Rate and factors associated with surgical site infection following aseptic revision fixation of orthopaedic trauma injuries.

PURPOSE: The primary aim of this study was to define the rate of infection following revision of fixation for aseptic failure. The secondary aims were to identify factors associated with an infection following revision and patient morbidity following deep infection. METHODS: A retrospective study was undertaken to identify patients who underwent aseptic revision surgery during a 3-year period (2017-2019). Regression analysis was used to identify independent factors associated with SSI. RESULTS: Eighty-six patients were identified that met the inclusion criteria, with a mean age of 53 (range 14-95) years and 48 (55.8%) were female. There were 15 (17%) patients with an SSI post revision surgery (n = 15/86). Ten percent (n = 9) of all revisions acquired a 'deep infection', which carried a high morbidity with a total of 23 operations, including initial revision, being undertaken for these patients as salvage procedures and three progressed to an amputation. Alcohol excess (odds ratio (OR) 1.61, 95% CI 1.01-6.36, p = 0.046) and chronic obstructive pulmonary disease (OR 11.1, 95% CI 1.00-133.3, p = 0.050) were independently associated with an increased risk of SSI. CONCLUSION: Aseptic revision surgery had a high rate of SSI (17%) and deep infection (10%). All deep infections occurred in the lower limb with the majority of these seen in ankle fractures. Alcohol excess and COPD were independent risk factors associated with an SSI and patients with a history of these should be counselled accordingly. LEVEL OF EVIDENCE: Retrospective Case Series, Level IV.

Prognostic stratification of HPV-associated oropharyngeal cancer based on CD103+ immune cell abundance in patients treated on TROG 12.01 and De-ESCALaTE randomized trials.

BACKGROUND: High CD103+ intratumoral immune cell (ITIC) abundance is associated with better prognosis in unselected patients with human papilloma virus-associated oropharyngeal squamous cell carcinoma (HPV-associated OPSCC) treated with cisplatin and radiotherapy (CIS/RT). Substituting cetuximab (CETUX) for CIS with RT in HPV-associated OPSCC resulted in inferior efficacy. Our aim was to determine whether quantification of CD103 ITIC could be used to identify a population of HPV-associated OPSCC with superior prognosis. PATIENTS AND METHODS: We pooled data from the TROG 12.01 and De-ESCALaTE randomized trials that compared CETUX/70GyRT with CIS/70GyRT in low-risk HPV-associated OPSCC: American Joint Committee on Cancer 7 stage III (excluding T1-2N1) or stage IV (excluding N2b-c if smoking history >10 pack-years and/or distant metastases), including all patients with available tumor samples. The primary endpoint was failure-free survival (FFS) in patients receiving CETUX/RT comparing CD103+ ITIC high (≥30%) versus low (<30%). High and low CD103 were compared using Cox regression adjusting for age, stage and trial. RESULTS: Tumor samples were available in 159/182 patients on TROG 12.01 and 145/334 on De-ESCALaTE. CD103+ ITIC abundance was high in 27% of patients. The median follow-up was 3.2 years. The 3-year FFS in patients treated with CETUX/RT was 93% [95% confidence interval (CI) 79% to 98%] in high CD103 and 74% (95% CI 63% to 81%) in low CD103 [adjusted hazard ratio = 0.22 (95% CI 0.12-0.41), P < 0.001]. The 3-year overall survival in patients treated with CETUX/RT was 100% in high CD103 and 86% (95% CI 76% to 92%) in low CD103, P < 0.001. In patients treated with CIS/RT, there was no significant difference in FFS. CONCLUSIONS: CD103+ ITIC expression separates CETUX/RT-treated low-risk HPV-associated OPSCC into excellent and poor prognosis subgroups. The high CD103 population is a rational target for de-intensification trials.

Long-term efficacy and safety of addition of carboplatin with or without veliparib to standard neoadjuvant chemotherapy in triple-negative breast cancer: 4-year follow-up data from BrighTNess, a randomized phase III trial.

BACKGROUND: Primary analyses of the phase III BrighTNess trial showed addition of carboplatin with/without veliparib to neoadjuvant chemotherapy significantly improved pathological complete response (pCR) rates with manageable acute toxicity in patients with triple-negative breast cancer (TNBC). Here, we report 4.5-year follow-up data from the trial. PATIENTS AND METHODS: Women with untreated stage II-III TNBC were randomized (2 : 1 : 1) to paclitaxel (weekly for 12 doses) plus: (i) carboplatin (every 3 weeks for four cycles) plus veliparib (twice daily); (ii) carboplatin plus veliparib placebo; or (iii) carboplatin placebo plus veliparib placebo. All patients then received doxorubicin and cyclophosphamide every 2-3 weeks for four cycles. The primary endpoint was pCR. Secondary endpoints included event-free survival (EFS), overall survival (OS), and safety. Since the co-primary endpoint of increased pCR with carboplatin plus veliparib with paclitaxel versus carboplatin with paclitaxel was not met, secondary analyses are descriptive. RESULTS: Of 634 patients, 316 were randomized to carboplatin plus veliparib with paclitaxel, 160 to carboplatin with paclitaxel, and 158 to paclitaxel. With median follow-up of 4.5 years, the hazard ratio for EFS for carboplatin plus veliparib with paclitaxel versus paclitaxel was 0.63 [95% confidence interval (CI) 0.43-0.92, P = 0.02], but 1.12 (95% CI 0.72-1.72, P = 0.62) for carboplatin plus veliparib with paclitaxel versus carboplatin with paclitaxel. In post hoc analysis, the hazard ratio for EFS was 0.57 (95% CI 0.36-0.91, P = 0.02) for carboplatin with paclitaxel versus paclitaxel. OS did not differ significantly between treatment arms, nor did rates of myelodysplastic syndromes, acute myeloid leukemia, or other secondary malignancies. CONCLUSIONS: Improvement in pCR with the addition of carboplatin was associated with long-term EFS benefit with a manageable safety profile, and without increasing the risk of second malignancies, whereas adding veliparib did not impact EFS. These findings support the addition of carboplatin to weekly paclitaxel followed by doxorubicin and cyclophosphamide neoadjuvant chemotherapy for early-stage TNBC.

Mode of delivery following obstetric anal sphincter injury: a 7-year retrospective review and follow-up cohort survey.

INTRODUCTION AND HYPOTHESIS: Limited evidence exists regarding long-term outcomes following birth after prior obstetric anal sphincter injury (OASI). This article set out to describe outcomes following birth after OASI by reviewing the grades of tear, endoanal ultrasound (EAUS) findings, subsequent delivery outcomes and long-term symptoms. METHODS: This study was conducted in two parts. The first involved a retrospective review of all OASI at a tertiary hospital in Australia over 7 years (2013-2019 inclusive) where the patient underwent a subsequent delivery. Following this, a retrospective cohort survey of this group was performed. RESULTS: There were 27,284 vaginal births and 828 OASIs (3.03%); 247 (29.8%) had at least one subsequent birth by January 2021. Vaginal delivery occurred in 68%; recurrence of OASI was 5.4%. There were 90 responses (36.4%) to the follow-up survey. EAUS had been performed in 87.5%; none demonstrated a defect. Vaginal birth was the preferred mode for 77.8%; this occurred in 64%. The majority had high levels of satisfaction, this related to communication rather than the mode of delivery itself. Ongoing faecal or flatal incontinence was reported by 12%. There was no statistically significant difference in St Mark's incontinence scores between modes of birth. CONCLUSIONS: In our unit most women who sustain OASI will have a subsequent vaginal delivery in future pregnancies. The majority remain asymptomatic at long-term follow-up with no statistically significant difference in incontinence scores regardless of mode of delivery. The rate of recurrent OASI was 5.4%.

Evaluation of BCL6 and SIRT1 as Non-Invasive Diagnostic Markers of Endometriosis.

(1) Background: Endometriosis is characterized by the presence of endometrial glands and stroma outside of the uterus and is often associated with severe pelvic pain and infertility. Our study explored the utilization of B-Cell Lymphoma 6 (BCL6) and Sirtuin 1 (SIRT1) as potential biomarkers in serum, plasma, urine, and cervical mucus for a non-invasive diagnostic test for endometriosis. BCL6 was chosen based on its previously reported elevated expression in endometrial biopsies, and SIRT1 is co-expressed and upregulated in the endometrium of women with endometriosis. (2) Methods: BCL6 and SIRT1 levels were measured using enzyme-linked immunoassay (ELISA) in samples from 20 women with endometriosis (ten with stages I/II and ten with stages III/IV) and ten women without endometriosis. (3) Results: Levels of SIRT1 in sera showed a statistically significant elevation in advanced stages III/IV compared to controls and stages I/II. No significant differences were found in other bodily fluids for SIRT1 or any bodily fluids tested for BCL6. (4) Conclusions: These results suggest some potential of SIRT1 expression within serum as a predictor of advanced asymptomatic stages of endometriosis. Using immunohistochemistry (IHC) staining and H-SCORE values for the elevated BCL6 (and potentially SIRT1) levels in endometrial biopsy samples seems to have higher diagnostic potential based on the previously published studies.

Recidivism rates of sex offenders managed under the Dangerous Prisoners (Sexual Offenders) Act 2003: an evaluation of actuarial justice.

According to the Dangerous Prisoners Sexual Offenders Act 2003 (DPSOA), an offender is considered 'dangerous' if there is an 'unacceptable risk' that he will commit 'serious sexual harm'. Current legislation operates within an actuarial justice framework, whereby increasing resources are spent on those considered at greater risk. There is limited research on the efficacy of this approach. The current study examines sexual recidivism rates of a sample of DPSOA offenders. Court files of 104 community-supervised dangerous sex offenders (M age = 50.7 SD = 10.8) were examined to determine date and type of re-offending. Recidivism was operationalised as time until arrest (for a sexual conviction/contravention). The overall level of sexual recidivism was low (7.69%). Kaplan-Meier analyses of survival curves identified no difference in rates between risk categories. While this likely suggests that they are not dangerous or an unacceptable risk, the strict conditions of supervision may be effective in preventing sexual re-offending. Further, limitations in empirically understanding the construct need to be considered.

Accelerating Lattice Quantum Field Theory Calculations via Interpolator Optimization Using Noisy Intermediate-Scale Quantum Computing.

The only known way to study quantum field theories in nonperturbative regimes is using numerical calculations regulated on discrete space-time lattices. Such computations, however, are often faced with exponential signal-to-noise challenges that render key physics studies untenable even with next generation classical computing. Here, a method is presented by which the output of small-scale quantum computations on noisy intermediate-scale quantum era hardware can be used to accelerate larger-scale classical field theory calculations through the construction of optimized interpolating operators. The method is implemented and studied in the context of the 1+1-dimensional Schwinger model, a simple field theory which shares key features with the standard model of nuclear and particle physics.

Evaluation of the wear and retention performance of a shape-memory alloy abutment system after 6 months of clinical use.

STATEMENT OF PROBLEM: A nitinol sleeve that uses shape memory to rapidly unlock dental restorations from implant abutments has been developed to allow prosthesis removal for assessment and maintenance, and clinical treatment has been promising. However, objective studies that evaluate the wear and retention performance after short-term clinical use are lacking. PURPOSE: The purpose of this clinical study was to evaluate the wear and retention performance of a shape-memory abutment system after 6 months of clinical use. MATERIAL AND METHODS: Shape-memory alloy sleeves on posterior osseointegrated implants were retrieved after 6 months of clinical use. Scanning electron microscopy (SEM) was used to evaluate the surfaces of the retention sleeve's arms for wear. Uniaxial tensile testing was performed to measure the change in retention force after clinical use. Average retention values of the shape-memory abutment system were compared with previously reported in vitro retention values for definitive and interim cements used in titanium abutment and coping assemblies by using the Welch t test. RESULTS: No evidence of wear, fracture, or chipping was observed during SEM analysis on the shape-memory alloy sleeves. Additionally, no statistically significant difference was found in the median retention force for new (484.5 N) and clinically retrieved (476 N) nitinol sleeve specimens. Compared with a commercially available resin cement, the mean retention force for the control sleeves (480 ±37 N) was higher than that for the freshly cemented specimens (336.3 ±188 N). After 5000 cycles of compressive loads, the mean retention force for cement specimens decreased (209.4 ±83 N), while the clinical sleeves (476 ±50 N) remained unchanged. CONCLUSIONS: According to the results of this study, after 6 months of clinical use, the engaging surfaces of the shape-memory alloy sleeve did not show signs of wear, and the retention force was unchanged.

Identification of an excellent prognosis subset of human papillomavirus-associated oropharyngeal cancer patients by quantification of intratumoral CD103+ immune cell abundance.

BACKGROUND: Accurate prognostic stratification of human papillomavirus-associated oropharyngeal cancers (HPV+OPSCC) is required to identify patients potentially suitable for treatment deintensification. We evaluated the prognostic significance of CD103, a surface marker associated with tissue-resident memory T cells (TRMs), in two independent cohorts of patients with HPV+OPSCC. PATIENTS AND METHODS: The abundance and distribution of CD103+ immune cells were quantified using immunohistochemistry in a cohort of 189 HPV+OPSCC patients treated with curative intent and correlated with outcome. Findings were then validated in an independent cohort comprising 177 HPV+OPSCCs using univariable and multivariable analysis. Intratumoral CD103+ immune cells were characterized by multispectral fluorescence immunohistochemistry and gene expression analysis. RESULTS: High intratumoral abundance of CD103+ immune cells using a ≥30% cut-off was found in 19.8% of tumors in the training cohort of HPV+OPSCC patients and associated with excellent prognosis for overall survival (OS) with adjusted hazard ratio (HR) of 0.13 [95% confidence interval (CI) 0.02-0.94, P = 0.004]. In the independent cohort of HPV+OPSCCs, 20.4% had high intratumoral CD103+ abundance and an adjusted HR for OS of 0.16 (95% CI 0.02-1.22, P = 0.02). Five year OS of patients with high intratumoral CD103 was 100% across both cohorts. The C-statistic for the multivariate prognostic model with stage and age was significantly improved in both cohorts with the addition of intratumoral CD103+ cell abundance. On the basis of spatial location, co-expression of CD8 and CD69, and gene expression profiles, intratumoral CD103+ cells were consistent with TRMs. CONCLUSION: Quantification of intratumoral CD103+ immune cell abundance provides prognostic information beyond that provided by clinical parameters such as TNM-staging, identifying a population of low risk HPV+OPSCC patients who are good candidates for trials of deintensification strategies.

Genomic and Biochemical Characterization of Acinetobacter Podophage Petty Reveals a Novel Lysis Mechanism and Tail-Associated Depolymerase Activity.

The increased prevalence of drug-resistant, nosocomial Acinetobacter infections, particularly from pathogenic members of the Acinetobacter calcoaceticus-baumannii complex, necessitates the exploration of novel treatments such as phage therapy. In the present study, we characterized phage Petty, a novel podophage that infects multidrug-resistant Acinetobacter nosocomialis and Acinetobacter baumannii Genome analysis reveals that phage Petty is a 40,431-bp ϕKMV-like phage, with a coding density of 92.2% and a G+C content of 42.3%. Interestingly, the lysis cassette encodes a class I holin and a single-subunit endolysin, but it lacks canonical spanins to disrupt the outer membrane. Analysis of other ϕKMV-like genomes revealed that spaninless lysis cassettes are a feature of phages infecting Acinetobacter within this subfamily of bacteriophages. The observed halo surrounding Petty's large clear plaques indicated the presence of a phage-encoded depolymerase capable of degrading capsular exopolysaccharides (EPS). The product of gene 39, a putative tail fiber, was hypothesized to possess depolymerase activity based on weak homology to previously reported phage tail fibers. The 101.4-kDa protein gene product 39 (gp39) was cloned and expressed, and its activity against Acinetobacter EPS in solution was determined. The enzyme degraded purified EPS from its host strain A. nosocomialis AU0783, reducing its viscosity, and generated reducing ends in solution, indicative of hydrolase activity. Given that the accessibility to cells within a biofilm is enhanced by degradation of EPS, phages with depolymerases may have enhanced diagnostic and therapeutic potential against drug-resistant Acinetobacter strains.IMPORTANCE Bacteriophage therapy is being revisited as a treatment for difficult-to-treat infections. This is especially true for Acinetobacter infections, which are notorious for being resistant to antimicrobials. Thus, sufficient data need to be generated with regard to phages with therapeutic potential, if they are to be successfully employed clinically. In this report, we describe the isolation and characterization of phage Petty, a novel lytic podophage, and its depolymerase. To our knowledge, it is the first phage reported to be able to infect both A. baumannii and A. nosocomialis The lytic phage has potential as an alternative therapeutic agent, and the depolymerase could be used for modulating EPS both during infections and in biofilms on medical equipment, as well as for capsular typing. We also highlight the lack of predicted canonical spanins in the phage genome and confirm that, unlike the rounding of lambda lysogens lacking functional spanin genes, A. nosocomialis cells infected with phage Petty lyse by bursting. This suggests that phages like Petty employ a different mechanism to disrupt the outer membrane of Acinetobacter hosts during lysis.

Magnetized Disruption of Inertially Confined Plasma Flows.

The creation and disruption of inertially collimated plasma flows are investigated through experiment, simulation, and analytical modeling. Supersonic plasma jets are generated by laser-irradiated plastic cones and characterized by optical interferometry measurements. Targets are magnetized with a tunable B field with strengths of up to 5 T directed along the axis of jet propagation. These experiments demonstrate a hitherto unobserved phenomenon in the laboratory, the magnetic disruption of inertially confined plasma jets. This occurs due to flux compression on axis during jet formation and can be described using a Lagrangian-cylinder model of plasma evolution implementing finite resistivity. The basic physical mechanisms driving the dynamics of these systems are described by this model and then compared with two-dimensional radiation-magnetohydrodynamic simulations. Experimental, computational, and analytical results discussed herein suggest that contemporary models underestimate the electrical conductivity necessary to drive the amount of flux compression needed to explain observations of jet disruption.

Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia.

BACKGROUND: BRAF V600E is the genetic lesion underlying hairy-cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy-cell leukemia that had relapsed after treatment with a purine analogue or who had disease that was refractory to purine analogues. METHODS: We conducted two phase 2, single-group, multicenter studies of vemurafenib (at a dose of 960 mg twice daily)--one in Italy and one in the United States. The therapy was administered for a median of 16 weeks in the Italian study and 18 weeks in the U.S. study. Primary end points were the complete response rate (in the Italian trial) and the overall response rate (in the U.S. trial). Enrollment was completed (28 patients) in the Italian trial in April 2013 and is still open (26 of 36 planned patients) in the U.S. trial. RESULTS: The overall response rates were 96% (25 of 26 patients who could be evaluated) after a median of 8 weeks in the Italian study and 100% (24 of 24) after a median of 12 weeks in the U.S. study. The rates of complete response were 35% (9 of 26 patients) and 42% (10 of 24) in the two trials, respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free survival was 19 months among patients with a complete response and 6 months among those with a partial response; the median treatment-free survival was 25 months and 18 months, respectively. In the U.S. trial, at 1 year, the progression-free survival rate was 73% and the overall survival rate was 91%. Drug-related adverse events were usually of grade 1 or 2, and the events most frequently leading to dose reductions were rash and arthralgia or arthritis. Secondary cutaneous tumors (treated with simple excision) developed in 7 of 50 patients. The frequent persistence of phosphorylated ERK-positive leukemic cells in bone marrow at the end of treatment suggests bypass reactivation of MEK and ERK as a resistance mechanism. CONCLUSIONS: A short oral course of vemurafenib was highly effective in patients with relapsed or refractory hairy-cell leukemia. (Funded by the Associazione Italiana per la Ricerca sul Cancro and others; EudraCT number, 2011-005487-13; ClinicalTrials.gov number NCT01711632.).

nab-Paclitaxel plus carboplatin or gemcitabine versus gemcitabine plus carboplatin as first-line treatment of patients with triple-negative metastatic breast cancer: results from the tnAcity trial.

Background: Metastatic triple-negative breast cancer (mTNBC) has a poor prognosis and aggressive clinical course. tnAcity evaluated the efficacy and safety of first-line nab-paclitaxel plus carboplatin (nab-P/C), nab-paclitaxel plus gemcitabine (nab-P/G), and gemcitabine plus carboplatin (G/C) in patients with mTNBC. Patients and methods: Patients with pathologically confirmed mTNBC and no prior chemotherapy for metastatic BC received (1 : 1 : 1) nab-P 125 mg/m2 plus C AUC 2, nab-P 125 mg/m2 plus G 1000 mg/m2, or G 1000 mg/m2 plus C AUC 2, all on days 1, 8 q3w. Phase II primary end point: investigator-assessed progression-free survival (PFS); secondary end points included overall response rate (ORR), overall survival (OS), percentage of patients initiating cycle 6 with doublet therapy, and safety. Results: In total, 191 patients were enrolled (nab-P/C, n = 64; nab-P/G, n = 61; G/C, n = 66). PFS was significantly longer with nab-P/C versus nab-P/G [median, 8.3 versus 5.5 months; hazard ratio (HR), 0.59 [95% CI, 0.38-0.92]; P = 0.02] or G/C (median, 8.3 versus 6.0 months; HR, 0.58 [95% CI, 0.37-0.90]; P = 0.02). OS was numerically longer with nab-P/C versus nab-P/G (median, 16.8 versus 12.1 months; HR, 0.73 [95% CI, 0.47-1.13]; P = 0.16) or G/C (median, 16.8 versus 12.6 months; HR, 0.80 [95% CI, 0.52-1.22]; P = 0.29). ORR was 73%, 39%, and 44%, respectively. In the nab-P/C, nab-P/G, and G/C groups, 64%, 56%, and 50% of patients initiated cycle 6 with a doublet. Grade ≥3 adverse events were mainly hematologic. Conclusions: First-line nab-P/C was active in mTNBC and resulted in a significantly longer PFS and improved risk/benefit profile versus nab-P/G or G/C.

#cutting: Non-suicidal self-injury (NSSI) on Instagram.

BACKGROUND: Social media presents an important means for social interaction, especially among adolescents, with Instagram being the most popular platform in this age-group. Pictures and communication about non-suicidal self-injury (NSSI) can frequently be found on the internet. METHODS: During 4 weeks in April 2016, n = 2826 (from n = 1154 accounts) pictures which directly depicted wounds on Instagram were investigated. Those pictures, associated comments, and user accounts were independently rated for content. Associations between characteristics of pictures and comments as well as weekly and daily trends of posting behavior were analyzed. RESULTS: Most commonly, pictures depicted wounds caused by cutting on arms or legs and were rated as mild or moderate injuries. Pictures with increasing wound grades and those depicting multiple methods of NSSI generated elevated amounts of comments. While most comments were neutral or empathic with some offering help, few comments were hostile. Pictures were mainly posted in the evening hours, with a small peak in the early morning. While there was a slight peak of pictures being posted on Sundays, postings were rather evenly spread across the week. CONCLUSIONS: Pictures of NSSI are frequently posted on Instagram. Social reinforcement might play a role in the posting of more severe NSSI pictures. Social media platforms need to take appropriate measures for preventing online social contagion.

Route to improving Type 1 diabetes mellitus glycaemic outcomes: real-world evidence taken from the National Diabetes Audit.

AIM: To use general practice-level data for England, available through the National Diabetes Audit, and primary care prescribing data to identify prescription treatment factors associated with variations in achieved glucose control (HbA1c ). METHODS: General practice-level National Diabetes Audit data on Type 1 diabetes, including details of population characteristics, services, proportion of people achieving target glycaemic control [HbA1c ≤58 mmol/mol (7.5%)] and proportion of people at high glycaemic risk [HbA1c >86 mmol/ml (10%)], were linked to 2013-2016 primary care diabetes prescribing data on insulin types and blood glucose monitoring for all people with diabetes. RESULTS: A wide variation was found between the 10th percentile and the 90th percentile of general practices in both target glycaemic control (15.6% to 44.8%, respectively) and high glycaemic risk (4.8% to 28.6%, respectively). Our analysis suggests that, given the extrapolated total of 280 000 people with Type 1 diabetes in the UK, there may be the potential to increase the number of those within target glycaemic control from 80 000 to 101 000; 53% of this increase (11 000 people) would result from service improvements and 47% (10 000 people) from medication and technology changes. The same improvements would also provide the opportunity to reduce the number of people at high glycaemic risk from 42 000 to 26 500. A key factor associated with practice-level target HbA1c achievement would be greater use of insulin pumps for up to an additional 56 000 people. CONCLUSION: If the HbA1c achievement rates in service provision, medication and use of technology currently seen in practices in the 90th percentile were to be matched with regard to HbA1c achievement rates in all general practices, glycaemic control might be improved for 36 500 people, with all the attendant health benefits.

Meropenem-vaborbactam: a carbapenem and beta-lactamase inhibitor with activity against carbapenem-resistant Enterobacteriaceae.

Meropenem-vaborbactam is a carbapenem and ß-lactamase inhibitor combination that is newly indicated for the treatment of complicated urinary tract infections (cUTI), including adult pyelonephritis. Vaborbactam was developed due to emergence of carbapenem-resistant strains of Enterobacteriaceae. In a phase I trial, patients that received meropenem-vaborbactam 2-2 g intravenously over 3 h every 8 h, Cmax was 58.2 ± 10.8 µg/mL for meropenem and 59.0 ± 8.4 µg/mL for vaborbactam. AUC0-8 was 186 ± 33.6 µg â€¢ h/mL for meropenem and 204 ± 34.6 µg â€¢ h/mL for vaborbactam. Vss = 16.3 ± 2.6 L for meropenem and 17.6 ± 2.6 L for vaborbactam. Protein binding for vaborbactam averaged 33% in humans. Plasma clearance ranged from 10.42 ± 1.85 to 14.77 ± 2.84 L/h. One phase III trial evaluated efficacy for meropenem-vaborbactam 2-2 g intravenously every 8 h versus piperacillin-tazobactam 4-0.5 g intravenously every 8 h in complicated UTI. It found non-inferiority and statistical superiority for meropenem in overall success at the end of treatment primary end point. In another phase III trial evaluating efficacy in carbapenem-resistant Enterobacteriaceae (CRE) infections, meropenem-vaborbactam 2-2 g intravenously every 8 h was associated with decreased 28-day mortality and increased clinical cure compared with a best available therapy group.

Clinical Outcomes of Extended-Spectrum Beta-Lactamase-Producing Enterobacteriaceae Infections with Susceptibilities among Levofloxacin, Cefepime, and Carbapenems.

PURPOSE: Highly resistant Gram-negative bacterial infections are associated with high mortality. Increasing resistance to standard therapy illustrates the need for alternatives when treating resistant organisms, especially extended-spectrum beta-lactamase- (ESBL-) producing Enterobacteriaceae. METHODS: A retrospective chart review at a community hospital was performed. Patients who developed ESBL-producing infections were included. Patients less than eighteen years old, who were pregnant, or who were incarcerated were excluded. The primary outcome was hospital mortality. The secondary outcomes included intensive care unit (ICU) mortality, ICU length of stay, and hospital length of stay. RESULTS: 113 patients with ESBL-producing infections met the criteria for review. Hospital mortality: carbapenem (16.6%), cefepime (0%), and levofloxacin (15.3%) (p=0.253). ICU mortality: carbapenem (4.5%), cefepime, (0%), and levofloxacin (3.7%) (p=0.616). Mean ICU and hospital length of stay: carbapenem (9.8 ± 16, 12.1 ± 1 days), cefepime (7.8 ± 6, 11.1 ± 10.5 days), and levofloxacin (5.4 ± 4.1, 11.1 ± 10.4 days) (p=0.805, 0.685). No predictors were clearly found between the source of infection and mortality. CONCLUSION: Cefepime or levofloxacin can be a potential alternative agent for infections with ESBL-producing Enterobacteriaceae, and larger clinical trials investigating these outcomes are warranted.

Lipid stimulation of fatty acid sensors in the human duodenum: relationship with gastrointestinal hormones, BMI and diet.

BACKGROUND AND AIMS: The small intestinal free fatty acid (FFA) sensors, FFA receptor 1 (FFAR1), FFAR4, G-protein receptor 119 (GPR119) and cluster of differentiation-36 (CD36), mediate the fat-induced release of gastrointestinal (GI) hormones. We investigated whether expression of duodenal FFA sensors in humans was (i) altered by intraduodenal (ID) lipid infusion, (ii) disordered in overweight or obese individuals, (iii) related to lipid-induced GI hormone secretion or (iv) affected by habitual dietary patterns. METHODS: Endoscopic duodenal biopsies were collected from 20 lean (body mass index (BMI): 22±1 kg m-2), 18 overweight (BMI: 27±1 kg m-2) and 19 obese (BMI: 35±1 kg m-2) participants at baseline, and following a 30 min ID Intralipid infusion (2 kcal min-1); FFA sensor expression was quantified by reverse transcription-PCR. On a separate day, participants underwent ID Intralipid infusion (2 kcal min-1) for 120 min, to assess GI hormone responses. Habitual diet was evaluated using food frequency questionnaires. RESULTS: Baseline FFAR1 and FFAR4 expression were lower, and CD36 was higher, in obese participants compared with lean participants. ID lipid increased GPR119 and FFAR1 expression equally across study groups, but did not alter FFAR4 or CD36 expression. Increased FFAR1 expression correlated positively with glucose-dependent insulinotropic polypeptide (GIP) secretion (r=0.3, P<0.05), whereas there was no relationship between habitual diet with the expression of FFA sensors. CONCLUSIONS: Obesity is associated with altered duodenal expression of FFAR1, FFAR4 and CD36, suggesting altered capacity for the sensing, absorption and metabolism, of dietary lipids. GPR119 and FFAR1 are early transcriptional responders to the presence of ID lipid, whereas FFAR1 may be an important trigger for lipid-induced GIP release in humans.

Nucleon Structure Functions from Operator Product Expansion on the Lattice.

Deep-inelastic scattering, in the laboratory and on the lattice, is most instructive for understanding how the nucleon is built from quarks and gluons. The long-term goal is to compute the associated structure functions from first principles. So far this has been limited to model calculations. In this Letter we propose a new method to compute the structure functions directly from the virtual, all-encompassing Compton amplitude, utilizing the operator product expansion. This overcomes issues of renormalization and operator mixing, which so far have hindered lattice calculations of power corrections and higher moments.