 9 (33%) or 6 out of 9 (67%) volunteers, respectively. Three doses of 5.12 × 104 PfSPZ at five-day intervals protected 5 out of 8 (63%) volunteers. The frequency of Pf-specific polyfunctional CD4 memory T cells was associated with protection. On a 7,455 peptide Pf proteome array, immune sera from at least 5 out of 9 group III vaccinees recognized each of 22 proteins. PfSPZ-CVac is a highly efficacious vaccine candidate; when we are able to optimize the immunization regimen (dose, interval between doses, and drug partner), this vaccine could be used for combination mass drug administration and a mass vaccination program approach to eliminate malaria from geographically defined areas.

Intususcepción íleo-ileal secundaria a un pólipo fibrinoide inflamatorio / Ileoileal intussusception secondary to inflammatory fibrinoid polyp

Introducción. El pólipo fibrinoide inflamatorio es una lesión inflamatoria no neoplásica que se presenta especialmente en el estómago, aunque puede ocurrir en cualquier parte del tubo digestivo, en donde puede ocasionar episodios de intususcepción y obstrucción intestinal. Presentación del caso. Se presenta el caso de una mujer de 49 años de edad, con un cuadro clínico de una semana de evolución consistente en episodios intermitentes de dolor abdominal, distensión abdominal y emesis. Ingresó a urgencias de la Clínica CES de Medellín, donde se le practicó una tomografía de abdomen que mostró una invaginación intestinal en el íleon, por lo que se programó para una laparotomía exploratoria. Se encontró una intususcepción secundaria a una lesión polipoide que ocupaba la luz del íleon, se resecó el segmento comprometido y se hizo una anastomosis látero-lateral, sin complicaciones. El estudio anatomo-patológico y la inmunohistoquímica confirmaron el diagnóstico de pólipo fibrinoide inflamatorio. Conclusión. El pólipo fibrinoide inflamatorio es una entidad poco frecuente, benigna, que al presentarse en el íleon puede causar intususcepción y obstrucción intestinal. Los estudios imaginológicos proporcionan hallazgos indirectos. Sin embargo, su diagnóstico definitivo se logra con los estudios anatomo-patológico y de inmunohistoquímica después la resección quirúrgica completa, la cual es curativa en la inmensa mayoría de los casos.Palabras clave: enfermedades intestinales; pólipos intestinales; neoplasias intestinales; obstrucción intestinal.

Introduction: Inflammatory fibrinoid polyp is a non-neoplastic inflammatory lesion, which occurs especially at gastric level, but may also occur anywhere in the gastrointestinal tract, where it can cause episodes of intussusceptions and intestinal obstruction. Case report: We report the case of a 49 year old woman with clinical presentation of one week of evolution consisting in episodes of intermittent abdominal pain, abdominal distension and emesis. She presented at the emergency department of Clinica CES (Medellín, Colombia), where a CT scan of the abdomen reported ileal intussusception. At exploratory laparotomy an intussusception secondary to a polypoid lesion that occupied the ileal lumen was found, and resection of the involved segment and anastomosis were performed without complications. Pathology and immunohistochemistry study confirmed the diagnosis of Inflammatory fibrinoid polyp. Conclusion: The inflammatory fibrinoid polyp is a rare, benign entity that when located in the ileum may cause intussusception and intestinal obstruction. Imagening studies exhibit indirect findings. However, definitive diagnosis is made with pathology and immunohistochemistry studies followimg complete surgical resection, which is curative in the majority of cases.