Global Financing and Long-Term Technical Assistance for Multidrug-Resistant Tuberculosis: Scaling Up Access to Treatment

Thomas Hwang and Salmaan Keshavjee argue that a market-based strategy combined with long-term in-country technical assistance should be used to scale-up access to the treatment of multi-drug resistant tuberculosis Please see later in the article for the Editors' Summar

Mutation supply and the repeatability of selection for antibiotic resistance

Whether evolution can be predicted is a key question in evolutionary biology. Here we set out to better understand the repeatability of evolution. We explored experimentally the effect of mutation supply and the strength of selective pressure on the repeatability of selection from standing genetic variation. Different sizes of mutant libraries of an antibiotic resistance gene, TEM-1 $\beta$-lactamase in Escherichia coli, were subjected to different antibiotic concentrations. We determined whether populations went extinct or survived, and sequenced the TEM gene of the surviving populations. The distribution of mutations per allele in our mutant libraries- generated by error-prone PCR- followed a Poisson distribution. Extinction patterns could be explained by a simple stochastic model that assumed the sampling of beneficial mutations was key for survival. In most surviving populations, alleles containing at least one known large-effect beneficial mutation were present. These genotype data also support a model which only invokes sampling effects to describe the occurrence of alleles containing large-effect driver mutations. Hence, evolution is largely predictable given cursory knowledge of mutational fitness effects, the mutation rate and population size. There were no clear trends in the repeatability of selected mutants when we considered all mutations present. However, when only known large-effect mutations were considered, the outcome of selection is less repeatable for large libraries, in contrast to expectations. Furthermore, we show experimentally that alleles carrying multiple mutations selected from large libraries confer higher resistance levels relative to alleles with only a known large-effect mutation, suggesting that the scarcity of high-resistance alleles carrying multiple mutations may contribute to the decrease in repeatability at large library sizes.Comment: 31pages, 9 figure

Therapeutic Value of Drugs Granted Accelerated Approval or Conditional Marketing Authorization in the US an Europe From 2007 to 2021

IMPORTANCE: The number of drugs approved through the accelerated approval or conditional marketing authorization pathways has increased with unclear evidence of their therapeutic value. OBJECTIVES: To assess the therapeutic value of drug indications granted accelerated approval in the US or conditional marketing authorization in the European Union (EU) overall and for cancer indications. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used the public databases of the US Food and Drug Administration and the European Medicines Agency to identify all drugs (initial and supplemental indications) granted accelerated approval in the US or conditional marketing authorization (initial indications only) in the EU between January 1, 2007, and December 31, 2021. Therapeutic value ratings were obtained from national health authorities in Germany, France, and Canada. MAIN OUTCOMES AND MEASURES: Descriptive statistics were used to assess the proportion of accelerated approvals and conditional marketing authorizations overall and for cancer vs noncancer indications rated as having high added therapeutic value. RESULTS: The cohort included 146 drug indications (94 first indications, 52 supplemental indications) in the US and 58 (all first indications) in the EU. Most drugs were approved for cancer (122 [83.6%] in the US; 40 [69.0%] in the EU). Therapeutic value ratings were available for 90 drug indications (61.6%) in the US and 56 (96.6%) in the EU. Overall, 35 drug indications granted accelerated approval (38.9%) and 21 granted conditional marketing authorization (37.5%) had high added therapeutic value in the US and EU, respectively, at the time of approval. The proportions of indications rated as having high added therapeutic value were 36.0% (27 of 75) for cancer vs 53.3% (8 of 15) for noncancer indications in the US and 30.8% (12 of 39) for cancer vs 52.9% (9 of 17) for noncancer indications in the EU. CONCLUSIONS AND RELEVANCE: In this cohort study, among new drug indications approved through the accelerated approval or conditional marketing authorization pathways in the US and Europe from 2007 to 2021, 38.9% and 37.5%, respectively, demonstrated high therapeutic value. A substantially lower proportion of cancer indications than noncancer indications were rated as having high therapeutic value. Policy makers and regulators should increase enforcement of timely postapproval study completion for drugs qualifying for these pathways

Effects of Hypohydration on Muscular Performance in Females: An Ongoing Study

Dehydration (~3%) has been shown to negatively affect anaerobic performance. A majority of this research has been conducted using male participants. Like males, females have been shown to underestimate sweat loss, which could lead to insufficient rehydration and thus hypohydration. Additionally, due to differences in thermoregulation, it is possible that females respond to hypohydration differently than males. To date, no research has examined the effects of previous night dehydration on muscular performance in females. PURPOSE: The purpose of this ongoing study was to determine the effects of previous night dehydration on muscular strength, muscular endurance, lower body power, and perceptual measures in resistance trained females. METHODS: Healthy, resistance trained females (n = 7) completed two bouts of resistance exercise, either dehydrated (~3% body weight) (DT) or heat exposed with fluid replacement (HT). Each exercise bout consisted of one rep maximum (1RM) for bench press followed by 5 sets to failure of 75% of 1RM, 1RM for leg press followed by 5 sets to failure of 75% of 1RM, and vertical jump assessment. Participants estimated ratings of perceived exertion (RPE) after each exercise. Session RPE (SRPE) was estimated 5 minutes following completion of the protocol and estimations for feelings of recovery (PRS), perceived readiness to exercise (PR), thirst, and sleep quality were estimated prior to workouts. RESULTS: Analysis revealed a bench press 1RM (p = 0.05) and leg press 1RM (p = 0.03) were significantly lower for DT (bench: 95.0 ± 34.0; leg press: 461.4 ± 141.7) compared to HT (bench: 97.9 ± 34.3; leg press: 500.0 ± 141.0). There was no difference in total reps completed for bench press (p = 0.32) or leg press (p = 0.37) for DT (bench press: 31.0 ± 6.7; leg press: 47.9 ± 21.6) compared to HT (bench press: 31.7 ± 5.0; leg press: 49.6 ± 22.8). There was no significant difference (p = 0.15) for vertical jump height (DT: 17.6 ± 2.2, HT: 18.1 ± 2.6). RPE was not significantly different following bench press (p = 0.5) (DT: 7.1 ± 1.1, HT: 7.1 ± 0.9) or leg press (p = 0.41) (DT: 6.7 ± 0.5, HT: 6.9 ± 1.7). SRPE was significantly higher (p = 0.05) for DT (6.6 ± 0.5) vs HT (5.9 ± 0.7). Significant differences for PRS (p = 0.03) (DT: 5.4 ± 2.2, HT: 7.05 ± 1.3) and PR (p = 0.01) (DT: 3.9 ± 0.9, HT: 2.6 ± 0.5) indicate participants expected impaired performance during DT. Feelings of thirst were significantly higher (p = 0.001) for DT (6.5 ± 2.5) vs HT (2.1 ± 2.3). Estimations of sleep quality were significantly lower (p = 0.05) for DT (4.3 ± 3.3) vs HT (7.2 ± 2.1). CONCLUSION: Even though only preliminary data from a presently ongoing study, the current results suggest that previous night dehydration has a negative influence on both performance and perceptual measures in resistance trained females

Model for the Quasifree Polarization-Transfer Measurements in the (p,n) reaction at 495 MeV

The recent (p,n) polarization transfer experiments at LAMPF are explained in terms of a dropping rho-meson mass in the medium.Comment: 12 pages of text (LATEX), 4 figures (not included, available from the authors). February 199

Plate versus bulk trolley food service in a hospital: comparison of patients’ satisfaction

Objective The aim of this research was to compare plate with bulk trolley food service in hospitals in terms of patient satisfaction. Key factors distinguishing satisfaction with each system would also be identified. Methods A consumer opinion card (n = 180), concentrating on the quality indicators of core foods, was used to measure patient satisfaction and compare two systems of delivery, plate and trolley. Binary logistic regression analysis was used to build a model that would predict food service style on the basis of the food attributes measured. Further investigation used multinomial logistic regression to predict opinion for the assessment of each food attribute within food service style. Results Results showed that the bulk trolley method of food distribution enables all foods to have a more acceptable texture, and for some foods (potato, P = 0.007; poached fish, P = 0.001; and minced beef, P ≤ 0.0005) temperature, and for other foods (broccoli, P ≤ 0.0005; carrots, P ≤ 0.0005; and poached fish, P = 0.001) flavor, than the plate system of delivery, where flavor is associated with bad opinion or dissatisfaction. A model was built indicating patient satisfaction with the two service systems. Conclusion This research confirms that patient satisfaction is enhanced by choice at the point of consumption (trolley system); however, portion size was not the controlling dimension. Temperature and texture were the most important attributes that measure patient satisfaction with food, thus defining the focus for hospital food service managers. To date, a model predicting patient satisfaction with the quality of food as served has not been proposed, and as such this work adds to the body of knowledge in this field. This report brings new information about the service style of dishes for improving the quality of food and thus enhancing patient satisfaction