Search

Background Coronavirus disease 2019 (COVID-19) remains a major public health concern, with continued resurgences of cases and substantial risk of mortality for hospitalized patients. Remdesivir has become standard-of-care for hospitalized COVID-19 patients. Given the continued evolution of the disease, clinical management of COVID-19 relies on evidence from the current endemic period. Methods Using the PINC AI Healthcare Database, remdesivir effectiveness was evaluated among adults hospitalized with primary diagnosis of COVID-19 between December 2021 and February 2024. Three cohorts were analyzed: adults (≥18 years), elderly (≥65 years), and those with documented COVID-19 pneumonia. Analyses were stratified by oxygen requirements. Patients who received remdesivir were matched to those who did not receive remdesivir using propensity score matching. Cox proportional hazards models were used to examine in-hospital mortality. Results 169 965 adults hospitalized for COVID-19 were included, of whom 94 129 (55.4%) initiated remdesivir in the first 2 days of hospitalization. Remdesivir was associated with significantly lower mortality rate compared to no remdesivir among patients with no supplemental oxygen charges (adjusted HR [95% CI]: 14-day, 0.75 [.69–.82]; 28-day, 0.77 [.72–.83]) and those requiring supplemental oxygen: 14-day, 0.76 [.72–.81]; 28-day, 0.79 [.74–.83]; P <.0001 for all). Similar findings were observed for elderly patients and those hospitalized with COVID-19 pneumonia. Conclusions This evidence builds on what has been learned from randomized controlled trials from the pandemic era to inform clinical practices. Remdesivir was associated with significant reduction in mortality for hospitalized patients including the elderly and those with COVID-19 pneumonia. [ABSTRACT FROM AUTHOR]

This study examines the possibility that interaction through social network platforms can serve as an informal means of developing intercultural competence among international students in higher education settings. Japanese students studying in the United States at a university in the Northwestern US were invited to participate in a mixed-method study involving interviews about their social network use and interactions, and a structured questionnaire measure of intercultural competence development. Overall, the results indicate that those in the top tertile of intercultural competence development tended to describe more proactive social ways and benefits of interacting with potential sources of support over social media, whereas those in the bottom tertile tended to describe the importance and use of social media for passive consumption of information. The implications for the incorporation of social network platforms into higher-education programs for internationalisation and intercultural competence development are discussed.

Background Ceftriaxone-resistant (CRO-R) Escherichia coli bloodstream infections (BSIs) are common. Methods This is a prospective cohort of patients with E coli BSI at 14 United States hospitals between November 2020 and April 2021. For each patient with a CRO-R E coli BSI enrolled, the next consecutive patient with a ceftriaxone-susceptible (CRO-S) E coli BSI was included. Primary outcome was desirability of outcome ranking (DOOR) at day 30, with 50% probability of worse outcomes in the CRO-R group as the null hypothesis. Inverse probability weighting (IPW) was used to reduce confounding. Results Notable differences between patients infected with CRO-R and CRO-S E coli BSI included the proportion with Pitt bacteremia score ≥4 (23% vs 15%, P =.079) and the median time to active antibiotic therapy (12 hours [interquartile range {IQR}, 1–35 hours] vs 1 hour [IQR, 0–6 hours]; P <.001). Unadjusted DOOR analyses indicated a 58% probability (95% confidence interval [CI], 52%–63%) for a worse clinical outcome in CRO-R versus CRO-S BSI. In the IPW-adjusted cohort, no difference was observed (54% [95% CI, 47%–61%]). Secondary outcomes included unadjusted and adjusted differences in the proportion of 30-day mortality between CRO-R and CRO-S BSIs (−5.3% [95% CI, −10.3% to −.4%] and −1.8 [95% CI, −6.7% to 3.2%], respectively), postculture median length of stay (8 days [IQR, 5–13 days] vs 6 days [IQR, 4–9 days]; P <.001), and incident admission to a long-term care facility (22% vs 12%, P =.045). Conclusions Patients with CRO-R E coli BSI generally have poorer outcomes compared to patients infected with CRO-S E coli BSI, even after adjusting for important confounders. [ABSTRACT FROM AUTHOR]

Background: Pseudomonas aeruginosa (PA) is a common cause of respiratory infection and morbidity. Pseudomonas elastase is an important virulence factor regulated by the lasR gene. Whether PA elastase activity is associated with worse clinical outcomes in ICU patients is unknown.Research Question: Is there an association between PA elastase activity and worse host outcomes in a cohort of ICU patients?Methods: PA respiratory isolates from 238 unique ICU patients from two tertiary-care centers within the University of Pittsburgh Medical Center health system were prospectively collected and screened for total protease and elastase activity, biofilm production, antimicrobial resistance, and polymicrobial status. The association between pathogen characteristics and 30-day and 90-day mortality was calculated using logistic regression. For subgroup analysis, two patterns of early (≤72 h) and late sample (>72 h) collection from the index ICU admission were distinguished using a finite mixture model. Lung inflammation and injury was evaluated in a mouse model using a PA high elastase vs low elastase producer.Results: PA elastase activity was common in ICU respiratory isolates representing 75% of samples and was associated with increased 30-day mortality (adjusted OR [95% CI]: 1.39 [1.05-1.83]). Subgroup analysis demonstrated that elastase activity was a risk factor for 30- and 90-day mortality in the early sample group, whereas antimicrobial resistance was a risk factor for 90-day mortality in the late sample group. Whole genome sequencing of high and low elastase producers showed that predicted loss-of-function lasR genotypes were less common among high elastase producers. Mice infected with a high elastase producer showed increased lung bacterial burden and inflammatory profile compared with mice infected with a low elastase producer.Interpretation: Elastase activity is associated with 30-day ICU mortality. A high elastase producing clinical isolate confers increased lung tissue inflammation compared with a low elastase producer in vivo. [ABSTRACT FROM AUTHOR]

Background: Overuse of antibiotics is a major public health problem, contributing to growing antibiotic resistance. Procalcitonin has been reported to be commonly elevated in bacterial, but not viral infection. Multiple European trials found procalcitonin-guided care reduced antibiotic use in lower respiratory tract infection, with no apparent harm. However, applicability to US practice is limited due to trial design features impractical in the US, between-country differences, and residual safety concerns.Methods: The Procalcitonin Antibiotic Consensus Trial (ProACT) is a multicenter randomized trial to determine the impact of a procalcitonin antibiotic prescribing guideline, implemented with basic reproducible strategies, in US patients with lower respiratory tract infection.Discussion: We describe the trial methods using the Consolidated Standards of Reporting Trials (CONSORT) framework, and the rationale for key design decisions, including choice of eligibility criteria, choice of control arm, and approach to guideline implementation.Trial Registration: ClinicalTrials.gov NCT02130986 . Registered May 1, 2014. [ABSTRACT FROM AUTHOR]

Background: The number of diabetes patients is steadily increasing worldwide. Consequently, the social burden of diabetes is huge, requiring urgent countermeasures. We performed an intensive survey of antidiabetic drugs approved in Japan, the United States, and the European Union. Methods: Information about approved antidiabetic drugs was obtained by searching databases of regulatory authorities in the 3 regions. Other relevant information was also obtained from publicly available literature and documents. Results: No difference in the total number and types of approved drugs among the 3 regions was found (P =.173 by log-rank test). However, the numbers of approved dipeptidyl peptidase-4 and sodium-glucose cotransporter 2 inhibitors in Japan were almost double of those in the other regions. The average sample size in clinical trials used for antidiabetic drug approval in Japan (1134 patients) was much smaller than that in the other regions (P <.001 by analysis of variance repeated measures test adjusted by the Holm method). Currently, 6 drugs with known modes of action are being developed for type 1 diabetes in Japan, whereas at the end of 2016, nearly 7-fold more products with novel modes of action were in clinical development in the United States. Conclusion: Antidiabetic drug development in Japan costs less than that in the other regions, although novel development is less active because of regulatory differences. To achieve better pharmacotherapy for diabetes, the regulatory framework requires careful consideration. [ABSTRACT FROM AUTHOR]

Background: Trifluridine/tipiracil showed activity and was well tolerated in a phase 2 study of pretreated patients with advanced gastric cancer done in Japan. We investigated whether the treatment was efficacious compared with placebo in a global population.Methods: TAGS was a randomised, double-blind, placebo-controlled, phase 3 trial done in 110 academic hospitals in 17 countries. Patients aged 18 years or older with histologically confirmed, non-resectable, metastatic gastric adenocarcinoma (including adenocarcinoma of the gastroesophageal junction) as defined by the American Joint Committee on Cancer staging classification (7th edition) who had received at least two previous chemotherapy regimens and had experienced radiological disease progression were eligible for inclusion. Patients were randomly assigned (2:1) via dynamic randomisation from a centralised interactive voice-response system to receive either oral trifluridine/tipiracil (35 mg/m2 twice daily on days 1-5 and days 8-12 every 28 days) plus best supportive care or placebo plus best supportive care. Participants were allocated to groups by study-site personnel. Randomisation was stratified by region (Japan vs rest of world), ECOG performance status (0 vs 1), and previous treatment with ramucirumab (yes vs no). Both patients and investigators were masked to treatment allocation. The primary endpoint was overall survival. Efficacy was assessed in the intention-to-treat population and safety in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT02500043. The trial, including follow-up of all participants, has been completed.Findings: Between Feb 24, 2016, and Jan 5, 2018, 507 patients were enrolled and randomly assigned, 337 to the trifluridine/tipiracil group and 170 to the placebo group. Median overall survival was 5·7 months (95% CI 4·8-6·2) in the trifluridine/tipiracil group and 3·6 months (3·1-4·1) in the placebo group (hazard ratio 0·69 [95% CI 0·56-0·85]; one-sided p=0·00029, two-sided p=0·00058). Grade 3 or worse adverse events of any cause occurred in 267 (80%) patients in the trifluridine/tipiracil group and 97 (58%) in the placebo group. The most frequent grade 3 or worse adverse events of any cause were neutropenia (n=114 [34%]) and anaemia (n=64 [19%]) in the trifluridine/tipiracil group and abdominal pain (n=15 [9%]) and general deterioration of physical health (n=15 [9%]) in the placebo group. Serious adverse events of any cause were reported in 143 (43%) patients in the trifluridine/tipiracil group and 70 (42%) in the placebo group. One treatment-related death was reported in each group (because of cardiopulmonary arrest in the trifluridine/tipiracil group and because of toxic hepatitis in the placebo group).Interpretation: Trifluridine/tipiracil significantly improved overall survival compared with placebo and was well tolerated in this heavily pretreated population of patients with advanced gastric cancer. Trifluridine/tipiracil could be a new treatment option in this population who represent a high unmet medical need.Funding: Taiho Oncology and Taiho Pharmaceutical. [ABSTRACT FROM AUTHOR]

Background: Serum creatinine (SCr) levels are decreased following traumatic amputation, leading to the overestimation of glomerular filtration rate (GFR). β-Trace protein (BTP) and β2-microglobulin (B2M) strongly correlate with measured GFR and have not been studied following amputation. We hypothesized that BTP and B2M would be unaffected by traumatic amputation.Methods: We used the Department of Defense Serum Repository to compare pre- and post-traumatic amputation serum BTP and B2M levels in 33 male soldiers, via the N Latex BTP and B2M nephelometric assays (Siemens Diagnostics, Tarrytown, N.Y., USA). Osterkamp estimation using DEXA scan measurements was used to establish percent estimated body weight loss (%EBWL). Results were analyzed for small (3-5.9% EBWL), medium (6-13.5%), and large (>13.5%) amputation subgroups; and for a control group matched 1:1 to the 12 large amputation subjects. Paired Student's t test was used for comparisons.Results: Mean serum BTP levels were unchanged in controls, all amputees, and the small and medium amputation subgroups. BTP appeared to decrease following large %EBWL amputation (p = 0.05). Mean serum B2M levels were unchanged in controls, all amputees, and the small and medium amputation subgroups. B2M appeared to increase following large %EBWL amputation (p = 0.05).Conclusions: BTP and B2M levels are less affected than SCr by amputation, and should be considered for future study of GFR estimation. BTP and B2M changes following large %EBWL amputation require validation and may offer insight into non-GFR BTP and B2M determinants as well as increased cardiovascular disease and mortality following amputation. [ABSTRACT FROM AUTHOR]

During 2009 and 2010, an observational study in US hospitals found that a substantial portion community-onset, ESBL-producing E. coli infections now occur among patients without discernible healthcare-associated risk factors. This epidemiologic shift has implications for the empiric management of community-associated infection when involvement of E. coli is suspected. Background. The occurrence of community-associated infections due to extended-spectrum β-lactamase (ESBL)–producing Escherichia coli has been recognized as a major clinical problem in Europe and other regions.Methods. We conducted a prospective observational study to examine the occurrence of community-associated infections due to ESBL-producing E. coli at centers in the United States. Five academic and community hospitals and their affiliated clinics participated in this study in 2009 and 2010. Sites of acquisition of the organisms (community-associated or healthcare-associated), risk factors, and clinical outcome were investigated. Screening for the global epidemic sequence type (ST) 131 and determination of the ESBL types was conducted by polymerase chain reaction and sequencing.Results. Of the 291 patients infected or colonized with ESBL-producing E. coli as outpatients or within 48 hours of hospitalization, 107 (36.8%) had community-associated infection (81.5% of which represented urinary tract infection), while the remainder had healthcare-associated infection. Independent risk factors for healthcare-associated infection over community-associated infection were the presence of cardiovascular disease, chronic renal failure, dementia, solid organ malignancy, and hospitalization within the previous 12 months. Of the community-associated infections, 54.2% were caused by the globally epidemic ST131 strain, and 91.3% of the isolates produced CTX-M–type ESBL.Conclusions. A substantial portion of community-onset, ESBL-producing E. coli infections now occur among patients without discernible healthcare-associated risk factors in the United States. This epidemiologic shift has implications for the empiric management of community-associated infection when involvement of E. coli is suspected. [ABSTRACT FROM PUBLISHER]

Background: Population-level mortality indicators can be useful outcome measures of diabetes care. Death registration systems serve as the main source of data for such measures. However, standard mortality indicators based on underlying causes do not adequately reflect the burden from diabetic renal disease. Methods: This article presents findings from analysis of multiple causes of death available from death registration data for Australia and USA. Both countries use an automated system that applies prescribed rules to select and code the underlying cause for each registered death. Deaths with diabetes as underlying cause were grouped according to their diabetic complications as defined by the International Classification of Diseases. Age-standardized mortality rates were calculated for the underlying cause rubric ‘diabetes with renal complications’. These were contrasted with rates calculated using additional deaths where diabetes was the underlying cause and renal failure was listed as a consequence. Results: These analyses identified that current automated programmes code three-fourths of all diabetes deaths to ‘diabetes without complications’, despite additional factors being listed. Estimated multiple cause death rates from diabetic renal disease are four to nine times higher than underlying cause rates for ‘diabetes with renal complications’ in both countries; and show a rising trend in contrast to the latter. Conclusion: These findings indicate that routine underlying cause statistics for USA and Australia grossly under estimate mortality from diabetic renal disease. Clear guidelines on the certification, coding and statistical presentation of diabetes mortality are needed for epidemiology and health policy. [ABSTRACT FROM AUTHOR]

Hypernuclear spectroscopy with electron beam at JLab Hall C has been studied since 2000. The first experiment, JLab E89-009, demonstrated the possibility of the (e, e′ K+) reaction for hypernuclear spectroscopy by achieving an energy resolution of better than 1 MeV (FWHM). The second experiment, JLab E01-011 employed a newly constructed high resolution kaon spectrometer and introduced a vertically tilted electron arm setup to avoid electrons from bremsstrahlung and Moeller scattering. The setup allowed us to have 10 times yield rate and 4 times better signal to accidental ratio with expected energy resolution of 400 keV (FWHM). The third experiment, JLab E05-115 will be performed in 2009 with employing newly constructed high resolution electron spectrometer and a new charge-separation magnet. With the fully customized third generation experimental setup, we can study a variety of targets up to medium-heavy ones such as 52Cr. [ABSTRACT FROM AUTHOR]

Background aims. Pancreatic cancer, sometimes called a ‘silent killer’, is one of the most aggressive human malignancies, with a very poor prognosis. It is the fourth leading cause of cancer-related morbidity and mortality in the USA. Methods. A mouse peritoneal model was used to test the ability of unengineered rat umbilical cord matrix-derived stem cells (UCMSC) to control growth of pancreatic cancer. In vivo results were supported by various in vitro assays, such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), direct cell count, [3H]thymidine uptake and soft agar colony assays. Results. Co-culture of rat UCMSC with PAN02 murine pancreatic carcinoma cells (UCMSC:PAN02, 1:6 and 1:3) caused G0/G1 arrest and significantly attenuated the proliferation of PAN02 tumor cells, as monitored by MTT assay, direct cell counts and [3H]thymidine uptake assay. Rat UCMSC also significantly reduced PAN02 colony size and number, as measured by soft agar colony assay. The in vivo mouse studies showed that rat UCMSC treatment significantly decreased the peritoneal PAN02 tumor burden 3 weeks after tumor transplantation and increased mouse survival time. Histologic study revealed that intraperitoneally administered rat UCMSC survived for at least 3 weeks, and the majority were found near or inside the tumor. Conclusions. These results indicate that naive rat UCMSC alone remarkably attenuate the growth of pancreatic carcinoma cells in vitro and in a mouse peritoneal model. This implies that UCMSC could be a potential tool for targeted cytotherapy for pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background. Knowledge of the clinical features of infections caused by Escherichia coli strains that produce plasmid-mediated AmpC β-lactamase is limited. Of the several groups of plasmid-mediated AmpC β-lactamases, CMY-type β-lactamase is the most common in the United States. Methods. We prospectively identified patients infected or colonized with E. coli strains that produce CMY-type β-lactamase, and we collected clinical data over a 7-month period. A retrospective cohort study was performed to identify features associated with these cases. Patients with extended-spectrum β-lactamase-producing E. coli were used as a control group. Pulsed-field gel electrophoresis, plasmid analysis, and phylogenetic typing were performed. Results. Twenty-two patients with infection or colonization due to CMY-type β-lactamase-producing E. coli and 25 patients with infection or colonization due to extended-spectrum β-lactamase-producing E. coli were identified. The demographic characteristics of the patients were similar in both cohorts. Patients with CMY-type β-lactamase-producing E. coli were significantly more likely to have symptomatic infection than were patients with extended-spectrum β-lactamase-producing E. coli (Pp.028). The CMY-type β-lactamase was identified as CMY-2 or its variants. Ninety-four percent of the CMY-type β-lactamase-producing isolates belonged to E. coli phylogenetic groups B2 and D, which are associated with virulence. Many of the isolates shared similar plasmid profiles, whereas the pulsed-field gel electrophoresis profiles were diverse. Co-resistance to non-β-lactam antimicrobials was common. Conclusion. In Pittsburgh, Pennsylvania, CMY-type β-lactamase-producing E. coli strains are almost as common as extended-spectrum β-lactamase-producing E. coli strains, and they cause symptomatic infection in the majority of cases. [ABSTRACT FROM AUTHOR]

Chemically induced renal neoplasms in male rats, developed coincident with α2u-globulin nephropathy, are not considered predictive of risk to humans by the International Agency for Research on Cancer (IARC) and the U.S. Environmental Protection Agency. Criteria have been defined to establish the role of α2u-globulin nephropathy in renal carcinogenesis, based on a proposed mode of action involving sustained tubular cell proliferation resulting from α2u-induced nephropathy, with consequent development of neoplastic lesions. Recent NTP studies demonstrated inconsistencies with this proposed mechanism, including in some cases, far weaker kidney tumor responses than expected based on the extent of α2u-globulin nephropathy. NTP studies with decalin, propylene glycol mono-t-butyl ether and Stoddard solvent IIC included extended evaluations of α2u-related nephropathy, and were thus used in assessing the linkage between key events in 90-day studies with renal tumors in 2-year studies. This review revealed no or at best weak associations of tumor responses with renal α2u-globulin concentrations, indices of cell turnover, or microscopic evidence of α2u-associated nephropathy in prechronic studies. While tumor responses corresponded somewhat with a measure of cumulative α2u-associated nephropathy (linear mineralization of the papilla) at the end of the 2-year studies, the severity of chronic nephropathy was generally in best agreement with the pattern of tumor response. These results suggest that while α2u-globulin nephropathy may contribute to the renal tumor response, the critical component(s) of the nephropathy most closely associated with the development of tumors could not be clearly identified in this review. [ABSTRACT FROM AUTHOR]

BACKGROUND: The expected ratio of male to female births is generally believed to be 1.05, also described as the male proportion of 0.515. OBJECTIVES: We describe trends in sex ratio at birth and in fetal deaths in the United States, in African Americans and in whites, and in Japan, two industrial countries with well-characterized health data infrastructures, and we speculate about possible explanations. METHODS: Public health records from national statistical agencies were assembled to create information on sex ratio at birth and in fetal deaths in the United States (1970-2002) and Japan (1970-1999), using SPSS. RESULTS: Sex ratio at birth has declined significantly in Japan and in U.S. whites, but not for African Americans, for whom sex ratio remains significantly lower than that of whites. The male proportion of fetal death has increased overall in Japan and in the United States. CONCLUSIONS: Sex ratio declines are equivalent to a shift from male to female births of 135,000 white males in the United States and 127,000 males in Japan. Known and hypothesized risk factors for reduced sex ratio at birth and in fetal deaths cannot account fully for recent trends or racial or national differences. Whether avoidable environmental or other factors--such as widespread exposure to metalloestrogens or other known or suspected endocrine-disrupting materials, changes in parental age, obesity, assisted reproduction, or nutrition--may account for some of these patterns is a matter that merits serious concern. [ABSTRACT FROM AUTHOR]

We analyze the economic impacts of industrial organizational struggles on the international liner shipping market. Operating ratios of different markets are discussed by incorporating rate, service level, and other variables into a standard microeconomic model. If two different carriers agree on a shipping conference price and/or share a strategic alliance service level, and maximize consolidated profit, a member carrier finds it easier to make its operation profitable than the individual profit optimization case; other carriers are worse off in becoming profitable. If the carriers face inelastic demand, the price continues rising until demand becomes elastic enough for the equilibrium to be relevant. The conference is expected to play a coordination role so that the market does not become unsustainable in the adjustment process to reach equilibrium. [ABSTRACT FROM AUTHOR]

Concurrent relationships among measures of naming speed, phonological awareness, orthographic skill, and other reading subskills were explored in a representative sample of second graders. Hierarchical regression analyses revealed that naming speed, as measured by the the rapid automatized naming (RAN) task, accounted for a sizable amount of unique variance in reading with vocabulary and phonemic awareness partialled out. The unique contribution of naming speed to reading was relatively stronger for orthographic skills, whereas the contribution of phonemic skills was stronger for nonword decoding. In further analyses, marked difficulties on a range of reading tasks, including orthographic processing, were seen in a subgroup with a double deficit (slow naming speed and low phonemic awareness) but not in groups with only a single deficit. These findings are broadly consistent with Bowers and Wolf's (1993a, 1993b; Wolf & Bowers, 1999) double-deficit hypothesis of reading disability. [ABSTRACT FROM AUTHOR]

Examines the relationship between rapid automatic naming (RAN) and reading achievement of elementary school children in Los Angeles, California. Effect of RAN, verbal ability and phonological awareness on phonological and orthographic skills; Interrelations among RAN, Sound Deletion and reading components; Value of RAN in predicting reading acquisition.

This paper addresses the relation between firm size and R&D activity for Japanese large manufacturing firms using patents granted in the U.S.. Japanese firms loom larger in world R&D agenda; therefore, the examination of the determinants of their R&D activity, in particular, the effects of firm size, may provide a suggestion of R&D activity. The firm size-patent count relationship varies across industry. In many industries, Japanese experience is not in favor of the assertion that there is a return to scale in R&D among large firms, indicating that Schumpeterian entrepreneurship is not likely to take place more than proportionately to firm size. This conclusion is not inconsistent with Schumpeter's theory. [ABSTRACT FROM AUTHOR]

Background Knowledge of whether Enterobacterales are not susceptible to ceftriaxone without understanding the underlying resistance mechanisms may not be sufficient to direct appropriate treatment decisions. As an example, extended-spectrum β-lactamase (ESBL)–producing organisms almost uniformly display nonsusceptibility to ceftriaxone. Regardless of susceptibility to piperacillin-tazobactam or cefepime, carbapenem antibiotics are the treatment of choice for invasive infections. No such guidance exists for ceftriaxone-nonsusceptible organisms with mechanisms other than ESBL production. We sought to investigate the molecular epidemiology of ceftriaxone-nonsusceptible Enterobacterales. Methods All consecutive Escherichia coli , Klebsiella pneumoniae , Klebsiella oxytoca , or Proteus mirabilis clinical isolates with ceftriaxone minimum inhibitory concentrations (MICs) of ≥2 mcg/mL from unique patients at a United States hospital over an 8-month period were evaluated for β-lactamase genes using a DNA microarray–based assay. Results Of 1929 isolates, 482 (25%) had ceftriaxone MICs of ≥2 mcg/mL and were not resistant to any carbapenem antibiotics. Of the 482 isolates, ESBL (bla CTX-M, bla SHV, bla TEM) and/or plasmid-mediated ampC (p- ampC) genes were identified in 376 (78%). ESBL genes were identified in 310 (82.4%), p- ampC genes in 2 (0.5%), and both ESBL and p- ampC genes in 64 (17.0%) of the 376 organisms. There were 211 (56%), 120 (32%), 41 (11%), and 4 (1%) isolates with 1, 2, 3, or ≥4 ESBL or p- ampC genes. The most common ESBL genes were of the bla CTX-M-1 group (includes bla CTX-M-15), and the most common p- ampC gene was bla CMY-2. Conclusions There is considerable diversity in the molecular epidemiology of ceftriaxone-nonsusceptible Enterobacterales. An understanding of this diversity can improve antibiotic decision-making. [ABSTRACT FROM AUTHOR]

Abstract: Since the 1st generation experiment, E89-009, which was successfully carried out as a pilot experiment of (e,e''K+) hypernuclear spectroscopy at JLab Hall C in 2000, precision hypernuclear spectroscopy by the (e,e''K+) reactions made considerable progress. It has evolved to the 2nd generation experiment, E01-011, in which a newly constructed high resolution kaon spectrometer (HKS) was installed and the “Tilt method” was adopted in order to suppress large electromagnetic background and to run with high luminosity. Preliminary high-resolution spectra of 7 ΛHe and 28 ΛAl together with that of 12 ΛB that achieved resolution better than 500 keV(FWHM) were obtained. The third generation experiment, E05-115, has completed data taking with an experimental setup combining a new splitter magnet, high resolution electron spectrometer (HES) and the HKS used in the 2nd generation experiment. The data were accumulated with targets of 7Li, 9Be, 10B, 12C and 52Cr as well as with those of CH2 and H2O for calibration. The analysis is under way with particular emphasis of determining precision absolute hypernuclear masses. In this article, hypernuclear spectroscopy program in the wide mass range at JLab Hall C that has undergone three generation is described. [Copyright &y& Elsevier]

Background: Carbapenem-resistant Enterobacterales (CRE) are a global threat. We aimed to describe the clinical and molecular characteristics of Centers for Disease Control and Prevention (CDC)-defined CRE in the USA.Methods: CRACKLE-2 is a prospective, multicentre, cohort study. Patients hospitalised in 49 US hospitals, with clinical cultures positive for CDC-defined CRE between April 30, 2016, and Aug 31, 2017, were included. There was no age exclusion. The primary outcome was desirability of outcome ranking (DOOR) at 30 days after index culture. Clinical data and bacteria were collected, and whole genome sequencing was done. This trial is registered with ClinicalTrials.gov, number NCT03646227.Findings: 1040 patients with unique isolates were included, 449 (43%) with infection and 591 (57%) with colonisation. The CDC-defined CRE admission rate was 57 per 100 000 admissions (95% CI 45-71). Three subsets of CDC-defined CRE were identified: carbapenemase-producing Enterobacterales (618 [59%] of 1040), non-carbapenemase-producing Enterobacterales (194 [19%]), and unconfirmed CRE (228 [22%]; initially reported as CRE, but susceptible to carbapenems in two central laboratories). Klebsiella pneumoniae carbapenemase-producing clonal group 258 K pneumoniae was the most common carbapenemase-producing Enterobacterales. In 449 patients with CDC-defined CRE infections, DOOR outcomes were not significantly different in patients with carbapenemase-producing Enterobacterales, non-carbapenemase-producing Enterobacterales, and unconfirmed CRE. At 30 days 107 (24%, 95% CI 20-28) of these patients had died.Interpretation: Among patients with CDC-defined CRE, similar outcomes were observed among three subgroups, including the novel unconfirmed CRE group. CDC-defined CRE represent diverse bacteria, whose spread might not respond to interventions directed to carbapenemase-producing Enterobacterales.Funding: National Institutes of Health. [ABSTRACT FROM AUTHOR]

Background: Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanised anti-HER2 antibody, cleavable peptide-based linker, and topoisomerase I inhibitor payload. A phase 1, non-randomised, open-label, multiple-dose study was done to assess the safety, tolerability, and activity of trastuzumab deruxtecan in HER2-expressing advanced solid tumours. The dose escalation (part 1) has previously been reported and the recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg were established. In this Article, we report the safety and preliminary activity results from this phase 1 trial in all patients with HER2-positive gastric or gastro-oesophageal junction cancer who received trastuzumab deruxtecan at the recommended doses for expansion.Methods: This was an open-label, dose-escalation and dose-expansion phase 1 trial done at eight hospitals and clinics in the USA and six in Japan. Eligible patients were at least 18 years old in the USA and at least 20 years old in Japan and had advanced solid tumours (regardless of HER2 expression in dose escalation or HER2 expression or mutation in dose expansion). The recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg trastuzumab deruxtecan were administered intravenously to patients once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. In this Article, all patients with HER2-positive gastric or gastro-oesophageal junction cancer with previous trastuzumab treatment who received trastuzumab deruxtecan were analysed together. The primary endpoints of the study were safety and preliminary activity (proportion of patients who achieved an objective response as assessed by the investigators). The activity evaluable set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion, and for whom both baseline and post-treatment activity data were available. The safety analysis set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. Enrolment for patients with gastric or gastro-oesophageal junction cancer has completed. This trial is registered at ClinicalTrials.gov, number NCT02564900, and ClinicalTrials.jp, number JapicCTI-152978.Findings: Between Aug 28, 2015, and Aug 10, 2018, 44 patients with HER2-positive gastric or gastro-oesophageal junction cancer received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. All patients had at least one treatment-emergent adverse event. The most frequent grade 3 or worse treatment-emergent adverse events included anaemia (13 [30%]) and decreases in neutrophil (nine [20%]), platelet (eight [18%]), and white blood cell (seven [16%]) counts. Serious treatment-emergent adverse events occurred in 11 (25%) patients. There were four pneumonitis cases (three grade 2 and one grade 3). There were no drug-related deaths due to treatment-emergent adverse events. 19 (43·2%; 95% CI 28·3-59·0) of 44 patients had a confirmed objective response.Interpretation: Trastuzumab deruxtecan had a manageable safety profile and showed preliminary activity in heavily pretreated patients with HER2-positive gastric or gastro-oesophageal junction cancer. These results support further investigation of trastuzumab deruxtecan for HER2-positive gastric or gastro-oesophageal junction cancer post-trastuzumab.Funding: Daiichi Sankyo Co, Ltd. [ABSTRACT FROM AUTHOR]

Background: Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanised anti-HER2 antibody, cleavable peptide-based linker, and potent topoisomerase I inhibitor payload. A phase 1, non-randomised, open-label, multiple-dose study was done to assess the safety, tolerability, and activity of trastuzumab deruxtecan in HER2-expressing, advanced solid tumours. The dose escalation (part 1) has previously been reported and the recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg were established. In this Article, we report the safety and preliminary activity results from this phase 1 trial in all patients with HER2-positive advanced-stage breast cancer with previous trastuzumab emtansine treatment who received trastuzumab deruxtecan at the recommended doses for expansion.Methods: We did an open-label, dose-escalation and dose-expansion phase 1 trial at eight hospitals and clinics in the USA and six in Japan. Eligible patients were at least 18 years old in the USA and at least 20 years of age in Japan and had advanced solid tumours (regardless of HER2 expression in dose escalation or HER2 expression or mutation in dose expansion). The recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg trastuzumab deruxtecan were administered intravenously to patients once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. In this Article, all patients with HER2-positive advanced-stage breast cancer with previous trastuzumab emtansine treatment who received trastuzumab deruxtecan at the recommended doses for expansion were analysed together. The primary endpoints of the study were safety and preliminary activity (proportion of patients who achieved an objective response as assessed by the investigators). The activity evaluable set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion, and for whom both baseline and post-treatment activity data were available. The safety analysis set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. Enrolment for patients with HER2-positive breast cancer has been completed. This trial is registered at ClinicalTrials.gov, number NCT02564900, and ClinicalTrials.jp, number JapicCTI-152978.Findings: Between Aug 28, 2015, and Aug 10, 2018, 115 of 118 patients with HER2-positive breast cancer were treated with at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. All patients had at least one treatment-emergent adverse event. Frequent grade 3 or worse treatment-emergent adverse events included anaemia (19 [17%] of 115) and decreased neutrophil (16 [14%]), white blood cell (ten [9%]), and platelet (nine [8%]) counts. At least one serious treatment-emergent adverse event occurred for 22 (19%) patients. Investigators reported 20 cases of interstitial lung disease, pneumonitis, or organising pneumonia, including one grade 3 event and two treatment-related deaths due to pneumonitis. One death unrelated to study treatment was due to progressive disease. 66 (59·5%; 95% CI 49·7-68·7) of 111 patients had a confirmed objective response.Interpretation: Trastuzumab deruxtecan had a manageable safety profile and showed preliminary activity in trastuzumab emtansine-pretreated patients with HER2-positive breast cancer. These results suggest that further development in phase 2 and 3 clinical trials for HER2-positive breast cancer is warranted.Funding: Daiichi Sankyo Co, Ltd. [ABSTRACT FROM AUTHOR]

Objectives: Evidence suggests superiority of breast conserving surgery (BCS) plus radiation over mastectomy alone for treatment of early stage breast cancer. Whether the superiority of BCS plus radiation is related to the surgical approach itself or to the addition of adjuvant radiation therapy following BCS remains unclear. Materials and Methods: We conducted a retrospective cohort study of women with breast cancer diagnosed from 1994-2012. Data regarding patient and tumor characteristics and treatment specifics were captured electronically. Kaplan-Meier survival analyses were performed with inverse probability of treatment weighting to reduce selection bias effects in surgical assignment. Results: Data from 5335 women were included, of which two-thirds had BCS and one-third had mastectomy. Surgical decision trends changed over time with more women undergoing mastectomy in recent years. Women who underwent BCS versus mastectomy differed significantly regarding age, cancer stage/grade, adjuvant radiation, chemotherapy, and endocrine treatment. Overall survival was similar for BCS and mastectomy. When BCS plus radiation was compared to mastectomy alone, 3-, 5-, and 10-year overall survival was 96.5% vs 93.4%, 92.9% vs 88.3% and 80.9% vs 67.2%, respectively. Conclusion: These analyses suggest that survival benefit is not related only to the surgery itself, but that the prognostic advantage of BCS plus radiation over mastectomy may also be related to the addition of adjuvant radiation therapy. This conclusion requires prospective confirmation in randomized trials. [ABSTRACT FROM AUTHOR]

Microbiological data regarding Klebsiella pneumoniae carbapenemase (KPC)–producing Enterobacter spp. are scarce. In this study, 11 unique KPC-producing Enterobacter isolates were identified among 44 ertapenem-nonsusceptible Enterobacter isolates collected between 2009 and 2013 at a hospital system in Western Pennsylvania. All cases were healthcare-associated and occurred in medically complex patients. While pulsed-field gel electrophoresis showed diverse restriction patterns overall, multilocus sequence typing identified Enterobacter cloacae isolates with sequence types 93 and 171 from 2 hospitals each. The levels of carbapenem minimum inhibitory concentrations were highly variable. All isolates remained susceptible to colistin and tigecycline, and the majority, to amikacin and doxycycline. A bla KPC -carrying IncN plasmid conferring trimethoprim-sulfamethoxazole resistance was identified in 3 of the isolates. Spread of bla KPC in Enterobacter spp. appears to be due to a combination of plasmid-mediated and clonal processes. [ABSTRACT FROM AUTHOR]

Although protein intakes in the United States are widely regarded as adequate, attention has been given to potential inadequacy of recommendations or patterns of intake in older adults. The objectives of this research were to update and expand estimates of protein intake and adequacy in older US adults, with additional focus on contributions of animal source protein. Data were obtained from 1,768 adults aged 51 years and older in the National Health and Nutrition Examination Survey 2005-2006, the Food and Nutrient Database for Dietary Studies, and US Department of Agriculture Standard Reference datasets. Estimates of inadequate intakes ranged from <1% to 5% of men aged 51 to 70 years to 9% to 24% of women aged ≥71 years, depending on whether adjusted or actual body weights were used to calculate grams of protein per kilogram of body weight. Mean usual protein intakes were 94±22 g/day and 56±13 g/day in those same groups, with 15.3%±2.3% and 15.4%±2.4% of energy from protein. Animal sources provided >60% of protein intake, on average. In regression models with energy intake, age, sex, ethnicity, and education as covariables, percent protein from animal sources predicted protein intake and odds of meeting the Recommended Dietary Allowances (P<0.001). Consumption of total and animal-source protein was skewed to the evening meal. Findings highlight the influence of body weight choice (actual vs adjusted) on estimates of protein inadequacy, and suggest the need for careful consideration of protein source in adults at risk for inadequacy. Research is needed to establish optimal protein intakes, sources, and patterns. [Copyright &y& Elsevier]