Protective efficacy and correlates of immunity of immunodominant recombinant Babesia microti antigens.

Babesia microti, an intraerythrocytic apicomplexan parasite, is the primary causative agent of human babesiosis and an emerging threat to public health in the United States and elsewhere. An effective vaccine against B. microti would reduce disease severity in acute babesiosis patients and shorten the parasitemic period in asymptomatic individuals, thereby minimizing the risk of transfusion-transmitted babesiosis. Here we report on immunogenicity, protective efficacy, and correlates of immunity following immunization with four immunodominant recombinantly produced B. microti antigens-Serine Reactive Antigen 1 (SERA1), Maltese Cross Form Related Protein 1 (MCFRP1), Piroplasm ß-Strand Domain 1 (PißS1), and Babesia microti Alpha Helical Cell Surface Protein 1 (BAHCS1)-delivered subcutaneously in Montanide ISA 51/CpG adjuvant in three doses to BALB/c mice. Following B. microti parasite challenge, BAHCS1 led to the highest reduction in peak parasitemia (67.8%), followed by SERA1 (44.8%) and MCFRP1 (41.9%); PißS1 (27.6%) had minimal protective effect. All four B. microti antigens induced high ELISA total IgG and each isotype; however, antibody levels did not directly correlate with anti-parasitic activity in mice. Increased prechallenge levels of some cell populations including follicular helper T cells (TFH) and memory B cells, along with a set of six cytokines [IL-1α, IL-2, IL-3, IL-6, IL-12(p40), and G-CSF] that belong to both innate and adaptive immune responses, were generally associated with protective immunity. Our results indicate that mechanisms driving recombinant B. microti antigen-induced immunity are complex and multifactorial. We think that BAHCS1 warrants further evaluation in preclinical studies.

Range of the perfluorooctanoate (PFOA) safe dose for human health: An international collaboration.

Many government agencies and expert groups have estimated a dose-rate of perfluorooctanoate (PFOA) that would protect human health. Most of these evaluations are based on the same studies (whether of humans, laboratory animals, or both), and all note various uncertainties in our existing knowledge. Nonetheless, the values of these various, estimated, safe-doses vary widely, with some being more than 100,000 fold different. This sort of discrepancy invites scrutiny and explanation. Otherwise what is the lay public to make of this disparity? The Steering Committee of the Alliance for Risk Assessment (2022) called for scientists interested in attempting to understand and narrow these disparities. An advisory committee of nine scientists from four countries was selected from nominations received, and a subsequent invitation to scientists internationally led to the formation of three technical teams (for a total of 24 scientists from 8 countries). The teams reviewed relevant information and independently developed ranges for estimated PFOA safe doses. All three teams determined that the available epidemiologic information could not form a reliable basis for a PFOA safe dose-assessment in the absence of mechanistic data that are relevant for humans at serum concentrations seen in the general population. Based instead on dose-response data from five studies of PFOA-exposed laboratory animals, we estimated that PFOA dose-rates 10-70 ng/kg-day are protective of human health.

The effect of insulin on response to intravitreal anti-VEGF injection in diabetic macular edema in type 2 diabetes mellitus.

OBJECTIVES: To assess whether insulin therapy impacts the effectiveness of anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of diabetic macular edema (DME) in type 2 diabetes mellitus. METHODS: This was a retrospective multi-center analysis. The best-corrected visual acuity (BCVA) at 12 months, BCVA change, central macular thickness (CMT), CMT change, and cumulative injection number were compared between the insulin and the oral hypoglycemic agent (OHA) groups. RESULTS: The mean final BCVA and CMT improved in both the insulin (N = 137; p < 0.001; p < 0.001, respectively) and the OHA group (N = 61; p = 0.199; p < 0.001, respectively). The two treatment groups were comparable for final BCVA (p = 0.263), BCVA change (p = 0.184), final CMT (p = 0.741), CMT change (p = 0.458), and the cumulative injections received (p = 0.594). The results were comparable between the two groups when stratified by baseline vision (p > 0.05) and baseline HbA1c (p > 0.05). CONCLUSION: Insulin therapy does not alter treatment outcomes for anti-VEGF therapy in DME.

The Conundrum of the PFOA human half-life, an international collaboration.

The Steering Committee of the Alliance for Risk Assessment (ARA) opened a call for scientists interested in resolving what appeared to be a conundrum in estimating of the half-life of perfluorooctanoate (PFOA) in humans. An Advisory Committee was formed from nominations received and a subsequent invitation led to the development of three small independent working groups to review appropriate information and attempt a resolution. Initial findings were shared among these groups and a conclusion developed from the ensuing discussions. Many human observational studies have estimated the PFOA half-life. Most of these studies note the likely occurrence of unmonitored PFOA exposures, which could inflate values of the estimated PFOA half-life. Also, few of these studies estimated the half-life of PFOA isomers, the branched chains of which likely have shorter half-lives. This could deflate values of the estimated linear PFOA half-life. Fortunately, several studies informed both of these potential problems. The majority opinion of this international collaboration is that the studies striking the best balance in addressing some of these uncertainties indicate the likely central tendency of the human PFOA half-life is less than 2 years. The single best value appears to be the geometric mean (GM) of 1.3 years (Zhang et al., 2013, Table 3), based on a GM = 1.7 years in young females (n = 20) and GM = 1.2 years in males of all ages and older females (n = 66). However, a combined median value from Zhang et al. (2013) of 1.8 years also adds value to this range of central tendency. While the Collaboration found this study to be the least encumbered with unmonitored PFOA exposures and branched isomers, more studies of similar design would be valuable. Also valuable would be clarification around background exposures in other existing studies in case adjustments to half-life estimates are attempted.

Identifying Genetic Biomarkers Predicting Response to Anti-Vascular Endothelial Growth Factor Injections in Diabetic Macular Edema.

Intraocular anti-vascular endothelial growth factor (VEGF) therapies are the front-line treatment for diabetic macular edema (DME); however, treatment response varies widely. This study aimed to identify genetic determinants associated with anti-VEGF treatment response in DME. We performed a genome-wide association study on 220 Australian patients with DME treated with anti-VEGF therapy, genotyped on the Illumina Global Screening Array, and imputed to the Haplotype Reference Consortium panel. The primary outcome measures were changes in central macular thickness (CMT in microns) and best-corrected visual acuity (BCVA in ETDRS letters) after 12 months. Association between single nucleotide polymorphism (SNP) genotypes and DME outcomes were evaluated by linear regression, adjusting for the first three principal components, age, baseline CMT/BCVA, duration of diabetic retinopathy, and HbA1c. Two loci reached genome-wide significance (p < 5 × 10−8) for association with increased CMT: a single SNP on chromosome 6 near CASC15 (rs78466540, p = 1.16 × 10−9) and a locus on chromosome 12 near RP11-116D17.1 (top SNP rs11614480, p = 2.69 × 10−8). Four loci were significantly associated with reduction in BCVA: two loci on chromosome 11, downstream of NTM (top SNP rs148980760, p = 5.30 × 10−9) and intronic in RP11-744N12.3 (top SNP rs57801753, p = 1.71 × 10−8); one near PGAM1P1 on chromosome 5 (rs187876551, p = 1.52 × 10−8); and one near TBC1D32 on chromosome 6 (rs118074968, p = 4.94 × 10−8). In silico investigations of each locus identified multiple expression quantitative trait loci and potentially relevant candidate genes warranting further analysis. Thus, we identified multiple genetic loci predicting treatment outcomes for anti-VEGF therapies in DME. This work may potentially lead to managing DME using personalized treatment approaches.

Triphenylphosphonium functionalized Ficus religiosa L. extract loaded nanoparticles improve the mitochondrial function in oxidative stress induced diabetes.

The present study was aimed to enhance the mitochondrial function in oxidative stress-induced diabetes. To achieve this, Ficus religiosa L. extract loaded solid lipid nanoparticles (ETNPs) were prepared and functionalized by using triphenylphosphonium. Developed nanoparticles demonstrated desired quality attributes with sustained release for up to 24 h and excellent storage stability for up to 180 days at 40 ± 2°C and 75 ± 5% relative humidity. In vitro cytotoxicity assessment showed no toxicity of ETNPs. Interestingly, oral administration of ETNPs to diabetic rats demonstrated improved mitochondrial function by normalizing the mitochondrial morphology, intracellular calcium ion concentration, complexes I, II, IV, and V activity, mitochondrial membrane potential, and antioxidant levels. Further, reduction in apoptotic markers viz. cytochrome-C, caspase-3, and caspase-9 was observed following the ETNP treatment. Moreover, significant reduction in blood glucose and glycosylated hemoglobin while significant improvement in plasma insulin was observed as compared to the diabetic group following the treatment with developed formulation. Furthermore, histopathology studies confirmed the safety of the developed formulation and thus, data in hand collectively suggest that proposed strategy can be effectively used to improve the mitochondrial function in oxidative stress-induced diabetes along with better control over blood glucose and glycosylated hemoglobin.

Middle East Respiratory Syndrome (MERS) Virus-Pathophysiological Axis and the Current Treatment Strategies.

Middle East respiratory syndrome (MERS) is a lethal respiratory disease with its first case reported back in 2012 (Jeddah, Saudi Arabia). It is a novel, single-stranded, positive-sense RNA beta coronavirus (MERS-CoV) that was isolated from a patient who died from a severe respiratory illness. Later, it was found that this patient was infected with MERS. MERS is endemic to countries in the Middle East regions, such as Saudi Arabia, Jordan, Qatar, Oman, Kuwait and the United Arab Emirates. It has been reported that the MERS virus originated from bats and dromedary camels, the natural hosts of MERS-CoV. The transmission of the virus to humans has been thought to be either direct or indirect. Few camel-to-human transmissions were reported earlier. However, the mode of transmission of how the virus affects humans remains unanswered. Moreover, outbreaks in either family-based or hospital-based settings were observed with high mortality rates, especially in individuals who did not receive proper management or those with underlying comorbidities, such as diabetes and renal failure. Since then, there have been numerous reports hypothesising complications in fatal cases of MERS. Over the years, various diagnostic methods, treatment strategies and preventive measures have been strategised in containing the MERS infection. Evidence from multiple sources implicated that no treatment options and vaccines have been developed in specific, for the direct management of MERS-CoV infection. Nevertheless, there are supportive measures outlined in response to symptom-related management. Health authorities should stress more on infection and prevention control measures, to ensure that MERS remains as a low-level threat to public health.

Risk assessment studies of the impact of occupational exposure of pharmaceutical workers on the development of antimicrobial drug resistance.

Pharmaceutical workers involved with the production of antimicrobial drugs are exposed to various antimicrobial chemicals in different steps of manufacturing such as grinding, sieving, compression, granulation, mixing, and filling. These exposures may lead to the development of multidrug resistance (MDR) in bacteria. Scientific reports on the occupational health hazard of pharmaceutical workers involved in manufacturing antibiotics are scarce. The present study aimed to compare the degree of bacterial resistance in pharmaceutical workers in India to that of individuals not involved in the pharmaceutical field. Twenty male workers from 5 local pharmaceutical companies and 20 male subjects not involved in the pharmaceutical field (non-pharmaceutical subjects) were randomly selected. Nasal fluid and mucus/cough specimens were collected from each subject and were cultured separately at 37 °C for 24 hr to obtain bacterial growth. The cultured species were then identified, isolated, and subjected to microbial sensitivity testing against 18 different antibiotics from 8 different groups by the disk diffusion method. Staphylococcus spp., Pseudomonas spp., and Escherichia coli were identified and isolated from the culture of nasal fluids and mucuses, respectively. All the isolated species of bacteria exhibited significant enhancement of the degree of MDR in pharmaceutical workers compared with non-pharmaceutical subjects. Workers with a longer working history had greater degree of antibiotic resistance and vice versa. It can be certainly considered that the exposure of pharmaceutical workers to antibiotic agents resulted in a high incidence of multidrug resistance. Effective steps should be taken to minimize inherent exposure of pharmaceutical workers to antibiotics during work to prevent antimicrobial drug resistance.

Building a national eye-care service in post-conflict Timor-Leste.

PROBLEM: Violent conflict left Timor-Leste with a dismantled health-care workforce and infrastructure after 2001. The absence of existing health and tertiary education sectors compounded the challenges of instituting a national eye-care system. APPROACH: From 2001, the East Timor Eye Program coordinated donations and initially provided eye care through visiting teams. From 2005, the programme reoriented to undertake concerted workforce and infrastructure development. In 2008 full-time surgical services started in a purpose-built facility in the capital city. In 2014 we developed a clinical training pipeline for local medical graduates to become ophthalmic surgeons, comprising a local postgraduate diploma, with donor funding supporting master's degree studies abroad. LOCAL SETTING: In the population of 1.26 million, an estimated 35 300 Timorese are blind and an additional 123 500 have moderate to severe visual impairment, overwhelmingly due to cataract and uncorrected refractive error. RELEVANT CHANGES: By April 2018, six Timorese doctors had completed the domestic postgraduate diploma, three of whom had enrolled in master's degree programmes. Currently, one consultant ophthalmologist, seven ophthalmic registrars, two optometrists, three refractionists and four nursing staff form a tertiary resident ophthalmic workforce, supported by an international advisor ophthalmologist and secondary eye-care workers. A recorded 12 282 ophthalmic operations and 117 590 consultations have been completed since 2001. LESSONS LEARNT: International organizations played a pivotal role in supporting the Timorese eye health system, in an initially vulnerable setting. We highlight how transition to domestic funding can be achieved through the creation of a domestic training pipeline and integration with national institutions.

Orbital Air Embolism After Intravenous Injection.

An asymptomatic air embolism in the right superior ophthalmic vein was discovered incidentally during a cerebral computed tomography, most likely due to a preceding intravenous fluid bolus. This case illustrates the potential risk of air emboli being propagated to the cerebral venous circulation during routine injections and fluid resuscitation.

A Novel Gametocyte Biomarker for Superior Molecular Detection of the Plasmodium falciparum Infectious Reservoirs.

Background: Complete malaria eradication and optimal use of transmission-reducing interventions require knowledge of submicroscopic infectious reservoirs among asymptomatic individuals. Even submicroscopic levels of Plasmodium falciparum gametocytes can infect mosquitoes and promote onward transmission. Most efforts to identify gametocyte carriers use polymerase chain reaction amplification of the gametocyte-specific transcript Pfs25. Methods: To expand the repertoire of biomarkers available for superior gametocyte detection, we compared the gene expression profiles of gametocytes and asynchronous blood-stage P. falciparum parasites by microarray technology. This allowed the identification of 56 molecules abundantly expressed in the gametocyte stage of the parasite. The analytical sensitivity for gametocyte detection was evaluated for 25 genes with the highest expression levels. Results: One candidate, Pfg17, exhibited superior analytical sensitivity against a panel of gametocyte-spiked whole blood, detecting 10 gametocytes/mL; in comparison, Pfs25 detected only 25.3 gametocytes/mL. Pfg17 also exhibited superior clinical sensitivity, identifying 19.1% more samples from blood-film microscopy-negative Ghanaian children and 40% more samples from asymptomatic adults as gametocyte positive. Conclusions: Cumulatively, our results suggest Pfg17 is an excellent biomarker for detecting asymptomatic infectious reservoirs otherwise missed by the most sensitive molecular method available. Our study has also improved the repertoire of transmission-stage antigens available for evaluation as candidate vaccines.

iCHRCloud: Web & Mobile based Child Health Imprints for Smart Healthcare.

Reducing child mortality with quality care is the prime-most concern of all nations. Thus in current IT era, our healthcare industry needs to focus on adapting information technology in healthcare services. Barring few preliminary attempts to digitalize basic hospital administrative and clinical functions, even today in India, child health and vaccination records are still maintained as paper-based records. Also, error in manually plotting the parameters in growth charts results in missed opportunities for early detection of growth disorders in children. To address these concerns, we present India's first hospital linked, affordable automated vaccination and real-time child's growth monitoring cloud based application- Integrated Child Health Record cloud (iCHRcloud). This application is based on HL7 protocol enabling integration with hospital's HIS/EMR system. It provides Java (Enterprise Service Bus and Hibernate) based web portal for doctors and mobile application for parents, enhancing doctor-parent engagement. It leverages highchart to automate chart preparation and provides access of data via Push Notification (GCM and APNS) to parents on iOS and Android mobile platforms. iCHRcloud has also been recognized as one of the best innovative solution in three nationwide challenges, 2016 in India. iCHRcloud offers a seamless, secure (256 bit HTTPS) and sustainable solution to reduce child mortality. Detail analysis on preliminary data of 16,490 child health records highlight the diversified need of various demographic regions. Thus, primary lesson would be to implement better validation strategies to fulfill the customize requisites of entire population. This paper presents first glimpse of data and power of the analytics in policy framework.

HDL cholesterol: all hope is not lost after the torcetrapib setback--emerging therapeutic strategies on the horizon.

Lowering low-density lipoprotein cholesterol (LDL) has been definitely shown to reduce cardiovascular events and improve clinical outcomes in the literature. As a result, LDL lowering has become the cornerstone of therapeutic approaches to cardiovascular disease prevention. Recently, there has been a focus on targeting other lipid fractions to improve the clinical risk profile of patients. Raising high-density lipoprotein (HDL) has received considerable attention. Low HDL levels are often seen in combination with elevated triglyceride levels. New therapeutic modalities are being developed to increase HDL levels. Recent failure of agents such as cholesteryl ester transferase protein inhibitor torcetrapib has highlighted the importance of measuring functionality of HDL particles and not just focus quantitatively on HDL-C levels. The heterogeneity of HDL within the systemic circulation results from constant remodeling of particles in response to several factors. Established dyslipidemia therapies such as stains, fibrates, and niacin have already been well known in the literature to have a substantial benefit. Lifestyle changes such as smoking cessation and moderate alcohol consumption have also shown to have some benefit. Several novel HDL therapies are currently being developed, but only the cholesteryl ester transferase protein inhibitors have received considerable attention. Although torcetrapib has received some negative attention due to adverse effects, this overall class of therapeutic agents still holds a lot of promise. Newer agents without the concerned toxicities are currently being developed. ApoA-1-related peptides, peroxisome proliferator-activated receptor agonists, endothelial lipase inhibitors, and liver X receptor agonists are some of the other novel agents currently in various stages of development.

The use of heterochromatic flicker photometry to determine macular pigment optical density in a healthy Australian population.

PURPOSE: To establish the normal macular pigment density (MPOD) in a healthy adult Australian sample using heterochromatic flicker photometry (HFP). METHODS: Macular pigment density was measured using heterochromatic flicker photometry in a total of 201 subjects ranging in age from 21 to 84 years with healthy macula. Fifty-seven of the healthy subjects also completed a food-frequency dietary questionnaire. Best-corrected visual acuity (BCVA) was measured using logMAR, chart and macular morphological profiles were assessed using high-resolution integrated Fourier-domain optical coherence tomography (OCT). RESULTS: The average MPOD value was 0.41 ± 0.20 (range 0.07-0.79). There was no statistically significant difference between values in the left and right eye, with good interocular agreement (0.41 vs 0.40, r = 0.893, p < 0.01). Age significantly predicted MPOD score (R (2) = 0.07, p < 0.05). A subgroup analysis of patients who completed the dietary questionnaire revealed a close correlation between higher diet scores and higher MPOD (r = 0.720 p = 0.031). There was no effect of smoking, gender, or iris colour on MPOD values. There was no significant correlation between BCVA, macular OCT profiles, and MPOD. CONCLUSION: Given that MPOD values are potentially affected by geographical variation, we have determined a mean MPOD value for healthy subjects in a population south of the equator, providing a reference point for future studies on Caucasian samples.

Chemotherapeutic and targeted biological agents for metastatic bladder cancer: a comprehensive review.

The American Cancer Society estimates that 73 510 new cases of bladder cancer will be diagnosed and 15 000 deaths will result this year. The paper summarizes the clinical evidence for the use of platinum-based, non-platinum-based and new targeted biological agents, while reporting the future directions in the treatment of metastatic bladder cancer. For cisplatin-base regimens, the combination of methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) has been the mainstream treatment for both advanced and metastatic bladder cancers. It showed significant improvement in the complete response rate and overall survival time in comparison with single-agent cisplatin. For cisplatin-ineligible patients, namely patients with renal impairment, symptomatic cardiac disease and poor performance status, alternative therapies consisting of paclitaxel, gemcitabine and carboplatin were shown to be of benefit. Pemetrexed and vinflunine have also shown effectiveness, with small but demonstrable overall survival benefits. Gemcitabine-based doublet therapies (combined with paclitaxel, docetaxel, irinotecan, oxaliplatin or epirubicin) have all been shown to be effective and well-tolerated. Several new targeted therapies, such as gefetinib, sorafenib and lapatinib, have received attention in recent years; however, their effectiveness as single agents in a relapse setting have not been optimal and more studies are warranted.

Guillain-Barre syndrome complicated by acute fatal rhabdomyolysis.

Guillain-Barre syndrome (GBS) is a heterogenous group of peripheral-nerve disorders with similar clinical presentation characterized by acute, self-limited, progressive, bilateral and relatively symmetric ascending flaccid paralysis, which peaks in 2-4 weeks and then subsides. The usual complications, which occur in a patient of GBS are pneumonia, sepsis, pulmonary embolism, respiratory insufficiency and cardiac arrest. The clinical course of GBS complicated by acute rhabdomyolysis is extremely rare. We present the case of GBS with marked elevation in serum creatine kinase, serum myoglobin levels and persistent hyperkalemia as a result of associated acute rhabdomyolysis.

Rapid Vision Loss Due to Multifocal Glioma: A Diagnostic Challenge.

INTRODUCTION: This is a unique case report in medical literature for its detailing of diagnostics of an uncommon presentation of a rapid unexplained bilateral vision loss of a 73-year-old male diabetic patient. This report highlights the crucial role of advanced molecular diagnostics in difficult neurological cases and also elucidates the difficulties involved in diagnosing optic nerve glioblastoma, an exceptionally rare and aggressive tumour. MAIN CONCERNS AND CLINICAL FINDINGS OF THE PATIENT: Slow and progressive loss of vision over 2 months, ultimately developing almost complete visual impairment in both eyes and a defect of right eye field of vision conclusively highlighted that the likely etiology was neuro-ophthalmic. Initially, the conditions were suspected to be an extended spectrum of diabetic eye disease complications but further deterioration was a hint towards something more substantive. PRIMARY DIAGNOSES, INTERVENTIONS AND OUTCOMES: This entailed in-depth diagnosis processes that included an MRI and the analysis of cerebrospinal fluid. The important discovery was through stereotactic biopsies of the optic nerve revealing a high-grade glial neoplasm. Next generation sequencing confirmed the pathology as IDH-wildtype glioblastoma. Despite management, his vision continued to deteriorate. Hence, an aggressive clinical course was followed. CONCLUSION: This case highlights the important learning need in considering glioblastoma of the optic chiasm as part of the differential diagnosis of rapid vision loss, which may present as multifocal brain lesions, especially in cases of rapid loss of vision where initial workup is negative. Quite a useful lesson that can be drawn from this case relates to the diagnostic process with advanced molecular profiling, more attention given to clinical suspicion and cutting-edge diagnostic tools applied in atypical presentation of neurological conditions.