Protein/Fiber Index Modulates Uremic Toxin Concentrations in Hemodialysis Patients

Background: Indoxyl sulfate (IS) and p-cresyl sulfate (PCS), two uremic toxins (UTs), are associated with increased mortality in patients with chronic kidney disease (CKD). These toxins are produced by the microbiota from the diet and excreted by the kidney. The purpose of this study was to analyze the effect of diet on IS and PCS concentration in hemodialysis (HD) patients. Methods: We performed a prospective monocentric study using a seven-day diet record and determination of serum IS and PCS levels in HD patients. We tested the association between toxin concentrations and nutritional data. Results: A total of 58/75 patients (77%) completed the diet record. Mean caloric intake was 22 ± 9.2 kcal/kg/day. The protein/fiber index was 4.9 ± 1.8. No correlation between IS or PCS concentration and protein/fiber index was highlighted. In the 18 anuric patients (31%) in whom residual renal function could not affect toxin concentrations, IS and PCS concentrations were negatively correlated with fiber intake and positively correlated with the protein/fiber index. In a multivariate analysis, IS serum concentration was positively associated with the protein/fiber index (p = 0.03). Conclusions: A low protein/fiber index is associated with low concentrations of uremic toxins in anuric HD patients. Diets with an increased fiber intake must be tested to determine whether they reduce PCS and IS serum concentrations.     

Brief Report: Top predator sea stars are the benthic equivalent to polar bears of the pelagic realm

The marine pelagic compartment spans numerous trophic levels and consists of numerous reticulate connections between species from primary producers to iconic apex predators, while the benthic compartment is perceived to be simpler in structure and comprised of only low trophic level species. Here, we challenge this paradigm by illustrating that the benthic compartment is home to a subweb of similar structure and complexity to that of the pelagic realm, including the benthic equivalent to iconic polar bears: megafaunal-predatory sea stars.     

Intranasal Exposure to Rift Valley Fever Virus Live-Attenuated Strains Leads to High Mortality Rate in Immunocompetent Mice

Rift Valley fever virus (RVFV) is a pathogenic arthropod-borne virus that can cause serious illness in both ruminants and humans. The virus can be transmitted by an arthropod bite or contact with contaminated fluids or tissues. Two live-attenuated veterinary vaccines—the Smithburn (SB) and Clone 13 (Cl.13)—are currently used during epizootic events in Africa. However, their residual pathogenicity (i.e., SB) or potential of reversion (i.e., Cl.13) causes important adverse effects, strongly limiting their use in the field. In this study, we infected immunocompetent mice with SB or Cl.13 by a subcutaneous or an intranasal inoculation. Interestingly, we found that, unlike the subcutaneous infection, the intranasal inoculation led to a high mortality rate. In addition, we detected high titers and viral N antigen levels in the brain of both the SB- and Cl.13-infected mice. Overall, we unveil a clear correlation between the pathogenicity and the route of administration of both SB and Cl.13, with the intranasal inoculation leading to a stronger neurovirulence and higher mortality rate than the subcutaneous infection.     

Timing and Identification of the Cause and Treatment of a Cardiac Arrest: A Potential Survival Benefit

ObjectiveThe aim of this study was to evaluate how mobile medical teams (MMTs) search for the etiology of a cardiac arrest (CA) and to investigate the association between the discovery of etiology and patient outcome.Subjects and MethodsResuscitations of all adult patients who experienced an in- or out-of-hospital CA between 2016 and 2018 were video recorded. All video recordings were reviewed. The time to start of “cause analysis” and time to treatment by the MMT were analyzed. Also, investigations performed during etiologic evaluation were examined: heteroanamnesis, medical history-taking, clinical examinations, technical investigations, and the use of the 4Hs and 4Ts method.ResultsOf the 139 CA events included in this study, the MMTs performed etiologic evaluation in only 75% of the resuscitations, and in 20% of the evaluations, they did not use the recommended 4Hs and 4Ts method. Medical history-taking and heteroanamnesis were performed in the large majority, but often without clear cause. A presumptive etiology was found in 46.8% of out-of-hospital CAs and 65.2% of in-hospital CAs. A significant association was found between return of spontaneous circulation and the discovery of presumable etiology for out-of-hospital CAs (p < 0.001). The median time to treatment was 492 s (recommended: 130–250 s) for nonshockable rhythms and 422 s (recommended: 270–390 s) for shockable rhythms, up to twice the time advised according to the guidelines.ConclusionThe current approach for etiologic evaluation is not ideal. Further research is needed to establish a more structured and simplified approach.     

Talazoparib,a Poly(ADP-ribose) Polymerase Inhibitor,for Metastatic Castration-resistant Prostate Cancer and DNA Damage Response Alterations: TALAPRO-1 Safety Analyses

BackgroundThe phase II TALAPRO-1 study ({"type":"clinical-trial","attrs":{"text":"NCT03148795","term_id":"NCT03148795"}}NCT03148795) demonstrated durable antitumor activity in men with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). Here, we detail the safety profile of talazoparib.Patients and MethodsMen received talazoparib 1 mg/day (moderate renal impairment 0.75 mg/day) orally until radiographic progression, unacceptable toxicity, investigator decision, consent withdrawal, or death. Adverse events (AEs) were evaluated: incidence, severity, timing, duration, potential overlap of selected AEs, dose modifications/discontinuations due to AEs, and new clinically significant changes in laboratory values and vital signs.ResultsIn the safety population (N = 127; median age 69.0 years), 95.3% (121/127) experienced all-cause treatment-emergent adverse events (TEAEs). Most common were anemia (48.8% [62/127]), nausea (33.1% [42/127]), decreased appetite (28.3% [36/127]), and asthenia (23.6% [30/127]). Nonhematologic TEAEs were generally grades 1 and 2. No grade 5 TEAEs or deaths were treatment-related. Hematologic TEAEs typically occurred during the first 4-5 months of treatment. The median duration of grade 3-4 anemia, neutropenia, and thrombocytopenia was limited to 7-12 days. No grade 4 events of anemia or neutropenia occurred. Neither BRCA status nor alteration origin significantly impacted the safety profile. The median (range) treatment duration was 6.1 (0.4-24.9) months; treatment duration did not impact the incidence of anemia. Only 3 of the 15 (11.8% [15/127]) permanent treatment discontinuations were due to hematologic TEAEs (thrombocytopenia 1.6% [2/127]; leukopenia 0.8% [1/127]).ConclusionCommon TEAEs associated with talazoparib could be managed through dose modifications/supportive care. Demonstrated efficacy and a manageable safety profile support continued evaluation of talazoparib in mCRPC.ClinicalTrials.gov identifier{"type":"clinical-trial","attrs":{"text":"NCT03148795","term_id":"NCT03148795"}}NCT03148795     

Private Interests and the Start of Fluoride-Supplemented High-Carbohydrate Nutritional Guidelines

Fluoride has no tangible health benefits other than preventing dental caries and there is a small difference between its minimum effective dose and its minimum toxic dose. Leading global organizations currently recommend fluoride supplementation because they recommend high-carbohydrate diets which can cause dental caries. Low-carbohydrate diets prevent dental caries making such fluoride recommendations largely unnecessary. A dental organization was among the first to initiate the public health recommendations which started fluoride-supplemented high-carbohydrate nutritional guidelines. This start required expert panels at this dental organization to reverse on three key scientific points between 1942 and 1949: (1) that topical fluoride had potential harms, (2) that dental caries was a marker for micronutrient deficiencies, and (3) that low-carbohydrate diets are to be recommended for dental caries prevention. Internal documents show that private interests motivated the events which led these expert panels to engage in pivotal scientific reversals. These private interests biased scientific processes and these reversals occurred largely in an absence of supporting evidence. It is concluded that private interests played a significant role in the start of public health endorsements of fluoride-supplemented high-carbohydrate nutritional guidelines.     

Recent Advances in Archaeological Science Techniques Special Feature: Dating the emergence of dairying by the first farmers of Central Europe using 14C analysis of fatty acids preserved in pottery vessels

Direct, accurate, and precise dating of archaeological pottery vessels is now achievable using a recently developed approach based on the radiocarbon dating of purified molecular components of food residues preserved in the walls of pottery vessels. The method targets fatty acids from animal fat residues, making it uniquely suited for directly dating the inception of new food commodities in prehistoric populations. Here, we report a large-scale application of the method by directly dating the introduction of dairying into Central Europe by the Linearbandkeramik (LBK) cultural group based on dairy fat residues. The radiocarbon dates (n = 27) from the 54th century BC from the western and eastern expansion of the LBK suggest dairy exploitation arrived with the first settlers in the respective regions and were not gradually adopted later. This is particularly significant, as contemporaneous LBK sites showed an uneven distribution of dairy exploitation. Significantly, our findings demonstrate the power of directly dating the introduction of new food commodities, hence removing taphonomic uncertainties when assessing this indirectly based on associated cultural materials or other remains.

The introduction of new food commodities into the human diet at the very beginnings of plant and animal domestication is one of the most critical questions in the Neolithization process, having far reaching consequences for human evolution and environmental change. Of major importance is milk exploitation, as it relates to animal domestication but also the ability of adult humans to digest lactose (1, 2). Clearly, identifying the beginnings of the exploitation of domesticated animals for their secondary products (i.e., those obtained during the life of animals, such as milk, wool, or blood) as opposed to primary products (i.e., those obtained by the death of the animal such as meat, skin, teeth, or horn) makes it extremely important to establish when and how dairying began (3, 4). Directly dating the introduction of a new food commodity is nonetheless challenging.Evidence for dairy exploitation in prehistory can be interpreted from iconography, diagnostic ceramics, or domesticated animal slaughter patterns based on sex and ages (3, 4). Additionally, direct evidence for dairy exploitation can be derived from lipid analyses of food residues preserved in pottery vessels. By determining the stable carbon isotope values of the two fatty acids (FAs) (C_16:0 and C_18:0) characteristic of degraded animal fats, dairy products can be distinguished from carcass products (5). Recent combined lipid residue analyses of pottery vessels and animal management assessments based on faunal remains (stable isotopes, butchery practices, kill-off patterns, and calving patterns) have provided invaluable knowledge of early dairying practices at archaeological sites. Currently, the earliest evidence for milk use from lipid residues and faunal assemblages recovered during the Neolithic was found in Anatolia during the 7th millennium BC (6), from several regions in the Balkans, eastern Europe, and the Mediterranean during the 6th millennium BC (7–12), in Saharan Africa (Libya and Algeria) during the 5th millennium BC (13–15), from the beginning of the Neolithic in Britain, Ireland, and Scandinavia during the 4th millennium BC (5, 16–19), and in the Baltic countries during the 3rd millennium BC (16). The dates of the introduction of dairying in these regions have been established largely indirectly based on associated materials (e.g., animal bone collagen, charcoal, charred seeds, etc.) recovered from the same archaeological contexts as the pottery yielding milk fat residues. However, uncertainties exist with indirect dating due to possible intrusion or residuality of datable materials, resulting from the disturbance of archaeological layers and the requirement for the datable materials to be short-lived and truly contemporaneous in date with the pottery vessels containing the dairy residues.Thus, the application of recently developed methods for the direct dating of lipids from pottery food residues offers a unique approach to obtain accurate and precise dates for the introduction of new food commodities. The direct ¹⁴C dating of dairy fat residues avoids all the aforementioned uncertainties, offering an unprecedented opportunity to accurately date the start of dairying practices. At the University of Bristol, United Kingdom, we recently reported a method for radiocarbon dating pottery vessels from their absorbed food residues. Our compound-specific radiocarbon analysis (CSRA) approach is based on the isolation of the C_16:0 and C_18:0 FAs from the clay matrix and freeing them from exogenous organic contaminants (20, 21). We have successfully applied this approach to a small number of dairy residues from the Libyan Sahara and Central Europe, with one of the oldest dated dairy residues coming from the 6th millennium in the Balkans (11, 22). Hence, this dating method offers the opportunity to directly date residues identified as dairy fats based on the compound-specific δ¹³C values of the C_16:0 and C_18:0 FAs, avoiding taphonomic uncertainties arising from dating-associated materials.In this paper, we focus on the Linearbandkeramik (LBK) culture, the first farming society in Central Europe, which emerged and expanded over much of northern Europe in the middle of the 6th millennium BC (23). This culture has been divided into five main phases: Earliest (I), Early (II), Middle (III), Late (IV), and Final (V) LBK, known as the Meier-Arendt chronology, whose timing and evolution differed in the different regions of the LBK (24). Hence, the ceramic phases discussed in the remainder of this paper use the regional and site classifications for the chronology of earliest, early, middle, and Late LBK, which are not necessarily contemporaneous. For example, phase I in Poland and phase I in Cuiry-lès-Chaudardes refer to the Earliest and Late LBK phases, respectively, in the Meier-Arendt chronology.Dairy residues were identified in varying quantities at LBK sites across Central Europe. Some sites show only a weak dairy signal (1 to 2 potsherds only), while others display much higher recovery, with over 20% of the residues displaying dairy fat molecular and carbon isotope characteristics. These results emphasize the spatial disparity in the exploitation of cattle and caprines for their milk in this period. We do not exclude the possibility that the use of organic containers other than clay vessels for dairy products at some sites may affect the overall dairy lipid recovery observed. Diachronic studies in certain regions also revealed dairy practices evolving from being nonexistent or at very low levels at LBK sites but becoming much more abundant in the following Middle Neolithic cultures [e.g., the Rössen culture in Lower Alsace, France (22) or Funnel Beaker culture at the site of Kopydłowo, Poland (25)]. Dating of dairy residues recovered from the earliest phases of the sites would provide calendar ages for the emergence of dairying between LBK regions based directly on the commodity itself rather than on associated materials. Critically, some sites cannot be dated by conventional materials due to their poor preservation, while at other sites where dairy evidence is scarce, the possibility exists for false-positive signal arising due to stratigraphic perturbations. In reporting here the application of our recently developed CSRA method to a wide range of potsherds, we begin to resolve the timing of appearance of dairying practices by LBK farmers during the Neolithic in the diverse regions of the settlements.     

Symptomatic Chikungunya Virus Infection and Pregnancy Outcomes: A Nested Case-Control Study in French Guiana

During the Chikungunya epidemic in the Caribbean and Latin America, pregnant women were affected by the virus in French Guiana. The question of the impact of the virus on pregnancy was raised because of the lack of scientific consensus and published data in the region. Thus, during the Chikungunya outbreak in French Guiana, a comparative study was set up using a cohort of pregnant women. The objective was to compare pregnancy and neonatal outcomes between pregnant women with Chikungunya virus (CHIKV) infection and pregnant women without CHIKV. Of 653 mothers included in the cohort, 246 mothers were included in the case-control study: 73 had CHIKV fever during pregnancy and 173 had neither fever nor CHIKV during pregnancy. The study did not observe any severe clinical presentation of CHIKV in the participating women. There were no intensive care unit admissions. In addition, the study showed no significant difference between the two groups with regard to pregnancy complications. However, the results showed a potential excess risk of neonatal ICU admission of the newborn when the maternal infection occurred within 7 days before delivery. These results suggest that special attention should be paid to neonates whose mothers were infected with CHIKV shortly before delivery.     

Brain functional connectivity alterations associated with neuropsychological performance 6–9 months following SARS‐CoV‐2 infection

Neuropsychological deficits and brain damage following SARS‐CoV‐2 infection are not well understood. Then, 116 patients, with either severe, moderate, or mild disease in the acute phase underwent neuropsychological and olfactory tests, as well as completed psychiatric and respiratory questionnaires at 223 ± 42 days postinfection. Additionally, a subgroup of 50 patients underwent functional magnetic resonance imaging. Patients in the severe group displayed poorer verbal episodic memory performances, and moderate patients had reduced mental flexibility. Neuroimaging revealed patterns of hypofunctional and hyperfunctional connectivities in severe patients, while only hyperconnectivity patterns were observed for moderate. The default mode, somatosensory, dorsal attention, subcortical, and cerebellar networks were implicated. Partial least squares correlations analysis confirmed specific association between memory, executive functions performances and brain functional connectivity. The severity of the infection in the acute phase is a predictor of neuropsychological performance 6–9 months following SARS‐CoV‐2 infection. SARS‐CoV‐2 infection causes long‐term memory and executive dysfunctions, related to large‐scale functional brain connectivity alterations.