Atp1a2 and Kcnj9 are candidate genes underlying oxycodone behavioral sensitivity and withdrawal in C57BL/6 substrains.

Opioid use disorder is heritable, yet its genetic etiology is largely unknown. Analysis of addiction model traits in rodents (e.g., opioid behavioral sensitivity and withdrawal) can facilitate genetic and mechanistic discovery. C57BL/6J and C57BL/6NJ substrains have extremely limited genetic diversity, yet can show reliable phenotypic diversity which together, can facilitate gene discovery. The C57BL/6NJ substrain was less sensitive to oxycodone (OXY)-induced locomotor activity compared to the C57BL/6J substrain. Quantitative trait locus (QTL) mapping in an F2 cross identified a distal chromosome 1 QTL explaining 7-12% of the variance in OXY locomotor sensitivity and anxiety-like withdrawal in the elevated plus maze. We identified a second QTL for withdrawal on chromosome 5 near the candidate gene Gabra2 (alpha-2 subunit of GABA-A receptor) explaining 9% of the variance. Next, we generated recombinant lines from an F2 founder spanning the distal chromosome 1 locus (163-181 Mb), captured the QTL for OXY sensitivity and withdrawal, and fine-mapped a 2.45-Mb region (170.16-172.61 Mb). There were five striatal cis-eQTL transcripts in this region (Pcp4l1, Ncstn, Atp1a2, Kcnj9, Igsf9), two of which were confirmed at the protein level (KCNJ9, ATP1A2). Kcnj9, a.k.a., GIRK3, codes for a potassium channel that is a major effector of mu opioid receptor signaling. Atp1a2 codes for a subunit of a Na+/K+ ATPase enzyme that regulates neuronal excitability and shows adaptations following chronic opioid administration. To summarize, we identified genetic sources of opioid behavioral differences in C57BL/6 substrains, two of the most widely and often interchangeably used substrains in opioid addiction research.

Adolescent intermittent alcohol exposure produces strain-specific cross-sensitization to nicotine and other behavioral adaptations in adulthood in C57BL/6J and DBA/2J mice.

Adolescent alcohol exposure is associated with lasting behavioral changes in humans and in mice. Prior work from our laboratory and others have demonstrated that C57BL/6J and DBA/2J mice differ in sensitivity to some effects of acute alcohol exposure during adolescence and adulthood. However, it is unknown if these strains differ in cognitive, anxiety-related, and addiction-related long-term consequences of adolescent intermittent alcohol exposure. This study examined the impact of a previously validated adolescent alcohol exposure paradigm (2-3 g/kg, i.p., every other day PND 30-44) in C57BL/6J and DBA/2J male and female mice on adult fear conditioning, anxiety-related behavior (elevated plus maze), and addiction-related phenotypes including nicotine sensitivity (hypothermia and locomotor depression) and alcohol sensitivity (loss of righting reflex; LORR). Both shared and strain-specific long-term consequences of adolescent alcohol exposure were found. Most notably, we found a strain-specific alcohol-induced increase in sensitivity to nicotine's hypothermic effects during adulthood in the DBA/2J strain but not in the C57BL/6J strain. Conversely, both strains demonstrated a robust increased latency to LORR during adulthood after adolescent alcohol exposure. Thus, we observed strain-dependent cross-sensitization to nicotine and strain-independent tolerance to alcohol due to adolescent alcohol exposure. Several strain and sex differences independent of adolescent alcohol treatment were also observed. These include increased sensitivity to nicotine-induced hypothermia in the C57BL/6J strain relative to the DBA/2J strain, in addition to DBA/2J mice showing more anxiety-like behaviors in the elevated plus maze relative to the C57BL/6J strain. Overall, these results suggest that adolescent alcohol exposure results in altered adult sensitivity to nicotine and alcohol with some phenotypes mediated by genetic background.

Hospital Days Reduced for Moderate and Severe COVID-19 Patients Through a Home Monitoring Program With Oxygen.

While the COVID-19 pandemic continues to strain the healthcare system, it has also expanded telemedicine. There is a subset of hospitalized moderate to severe COVID-19 patients requiring oxygen but no other intervention. This is a retrospective study of patients ≥18 years with moderate to severe COVID-19 that participated in a home monitoring program with supplemental oxygen (HMP-O2) (N = 25). For study outcomes, HMP-O2 participants were compared to patients meeting the same inclusion criteria but did not participate in the program (N = 60). On average, the HMP-O2 patients spent 5.8 days (±5.5 days) in the hospital compared to 8.12 days (±5.5 days) for non-program patients. This resulted in 19% cost-savings for HMP-O2 patients. Lessons learned from this program can be applied to future HMPs for either COVID-19 or other conditions that would benefit from telecare.

James-Stein for the leading eigenvector.

Recent research identifies and corrects bias, such as excess dispersion, in the leading sample eigenvector of a factor-based covariance matrix estimated from a high-dimension low sample size (HL) data set. We show that eigenvector bias can have a substantial impact on variance-minimizing optimization in the HL regime, while bias in estimated eigenvalues may have little effect. We describe a data-driven eigenvector shrinkage estimator in the HL regime called "James-Stein for eigenvectors" (JSE) and its close relationship with the James-Stein (JS) estimator for a collection of averages. We show, both theoretically and with numerical experiments, that, for certain variance-minimizing problems of practical importance, efforts to correct eigenvalues have little value in comparison to the JSE correction of the leading eigenvector. When certain extra information is present, JSE is a consistent estimator of the leading eigenvector.

Interstrain differences in adolescent fear conditioning after acute alcohol exposure.

Adolescent sensitivity to alcohol is a predictor of continued alcohol use and misuse later in life. Thus, it is important to understand the many factors that can impact alcohol sensitivity. Data from our laboratory suggested that susceptibility to alcohol-associated contextual fear learning deficits varied among adolescent and adult mice from two mouse strains. To investigate the extent of genetic background's influences on adolescent learning after alcohol exposure, we examined how 9 inbred mouse strains differed in vulnerability to alcohol-induced contextual and cued fear conditioning deficits. We demonstrated significant strain- and sex-dependent effects of acute alcohol exposure on adolescent fear learning, with alcohol having most pronounced effects on contextual fear learning. Female adolescents were more susceptible than males to alcohol-induced impairments in contextual, but not cued, fear learning, independent of genetic background. Heritability for contextual and cued fear learning after alcohol exposure was estimated to be 31 % and 18 %, respectively. Learning data were compared to Blood Ethanol Concentrations (BEC) to assess whether strain differences in alcohol metabolism contributed to strain differences in learning after alcohol exposure. There were no clear relationships between BEC and learning outcomes, suggesting that strains differed in learning outcomes for reasons other than strain differences in alcohol metabolism. Genetic analyses revealed polymorphisms across strains in notable genes, such as Chrna7, a promising genetic candidate for susceptibility to alcohol-induced fear conditioning deficits. These results are the first to demonstrate the impact of genetic background on alcohol-associated fear learning deficits during adolescence and suggest that the mechanisms underlying this sensitivity are distinct from alcohol metabolism.

A synthesis of pathways linking diet, metabolic risk and cardiovascular disease: a framework to guide further research and approaches to evidence-based practice.

Cardiovascular disease (CVD) is the most common non-communicable disease occurring globally. Although previous literature has provided useful insights into the important role that diet plays in CVD prevention and treatment, understanding the causal role of diets is a difficult task considering inherent and introduced weaknesses of observational (e.g. not properly addressing confounders and mediators) and experimental research designs (e.g. not appropriate or well designed). In this narrative review, we organised current evidence linking diet, as well as conventional and emerging physiological risk factors, with CVD risk, incidence and mortality in a series of diagrams. The diagrams presented can aid causal inference studies as they provide a visual representation of the types of studies underlying the associations between potential risk markers/factors for CVD. This may facilitate the selection of variables to be considered and the creation of analytical models. Evidence depicted in the diagrams was systematically collected from studies included in the British Nutrition Task Force report on diet and CVD and database searches, including Medline and Embase. Although several markers and disorders linked to conventional and emerging risk factors for CVD were identified, the causal link between many remains unknown. There is a need to address the multifactorial nature of CVD and the complex interplay between conventional and emerging risk factors with natural and built environments, while bringing the life course into the spotlight.

Genetic differences in nicotine sensitivity and metabolism in C57BL/6J and NOD/ShiLtJ mouse strains.

Genetic background impacts sensitivity to nicotine's rewarding and aversive effects and metabolism, which influences susceptibility to nicotine addiction. This is important because sensitivity to nicotine influences susceptibility to nicotine addiction. Thus, understanding genetic contribution to nicotine sensitivity can aid in identifying risk factors for nicotine addiction. Genetic variability in addiction phenotypes can be modeled in rodent systems, and comparisons of nicotine sensitivity in inbred mice can identify contributing genetic substrates. Our laboratory has identified differences in nicotine sensitivity in male mice from two inbred mouse strains, C57BL/6J and NOD/ShiLtJ. We found that the NOD/ShiLtJ strain experienced greater nicotine-induced locomotor depression and hypothermia than the C57BL/6J strain. To investigate possible differences in nicotine metabolism between strains, subjects were treated with acute nicotine and serum and urine samples were analyzed using LC-MS/MS to quantify nicotine and metabolites. This analysis revealed that NOD/ShiLtJ mice had similar serum nicotine but lower cotinine and 3'-hydroxycotinine levels after nicotine treatment when compared to C57BL/6J mice. Possible genetic factors mediating strain differences were identified by surveying nicotine sensitivity- and metabolism-related genes within the Mouse Phenome Database SNP retrieval tool. Polymorphisms were found in 15 of the 26 examined gene sequences. Liver expression levels of nicotine metabolism-related genes (Cyp2a5, Cyp2a4, and Aox1) were measured using qPCR. NOD/ShiLtJ mice showed lower expression of Cyp2a5 and Cyp2a4 and greater expression of Aox1 in liver tissue. These data demonstrate complex differences in nicotine sensitivity and metabolism driven by genetic differences between C57BL/6J and NOD/ShiLtJ inbred mouse strains.

Genetic influences impacting nicotine use and abuse during adolescence: Insights from human and rodent studies.

Nicotine use continues to be a major public health concern, with an alarming recent rise in electronic cigarette consumption. Heritability estimates of nicotine use and abuse range from 40% to 80%, providing strong evidence that genetic factors impact nicotine addiction-relevant phenotypes. Although nicotine use during adolescence is a key factor in the development of addiction, it remains unclear how genetic factors impact adolescent nicotine use and abuse. This review will discuss studies investigating genetic factors impacting nicotine use during adolescence. Evidence from both rodent and human studies will be summarized and integrated when possible. Human adolescent studies have largely included candidate gene studies for genes identified in adult populations, such as genes involved in nicotine metabolism, nicotinic acetylcholine receptor signaling, dopaminergic signaling, and other neurotransmitter signaling systems. Alternatively, rodent studies have largely taken a discovery-based approach identifying strain differences in adolescent nicotine addiction-relevant behaviors. Here, we aim to answer the following three questions by integrating human and rodent findings: (1) Are there genetic variants that uniquely impact nicotine use during adolescence? (2) Are there genetic variants that impact both adolescent and adult nicotine use? and (3) Do genetic factors in adolescence significantly impact long-term consequences of adolescent nicotine use? Determining answers for these three questions will be critical for the development of preventative measures and treatments for adolescent nicotine use and addiction.

Pooled microbiological findings and efficacy outcomes by pathogen in adults with community-acquired bacterial pneumonia from the Lefamulin Evaluation Against Pneumonia (LEAP) 1 and LEAP 2 phase 3 trials of lefamulin versus moxifloxacin.

OBJECTIVES: Lefamulin, a pleuromutilin antibiotic approved for community-acquired bacterial pneumonia (CABP), was evaluated for microbiological efficacy in a prespecified pooled analysis of LEAP 1 and 2 phase 3 clinical trial data in patients with CABP. METHODS: In LEAP 1, adults (PORT risk class III‒V) received intravenous (IV) lefamulin 150 mg every 12 h (q12h) for 5‒7 days or moxifloxacin 400 mg every 24 h (q24h) for 7 days, with optional IV-to-oral switch. In LEAP 2, adults (PORT II‒IV) received oral lefamulin 600 mg q12h for 5 days or moxifloxacin 400 mg q24h for 7 days. Primary outcomes were early clinical response (ECR) at 96 ± 24 h after treatment start and investigator assessment of clinical response (IACR) 5‒10 days after the last dose. Secondary outcomes included ECR and IACR in patients with a baseline CABP pathogen (detected via culture, urinary antigen testing, serology and/or real-time PCR). RESULTS: Baseline CABP pathogens were detected in 709/1289 patients (55.0%; microbiological intention-to-treat population). The most frequently identified pathogens were Streptococcus pneumoniae (61.9% of patients) and Haemophilus influenzae (29.9%); 25.1% had atypical pathogens and 33.1% had polymicrobial infections. Pathogens were identified most frequently by PCR from sputum, followed by culture from respiratory specimens. In patients with baseline CABP pathogens, ECR rates were 89.3% (lefamulin) and 93.0% (moxifloxacin); IACR success rates were 83.2% and 86.7%, respectively. Results were consistent across CABP pathogens, including drug-resistant isolates and polymicrobial infections. CONCLUSION: Lefamulin is a valuable IV and oral monotherapy option for empirical and directed CABP treatment in adults.

Empowering Public Health Nurses and Community Home Visitors through Effective Communication Relationships.

Home visiting programs for marginalized families have included both Public Health Nurses (PHNs) and Community Home Visitors (CHV). Support for families requires health care providers to implement effective communication and collaboration practices; however, few studies have examined how this is carried out. The purpose of this qualitative research study was to explore how an Enhanced Home Visiting (EHV) program in Nova Scotia Canada was organized, delivered through the experiences of PHNs and CHVs. Feminist post-structuralism informed by discourse analysis was used to understand how their experiences were socially and institutionally constructed. Individual semi-structured interviews were conducted with 6 PHNs and 8 CHVs and one focus group was held with 10 of the participants. A social discourse on mothering layered within a social discourse of working with a vulnerable population added a deeper understanding of how communication was constructed through the everyday practices of PHNs and CHVs. Findings may be used to inform reporting and communication practices between health care providers who work with marginalized families.

A quantitative trait variant in Gabra2 underlies increased methamphetamine stimulant sensitivity.

Psychostimulant (methamphetamine, cocaine) use disorders have a genetic component that remains mostly unknown. We conducted genome-wide quantitative trait locus (QTL) analysis of methamphetamine stimulant sensitivity. To facilitate gene identification, we employed a Reduced Complexity Cross between closely related C57BL/6 mouse substrains and examined maximum speed and distance traveled over 30 min following methamphetamine (2 mg/kg, i.p.). For maximum methamphetamine-induced speed following the second and third administration, we identified a single genome-wide significant QTL on chromosome 11 that peaked near the Cyfip2 locus (LOD = 3.5, 4.2; peak = 21 cM [36 Mb]). For methamphetamine-induced distance traveled following the first and second administration, we identified a genome-wide significant QTL on chromosome 5 that peaked near a functional intronic indel in Gabra2 coding for the alpha-2 subunit of the GABA-A receptor (LOD = 3.6-5.2; peak = 34-35 cM [66-67 Mb]). Striatal cis-expression QTL mapping corroborated Gabra2 as a functional candidate gene underlying methamphetamine-induced distance traveled. CRISPR/Cas9-mediated correction of the mutant intronic deletion on the C57BL/6J background to the wild-type C57BL/6NJ allele was sufficient to reduce methamphetamine-induced locomotor activity toward the wild-type C57BL/6NJ-like level, thus validating the quantitative trait variant (QTV). These studies show the power and efficiency of Reduced Complexity Crosses in identifying causal variants underlying complex traits. Functionally restoring Gabra2 expression decreased methamphetamine stimulant sensitivity and supports preclinical and human genetic studies implicating the GABA-A receptor in psychostimulant addiction-relevant traits. Importantly, our findings have major implications for studying psychostimulants in the C57BL/6J strain-the gold standard strain in biomedical research.

Terc Gene Cluster Variants Predict Liver Telomere Length in Mice.

Variants in a gene cluster upstream-adjacent to TERC on human chromosome 3, which includes genes APRM, LRRC31, LRRC34 and MYNN, have been associated with telomere length in several human populations. Currently, the mechanism by which variants in the TERC gene cluster influence telomere length in humans is unknown. Given the proximity between the TERC gene cluster and TERC (~0.05 Mb) in humans, it is speculated that cluster variants are in linkage disequilibrium with a TERC causal variant. In mice, the Terc gene/Terc gene cluster are also located on chromosome 3; however, the Terc gene cluster is located distantly downstream of Terc (~60 Mb). Here, we initially aim to investigate the interactions between genotype and nicotine exposure on absolute liver telomere length (aTL) in a panel of eight inbred mouse strains. Although we found no significant impact of nicotine on liver aTL, this first experiment identified candidate single nucleotide polymorphisms (SNPs) in the murine Terc gene cluster (within genes Lrrc31, Lrriq4 and Mynn) co-varying with aTL in our panel. In a second experiment, we tested the association of these Terc gene cluster variants with liver aTL in an independent panel of eight inbred mice selected based on candidate SNP genotype. This supported our initial finding that Terc gene cluster polymorphisms impact aTL in mice, consistent with data in human populations. This provides support for mice as a model for telomere dynamics, especially for studying mechanisms underlying the association between Terc cluster variants and telomere length. Finally, these data suggest that mechanisms independent of linkage disequilibrium between the Terc/TERC gene cluster and the Terc/TERC gene mediate the cluster's regulation of telomere length.

Compassionate Bodies, Compassionate Practice: Navigating Body Image Tensions among Gay Men.

Our purpose in writing this Perspective in Practice is to create awareness about the role of compassion within dietetic practice, particularly the role of compassion for body image tensions. Nine self-identifying gay men were recruited to a photovoice research study that explored their beliefs, values, and practices relating to food and their bodies. Compassion was found as one way to navigate body images tensions. It is not the intent of this article to review all aspects of this research study but to use it as an example to illustrate compassion in dietetics. We suggest that our findings reveal the strength of using compassionate practice within the dietetic profession. In doing so, we call upon dietitians to incorporate compassion into their clinical and client care practices to foster health and healing for all communities, especially among those who struggle with body image tensions.

Lefamulin efficacy and safety in a pooled phase 3 clinical trial population with community-acquired bacterial pneumonia and common clinical comorbidities.

BACKGROUND: Lefamulin, a first-in-class pleuromutilin antibiotic approved for intravenous and oral use in adults with community-acquired bacterial pneumonia (CABP), was noninferior to moxifloxacin in the Lefamulin Evaluation Against Pneumonia (LEAP) 1 intravenous-to-oral switch study and the LEAP 2 oral-only study. Using pooled LEAP 1/2 data, we examined lefamulin efficacy/safety overall and within subgroups of patients presenting with comorbidities typical in CABP management. METHODS: In LEAP 1, adults with CABP were randomized to receive intravenous lefamulin (150 mg every 12 h) for 5‒7 days or moxifloxacin (400 mg every 24 h) for 7 days, with optional intravenous-to-oral switch if predefined improvement criteria were met. In LEAP 2, adults with CABP were randomized to receive oral lefamulin (600 mg every 12 h) for 5 days or moxifloxacin (400 mg every 24 h) for 7 days. Both studies assessed early clinical response (ECR) at 96 ± 24 h after first study drug dose and investigator assessment of clinical response (IACR) at test-of-cure (5‒10 days after last dose). Pooled analyses of the overall population used a 10% noninferiority margin. RESULTS: Lefamulin (n = 646) was noninferior to moxifloxacin (n = 643) for ECR (89.3% vs 90.5%, respectively; difference - 1.1%; 95% CI - 4.4 to 2.2); IACR success rates at test-of-cure were similarly high (≥ 85.0%). High efficacy with both lefamulin and moxifloxacin was also demonstrated across all well-represented patient subgroups, including those with advanced age, diabetes mellitus, a history of cardiovascular diseases (e.g., hypertension, congestive heart failure, or arrhythmia) or chronic lung diseases (e.g., asthma or chronic obstructive pulmonary disease), elevated liver enzymes, or mild-to-moderate renal dysfunction. No new safety signals were identified. CONCLUSIONS: Lefamulin may provide a valuable intravenous/oral monotherapy alternative to fluoroquinolones or macrolides for empiric treatment of patients with CABP, including cases of patients at risk for poor outcomes due to age or various comorbidities. TRIAL REGISTRATION: ClinicalTrials.gov LEAP 1 (NCT02559310; Registration Date: 24/09/2015) and LEAP 2 (NCT02813694; Registration Date: 27/06/2016).

Systems genetic analysis of nicotine withdrawal deficits in hippocampus-dependent learning.

Cognitive deficits, such as disrupted learning, are a major symptom of nicotine withdrawal. These deficits are heritable, yet their genetic basis is largely unknown. Our lab has developed a mouse model of nicotine withdrawal deficits in learning, using chronic nicotine exposure via osmotic minipumps and fear conditioning. Here, we utilized the BXD genetic reference panel to identify genetic variants underlying nicotine withdrawal deficits in learning. Male and female mice (n = 6-11 per sex per strain, 31 strains) received either chronic saline or nicotine (6.3 mg/kg per day for 12 days), and were then tested for hippocampus-dependent learning deficits using contextual fear conditioning. Quantitative trait locus (QTL) mapping analyses using GeneNetwork identified a significant QTL on Chromosome 4 (82.13 Mb, LRS = 20.03, p < 0.05). Publicly available hippocampal gene expression data were used to identify eight positional candidates (Snacpc3, Mysm1, Rps6, Plaa, Lurap1l, Slc24a2, Hacd4, Ptprd) that overlapped with our behavioral QTL and correlated with our behavioral data. Overall, this study demonstrates that genetic factors impact cognitive deficits during nicotine withdrawal in the BXD recombinant inbred panel and identifies candidate genes for future research.

Multigenerational nicotine exposure affects offspring nicotine metabolism, nicotine-induced hypothermia, and basal corticosterone in a sex-dependent manner.

Parental nicotine exposure can impact phenotypes in unexposed offspring. Our laboratory recently published data showing that nicotine reward and hippocampal gene expression involved in stress pathways were perturbed in F1 offspring of male C57BL/6J mice chronically exposed to nicotine. For the current study, we aimed to further test nicotine and stress-sensitivity phenotypes that may predict vulnerability to nicotine addiction in new cohorts of F1 offspring derived from nicotine-exposed males. We tested locomotor and body temperature sensitivity to acute nicotine administration, serum concentration of nicotine and nicotine metabolites after acute nicotine dosing, and serum corticosterone levels in male and female F1 offspring of nicotine- or saline-exposed males. Paternal nicotine exposure reduced sensitivity to nicotine-induced hypothermia in males, altered nicotine metabolite concentrations in males and females, and reduced serum basal corticosterone levels in females. These findings may point to reduced susceptibility to nicotine addiction-related phenotypes as a result of parental nicotine exposure.

Paternal nicotine enhances fear memory, reduces nicotine administration, and alters hippocampal genetic and neural function in offspring.

Nicotine use remains highly prevalent with tobacco and e-cigarette products consumed worldwide. However, increasing evidence of transgenerational epigenetic inheritance suggests that nicotine use may alter behavior and neurobiology in subsequent generations. We tested the effects of chronic paternal nicotine exposure in C57BL6/J mice on fear conditioning in F1 and F2 offspring, as well as conditioned fear extinction and spontaneous recovery, nicotine self-administration, hippocampal cholinergic functioning, RNA expression, and DNA methylation in F1 offspring. Paternal nicotine exposure was associated with enhanced contextual and cued fear conditioning and spontaneous recovery of extinguished fear memories. Further, nicotine reinforcement was reduced in nicotine-sired mice, as assessed in a self-administration paradigm. These behavioral phenotypes were coupled with altered response to nicotine, upregulated hippocampal nicotinic acetylcholine receptor binding, reduced evoked hippocampal cholinergic currents, and altered methylation and expression of hippocampal genes related to neural development and plasticity. Gene expression analysis suggests multigenerational effects on broader gene networks potentially involved in neuroplasticity and mental disorders. The changes in fear conditioning similarly suggest phenotypes analogous to anxiety disorders similar to post-traumatic stress.

Health-Related Quality of Life as Measured by the 12-Item Short-Form Survey Among Adults With Community-Acquired Bacterial Pneumonia who Received Either Lefamulin or Moxifloxacin in 2 Phase III Randomized, Double-Blind, Double-Dummy Clinical Trials.

BACKGROUND: Interest in patient-reported outcomes (PROs) as part of benefit-risk assessment for new drug approvals is increasing. Lefamulin is the first intravenous (IV) and oral pleuromutilin antibiotic for treatment of adults with community-acquired bacterial pneumonia (CABP). Assessment of health-related quality of life (HRQoL) was prospectively incorporated in its CABP trials (Lefamulin Evaluation Against Pneumonia [LEAP] 1 and 2) via the 12-Item Short-Form Survey (SF-12), a widely used PRO that measures general health status in 8 domains. METHODS: HRQoL was evaluated by SF-12 at baseline and test of cure (TOC; 5-10 days after the last study drug dose) in patients who received lefamulin or moxifloxacin in LEAP 1 (IV/oral treatment) and LEAP 2 (oral-only treatment). SF-12 outcomes included the 8 domains, physical component and mental component summary scores, and the Short-Form Six-Dimension health utility score. RESULTS: Analysis included 1215 patients (lefamulin: n = 607; moxifloxacin: n = 608). At baseline, all mean SF-12 scores in both treatment groups were well below the United States reference mean. Clinically meaningful and significant improvements from baseline to TOC were observed in all SF-12 scores. No significant differences in mean score improvements from baseline to TOC between treatment groups were observed. SF-12 score improvements at TOC across predefined subgroups were comparable between treatment groups. CONCLUSIONS: Results indicate that adults with CABP experienced comparable HRQoL improvements with lefamulin relative to moxifloxacin, and treatment with either agent resulted in returns to population norm HRQoL levels. These data suggest that lefamulin is a potential alternative to moxifloxacin for treatment of adults with CABP.

Post Hoc Assessment of Time to Clinical Response Among Adults Hospitalized with Community-Acquired Bacterial Pneumonia Who Received Either Lefamulin or Moxifloxacin in 2 Phase III Randomized, Double-Blind, Double-Dummy Clinical Trials.

Time to clinical response, a proxy for hospital "discharge readiness," was compared between CABP inpatients who received lefamulin or moxifloxacin in the Lefamulin Evaluation Against Pneumonia (LEAP) trials. The analysis included 926 inpatients. A short and comparable median time to clinical response (4 days) was observed in both treatment groups.