Probing single electrons across 300-mm spin qubit wafers.

Building a fault-tolerant quantum computer will require vast numbers of physical qubits. For qubit technologies based on solid-state electronic devices1-3, integrating millions of qubits in a single processor will require device fabrication to reach a scale comparable to that of the modern complementary metal-oxide-semiconductor (CMOS) industry. Equally important, the scale of cryogenic device testing must keep pace to enable efficient device screening and to improve statistical metrics such as qubit yield and voltage variation. Spin qubits1,4,5 based on electrons in Si have shown impressive control fidelities6-9 but have historically been challenged by yield and process variation10-12. Here we present a testing process using a cryogenic 300-mm wafer prober13 to collect high-volume data on the performance of hundreds of industry-manufactured spin qubit devices at 1.6 K. This testing method provides fast feedback to enable optimization of the CMOS-compatible fabrication process, leading to high yield and low process variation. Using this system, we automate measurements of the operating point of spin qubits and investigate the transitions of single electrons across full wafers. We analyse the random variation in single-electron operating voltages and find that the optimized fabrication process leads to low levels of disorder at the 300-mm scale. Together, these results demonstrate the advances that can be achieved through the application of CMOS-industry techniques to the fabrication and measurement of spin qubit devices.

EGFR amplification and EGFRvIII predict and participate in TAT-Cx43266-283 antitumor response in preclinical glioblastoma models.

BACKGROUND: Glioblastoma (GBM) commonly displays epidermal growth factor receptor (EGFR) alterations (mainly amplification and EGFRvIII) and TAT-Cx43266-283 is a Src-inhibitory peptide with antitumor properties in preclinical GBM models. Given the link between EGFR and Src, the aim of this study was to explore the role of EGFR in the antitumor effects of TAT-Cx43266-283. METHODS: The effect of TAT-Cx43266-283, temozolomide (TMZ) and erlotinib (EGFR inhibitor) was studied in patient-derived GBM stem cells (GSCs) and murine neural stem cells (NSCs) with and without EGFR alterations, in vitro and in vivo. EGFR alterations were analyzed by Western blot (WB) and Fluorescence In Situ Hybridization (FISH) in these cells, and compared with Src activity and survival in GBM samples from TCGA. RESULTS: The effect of TAT-Cx43266-283 correlated with EGFR alterations in a set of patient-derived GSCs and was stronger than that exerted by TMZ and erlotinib. In fact, TAT-Cx43266-283 only affected NSCs with EGFR alterations, but not healthy NSCs. EGFR alterations correlated with Src activity and poor survival in GBM patients. Finally, tumors generated from NSCs with EGFR alterations, showed a decrease in growth, invasiveness and vascularization after treatment with TAT-Cx43266-283, which enhanced the survival of immunocompetent mice. CONCLUSION: Clinically relevant EGFR alterations are predictors of TAT-Cx43266-283 response and part of its mechanism of action, even in TMZ- and erlotinib-resistant GSCs. TAT-Cx43266-283 targets NSCs with GBM-driver mutations, including EGFR alterations, in an immunocompetent GBM model in vivo, suggesting a promising effect on GBM recurrence. Together, this study represents an important step towards the clinical application of TAT-Cx43266-283.

Osteoblastoma in the Proximal Phalanx of the Hand: A Case Report.

Osteoblastoma is a benign bone tumor that can spread aggressively and is commonly found in the spine and long bones. When present in other areas of the body, it can be difficult to diagnose. While this tumor is rarely found in the hand, in reported cases, it typically presents with pain. Treatment is usually curettage and marginal excision. We report a rare case of osteoblastoma in the fifth proximal phalanx of the left hand in a 14-year-old right-handed female, presenting as a painless, progressively growing mass with associated flexion contracture over a seven-month period, with no history of trauma. An excision biopsy with curettage was performed, and histopathologic examination confirmed the diagnosis of osteoblastoma. This is a rare case of osteoblastoma of the proximal phalanx presenting as a painless mass in the finger with a progressive flexion contracture. Histopathologic examination is important in diagnosing osteoblastoma to determine the appropriate treatment and surgery. Post-operatively, close monitoring is important due to the high recurrence rates in these tumors.

Transversus abdominis plane blocks in laparoscopic inguinal hernia repair: a review.

INTRODUCTION: Throughout its history, there have been significant advances in pain control of inguinal hernia repairs. One of the most recent developments is locoregional pain blocks. There is a multitude of literature available on laparoscopic inguinal hernia repair and transversus abdominis plane (TAP) blocks. OBJECTIVES: This paper seeks to provide a thorough and systematic literature review on the role of TAP blocks in laparoscopic inguinal hernia repairs. METHODS: PubMed and Google Scholar were searched for relevant literature using predetermined medical subject heading (MeSH) terms: "(TAP block)" AND "(Laparoscopic inguinal hernia repair)". RESULTS: A total of 166 publications were identified, from which 18 publications were included in the final review after eligibility criteria were applied. CONCLUSION: The majority of studies conclude that TAP blocks performed in the setting of laparoscopic inguinal hernia repair improve post-operative pain and mobility, decrease opiate analgesic usage, and are superior in pain control compared to other modalities of regional anesthesia. Thus, to improve post-operative outcomes and patient satisfaction, TAP blocks should be heavily considered for routine use in surgical practice for laparoscopic inguinal hernia repair.

Maternal opioid addiction: A potential cause of elevated 17-OH progesterone in neonatal screening.

BACKGROUND: Congenital adrenal hyperplasia (CAH) is a disease that is part of neonatal screening. There are many causes of false-positive results on neonatal screening, and maternal opioid consumption during pregnancy is suspected to increase 17-hydroxyprogesterone (17-OHP) levels at birth. The aim of this study was to determine the effect of maternal drug consumption on 17-OHP values on neonatal screening. MATERIAL AND METHODS: We studied 17-OHP levels of term newborns with reported maternal drug consumption born at the Maternity Hospital of Nancy between 2002 and 2018. These infants were matched with newborns of mothers without drug addiction. The 17-OHP levels, withdrawal syndromes, birth parameters, and maternal characteristics were compared between the two groups. RESULTS: The study included 241 patients (121 in the drug-exposed group, 120 in the control group). The mean 17-OHP levels in newborns of mothers with substance addiction were 9.83 nmol/L compared to 4.90 nmol/L (p=0.0001) in the control group. Newborns exposed to drugs were smaller (p=0.0001), lighter (p=0.0001), had smaller head circumference (p=0.0001), and had lower Apgar scores (p=0.004 at 1 min and p=0.0001 at 5 min). The 17-OHP level did not differ in cases of withdrawal syndrome in drug-exposed newborn (p=0.911). CONCLUSION: A significant increase in 17-OHP levels was observed in newborns exposed to drugs, with no influence of withdrawal syndrome on 17-OHP levels. Maternal substance addiction may be associated with moderately increased 17-OHP levels during neonatal screening.

Increased Stroke Risk Following Herpes Zoster Infection and Protection With Zoster Vaccine.

BACKGROUND: Studies evaluating stroke following varicella zoster virus (VZV) infection are limited, and the utility of zoster vaccination against this phenomenon is unclear. This study aimed to determine the risk of stroke 30 days following zoster infection and to evaluate the impact of zoster vaccinations on the risk of stroke in VZV-infected patients. METHODS: This retrospective case-control study was conducted from January 2010 to January 2020 utilizing nationwide patient data retrieved from the Veterans Affairs' Corporate Data Warehouse. RESULTS: A total of 2 165 505 patients ≥18 years of age who received care at a Veterans Affairs facility were included in the study, of whom 71 911 had a history of zoster infection. Zoster patients were found to have 1.9 times increased likelihood of developing a stroke within 30 days following infection (odds ratio [OR], 1.93 [95% confidence interval {CI}, 1.57-2.4]; P < .0001). A decreased risk of stroke was seen in patients who received the recombinant zoster vaccine (OR, 0.57 [95% CI, .46-.72]; P < .0001) or the live zoster vaccine (OR, 0.77 [95% CI, .65-.91]; P = .002). CONCLUSIONS: Patients had a significantly higher risk of stroke within the first month following recent herpes zoster infection. Receipt of at least 1 zoster vaccination was found to mitigate this increased risk. Vaccination may therefore be viewed as a protective tool against the risk of neurologic postinfection sequelae.

Optimizing Clinical Outcomes Through Rational Dosing Strategies: Roles of Pharmacokinetic/Pharmacodynamic Modeling Tools.

Significant progress in previous decades has led to several methodologies developed to facilitate the design of optimal antimicrobial dosing. In this review, we highlight common pharmacokinetic/pharmacodynamic (PKPD) modeling techniques and their roles in guiding rational dosing regimen design. In the early drug development phases, dose fractionation studies identify the PKPD index most closely associated with bacterial killing. Once discerned, this index is linked to clinical efficacy end points, and classification and regression tree analysis can be used to define the PKPD target goal. Monte Carlo simulations integrate PKPD and microbiological data to identify dosing strategies with a high probability of achieving the established PKPD target. Results then determine dosing regimens to investigate and/or validate the findings of randomized controlled trials. Further improvements in PKPD modeling could lead to an era of precision dosing and personalized therapeutics.

Significant Publications on Infectious Diseases Pharmacotherapy in 2021.

Purpose: To summarize the most noteworthy infectious diseases (ID) pharmacotherapy articles published in peer-reviewed literature in 2021. Summary: Members of the Houston Infectious Diseases Network (HIDN) nominated articles that were deemed to have significant contributions to ID pharmacotherapy in 2021. These nominations included articles pertaining to both general ID, including coronavirus disease 2019 (COVID-19), and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) pharmacotherapy. A total of 35 articles were nominated by HIDN: 30 articles pertaining to general ID pharmacotherapy and 5 articles with HIV/AIDS focus. To select the most influential articles of 2021, a survey was created and distributed to members of the Society of Infectious Diseases Pharmacists (SIDP). Of the 239 SIDP members who responded to the survey, there were 192 recorded votes for the top 10 general ID pharmacotherapy articles and 47 recorded votes for the top HIV/AIDS article, respectively. The top publications are summarized. Conclusion: Antimicrobial stewardship and the optimal management of infectious disease states continues to be a priority in the midst of the ongoing coronavirus disease 2019 (COVID-19) global pandemic. In light of the sheer volume of ID-related articles published in the past year, this review aims to aid clinicians in remaining up-to-date on key practice-changing ID pharmacotherapy publications from 2021.

Inflammation of the Human Dental Pulp Induces Phosphorylation of eNOS at Thr495 in Blood Vessels.

The activity of endothelial nitric oxide synthase (eNOS) in endothelial cells increased with the phosphorylation of the enzyme at Ser1177 and decreased at Thr495. The regulation of the phosphorylation sites of eNOS at Ser1177 and Thr495 in blood vessels of the healthy and inflamed human dental pulp is unknown. To investigate this, healthy and carious human third molars were immersion-fixed and decalcified. The localization of eNOS, Ser1177, and Thr495 in healthy and inflamed blood vessels was examined in consecutive cryo-sections using quantitative immunohistochemical methods. We found that the staining intensity of Ser1177 in healthy blood vessels decreased in inflamed blood vessels, whereas the weak staining intensity of Thr495 in healthy blood vessels strongly increased in inflamed blood vessels. In blood vessels of the healthy pulp, eNOS is active with phosphorylation of the enzyme at Ser1177. The phosphorylation of eNOS at Thr495 in inflamed blood vessels leads to a decrease in eNOS activity, contributing to eNOS uncoupling and giving evidence for a decrease in NO and an increase in O2- production. Since the formation of the tertiary dentin matrix depends on intact pulp circulation, eNOS uncoupling and phosphorylation of eNOS at Thr495 in the inflamed pulp blood vessels should be considered during caries therapy.

Longitudinal craze line propagation in human root dentin after instrumentation with NiTi rotary files of different instrument tapers after long-term chewing simulation.

OBJECTIVES: The aim of this study was to investigate whether file design and taper significantly influence microcrack initiation during machine preparation. MATERIALS AND METHODS: Sixty extracted teeth with straight single canals were selected. The teeth were randomly assigned to four groups based on their root canal anatomy and the corresponding NiTi rotary file system (I, Mtwo; II, ProTaper Universal; III, F6 SkyTaper; control, no preparation and filling). The root canals of the experimental groups were filled using the single-cone technique. The tested teeth were all subjected to a mechanical chewing simulation with flat lead loading over a period of 3 years (corresponding to 150,000 cycles). The teeth were checked for dentinal defects (accumulative crack growth in length) under the digital microscope (Keyence VHX-5000) at time 0 (baseline prior to chewing simulation) and after 3, 6, 12, 24, and 36 months of loading. The cumulative crack increase was statistically analyzed using the Kruskal-Wallis test, Jonckheere-Terpstra test, and the Wilcoxon rank-sum test. The significance was set at p < 0.05. RESULTS: In contrast to preparation with greater-tapered instruments, ProTaper Universal (group II) and F6 SkyTaper (group III) instrumentation with the smaller tapered Mtwo files (group I) showed less accumulative propagation of craze lines (p < 0.05) at all time points. CONCLUSION: Instruments with greater taper for root canal instrumentation should be used with care to avoid negative long-term effects in the form of propagation of dentinal defects over time. A positive cutting-edge angle and a smaller taper have a positive effect on a lower craze line development. CLINICAL RELEVANCE: Instruments with a positive cutting-edge angle and a smaller taper are beneficial for the long-term preservation of dentinal tooth structure.

Dupuytren's contracture in a Filipino male: A case report and review of the literature

@#Dupuytren’s disease (DD) is a heritable, benign, chronic fibroproliferative process which affects the connective tissue of the palmar fascia. DD is rare among Asians with a prevalence of 0.004 to 0.032 percent. There are only 74 cases of DD among Asians identified in literature, and there are no published cases from the Philippines. We discuss a rare case of DD in a 60-year-old male Filipino presenting with bilateral loss of range of motion of the middle, ring, and little finger of both hands.

Open-source maximum a posteriori-bayesian dosing AdDS to current therapeutic drug monitoring: Adapting to the era of individualized therapy.

Recent updates in the therapeutic drug monitoring (TDM) guidelines for vancomycin have rekindled interest in maximum a posteriori-Bayesian (MAP-Bayesian) estimation of patient-specific pharmacokinetic parameters. To create a versatile infrastructure for MAP-Bayesian dosing of vancomycin or other drugs, a freely available, R-based software package, Advanced Dosing Solutions (AdDS), was created to facilitate clinical implementation of these improved TDM methods. The objective of this study was to utilize AdDS for pre- and post-processing of data in order to streamline the therapeutic management of vancomycin in healthy and obese veterans. Patients from a local Veteran Affairs hospital were utilized to compare the process of full re-estimation versus Bayesian updating of priors on healthy adult and obese patient populations for use with AdDS. Twenty-four healthy veterans were utilized to train (14/24) and test (10/24) the base pharmacokinetic model of vancomycin while comparing the effects of updated and fully re-estimated priors. This process was repeated with a total of 18 obese veterans for both training (11/18) and testing (7/18). Comparison of MAP objective function between the original and re-estimated models for healthy adults indicated that 78.6% of the subjects in the training and 70.0% of the subjects in the testing datasets had similar or improved predictions by the re-estimated model. For obese veterans, 81.8% of subjects in the training dataset and 85.7% of subjects in the testing dataset had similar or improved predictions. Re-estimation of model parameters provided more significant improvements in objective function compared with Bayesian updating, which may be a useful strategy in cases where sufficient samples and subjects are available. The generation of bespoke regimens based on patient-specific clearance and minimal sampling may improve patient care by addressing fundamental pharmacokinetic differences in healthy and obese veteran populations.

Safety and immunogenicity of Px563L, a recombinant anthrax vaccine candidate, in a two-dose regimen for post-exposure prophylaxis in healthy adults.

Px563L is a next-generation anthrax vaccine candidate consisting of a protein subunit, mutant recombinant protective antigen SNKE167-ΔFF-315-E308D (mrPA), and liposome-embedded monophosphoryl lipid A (MPLA) adjuvant. Px563L has the potential to deliver an improved safety and immunogenicity profile relative to the currently licensed vaccine, which is produced from filtered B. anthracis culture supernatants. We conducted a Phase 1, double-blind, placebo-controlled, dose-escalation study in 54 healthy subjects to evaluate Px563L at 3 dose levels of mrPA (10, 50, and 80 mcg). For each dose level, 18 subjects were randomized in an 8:8:2 ratio to Px563L (mrPA with adjuvant), RPA563 (mrPA only) or placebo (saline). Each subject received an intramuscular (IM) injection on Day 0 and Day 28. Primary safety and immunogenicity analysis was conducted after all subjects completed the Day70 visit, a duration deemed clinically relevant for post-exposure prophylaxis. Long-term safety was assessed through Day 393. Vaccinations with Px563L at all dose levels were well-tolerated. There were no serious adverse events or adverse events (AE) leading to early withdrawal. In all treatment groups, most AEs were due to injection site reactions, and all AEs at the 10 and 50 mcg dose levels were mild. For the primary immunogenicity endpoint (protective toxin neutralizing antibody 50% neutralization factor [TNA NF50]), titers started to increase significantly after the second administration of Px563L, from Day35 through Day70, with the geometric mean and lower bound of the 95% confidence interval exceeding 0.56, a threshold correlating with significant survival in animal models of anthrax exposure. In conclusion, Px563L, administered as two IM doses 28 days apart, was well-tolerated and elicited a protective antibody response starting at seven days after the second vaccination. These findings support the continued development of Px563L in a two-dose regimen for anthrax post-exposure prophylaxis. ClinicalTrials.gov identifier NCT02655549.

Experimental Assessment of Workplace Radiation Exposure in Diagnostic X-ray Medical Imaging Centres in Benin from 2019 to 2020.

The ease of prescribing radiological examinations has prompted an expansion in radiological procedures and, consequently, an increase of occupational dose to medical imaging workers. However, little is known about radiation exposure in the workplace of medical radiology professionals in many countries, and in Benin particularly. The purpose of this study was to assess ambient radiation doses in diagnostic X-ray medical facilities in Benin and to observe whether exposure levels are below reference levels. A total of 72 public and private medical imaging centres participated in a cross-sectional study carried out from June 2019 to February 2020 in Benin. These centres had 59 X-ray, four chest and six computed tomography (CT) scan rooms. A calibrated radiameter able to measure short, pulsed or continuous X fields and gamma/beta (50 nSv to 10 Sv) was used to measure exposure levels in these functional rooms. Scattered X-ray doses and exposure time from radiological examinations both behind the lead glass of the control area to assess the levels of exposure of professionals and outside of the examination room to evaluate the level of exposure of the public (including non-exposed workers) have been provided. Equivalent doses estimated per hour were compared with the reference levels of 7.50 and 0.05 µSv per hour for workers and the public, respectively. At the control area, the mean/median (min-max) equivalent doses were 0.09/0.07 (0.00-0.21), 2.39/0.13 (0.00-75.67), and 228.39/28.65 (0.39-869.75) µSv per hour for the chest, X-ray, and CT-scan rooms, respectively. Among 69 examination rooms, 13.04% of the equivalent dose estimated in the workplace behind the lead glass was greater than 7.50 µSv per hour; 65 out of 69 examination rooms showed that 40.00% of the equivalent dose estimated behind the doors was greater than 0.05 µSv per hour. These results demonstrated that current controls, including leaded glass separating the control panel and leaded doors between the examination room and the corridor, are inadequate to limit radiation exposures. The controls must be upgraded and a dosimetry program should be implemented to monitor exposures of employees, patients, and visitors.

Week 4 Liver Fat Reduction on MRI as an Early Predictor of Treatment Response in Participants with Nonalcoholic Steatohepatitis.

Background Pharmacologic treatment of nonalcoholic steatohepatitis (NASH) is long term in nature; thus, early noninvasive treatment response assessment is important for therapeutic decision making. Purpose To investigate potential early predictors of the 12-week treatment response estimated by using the MRI-based proton-density fat fraction (PDFF). Materials and Methods In this secondary analysis of a prospective phase Ib clinical trial evaluating a candidate treatment (MET409, a farnesoid X receptor agonist) for NASH, participants were analyzed at baseline and at 4 and 12 weeks after either active treatment with MET409 or placebo treatment between June 2019 and January 2020. Correlation and multiple linear regression analyses were used to identify clinical, laboratory, and imaging predictors of the relative PDFF change at week 12 (W12). Multivariate logistic regression analysis was used to develop predictive models for an at least 30% relative PDFF reduction at W12, a well-validated indicator of histologic improvement. Model performance was characterized by using area under the receiver operating characteristic curve (AUC) analysis, sensitivity, and specificity. Results A total of 48 participants were analyzed (median age, 57 years; age range, 40-62 years; 32 women), among whom 30 received MET409 and 18 received a placebo. The week 4 (W4) relative changes in PDFF (regression coefficient = 1.24, P < .001) and the serum alkaline phosphatase (ALP) level (regression coefficient = -0.29, P = .03) were predictors of the W12 relative PDFF change. An at least 19.3% relative PDFF reduction at W4 yielded an AUC of 0.98 (sensitivity, 89%; specificity, 95%) for predicting an at least 30% relative PDFF reduction at W12. The addition of ALP to the predictive model did not improve model performance. Conclusion In participants with nonalcoholic steatohepatitis enrolled in a phase Ib treatment trial, the relative change in the MRI-based proton-density fat fraction (PDFF) at week 4 was highly predictive of the treatment response estimated by using the week 12 MRI-based PDFF. © RSNA, 2021 Online supplemental material is available for this article.

A structurally optimized FXR agonist, MET409, reduced liver fat content over 12 weeks in patients with non-alcoholic steatohepatitis.

BACKGROUND & AIMS: The benefits of farnesoid X receptor (FXR) agonists in patients with non-alcoholic steatohepatitis (NASH) have been validated, although improvements in efficacy and/or tolerability remain elusive. Herein, we aimed to assess the performance of a structurally optimized FXR agonist in patients with NASH. METHODS: In this 12-week, randomized, placebo-controlled study, we evaluated MET409 - a non-bile acid agonist with a unique chemical scaffold - in patients with NASH. Patients were randomized to receive either 80 mg (n = 20) or 50 mg (n = 19) of MET409, or placebo (n = 19). RESULTS: At Week 12, MET409 lowered liver fat content (LFC), with mean relative reductions of 55% (80 mg) and 38% (50 mg) vs. 6% in placebo (p <0.001). MET409 achieved ≥30% relative LFC reduction in 93% (80 mg) and 75% (50 mg) of patients vs. 11% in placebo (p <0.001) and normalized LFC (≤5%) in 29% (80 mg) and 31% (50 mg) of patients vs. 0% in placebo (p <0.05). An increase in alanine aminotransferase (ALT) was observed with MET409, confounding Week 12 changes from baseline (-25% for 80 mg, 28% for 50 mg). Nonetheless, MET409 achieved ≥30% relative ALT reduction in 50% (80 mg) and 31% (50 mg) of patients vs. 17% in placebo. MET409 was associated with on-target high-density lipoprotein cholesterol decreases (mean changes of -23.4% for 80 mg and -20.3% for 50 mg vs. 2.6% in placebo) and low-density lipoprotein cholesterol (LDL-C) increases (mean changes of 23.7% for 80 mg and 6.8% for 50 mg vs. -1.5% in placebo). Pruritus (mild-moderate) occurred in 16% (50 mg) and 40% (80 mg) of MET409-treated patients. CONCLUSION: MET409 lowered LFC over 12 weeks in patients with NASH and delivered a differentiated pruritus and LDL-C profile at 50 mg, providing the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced through structural optimization. LAY SUMMARY: Activation of the farnesoid X receptor (FXR) is a clinically validated approach for treating non-alcoholic steatohepatitis (NASH), although side effects such as itching or increases in low-density lipoprotein cholesterol are frequently dose-limiting. MET409, an FXR agonist with a unique chemical structure, led to significant liver fat reduction and delivered a favorable side effect profile after 12 weeks of treatment in patients with NASH. These results provide the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced.

Combatting the Rising Tide of Antimicrobial Resistance: Pharmacokinetic/Pharmacodynamic Dosing Strategies for Maximal Precision.

OBJECTIVE: Antimicrobial pharmacokinetics/pharmacodynamics (PK/PD) principles and PK/PD models have been essential in characterizing the mechanism of antibiotic bacterial killing and determining the most optimal dosing regimen that maximizes clinical outcomes. This review summarized the fundamentals of antimicrobial PK/PD and the various types of PK/PD experiments that shaped the utilization and dosing strategies of antibiotics today. METHODS: Multiple databases - including PubMed, Scopus, and EMBASE - were searched for published articles that involved PK/PD modelling and precision dosing. Data from in vitro, in vivo and mechanistic PK/PD models were reviewed as a basis for compiling studies that guide dosing regimens used in clinical trials. RESULTS: Literature regarding the utilization of exposure-response analyses, mathematical modelling and simulations that were summarized are able to provide a better understanding of antibiotic pharmacodynamics that influence translational drug development. Optimal pharmacokinetic sampling of antibiotics from patients can lead to personalized dosing regimens that attain target concentrations while minimizing toxicity. Thus the development of a fully integrated mechanistic model based on systems pharmacology can continually adapt to data generated from clinical responses, which can provide the framework for individualized dosing regimens. CONCLUSIONS: The promise of what PK/PD can provide through precision dosing for antibiotics has not been fully realized in the clinical setting. Antimicrobial resistance, which has emerged as a significant public health threat, has forced clinicians to empirically utilize therapies. Future research focused on implementation and translation of PK/PD-based approaches integrating novel approaches that combine knowledge of combination therapies, systems pharmacology and resistance mechanisms are necessary. To fully realize maximally precise therapeutics, optimal PK/PD strategies are critical to maximize antimicrobial efficacy against extremely-drug-resistant organisms, while minimizing toxicity.

Identifying clusters of health risk behaviors and their predictors in adult survivors of childhood cancer: A report from the French Childhood Cancer Survivor Study.

OBJECTIVE: Health risk behaviors (HRB) of childhood cancer survivors (CCS) are generally studied separately, despite the evidence suggesting that HRB are not independent. To our knowledge, few studies have examined HRB profiles in the former pediatric cancer patients. In this study, we identified HRB profiles and examined predictors engaging in unhealthy behaviors in CCS. METHODS: We used data from a French cohort of CCS that includes five-year survivors diagnosed between 1945 and 2000 and treated before reaching age 18, in five centers in France. A total of 2961 adult CCS answered a self-reported questionnaire pertaining to HRB. Latent class analysis was used to identify HRB profiles combining physical activity, smoking, cannabis use, and alcohol drinking. Multinomial logistic analyses examined predictors for engaging in unhealthy behaviors. RESULTS: Three HRB patterns emerged: "Low-risk" (n = 1846, 62.3%) included CCS who exhibited the highest frequency for usual physical activity and the lowest probabilities for current smoking or cannabis use, but most drank at least moderately; "Moderate-risk behaviors" (n = 291, 9.8%), and "High-risk behaviors" (n = 824, 27.8%) for CCS who exhibited the highest frequencies for current smoking, cannabis use, and heavy drinking. The multivariable regression revealed that male CCS, less educated or not married were significantly more likely to be in the high-risk behaviors group than the low-risk group. CONCLUSIONS: As CCS remain a vulnerable population, screening for HRB should be routinized in long-term follow-up care and interventions targeting multiple HRB simultaneously among survivors should be developed.

A systematic review of occupational radiation individual dose monitoring among healthcare workers exposed in Africa.

Dosimetric monitoring is useful to limit exposures to ionising radiation in medical occupational settings, and reduce subsequent health risks. Scientific literatures, such as the UNSCEAR report 2017 and International Atomic Energy Agency Report 2014b, updated information on this subject; however, few African works have been found. This is the reason why we undertook this study, which summarises existing information on monitoring external radiation exposure doses for the whole body, using data from medical workers on this continent. Using standard terms and combining different keyword searches for radiation dose monitoring among radiology healthcare workers in Africa, from the titles, abstracts, and full texts, we found 3139 articles in the PubMed/MEDLINE, Google Scholar and INIS databases. Two reviewers screened the retrieved publications based on predefined eligibility criteria to identify relevant studies, extract key information from each, and summarise the data in table form. A total of 20 potentially relevant articles were identified. Among these 20 articles, 15 reported the overall average annual effective dose. Studies included in this systematic review represent an inventory of the radiation protection of medical workers in various African countries, with a focus on the monitoring of occupational radiation exposure. The size of studied populations ranged between 81 and 5152 occupational exposed workers. The mean annual effective doses ranged from 0.44 to 8.20 mSv in all specialities of medical sectors, while diagnostic radiology ranged from 0.07 to 4.37 mSv. For the nuclear medicine and radiotherapy from medical groups, the mean annual effective dose varied between 0.56 and 6.30 mSv. Industrial and research/teaching sectors data varied between 0.38 to 19.40 mSv. In conclusion, more studies implemented on dosimetric monitoring in Africa are needed to get a real picture of occupational exposure in the continent.

Mitochondrial functions and rare diseases.

Mitochondria are dynamic cellular organelles responsible for a large variety of biochemical processes as energy transduction, REDOX signaling, the biosynthesis of hormones and vitamins, inflammation or cell death execution. Cell biology studies established that 1158 human genes encode proteins localized to mitochondria, as registered in MITOCARTA. Clinical studies showed that a large number of these mitochondrial proteins can be altered in expression and function through genetic, epigenetic or biochemical mechanisms including the interaction with environmental toxics or iatrogenic medicine. As a result, pathogenic mitochondrial genetic and functional defects participate to the onset and the progression of a growing number of rare diseases. In this review we provide an exhaustive survey of the biochemical, genetic and clinical studies that demonstrated the implication of mitochondrial dysfunction in human rare diseases. We discuss the striking diversity of the symptoms caused by mitochondrial dysfunction and the strategies proposed for mitochondrial therapy, including a survey of ongoing clinical trials.