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Background and Objective: Unbound daptomycin concentrations are responsible for pharmacologically beneficial and adverse effects, although most previous reports have been limited to the use of total concentrations. We developed a population pharmacokinetic model to predict both total and unbound daptomycin concentrations. Methods: Clinical data were collected from 58 patients with methicillin-resistant Staphylococcus aureusincluding patients undergoing hemodialysis. A total of 339 serum total and 329 unbound daptomycin concentrations were used for model construction. Results: Total and unbound daptomycin concentration was explained by a model that assumed first-order distribution with two compartments, and first-order elimination. Normal fat body mass was identified as covariates. Renal function was incorporated as a linear function of renal clearance and independent non-renal clearance. The unbound fraction was estimated to be 0.066 with a standard albumin of 45 g/L and standard creatinine clearance of 100 mL/min. Simulated unbound daptomycin concentration was compared with minimum inhibitory concentration as a measure of clinical effectiveness and exposure-level-related induction of creatine phosphokinase elevation. The recommended doses were 4 mg/kg for patients with severe renal function [creatinine clearance (CLcr) ≤ 30 mL/min] and 6 mg/kg for patients with mild to moderate renal function (CLcr > 30 and ≤ 60 mL/min). A simulation indicated that dose adjusted by body weight and renal function improved target attainment. Conclusions: This population pharmacokinetics model for unbound daptomycin could help clinicians to select the appropriate dose regimen for patients undergoing daptomycin treatment and reduce associated adverse effects.

The twenty-first century has witnessed a wave of severe infectious disease outbreaks, not least the COVID-19 pandemic, which has had a devastating impact on lives and livelihoods around the globe. The 2003 severe acute respiratory syndrome coronavirus outbreak, the 2009 swine flu pandemic, the 2012 Middle East respiratory syndrome coronavirus outbreak, the 2013–2016 Ebola virus disease epidemic in West Africa and the 2015 Zika virus disease epidemic all resulted in substantial morbidity and mortality while spreading across borders to infect people in multiple countries. At the same time, the past few decades have ushered in an unprecedented era of technological, demographic and climatic change: airline flights have doubled since 2000, since 2007 more people live in urban areas than rural areas, population numbers continue to climb and climate change presents an escalating threat to society. In this Review, we consider the extent to which these recent global changes have increased the risk of infectious disease outbreaks, even as improved sanitation and access to health care have resulted in considerable progress worldwide.

Acute kidney injury (AKI) is an important risk factor for the development of chronic kidney disease (CKD), and an alteration in renal water handling has been observed during the transition of AKI to CKD. Urinary exosomal release of aquaporin-1 (AQP1) and AQP2, important proteins for renal water handling, has recently been reported to predict their levels of renal expression. Therefore, we examined the patterns of urinary exosomal release of AQP1 and AQP2, and the exosomal marker proteins tumor susceptibility 101 protein (TSG101) and ALG-2 interacting protein X (Alix), in the acute and chronic phases following induction of AKI by renal bilateral ischemia/reperfusion (I/R) in rats. Blood tests and histological examinations indicated that AKI occurred before at 7 days after renal I/R (day 7) and that renal fibrosis developed progressively thereafter. Immunoblotting demonstrated significant decreases in the urinary exosomal release of AQP1 and AQP2 during severe AKI. Urinary exosomal release of Alix and TSG101 was significantly increased on day 7. These data were also confirmed in rats with unilateral renal I/R causing more serious AKI. Urinary exosomal release of either the Ser-256- or Ser-269-phosphorylated form of AQP2, both of which are involved in apical trafficking of AQP2, was positively correlated with that of total AQP2. These results suggest that urinary exosomal release of AQP1 and AQP2 is reduced in I/R-induced AKI, whereas that of Alix and TSG101 is increased in the initial phase of renal fibrosis. Furthermore, apical trafficking of AQP2 appears to be related to urinary exosomal release of AQP2.

Natural killer (NK) cells likely play an important role in immunity to malaria, but the effect of repeated malaria on NK cell responses remains unclear. Here, we comprehensively profiled the NK cell response in a cohort of 264 Ugandan children. Repeated malaria exposure was associated with expansion of an atypical, CD56negpopulation of NK cells that differed transcriptionally, epigenetically, and phenotypically from CD56dimNK cells, including decreased expression of PLZF and the Fc receptor γ-chain, increased histone methylation, and increased protein expression of LAG-3, KIR, and LILRB1. CD56negNK cells were highly functional and displayed greater antibody-dependent cellular cytotoxicity than CD56dimNK cells. Higher frequencies of CD56negNK cells were associated with protection against symptomatic malaria and high parasite densities. After marked reductions in malaria transmission, frequencies of these cells rapidly declined, suggesting that continuous exposure to Plasmodium falciparumis required to maintain this modified, adaptive-like NK cell subset.

OCTN1/SLC22A4 is expressed on apical membranes of small intestine, and is involved in gastrointestinal absorption of its substrates, including the food-derived antioxidant ergothioneine (ERGO). ERGO concentration in circulating blood of patients with inflammatory bowel disease (Crohn's disease) is lower than that in healthy volunteers; thus, circulating ERGO is a potential diagnostic marker, although the mechanisms underlying low ERGO concentration in patients are unknown. Here, we focused on intestinal macrophages, which infiltrate sites of inflammation, and examined possible first-pass uptake of ERGO by macrophages. ERGO concentration in blood was lower in mice with dextran sodium sulfate (DSS)-induced colitis than in controls. On the other hand, expression of octn1gene product and ERGO concentration in intestinal tissues of DSS-treated mice were higher than in controls. Interestingly, lamina propria mononuclear cells (LPMCs) isolated from DSS-treated mice contained ERGO and showed [3H]ERGO uptake and Octn1 expression, whereas ERGO was undetectable in LPMCs of control mice. Functional expression of OCTN1 was also confirmed in LPS-stimulated human macrophage-like cell line, THP-1. In conclusion, OCTN1 is functionally expressed on activated intestinal macrophages, and ERGO uptake into these immune cells could contribute at least in part to the altered disposition of ERGO in intestinal inflammation.

Urinary exosomes are nano-sized vesicles secreted into urine from all types of renal epithelial cells and are known to contain possible biomarker proteins for renal diseases. Gentamicin has been reported to decrease the level of renal aquaporin (AQP)2, which is known to be mainly expressed in renal collecting ducts and excreted into the urine via exosomes. In the present study, we investigated whether urinary exosomal AQP2 could serve as a potential biomarker for gentamicin-induced nephrotoxicity, especially collecting duct cell dysfunction. Gentamicin was given to rats intraperitoneally once every day starting on day 0. Gentamicin significantly increased the plasma creatinine concentration from day 5and beyond. Also, gentamicin induced polyuria and a defective urine concentration mechanism on day 7, suggesting gentamicin-induced collecting duct cell dysfunction. Immunoblot analysis showed that gentamicin significantly increased urinary exosomal AQP2 excretion on day 1but decreased it on day 7compared with the control group. Similarly, increased excretion of exosomal tumor susceptibility gene 101 protein, frequently used as an exosome marker protein, was observed on day 1. However, gentamicin did not significantly affect the urinary excretion of exosomal tumor susceptibility gene 101 on day 7. Gentamicin slightly decreased renal AQP2 expression on day 2and markedly decreased it on day 8. These data strongly suggest that the use of urinary exosomal AQP2 as a biomarker may allow detection of gentamicin-induced collecting duct cell dysfunction. Furthermore, urinary exosomal AQP2 might also be useful for the early detection of gentamicin-induced renal injury in addition to collecting duct injury.

Urinary exosomes are small vesicles secreted into urine from all renal epithelial cell types and known to contain proteins that are involved in renal secretion and reabsorption. Among these proteins, urinary exosomal aquaporin-2 (AQP2) has been suggested to be useful for diagnosis of renal disease. However, the mechanisms underlying the excretion of urinary exosomal AQP2 are largely unknown. In this study, we examined the mechanisms of urinary exosomal AQP2 excretion in vivo, using diuretics including furosemide (FS), an inhibitor of the sodium-potassium-chloride symporter; acetazolamide (ACTZ), an inhibitor of carbonic anhydrase; OPC-31260 (OPC), a vasopressin type 2 receptor antagonist; and NaHCO3, a urinary alkalizing agent. Samples of urine from rats were collected for 2 h just after treatment with each diuretic, and urinary exosomes were isolated by ultracentrifugation. Urinary exosomal AQP2 excretion was dramatically increased by treatment with FS accompanied by urine acidification or with ACTZ accompanied by urine alkalization. Immunohistochemistry showed that apical localization of AQP2 was clearly evident and the plasma vasopressin level was increased after each treatment. Although treatment with OPC alone had no significant effect, coadministration of OPC completely inhibited the FS-induced and partially reduced the ACTZ-induced responses, respectively. Treatment with NaHCO3increased the excretion of urinary exosomal AQP2 accompanied by urine alkalization. This increased response was partially inhibited by coadministration of OPC. These data suggest that an increased plasma level of vasopressin promoted the excretion of urinary exosomal AQP2 and that urine alkalinization also increased it independently of vasopressin.

Aquaporin 11 (AQP11) is a newly described member of the protein family of transport channels. AQP11 associates with the endoplasmic reticulum (ER) and is highly expressed in proximal tubular epithelial cells in the kidney. Previously, we identified and characterized a recessive mutation of the highly conserved Cys227 to Ser227 in mouse AQP11 that caused proximal tubule (PT) injury and kidney failure in mutant mice. The current study revealed induction of ER stress, unfolded protein response, and apoptosis as molecular mechanisms of this PT injury. Cys227Ser mutation interfered with maintenance of AQP11 oligomeric structure. AQP11 is abundantly expressed in the S1 PT segment, a site of major renal glucose flux, and Aqp11mutant mice developed PT-specific mitochondrial injury. Glucose increased AQP11 protein expression in wild-type kidney and upregulation of AQP11 expression by glucose in vitro was prevented by phlorizin, an inhibitor of sodium-dependent glucose transport across PT. Total AQP11 levels in heterozygotes were higher than in wild-type mice but were not further increased in response to glucose. In Aqp11insufficient PT cells, glucose potentiated increases in reactive oxygen species (ROS) production. ROS production was also elevated in Aqp11mutation carriers. Phenotypically normal mice heterozygous for the Aqp11mutation repeatedly treated with glucose showed increased blood urea nitrogen levels that were prevented by the antioxidant sulforaphane or by phlorizin. Our results indicate an important role for AQP11 to prevent glucose-induced oxidative stress in proximal tubules.

Microporous silica was synthesized by the salt catalytic sol-gel process with extremely low content of water to tetramethoxysilane. Silica particles were precipitated even when the extent of hydrolysis was very low, since ammonium carbonate as a salt catalyst made the polycondensation faster than an acid catalyst. Microporous silica with a high surface area (680 m2g−1) was obtained by combustion of methoxy groups at 450°C. The methoxy groups can be removed by the post-hydrolysis before heating. A high specific surface area (>750 m2g−1) of microporous silica was obtained with pore diameter between 1.2 and 2.0 nm.

SARS-CoV-2-specific CD4+T cells are likely important in immunity against COVID-19, but our understanding of CD4+longitudinal dynamics following infection, and specific features that correlate with the maintenance of neutralizing antibodies, remains limited. Here, we characterize SARS-CoV-2-specific CD4+T cells in a longitudinal cohort of 109 COVID-19 outpatients enrolled during acute infection. The quality of the SARS-CoV-2-specific CD4+response shifts from cells producing IFNγ to TNFα from five days to four months post-enrollment, with IFNγ-IL21-TNFα+CD4+T cells the predominant population detected at later timepoints. Greater percentages of IFNγ-IL21-TNFα+CD4+T cells on day 28 correlate with SARS-CoV-2 neutralizing antibodies measured seven months post-infection (⍴=0.4, P=0.01). mRNA vaccination following SARS-CoV-2 infection boosts both IFNγ and TNFα producing, spike protein-specific CD4+T cells. These data suggest that SARS-CoV-2-specific, TNFα-producing CD4+T cells may play an important role in antibody maintenance following COVID-19.

We describe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell responses, soluble markers of inflammation, and antibody levels and neutralization capacity longitudinally in 70 individuals with PCR-confirmed SARS-CoV-2 infection. Participants represent a spectrum of illness and recovery, including some with persistent viral shedding in saliva and many experiencing post-acute sequelae of SARS-CoV-2 infection (PASC). T cell responses remain stable for up to 9 months. Whereas the magnitude of early CD4+T cell immune responses correlates with severity of initial infection, pre-existing lung disease is independently associated with higher long-term SARS-CoV-2-specific CD8+T cell responses. Among participants with PASC 4 months following coronavirus disease 2019 (COVID-19) symptom onset, we observe a lower frequency of CD8+T cells expressing CD107a, a marker of degranulation, in response to Nucleocapsid (N) peptide pool stimulation, and a more rapid decline in the frequency of N-specific interferon-γ-producing CD8+T cells. Neutralizing antibody levels strongly correlate with SARS-CoV-2-specific CD4+T cell responses.

Outbreaks of hand, foot and mouth disease have been documented in Japan since 1963. This disease is primarily caused by the two closely related serotypes of Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CV-A16). Here, we analyse Japanese virologic and syndromic surveillance time-series data from 1982 to 2015. As in some other countries in the Asia Pacific region, EV-A71 in Japan has a 3 year cyclical component, whereas CV-A16 is predominantly annual. We observe empirical signatures of an inhibitory interaction between the serotypes; virologic lines of evidence suggest they may indeed interact immunologically. We fit the time series to mechanistic epidemiological models: as a first-order effect, we find the data consistent with single-serotype susceptible–infected–recovered dynamics. We then extend the modelling to incorporate an inhibitory interaction between serotypes. Our results suggest the existence of a transient cross-protection and possible asymmetry in its strength such that CV-A16 serves as a stronger forcing on EV-A71. Allowing for asymmetry yields accurate out-of-sample predictions and the directionality of this effect is consistent with the virologic literature. Confirmation of these hypothesized interactions would have important implications for understanding enterovirus epidemiology and informing vaccine development. Our results highlight the general implication that even subtle interactions could have qualitative impacts on epidemic dynamics and predictability.

Measles containing vaccine was introduced to Madagascar in 1985. Since 2007, intensification of efforts has bought Madagascar closer to the goal of elimination. Nevertheless, recent data also indicate that population immunity might be eroding in the face of high birth rates and barriers to vaccine delivery. Despite evidence that many factors likely to shape vaccination programme effectiveness are seasonal (including transmission, which responds to seasonal human behaviour, and birth rates), how seasonal fluctuations in vaccination shape outbreak risk and timeliness of vaccination is rarely considered. We aimed to evaluate this here.