Desirable Characteristics of Hepatitis C Treatment Regimens: A Review of What We Have and What We Need.

There have been dramatic advancements in the treatment of chronic hepatitis C (HCV) infection. This is largely due to the approval of several direct-acting antiviral agents (DAAs) from a variety of medication classes with novel mechanisms of action. These therapies are a welcomed advancement given their improved efficacy and tolerability compared to pegylated interferon and ribavirin (RBV)-based regimens. These convenient, all-oral regimens treat a variety of genotypes and often offer high cure rates in a variety of HCV-infected populations. While there are several benefits associated with these therapies, there are also notable shortcomings. Shortcomings include diminished response or need for adjunctive RBV in difficult-to-treat populations (decompensated cirrhosis, active substance abuse patients, advanced kidney disease, etc.), activity against select genotypes, substantial drug-drug interaction potential, and high cost. Therefore, while current DAA-based therapies have several favorable attributes, each also has its limitations. The purpose of this review is to (1) identify the characteristics of an ideal HCV treatment regimen, (2) describe desirable features of existing regimens, (3) summarize limitations of existing regimens, and (4) introduce promising emerging therapies. This manuscript will serve as a guide for evaluating the caliber of future HCV treatment regimens

Pneumonia failing to respond to treatment

SummaryHerpes simplex virus type 1 (HSV-1) is frequently isolated from the respiratory tract of critically ill patients. However, diagnosis of clinically significant HSV-1 pneumonia is difficult as the presentation is non-specific and there is no diagnostic reference standard to differentiate from non-infectious contamination.We present a case of HSV-1 pneumonia in a young asthmatic patient who was potentially immunocompromised through long-term corticosteroid usage. The quantitative PCR titre from bronchoalveolar lavage fluid was high (9×103copies/ml) and the patient made a dramatic clinical and radiographic recovery upon treatment with acyclovir. We suggest that similar PCR levels in the appropriate clinical setting should prompt consideration of anti-viral therapy

Patient vital signs in relation to ICU admission in treatment of acute leukemia: a retrospective chart review

Objectives: The objective of the current study was to investigate the relationship between changes in vital signs and intensive care unit (ICU) admission. Windsor Regional Hospital treats 15–20 new patients a year with acute leukemia. These patients are at increased risk of neutropenic fevers and admission to the ICU following induction chemotherapy. Methods: Retrospective review examined the correlation between acute leukemia patient vitals and ICU admission. The analysis included 37 patients: 7 ICU versus 30 controls. Changes were compared to baseline over 24 hours prior to ICU admission or 5 days after the initiation of induction chemotherapy in the following vital signs: heart rate (HR), mean arterial pressure (MAP), temperature (T), respiratory rate (RR), and fraction of inspired oxygen (FiO2) required to maintain a stable oxygen saturation. Results: RR and FiO2 demonstrated significant change over baseline leading up to ICU admission within the ICU group. T, HR and MAP did not demonstrate significant changes over time in either group. RR, FiO2 and HR were significantly higher in the ICU group at time zero compared with the control group. RR was recorded least frequently in the 24 hours leading up to ICU admission. Discussion: Changes in RR and FiO2 predicted clinical deterioration requiring ICU admission in acute leukemia patients. This is consistent with the predominant reason for ICU admission which was respiratory failure. Conclusion: We present preliminary evidence to support enhanced monitoring of RR and FiO2 in acute leukemia patients following induction chemotherapy with early intervention if identified

Oral Cytokine Levels Are More Linked to Levels of Plasma and Oral HIV-1 RNA Than to CD4+ T-Cell Counts in People With HIV.

BackgroundWe determined the levels of 11 soluble immune mediators in oral washings of AIDS Clinical Trials Group A5254 participants with varying degrees of plasma viremia and CD4 T-cell counts to characterize the mucosal immune response at different stages of HIV-1 infection.MethodsA5254 was a multicenter, cross-sectional study in people with HIV (PWH) recruited into 4 strata based on CD4 count and levels of plasma viremia: stratum (St) A: CD4 ≤200 cells/mm3, HIV-1 RNA (viral load [VL]) >1000 cps/mL; St B: CD4 ≤200, VL ≤1000; St C: CD4 >200, VL >1000; St D: CD4 >200, VL ≤1000. Oral/throat washings were obtained from all participants. Soluble markers were tested in oral/throat washings using a multibead fluorescent platform and were compared across strata. Linear regression was used to determine the associations between cytokines and HIV-1 in plasma and oral fluid.ResultsSt A participants had higher levels of interleukin (IL)-1β, IL-6, IL-17, tumor necrosis factor alpha (TNFα), and interferon gamma (IFNγ) compared with St B and D (P = .02; P < .0001) but were not different from St C. IL-8, IL-10, and IL-12 were elevated in St A compared with the other 3 strata (P = .046; P < .0001). Linear regression demonstrated that oral HIV-1 levels were associated with IL-1β, IL-6, IL-8, and TNFα production (R > .40; P < .001) when controlling for CD4 count and opportunistic infections.ConclusionsOur results show that high levels of oral HIV-1, rather than low CD4 counts, were linked to the production of oral immune mediators. Participants with AIDS and uncontrolled viremia demonstrated higher levels of pro- and anti-inflammatory soluble immune mediators compared with participants with lower HIV-1 RNA. The interplay of HIV-1 and these immune mediators could be important in the oral health of PWH

Progressing the care, husbandry and management of ageing mice used in scientific studies

Driven by the longer lifespans of humans, particularly in Westernised societies, and the need to know more about ‘healthy ageing’, ageing mice are being used increasingly in scientific research. Many departments and institutes involved with ageing research have developed their own systems to determine intervention points for potential refinements and to identify humane end points. Several good systems are in use, but variations between them could contribute to poor reproducibility of the science achieved. Working with scientific and regulatory communities in the UK, we have reviewed the clinical signs observed in ageing mice and developed recommendations for enhanced monitoring, behaviour assessment, husbandry and veterinary interventions. We advocate that the default time point for enhanced monitoring should be 15 months of age, unless prior information is available. Importantly, the enhanced monitoring should cause no additional harms to the animals. Where a mouse strain is well characterised, the onset of age-related enhanced monitoring may be modified based on knowledge of the onset of an expected age-related clinical sign. In progeroid models where ageing is accelerated, enhanced monitoring may need to be brought forward. Information on the background strain must be considered, as it influences the onset of age-related clinical signs. The range of ageing models currently used means that there will be no ‘one-size fits all’ solution. Increased awareness of the issues will lead to more refined and consistent husbandry of ageing mice, and application of humane end points will help to reduce the numbers of animals maintained for longer than is scientifically justified

Radiocarbon Dated Trends and Central Mediterranean Prehistory

Abstract: This paper reviews the evidence for long term trends in anthropogenic activity and population dynamics across the Holocene in the central Mediterranean and the chronology of cultural events. The evidence for this has been constituted in a database of 4608 radiocarbon dates (of which 4515 were retained for analysis following initial screening) from 1195 archaeological sites in southern France, Italy and Malta, spanning the Mesolithic to Early Iron Age periods, c. 8000 to 500 BC. We provide an overview of the settlement record for central Mediterranean prehistory and add to this an assessment of the available archaeological radiocarbon evidence in order to review the traditional narratives on the prehistory of the region. This new chronology has enabled us to identify the most significant points in time where activity levels, population dynamics and cultural change have together caused strong temporal patterning in the archaeological record. Some of these episodes were localized to one region, whereas others were part of pan-regional trends and cultural trajectories that took many centuries to play out fully, revealing prehistoric societies subject to collapse, recovery, and continuing instability over the long-term. Using the radiocarbon evidence, we model growth rates in the various regions so that the tempo of change at certain points in space and time can be identified, compared, and discussed in the context of demographic change. Using other published databases of radiocarbon data, we have drawn comparisons across the central Mediterranean to wider prehistoric Europe, and northern Africa. Finally, we include a brief response to the synchronously published but independently developed paper (Palmisano et al. in J World Prehist 34(3), 2021). While there are differences in our respective approaches, we share the general conclusions that large-scale trends can been identified through meta-analyses of the archaeological record, and these offer new perspectives on how society functioned

A randomized controlled trial of folic acid intervention in pregnancy highlights a putative methylation-regulated control element at ZFP57

Table S1. Pyrosequencing and transcriptional primer sets used in this study. Pyroassay primers are given as bisulfite converted sequence. The same primers were used for both RT-PCR and RT-qPCR. (DOCX 15 kb