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Positive modulation of hepatocyte growth factor (HGF) signaling may represent a promising therapeutic strategy for Alzheimer's disease (AD) based on its multimodal neurotrophic, neuroprotective, and anti-inflammatory effects addressing the complex pathophysiology of neurodegeneration. Fosgonimeton is a small-molecule positive modulator of the HGF system that has demonstrated neurotrophic and pro-cognitive effects in preclinical models of dementia. Herein, we evaluate the neuroprotective potential of fosgonimeton, or its active metabolite, fosgo-AM, in amyloid-beta (Aβ)-driven preclinical models of AD, providing mechanistic insight into its mode of action. In primary rat cortical neurons challenged with Aβ (Aβ 1-42 ), fosgo-AM treatment significantly improved neuronal survival, protected neurite networks, and reduced tau hyperphosphorylation. Interrogation of intracellular events indicated that cortical neurons treated with fosgo-AM exhibited a significant decrease in mitochondrial oxidative stress and cytochrome c release. Following Aβ injury, fosgo-AM significantly enhanced activation of pro-survival effectors ERK and AKT, and reduced activity of GSK3β, one of the main kinases involved in tau hyperphosphorylation. Fosgo-AM also mitigated Aβ-induced deficits in Unc-like kinase 1 (ULK1) and Beclin-1, suggesting a potential effect on autophagy. Treatment with fosgo-AM protected cortical neurons from glutamate excitotoxicity, and such effects were abolished in the presence of an AKT or MEK/ERK inhibitor. In vivo, fosgonimeton administration led to functional improvement in an intracerebroventricular Aβ 25-35 rat model of AD, as it significantly rescued cognitive function in the passive avoidance test. Together, our data demonstrate the ability of fosgonimeton to counteract mechanisms of Aβ-induced toxicity. Fosgonimeton is currently in clinical trials for mild-to-moderate AD (NCT04488419; NCT04886063)., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kevin J Church reports a relationship with Athira Pharma Inc that includes: employment, equity or stocks, and travel reimbursement. Sherif M Reda reports a relationship with Athira Pharma Inc that includes: employment, equity or stocks, and travel reimbursement. Sharay E Setti reports a relationship with Athira Pharma Inc that includes: employment, equity or stocks, and travel reimbursement. Andree-Anne Berthiaume reports a relationship with Athira Pharma Inc that includes: employment, equity or stocks, and travel reimbursement. Wei Wu reports a relationship with Athira Pharma Inc that includes: employment, equity or stocks, and travel reimbursement. Robert W Taylor reports a relationship with Athira Pharma Inc that includes: employment, equity or stocks, and travel reimbursement. Jewel L Johnston reports a relationship with Athira Pharma Inc that includes: employment, equity or stocks, and travel reimbursement. Liana R Stein reports a relationship with Athira Pharma Inc that includes: employment, equity or stocks, and travel reimbursement. Hans J Moebius reports a relationship with Athira Pharma Inc that includes: employment, equity or stocks, and travel reimbursement. Kevin J Church has patent issued to Athira Pharma Inc. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disorder, primarily affects the motor neurons of the brain and spinal cord. Like other neurodegenerative conditions, ongoing pathological processes such as increased inflammation, excitotoxicity, and protein accumulation contribute to neuronal death. Hepatocyte growth factor (HGF) signaling through the MET receptor promotes pro-survival, anti-apoptotic, and anti-inflammatory effects in multiple cell types, including the neurons and support cells of the nervous system. This pleiotropic system is therefore a potential therapeutic target for treatment of neurodegenerative disorders such as ALS. Here, we test the effects of ATH-1105, a small-molecule positive modulator of the HGF signaling system, in preclinical models of ALS., Methods: In vitro , the impact of ATH-1105 on HGF-mediated signaling was assessed via phosphorylation assays for MET, extracellular signal-regulated kinase (ERK), and protein kinase B (AKT). Neuroprotective effects of ATH-1105 were evaluated in rat primary neuron models including spinal motor neurons, motor neuron-astrocyte cocultures, and motor neuron-human muscle cocultures. The anti-inflammatory effects of ATH-1105 were evaluated in microglia- and macrophage-like cell systems exposed to lipopolysaccharide (LPS). In vivo , the impact of daily oral treatment with ATH-1105 was evaluated in Prp-TDP43 A315T hemizygous transgenic ALS mice., Results: In vitro , ATH-1105 augmented phosphorylation of MET, ERK, and AKT. ATH-1105 attenuated glutamate-mediated excitotoxicity in primary motor neurons and motor neuron- astrocyte cocultures, and had protective effects on motor neurons and neuromuscular junctions in motor neuron-muscle cocultures. ATH-1105 mitigated LPS-induced inflammation in microglia- and macrophage-like cell systems. In vivo , ATH-1105 treatment resulted in improved motor and nerve function, sciatic nerve axon and myelin integrity, and survival in ALS mice. Treatment with ATH-1105 also led to reductions in levels of plasma biomarkers of inflammation and neurodegeneration, along with decreased pathological protein accumulation (phospho-TDP-43) in the sciatic nerve. Additionally, both early intervention (treatment initiation at 1 month of age) and delayed intervention (treatment initiation at 2 months of age) with ATH-1105 produced benefits in this preclinical model of ALS., Discussion: The consistent neuroprotective and anti-inflammatory effects demonstrated by ATH-1105 preclinically provide a compelling rationale for therapeutic interventions that leverage the positive modulation of the HGF pathway as a treatment for ALS., Competing Interests: A-AB, SR, KK, SS, WW, JJ, RT, LS, HM, and KC are employed by and hold stock and/or stock options in Athira Pharma, Inc. A-AB, JJ, RT, and KC are inventors in patent filings related to this work filed by Athira Pharma, Inc., (Copyright © 2024 Berthiaume, Reda, Kleist, Setti, Wu, Johnston, Taylor, Stein, Moebius and Church.)

Chronic kidney disease (CKD) is a prominent cause of death worldwide. Infliximab is one of the anti-TNF-α; herein, we studied the effect of infliximab on adenine-induced CKD. To inspect the role of infliximab, either ameliorative or curative, on CDK induced with adenine. Thirty Wistar albino rats were separated into five groups of 6 rats' each: rats of group Ι were kept as control given saline, rats of group II were treated with infliximab (5 mg/kg, i.p.) for 5 weeks, rats of group ΙΙΙ (the diseased group) had an adenine containing diet (0.25% W/W in feed) for 5 weeks, rats of group ΙV (the ameliorative group) had an adenine-containing diet and infliximab (5 mg/kg, i.p.) for 5 weeks simultaneously, and rats of group V (the curative group) had adenine containing diet then a single dose of infliximab (5 mg/kg, i.p.) was given in the 6th week. Infliximab treatment revealed a decrease in the plasma levels of urea, creatinine, NGAL, and MDA with a substantial increase in TAC. Also, inflammatory mediators such as IL-6 and NF-κB were significantly decreased with the down-regulation of the ASK1/MAPK/JNK pathway. Caspase 3 was downregulated. Also, infliximab treatment exhibited improvement in the histological and immunohistochemical kidney changes. Through its involvement in reducing oxidative stress, inflammation, and apoptosis, infliximab has an ameliorative and curative effect on CKD induced with adenine., (© 2023. The Author(s).)

All types of dementia, including Alzheimer's disease, are debilitating neurodegenerative conditions marked by compromised cognitive function for which there are few effective treatments. Positive modulation of hepatocyte growth factor (HGF)/MET, a critical neurotrophic signaling system, may promote neuronal health and function, thereby addressing neurodegeneration in dementia. Here, we evaluate a series of novel small molecules for their ability to (1) positively modulate HGF/MET activity, (2) induce neurotrophic changes and protect against neurotoxic insults in primary neuron culture, (3) promote anti-inflammatory effects in vitro and in vivo, and (4) reverse cognitive deficits in animal models of dementia. Through screening studies, the compound now known as fosgonimeton-active metabolite (fosgo-AM) was identified by use of immunocytochemistry to be the most potent positive modulator of HGF/MET and was selected for further testing. Primary hippocampal neurons treated with fosgo-AM showed enhanced synaptogenesis and neurite outgrowth, supporting the neurotrophic effects of positive modulators of HGF/MET. Additionally, fosgo-AM protected against neurotoxic insults in primary cortical neuron cultures. In vivo, treatment with fosgo-AM rescued cognitive deficits in the rat scopolamine amnesia model of dementia. Although fosgo-AM demonstrated several procognitive effects in vitro and in vivo, a prodrug strategy was used to enhance the pharmacological properties of fosgo-AM, resulting in the development of fosgonimeton (ATH-1017). The effect of fosgonimeton on cognition was confirmed in a lipopolysaccharide (LPS)-induced neuroinflammatory mouse model of dementia. Together, the results of these studies support the potential of positive modulators of HGF/MET to be used as novel therapeutics and suggest the drug candidate fosgonimeton might protect against neurodegeneration and be therapeutic in the management of Alzheimer's disease and other types of dementia., (© 2022. The Author(s).)

Human inborn errors of immunity (IEI) are a group of 485 distinct genetic disorders affecting children and adults. Signs and symptoms of IEI are heterogeneous, and accurate diagnosis can be challenging and depends on the available human expertise and laboratory resources. The Middle East and North Africa (MENA) region has an increased prevalence of IEI because of the high rate of consanguinity with a predominance of autosomal recessive disorders. This area also exhibits more severe disease phenotypes compared with other regions, probably due to the delay in diagnosis. The MENA-IEI registry network has designed protocols and guidelines for the diagnosis and treatment of IEI, taking into consideration the variable regional expertise and resources. These guidelines are primarily meant to improve the care of patients within the region, but can also be followed in other regions with similar patient populations., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978)., (© 2021. The Author(s).)

Alterations in length-dependent activation (LDA) may constitute a mechanism by which cardiomyopathy mutations lead to deleterious phenotypes and compromised heart function, because LDA underlies the molecular basis by which the heart tunes myocardial force production on a beat-to-beat basis (Frank-Starling mechanism). In this study, we investigated the effect of DCM-linked mutation (R173W) in human cardiac troponin T (TnT) on myofilament LDA. R173W mutation is associated with left ventricular dilatation and systolic dysfunction and is found in multiple families. R173W mutation is in the central region (residues 80-180) of TnT, which is known to be important for myofilament cooperativity and cross-bridge (XB) recruitment. Steady-state and dynamic contractile parameters were measured in detergent-skinned guinea pig left ventricular muscle fibers reconstituted with recombinant guinea pig wild-type TnT (TnT WT ) or mutant TnT (TnT R174W ; guinea pig analog of human R173W mutation) at two different sarcomere lengths (SL): short (1.9 µm) and long (2.3 µm). TnT R174W decreased pCa 50 (-log [Ca 2+ ] free required for half-maximal activation) to a greater extent at long than at short SL; for example, pCa 50 decreased by 0.12 pCa units at long SL and by 0.06 pCa units at short SL. Differential changes in pCa 50 at short and long SL attenuated the SL-dependent increase in myofilament Ca 2+ sensitivity (ΔpCa 50 ) in TnT R174W fibers; ΔpCa 50 was 0.10 units in TnT WT fibers but only 0.04 units in TnT R174W fibers. Furthermore, TnT R174W blunted the SL-dependent increase in the magnitude of XB recruitment. Our observations suggest that the R173W mutation in human cardiac TnT may impair Frank-Starling mechanism. NEW & NOTEWORTHY This work characterizes the effect of dilated cardiomyopathy mutation in cardiac troponin T (TnT R174W ) on myofilament length-dependent activation. TnT R174W attenuates the length-dependent increase in cross-bridge recruitment and myofilament Ca 2+ sensitivity.

Shifts in myosin heavy chain (MHC) isoforms in cardiac myocytes have been shown to alter cardiac muscle function not only in healthy developing hearts but also in diseased hearts. In guinea pig hearts, there is a large age-dependent shift in MHC isoforms from 80% α-MHC/20% β-MHC at 3 wk to 14% α-MHC/86% β-MHC at 11 wk. Because kinetic differences in α- and β-MHC cross-bridges (XBs) are known to impart different cooperative effects on thin filaments, we hypothesize here that differences in α- and β-MHC expression in guinea pig cardiac muscle impact sarcomere length (SL)-dependent contractile function. We therefore measure steady state and dynamic contractile parameters in detergent-skinned cardiac muscle preparations isolated from the left ventricles of young (3 wk old) or adult (11 wk old) guinea pigs at two different SLs: short (1.9 µm) and long (2.3 µm). Our data show that SL-dependent effects on contractile parameters are augmented in adult guinea pig cardiac muscle preparations. Notably, the SL-mediated increase in myofilament Ca 2+ sensitivity (ΔpCa 50 ) is twofold greater in adult guinea pig muscle preparations (ΔpCa 50 being 0.11 units in adult preparations but only 0.05 units in young preparations). Furthermore, adult guinea pig cardiac muscle preparations display greater SL-dependent changes than young muscle preparations in (1) the magnitude of length-mediated increase in the recruitment of new force-bearing XBs, (2) XB detachment rate, (3) XB strain-mediated effects on other force-bearing XBs, and (4) the rate constant of force redevelopment. Our findings suggest that increased β-MHC expression enhances length-dependent activation in the adult guinea pig cardiac myocardium., (© 2019 Reda et al.)

The main aim of this research is to assess the variation in phototherapy radiometer responsivities toward the optical power of the phototherapeutic devices and hence estimate the spectral mismatch correction factor f1'. Two conventional phototherapy devices were studied to verify their spectral irradiance and three different phototherapy radiometers were studied for their responsivity at the range 400-500 nm. The results show the dependence of total irradiance measurement of phototherapy sources on matching between phototherapy radiometer band responsivity and spectral irradiance of the phototherapy sources. The spectral mismatch values vary from 13% to 47% of the total measured irradiance for the three radiometers. These mismatch values could be added to the measured irradiance as a correction.

Introduction: Primary Immunodeficiency (PIDs) is a set of 330 rare hereditary diseases that increase susceptibility to infections, allergies, autoimmunity, and neoplasia. North American registries give higher prevalence than Maghreb ones, whereas consanguinity is high. The purpose of this study is to compare prevalence and coverage rate of Maghreb PID registries with estimates based on USA., Methods: We searched the prevalence of PIDs in the Maghreb registers. Next, we estimated the expected values based on recent publications. Finally, we calculated the coverage rate of the Maghreb registries compared to the new estimates and we evaluated the impact of consanguinity., Results: The total number is N1 = 2456 patients. The current Maghreb PID Prevalence is 2.56 / 100,000 inhabitants (population of 94,804,694 Million in 2017). Tunisia leads with a prevalence of 8.70 followed by Morocco 2.09, Libya 1.65 and Algeria 1.46/100.000 habitants. We did not find values for Mauritania. If we extrapolate the prevalence of the USA to the Maghreb population, the number of patients in the Maghreb would be N2 = 27,588 and the coverage rate (N1 / N2) would be 8.90%. This low coverage rate is however better than the World average (1.21%), that of Latin America 1.19% and Africa 0.36%. The Maghreb prevalence is close to that of the Arab world 2.04 / 100,000 (population of 391,449,544 in 2017). Using the incidence found in the USA, the number of patients would be 9765 new patients per year in the Maghreb and 40,319 in Arab countries., Conclusion: PID Maghreb patients number is very low compared to global estimates, whereas consanguinity is very high. Special attention should be given to PIDs by governments and research teams in this region.

Objectives: Regular and/or preventive dental services utilization is an indicator of healthcare access and associated with improved health outcomes. We assessed the proportion of individuals regularly/preventively utilizing dental services, and how this was affected by demographic, health-related and social factors., Sources: Three electronic databases (Medline, Embase, Central) were searched (2005-2017)., Study Selection: We included observational studies investigating the association between preventive/regular dental service utilization and age, oral and general health, edentulism, family structure and health literacy., Data: The proportion of individuals with regular/preventive utilization overall and in different sub-groups were extracted. Random-effects meta-analyses, with subgroup analyses by region, were performed. Meta-regression was used to assess whether and how associations changed with time and countries' human developmental status (HDI). 103 studies on 7,395,697 participants from 28 countries were included. The global mean (95% CI) proportion of individuals regularly/preventively utilizing dental services was 54% (50-59%). In countries with higher HDI, more individuals regularly/preventively utilized services (p < 0.001). Age did not have a significant impact on utilization in adults (OR = 1.00; 0.89-1.12). Utilization was significantly lower in younger than older children (OR = 0.52; 0.46-0.59), individuals with poorer general health (OR = 0.73; 0.65-0.80) and poorer oral health (OR = 0.64; 0.52-0.75), edentulous individuals (OR = 0.32; 0.23-0.41), and individuals with less supportive family structures (OR = 0.81; 0.73-0.89) or poor health literacy (OR = 0.41; 0.01-0.81). The observed differences within populations did not significantly change with time and were universally present., Conclusions: Regular/preventive utilization varied widely between and within countries. Understanding and tackling the reasons underlying this may help to consistently improve utilization., Clinical Significance: Higher developmental status of countries is reflected in greater regular/preventive utilization of dental services. However, large demographic, health-related and social differences in utilization remain. These may contribute to dental health inequalities., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Recent clinical studies have revealed a new hypertrophic cardiomyopathy-associated mutation (F87L) in the central region of human cardiac troponin T (TnT). However, despite its implication in several incidences of sudden cardiac death in young and old adults, whether F87L is associated with cardiac contractile dysfunction is unknown. Because the central region of TnT is important for modulating the muscle length-mediated recruitment of new force-bearing cross-bridges (XBs), we hypothesize that the F87L mutation causes molecular changes that are linked to the length-dependent activation of cardiac myofilaments. Length-dependent activation is important because it contributes significantly to the Frank-Starling mechanism, which enables the heart to vary stroke volume as a function of changes in venous return. We measured steady-state and dynamic contractile parameters in detergent-skinned guinea pig cardiac muscle fibers reconstituted with recombinant guinea pig wild-type TnT (TnT WT ) or the guinea pig analogue (TnT F88L ) of the human mutation at two different sarcomere lengths (SLs): short (1.9 µm) and long (2.3 µm). TnT F88L increases pCa 50 (-log [Ca 2+ ] free required for half-maximal activation) to a greater extent at short SL than at long SL; for example, pCa 50 increases by 0.25 pCa units at short SL and 0.17 pCa units at long SL. The greater increase in pCa 50 at short SL leads to the abolishment of the SL-dependent increase in myofilament Ca 2+ sensitivity (ΔpCa 50 ) in TnT F88L fibers, ΔpCa 50 being 0.10 units in TnT WT fibers but only 0.02 units in TnT F88L fibers. Furthermore, at short SL, TnT F88L attenuates the negative impact of strained XBs on force-bearing XBs and augments the magnitude of muscle length-mediated recruitment of new force-bearing XBs. Our findings suggest that the TnT F88L -mediated effects on cardiac thin filaments may lead to a negative impact on the Frank-Starling mechanism., (© 2018 Reda and Chandra.)

Background: Dental diseases are among the most prevalent conditions worldwide, with universal access to dental care being one key to tackling them. Systematic quantification of inequalities in dental service utilization is needed to identify where these are most pronounced, assess factors underlying the inequalities, and evaluate changes in inequalities with time., Objectives: To evaluate the presence and extent of inequalities in dental services utilization., Search Methods: We performed a systematic review and meta-analysis by searching 3 electronic databases (MEDLINE, Embase, Cochrane Central Database), covering the period from January 2005 to April 2017., Selection Criteria: We included observational studies investigating the association between regular dental service utilization and sex, ethnicity, place of living, educational or income or occupational position, or insurance coverage status. Two reviewers undertook independent screening of studies and made decisions by consensus., Data Collection and Analysis: Our primary outcome was the presence and extent of inequalities in dental service utilization, measured as relative estimates (usually odds ratios [ORs]) comparing different (high and low utilization) groups. We performed random effects meta-analysis and subgroup analyses by region, and we used meta-regression to assess whether and how associations changed with time., Main Results: A total of 117 studies met the inclusion criteria. On the basis of 7 830 810 participants, dental services utilization was lower in male than female participants (OR = 0.85; 95% confidence interval [CI] = 0.74, 0.95; P < .001); ethnic minorities or immigrants than ethnic majorities or natives (OR = 0.71; 95% CI = 0.59, 0.82; P < .001); those living in rural than those living in urban places (OR = 0.87; 95% CI = 0.76, 0.97; P = .011); those with lower than higher educational position (OR = 0.61; 95% CI = 0.55, 0.68; P < .001) or income (OR = 0.66; 95% CI = 0.54, 0.79; P < .001); and among those without insurance coverage status than those with such status (OR = 0.58; 95% CI = 0.49, 0.68; P < .001). Occupational status (OR = 0.95; 95% CI = 0.81, 1.09; P = .356) had no significant impact on utilization. The observed inequalities did not significantly change over the assessed 12-year period and were universally present., Authors' Conclusions: Inequalities in dental service utilization are both considerable and globally consistent. Public Health Implications. The observed inequalities in dental services utilization can be assumed to significantly cause or aggravate existing dental health inequalities. Policymakers should address the physical, socioeconomic, or psychological causes underlying the inequalities in utilization.

The tremendous increase in allergy in the African continent cannot simply be explained by the change in public hygiene. There are many "prehygiene" communities with sewage-contaminated water supplies, helminth infestations, bare footedness, and poor housing, and still there is a high prevalence of allergic disease. Africans can be exposed to many risk factors facilitating severe asthma and wheezing, including airborne viruses, smoke, indoor dampness, cockroaches, and poor access to health care. Although the reporting on food allergy is inadequate to perform systematic reviews or meta-analyses, the available data suggest that food allergy is underdiagnosed. The rate of new HIV infections in high-prevalence settings in Africa remains unacceptably high. Although the annual number of new HIV infections in Sub-Saharan Africa has decreased lately, new HIV infections in the Middle East and North Africa region have increased; however, the current prevalence of 0.1% is still among the lowest globally. Africa is densely populated, and consanguineous mating is high in some areas of North and Sub-Saharan Africa. This allows for emergence of many autosomal recessive primary immunodeficiency diseases. There is urgent need for the establishment of primary immunodeficiency disease registries, stem cell transplantation facilities, and neonatal screening programs. To address these expanding problems and perform local cutting-edge research, Africans need to be empowered by motivated governments, dedicated funds, and compassionate scientific partnership., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

In today's global economy and affordable vacation travel, it is increasingly important that visitors to another country and their physician be familiar with emerging infections, infections unique to a specific geographic region, and risks related to the process of travel. This is never more important than for patients with primary immunodeficiency disorders (PIDD). A recent review addressing common causes of fever in travelers provides important information for the general population Thwaites and Day (N Engl J Med 376:548-560, 2017). This review covers critical infectious and management concerns specifically related to travel for patients with PIDD. This review will discuss the context of the changing landscape of infections, highlight specific infections of concern, and profile distinct infection phenotypes in patients who are immune compromised. The organization of this review will address the environment driving emerging infections and several concerns unique to patients with PIDD. The first section addresses general considerations, the second section profiles specific infections organized according to mechanism of transmission, and the third section focuses on unique phenotypes and unique susceptibilities in patients with PIDDs. This review does not address most parasitic diseases. Reference tables provide easily accessible information on a broader range of infections than is described in the text.

Omecamtiv mecarbil (OM) is a pharmacological agent that augments cardiac contractile function by enhancing myofilament Ca 2+ sensitivity. Given that interventions that increase myofilament Ca 2+ sensitivity have the potential to alter length-dependent activation (LDA) of cardiac myofilaments, we tested the influence of OM on this fundamental property of the heart. This is significant not only because LDA is prominent in cardiac muscle but also because it contributes to the Frank-Starling law, a mechanism by which the heart increases stroke volume in response to an increase in venous return. We measured steady-state and dynamic contractile indices in detergent-skinned guinea pig (Cavia porcellus) cardiac muscle fibers in the absence and presence of 0.3 and 3.0 μM OM at two different sarcomere lengths (SLs), short SL (1.9 μm) and long SL (2.3 μm). Myofilament Ca 2+ sensitivity, as measured by pCa 50 (-log of [Ca 2+ ] free concentration required for half-maximal activation), increased significantly at both short and long SLs in OM-treated fibers when compared to untreated fibers; however, the magnitude of increase in pCa 50 was twofold greater at short SL than at long SL. A consequence of this greater increase in pCa 50 at short SL was that pCa 50 did not increase any further at long SL, suggesting that OM abolished the SL dependency of pCa 50 . Furthermore, the SL dependency of rate constants of cross-bridge distortion dynamics (c) and force redevelopment (k tr ) was abolished in 0.3-μM-OM-treated fibers. The negative impact of OM on the SL dependency of pCa 50 , c, and k tr was also observed in 3.0-μM-OM-treated fibers, indicating that cooperative mechanisms linked to LDA were altered by the OM-mediated effects on cardiac myofilaments., (Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Recombination-activating genes 1 and 2 ( RAG1 and RAG2 ) play a critical role in T and B cell development by initiating the recombination process that controls the expression of T cell receptor (TCR) and immunoglobulin genes. Mutations in the RAG1 and RAG2 genes in humans cause a broad spectrum of phenotypes, including severe combined immunodeficiency (SCID) with lack of T and B cells, Omenn syndrome, leaky SCID, and combined immunodeficiency with granulomas or autoimmunity (CID-G/AI). Using next-generation sequencing, we analyzed the TCR and B cell receptor (BCR) repertoire in 12 patients with RAG mutations presenting with Omenn syndrome ( n = 5), leaky SCID ( n = 3), or CID-G/AI ( n = 4). Restriction of repertoire diversity skewed usage of variable (V), diversity (D), and joining (J) segment genes, and abnormalities of CDR3 length distribution were progressively more prominent in patients with a more severe phenotype. Skewed usage of V, D, and J segment genes was present also within unique sequences, indicating a primary restriction of repertoire. Patients with Omenn syndrome had a high proportion of class-switched immunoglobulin heavy chain transcripts and increased somatic hypermutation rate, suggesting in vivo activation of these B cells. These data provide a framework to better understand the phenotypic heterogeneity of RAG deficiency., (Copyright © 2016, American Association for the Advancement of Science.)

The N-terminal extension of human cardiac troponin T (TnT), which modulates myofilament Ca 2+ sensitivity, contains several hypertrophic cardiomyopathy (HCM)-causing mutations including S69F. However, the functional consequence of S69F mutation is unknown. The human analog of S69F in rat TnT is L71F (TnT L71F ). Because the functional consequences due to structural changes in the N-terminal extension are influenced by the type of myosin heavy chain (MHC) isoform, we hypothesized that the TnT L71F -mediated effect would be differently modulated by α- and β-MHC isoforms. TnT L71F and wild-type rat TnT were reconstituted into de-membranated muscle fibers from normal (α-MHC) and propylthiouracil-treated rat hearts (β-MHC) to measure steady-state and dynamic contractile parameters. The magnitude of the TnT L71F -mediated attenuation of Ca 2+ -activated maximal tension was greater in α- than in β-MHC fibers. For example, TnT L71F attenuated maximal tension by 31% in α-MHC fibers but only by 10% in β-MHC fibers. Furthermore, TnT L71F reduced myofilament Ca 2+ sensitivity by 0.11 pCa units in α-MHC fibers but only by 0.05 pCa units in β-MHC fibers. TnT L71F augmented rate constants of crossbridge recruitment and crossbridge detachment dynamics in α-MHC fibers but not in β-MHC fibers. Collectively, our data demonstrate that TnT L71F induces greater contractile deficits against α-MHC than against β-MHC background.

This note corrects an error in the math of [Appl. Opt.55, 838 (2016)APOPAI0003-693510.1364/AO.55.000838] and reports a deletion of text that should have occurred in production.

Thin film and sheet PbS quantum dots (QDs) concentrators were synthesized by sol-gel method using three different PbS concentrations (0.14, 0.2, and 0.4 mol%). The structure and morphology of the prepared PbS QDs were characterized by X-ray diffraction (XRD), Scan electron microscopy (SEM), and Transmission electron microscopy (TEM). The photostability of the PbS QDs concentrators under outdoor exposure to sunlight for 8 weeks was studied. The results showed that the PbS QDs sheet with PbS concentration (0.14 mol%) has the highest luminescence intensity. The sheet PbS QDs concentrator was used to couple with PV solar cell and the corresponding photoelectric conversion efficiency was measured under sun light illumination. I-V characteristics of the photovoltaic devices, both open circuit voltage and short circuit current were improved as compared to the device without collector. This indicates that the proposed technique is very useful for improving the efficiency of solar cell.

Background: Severe combined immunodeficiency (SCID) is a syndrome characterized by profound T-cell deficiency. BCG vaccine is contraindicated in patients with SCID. Because most countries encourage BCG vaccination at birth, a high percentage of patients with SCID are vaccinated before their immune defect is detected., Objectives: We sought to describe the complications and risks associated with BCG vaccination in patients with SCID., Methods: An extensive standardized questionnaire evaluating complications, therapeutics, and outcomes regarding BCG vaccination in patients given a diagnosis of SCID was widely distributed. Summary statistics and association analysis was performed., Results: Data on 349 BCG-vaccinated patients with SCID from 28 centers in 17 countries were analyzed. Fifty-one percent of the patients had BCG-associated complications, 34% disseminated and 17% localized (a 33,000- and 400-fold increase, respectively, over the general population). Patients receiving early vaccination (≤1 month) showed an increased prevalence of complications (P = .006) and death caused by BCG-associated complications (P < .0001). The odds of experiencing complications among patients with T-cell numbers of 250/μL or less at diagnosis was 2.1 times higher (95% CI, 1.4-3.4 times higher; P = .001) than among those with T-cell numbers of greater than 250/μL. BCG-associated complications were reported in 2 of 78 patients who received antimycobacterial therapy while asymptomatic, and no deaths caused by BCG-associated complications occurred in this group. In contrast, 46 BCG-associated deaths were reported among 160 patients treated with antimycobacterial therapy for a symptomatic BCG infection (P < .0001)., Conclusions: BCG vaccine has a very high rate of complications in patients with SCID, which increase morbidity and mortality rates. Until safer and more efficient antituberculosis vaccines become available, delay in BCG vaccination should be considered to protect highly vulnerable populations from preventable complications., (Published by Mosby, Inc.)

Background: The recombination-activating gene (RAG) 1/2 proteins play a critical role in the development of T and B cells by initiating the VDJ recombination process that leads to generation of a broad T-cell receptor (TCR) and B-cell receptor repertoire. Pathogenic mutations in the RAG1/2 genes result in various forms of primary immunodeficiency, ranging from T(-)B(-) severe combined immune deficiency to delayed-onset disease with granuloma formation, autoimmunity, or both. It is not clear what contributes to such heterogeneity of phenotypes., Objective: We sought to investigate the molecular basis for phenotypic diversity presented in patients with various RAG1 mutations., Methods: We have developed a flow cytometry-based assay that allows analysis of RAG recombination activity based on green fluorescent protein expression and have assessed the induction of the Ighc locus rearrangements in mouse Rag1(-/-) pro-B cells reconstituted with wild-type or mutant human RAG1 (hRAG1) using deep sequencing technology., Results: Here we demonstrate correlation between defective recombination activity of hRAG1 mutant proteins and severity of the clinical and immunologic phenotype and provide insights on the molecular mechanisms accounting for such phenotypic diversity., Conclusions: Using a sensitive assay to measure the RAG1 activity level of 79 mutations in a physiologic setting, we demonstrate correlation between recombination activity of RAG1 mutants and the severity of clinical presentation and show that RAG1 mutants can induce specific abnormalities of the VDJ recombination process., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Purpose: To promote awareness of primary immunodeficiency (PID), the "10 warning signs" of PID and an immunodeficiency-related (IDR) score were developed. However, their efficiency in identifying PID cases was not sufficiently evaluated in clinical practice. The objective of this study was to test the validity of the 10 warning signs and IDR score in identifying PID among children with recurrent infections at a tertiary pediatric hospital in Egypt., Methods: A retrospective analysis of the medical records of 204 patients was performed. Of these patients, 92 had defined PID diseases and 112 were considered non-PID cases because investigations were inconclusive., Results: Demonstrating two warning signs and an IDR score of 6 led to sensitivities of 94 and 66%, respectively, and specificities of 64 and 75%, respectively, in identifying PID cases. The strongest predictor of PID was family history that, if combined with the need for intravenous antibiotics, recurrent deep-seated infections, and failure to thrive, could identify 81% of PID patients. A family history of PID, sibling death, and/or parental consanguinity would predict 92% of combined immunodeficiencies, 92% of phagocyte defects, 87% of well-identified immunodeficiency syndromes, and 84% of antibody deficiency if the need for intravenous antibiotics is considered in the latter., Conclusions: The 10 warning signs and IDR score do not aid in an early diagnosis of severe PID. Educational campaigns should target pediatricians aiming to increase PID awareness and to address family history of PID, parental consanguinity, and previous sibling death as key predictors of PID in communities with a high prevalence of consanguineous marriages.

Radioactive waste generated from the nuclear applications should be properly isolated by a suitable containment system such as, multi-barrier container. The present study aims to evaluate the isolation capacity of a new multi-barrier container made from cement and clay and including borate waste materials. These wastes were spiked by (137)Cs and (60)Co radionuclides to simulate that waste generated from the primary cooling circuit of pressurized water reactors. Leaching of both radionuclides in ground water was followed and calculated during ten years. Monte Carlo (MCNP5) simulations computed the photon flux distribution of the multi-barrier container, including radioactive borate waste of specific activity 11.22KBq/g and 4.18KBq/g for (137)Cs and (60)Co, respectively, at different periods of 0, 15.1, 30.2 and 302 years. The average total flux for 100cm radius of spherical cell was 0.192photon/cm(2) at initial time and 2.73×10(-4)photon/cm(2) after 302 years. Maximum waste activity keeping the surface radiation dose within the permissible level was calculated and found to be 56KBq/g with attenuation factors of 0.73cm(-1) and 0.6cm(-1) for cement and clay, respectively. The average total flux was 1.37×10(-3)photon/cm(2) after 302 years. Monte Carlo simulations revealed that the proposed multi-barrier container is safe enough during transportation, evacuation or rearrangement in the disposal site for more than 300 years., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Introduction: Sixty-four primary immunodeficiency patients were registered at the Pediatric Allergy and Immunology Department, Children's Hospital, Ain Shams University, Cairo, Egypt., Data: Predominantly antibody deficiencies were the most common category (35.9%) followed by combined T- and B-cell immunodeficiencies (29.7%), other well defined immunodeficiency syndromes (18.7%), congenital defects of phagocyte number, function or both (12.5%), and diseases of immune dysregulation (3.1%). The most frequent disorder was common variable immunodeficiency (18.7%). The mean age at diagnosis was 29.9 months. The consanguinity rate was 62.5%. Recurrent severe infections were seen in all categories. Fifteen patients died (23.4%) from infections with the highest mortality for combined T- and B-cell immunodeficiencies (15.6%)., Conclusions: Primary immunodeficiency disorders are not rare in Egyptian children. The observed frequency of combined T- and B-cell immunodeficiencies in our cohort is relatively higher than other countries. It is a prerequisite to establish a national registry of primary immunodeficiency in Egypt.

Background: Neurogenic inflammation may participate in the development and progression of bronchial asthma. The molecular mechanisms underlying neurogenic inflammation are orchestrated by a large number of neuropeptides including tachykinins such as neurokinin A (NKA) and substance P. Tachykinins are secreted from sensory airway nerves and inflammatory cells after allergens exposure. In clinical practice, assessment of airway inflammation is difficult. Therefore, detection of biological markers of airway inflammation in sputum might offer help for proper monitoring of asthma severity., Aim of the Study: We aimed to measure sputum NKA in relation to acute asthma exacerbations of varying severity., Methods: Sputum NKA was measured by enzyme-linked immunosorbent assay in 24 children and adolescents during and after acute asthma exacerbation and 24 healthy matched controls., Results: Sputum NKA was significantly higher in asthmatic patients during acute exacerbation than controls [217.5 (284) vs 10 (7) ng/ml, P < 0.001]. When patients with acute asthma exacerbation were followed-up till remission, sputum NKA levels decreased significantly, but they remained significantly higher than controls. Sputum NKA levels were significantly higher in severe than moderate and in moderate than mild exacerbations, and was negatively correlated to peak expiratory flow rate (r = -0.9, P < 0.001). Sputum NKA had significant positive correlations to eosinophil counts in blood and sputum (r = 0.6, P < 0.001 and r = 0.7, P < 0.001 respectively)., Conclusions: Sputum NKA is up-regulated during acute asthma exacerbation and it positively correlates to its severity. Thus, NKA may aid in objective classification of the exacerbation severity. In addition, NKA may be a target for new asthma therapy.