Safety and efficacy of outpatient parenteral antimicrobial therapy: a systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Outpatient parenteral antimicrobial therapy (OPAT) offers an alternative to inpatient (hospital bed-based) treatment of infections that require intravenous administration of antimicrobials. This meta-analysis aimed to summarise the evidence available from randomised controlled trials (RCTs) regarding the efficacy and safety of OPAT compared to inpatient parenteral antimicrobial therapy. METHODS: We searched the Cochrane Library, MEDLINE, Embase, PubMed, and Web of Sciences databases for RCTs comparing outpatient versus inpatient parenteral antimicrobial therapy. We included studies without restrictions on language or publication year. Eligibility was reviewed independently by two assessors, and data extraction was cross validated. We evaluated bias risk via the Cochrane tool and determined the evidence certainty using GRADE. Meta-analysis was conducted using a random effects model. The protocol of this review was registered on PROSPERO (CRD42023460389). RESULT: Thirteen RCTs, involving 1,310 participants were included. We found no difference in mortality (Risk Ratio (RR) 0.54, 95% Confidence Interval (CI) 0.23 to 1.26; p = 0.93), treatment failure (RR 1.0, CI 0.59 to 1.72; p = 0.99), adverse reaction related to antimicrobials (RR 0.89, CI 0.69 to 1.15; p = 0.38), and administration device (RR 0.58, CI 0.17 to 1.98; p = 0.87) between outpatient and inpatient parenteral antimicrobial therapy. The overall body of evidence had a low level of certainty. CONCLUSION: Existing evidence suggests OPAT is a safe and effective alternative to inpatient treatment. Further RCTs are warranted for a thorough comparison of inpatient and outpatient parenteral antimicrobial therapy with a high level of certainty.

Separation of full, empty, and partial adeno-associated virus capsids via anion-exchange chromatography with continuous recycling and accumulation.

The field of recombinant adeno-associated virus (rAAV) gene therapy has attracted increasing attention over decades. Within the ongoing challenges of rAAV manufacturing, the co-production of impurities, such as empty and partial capsids containing no or truncated transgenes, poses a significant challenge. Due to their potential impact on drug efficacy and clinical safety, it is imperative to conduct comprehensive monitoring and characterization of these impurities prior to the release of the final gene therapy product. Nevertheless, existing analytical techniques encounter notable limitations, encompassing low throughput, long turnaround times, high sample consumption, and/or complicated data analysis. Chromatography-based analytical methods are recognized for their current Good Manufacturing Practice (cGMP) alignment, high repeatability, reproducibility, low limit of detection, and rapid turnaround times. Despite these advantages, current anion exchange high pressure liquid chromatography (AEX-HPLC) methods struggle with baseline separation of partial capsids from full and empty capsids, resulting in inaccurate full-to-empty capsid ratio, as partial capsids are obscured within peaks corresponding to empty and full capsids. In this study, we present a unique analytical AEX method designed to characterize not only empty and full capsids but also partial capsids. This method utilizes continuous N-Rich chromatography with recycling between two identical AEX columns for the accumulation and isolation of partial capsids. The development process is comprehensively discussed, covering the preparation of reference materials representing full (rAAV-LacZ), partial (rAAV-GFP), and empty (rAAV-empty) capsids, N-rich method development, fraction analysis, determination of fluorescence response factors between capsid variants, and validation through comparison with other comparative techniques.

Saliva Production and Esophageal Motility Influence Esophageal Acid Clearance Related to Post-reflux Swallow-Induced Peristaltic Wave.

BACKGROUND: The post-reflux swallow-induced peristaltic wave (PSPW) brings salivary bicarbonate to neutralize residual distal esophageal mucosal acidification. AIMS: To determine if reduced saliva production and esophageal body hypomotility would compromise PSPW-induced pH recovery in the distal esophagus. METHODS: In this multicenter retrospective cross-sectional study, patients with confirmed Sjogren's syndrome and scleroderma/mixed connective tissue disease (MCTD) who underwent high resolution manometry (HRM) and ambulatory pH-impedance monitoring off antisecretory therapy were retrospectively identified. Patients without these disorders undergoing HRM and pH-impedance monitoring for GERD symptoms were identified from the same time-period. Acid exposure time, numbers of reflux episodes and PSPW, pH recovery with PSPW, and HRM metrics were extracted. Univariate comparisons and multivariable analysis were performed to determine predictors of pH recovery with PSPW. RESULTS: Among Sjogren's syndrome (n = 34), scleroderma/MCTD (n = 14), and comparison patients with reflux symptoms (n = 96), the scleroderma/MCTD group had significantly higher AET, higher prevalence of hypomotility, lower detected reflux episodes, and very low numbers of PSPW (p ≤ 0.004 compared to other groups). There was no difference in pH-impedance metrics between Sjogren's syndrome, and comparison patients (p ≥ 0.481). Proportions with complete pH recovery with PSPW was lower in Sjogren's patients compared to comparison reflux patients (p = 0.009), predominantly in subsets with hypomotility (p < 0.001). On multivariable analysis, diagnosis of Sjogren's syndrome, scleroderma/MCTD or neither (p = 0.014) and esophageal hypomotility (p = 0.024) independently predicted lack of complete pH recovery with PSPW, while higher total reflux episodes trended (p = 0.051). CONCLUSIONS: Saliva production and motor function are both important in PSPW related pH recovery.

The Milan score: A novel manometric tool for a more efficient diagnosis of gastro-esophageal reflux disease.

OBJECTIVE: A definitive diagnosis of gastroesophageal reflux disease (GERD) depends on endoscopic and/or pH-study criteria. However, high resolution manometry (HRM) can identify factors predicting GERD, such as ineffective esophageal motility (IEM), esophago-gastric junction contractile integral (EGJ-CI), evaluating esophagogastric junction (EGJ) type and straight leg raise (SLR) maneuver response. We aimed to build and externally validate a manometric score (Milan Score) to stratify the risk and severity of the disease in patients undergoing HRM for suspected GERD. METHODS: A population of 295 consecutive patients undergoing HRM and pH-study for persistent typical or atypical GERD symptoms was prospectively enrolled to build a model and a nomogram that provides a risk score for AET > 6%. Collected HRM data included IEM, EGJ-CI, EGJ type and SLR. A supplemental cohort of patients undergoing HRM and pH-study was also prospectively enrolled in 13 high-volume esophageal function laboratories across the world in order to validate the model. Discrimination and calibration were used to assess model's accuracy. Gastroesophageal reflux disease was defined as acid exposure time >6%. RESULTS: Out of the analyzed variables, SLR response and EGJ subtype 3 had the highest impact on the score (odd ratio 18.20 and 3.87, respectively). The external validation cohort consisted of 233 patients. In the validation model, the corrected Harrel c-index was 0.90. The model-fitting optimism adjusted calibration slope was 0.93 and the integrated calibration index was 0.07, indicating good calibration. CONCLUSIONS: A novel HRM score for GERD diagnosis has been created and validated. The MS might be a useful screening tool to stratify the risk and the severity of GERD, allowing a more comprehensive pathophysiologic assessment of the anti-reflux barrier. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT05851482).

Identification of Achalasia Within Absent Contractility Phenotypes on High-Resolution Manometry: Prevalence, Predictive Factors, and Treatment Outcome.

INTRODUCTION: Absent contractility on high-resolution manometry (HRM) defines severe hypomotility but needs distinction from achalasia. We retrospectively identified achalasia within absent contractility using HRM provocative maneuvers, barium esophagography, and functional lumen imaging probe (FLIP). METHODS: Adult patients with absent contractility on HRM during the 4-year study period were eligible for inclusion. Inadequate studies, achalasia after therapy, or prior foregut surgery were exclusions. Upright integrated relaxation pressure (IRP) >12 mm Hg, panesophageal pressurization, and/or elevated IRP on multiple rapid swallows and rapid drink challenge (RDC) were considered abnormal. Esophageal barium retention and abnormal esophagogastric junction distensibility index (<2.0 mm 2 /mm Hg) on FLIP defined achalasia. Clinical, endoscopic, and motor characteristics of patients with achalasia were compared with absent contractility without obstruction. RESULTS: Of 164 patients, 20 (12.2%) had achalasia (17.9% of 112 patients with adjunctive testing), while 92 did not, and 52 did not undergo adjunctive tests. Achalasia was diagnosed regardless of IRP value, but the median supine IRP was higher (odds ratio 1.196, 95% confidence interval 1.041-1.375, P = 0.012). Patients with achalasia were more likely to present with dysphagia (80.0% vs 35.9%, P < 0.001), with obstructive features on HRM maneuvers (83.3% vs 48.9%, P = 0.039), but lower likelihood of GERD evidence (20.0% vs 47.3%, P = 0.027) or large hiatus hernia (15.0% vs 43.8%, P = 0.002). On multivariable analysis, dysphagia presentation ( P = 0.006) and pressurization on RDC ( P = 0.027) predicted achalasia, while reflux and presurgical evaluations and lack of RDC obstruction predicted absent contractility without obstruction. DISCUSSION: Despite HRM diagnosis of absent contractility, achalasia is identified in more than 1 in 10 patients regardless of IRP value.

Artificial Intelligence Tools for Improving Manometric Diagnosis of Esophageal Dysmotility.

PURPOSE OF REVIEW: Artificial intelligence (AI) is a broad term that pertains to a computer's ability to mimic and sometimes surpass human intelligence in interpretation of large datasets. The adoption of AI in gastrointestinal motility has been slower compared to other areas such as polyp detection and interpretation of histopathology. RECENT FINDINGS: Within esophageal physiologic testing, AI can automate interpretation of image-based tests, especially high resolution manometry (HRM) and functional luminal imaging probe (FLIP) studies. Basic tasks such as identification of landmarks, determining adequacy of the HRM study and identification from achalasia from non-achalasia patterns are achieved with good accuracy. However, existing AI systems compare AI interpretation to expert analysis rather than to clinical outcome from management based on AI diagnosis. The use of AI methods is much less advanced within the field of ambulatory reflux monitoring, where challenges exist in assimilation of data from multiple impedance and pH channels. There remains potential for replication of the AI successes within esophageal physiologic testing to HRM of the anorectum, and to innovative and novel methods of evaluating gastric electrical activity and motor function. The use of AI has tremendous potential to improve detection of dysmotility within the esophagus using esophageal physiologic testing, as well as in other regions of the gastrointestinal tract. Eventually, integration of patient presentation, demographics and alternate test results to individual motility test interpretation will improve diagnostic precision and prognostication using AI tools.

Fifteen-year symptomatic outcome of patients with nonactionable motor findings on high-resolution manometry.

BACKGROUND: High-resolution manometry (HRM) is performed for evaluation of esophageal symptoms, but patient outcome is unclear when no actionable motor disorder is identified. We evaluated long-term symptomatic outcome of patients with nonactionable HRM findings. METHODS: Patients who underwent (HRM) studies in 2006-2008 were tracked. Patients with achalasia spectrum disorders, foregut surgery before or after HRM, and incomplete symptom documentation were excluded. Symptom questionnaires assessing dominant symptom intensity (DSI, product of symptom severity and frequency recorded on 5-point Likert scales) and global symptom severity (GSS, from 10 cm visual analog scale) were repeated. Change in symptom burden was compared against HRM motor findings using Chicago Classification 4.0 (CCv4.0), applied retroactively to 2006-2008 data. KEY RESULTS: Overall, 134 patients (median age 68 years, 64.5% female) could be contacted. The majority (73.1%) had normal motility; others had ineffective esophageal motility (8.2%), esophagogastric junction outflow obstruction (13.4%), hypercontractile esophagus (3.0%), or absent contractility (2.2%), none managed invasively. Over 15 years of follow-up, DSI decreased from 8.0 (4.0-16.0) to 1.0 (0.0-6.0) (p < 0.001) and GSS improved from 5.5 (3.3-7.7) to 2.0 (0.0-4.0) (p < 0.001); improvement was consistent across CCv4.0 diagnoses and subgroups. The majority (82.8%) reported improvement over time, and antisecretory medication was the most effective intervention (83.0% improvement). There was no difference in medication efficacy (p = 0.75) or improvement in symptoms (p = 0.20) based on CCv4 diagnosis. CONCLUSIONS AND INFERENCES: Esophageal symptoms improve with conservative symptomatic management over long-term follow-up when no conclusive obstructive motor disorders or achalasia spectrum disorders are found on HRM.

Adjunctive glucocorticoid therapy for Pneumocystis jirovecii pneumonia in solid organ transplant recipients: A multicenter cohort, 2015-2020.

Solid organ transplant recipients (SOTRs) frequently receive adjunctive glucocorticoid therapy (AGT) for Pneumocystis jirovecii pneumonia (PJP). This multicenter cohort of SOTRs with PJP admitted to 20 transplant centers in Canada, the United States, Europe, and Australia, was examined for whether AGT was associated with a lower rate of all-cause intensive care unit (ICU) admission, 90-day death, or a composite outcome (ICU admission or death). Of 172 SOTRs with PJP (median [IQR] age: 60 (51.5-67.0) years; 58 female [33.7%]), the ICU admission and death rates were 43.4%, and 20.8%, respectively. AGT was not associated with a reduced risk of ICU admission (adjusted odds ratio [aOR] [95% CI]: 0.49 [0.21-1.12]), death (aOR [95% CI]: 0.80 [0.30-2.17]), or the composite outcome (aOR [95% CI]: 0.97 [0.71-1.31]) in the propensity score-adjusted analysis. AGT was not significantly associated with at least 1 unit of the respiratory portion of the Sequential Organ Failure Assessment score improvement by day 5 (12/37 [32.4%] vs 39/111 [35.1%]; P = .78). We did not observe significant associations between AGT and ICU admission or death in SOTRs with PJP. Our findings should prompt a reevaluation of routine AGT administration in posttransplant PJP treatment and highlight the need for interventional studies.

Reflux Symptoms Increase Following Sleeve Gastrectomy Despite Triage of Symptomatic Patients to Roux-en-Y Gastric Bypass.

BACKGROUND AND AIMS: Bariatric surgical options in obese patients include sleeve gastrectomy (SG) and roux-en-Y gastric bypass (RYGB), which may not be equivalent in risk of postoperative reflux symptoms. We evaluated risk and predictive factors for postbariatric surgery reflux symptoms. METHODS: Patients with obesity evaluated for bariatric surgery over a 15-month period were prospectively followed with validated symptom questionnaires (GERDQ, dominant symptom index: product of symptom frequency and intensity from 5-point Likert scores) administered before and after SG and RYGB. Esophageal testing included high-resolution manometry in all patients, and ambulatory reflux monitoring off therapy in those with abnormal GERDQ or prior reflux history. Univariate comparisons and multivariable analysis were performed to determine if preoperative factors predicted postoperative reflux symptoms. RESULTS: Sixty-four patients (median age 49.0 years, 84% female, median BMI 46.5 kg/m 2 ) fulfilled inclusion criteria and underwent follow-up assessment 4.4 years after bariatric surgery. Baseline GERDQ and dominant symptom index for heartburn were significantly higher in RYGB patients ( P ≤0.04). Despite this, median GERDQ increased by 2 (0.0 to 4.8) following SG and decreased by 0.5 (-1.0 to 5.0) following RYGB ( P =0.02). GERDQ became abnormal in 43.8% after SG and 18.8% after RYGB ( P =0.058); abnormal GERDQ improved in 12.5% and 37.5%, respectively ( P =0.041). In a model that included age, gender, BMI, acid exposure time, and type of surgery, multivariable analysis identified SG as an independent predictor of postoperative heartburn (odds ratio 16.61, P =0.024). CONCLUSIONS: Despite preferential RYGB when preoperative GERD was identified, SG independently predicted worsening heartburn symptoms after bariatric surgery.

Too naïve to lead: When leaders fall for flattery.

Flattery is one of the oldest and most commonly used impression-management tactics in everyday life. Though it often brings benefits to the flatterer, less is known about how it affects the target. In the present research, we explore when and why being flattered can be costly for leaders-common targets of flattery-depending on how they respond to it. We suggest that leaders who are observed rewarding flatterers risk appearing naïve to others. Across seven studies and six supplementary studies (N = 4,612), we find evidence that leaders who grant favors to flatterers are often perceived to have naively "fallen for flattery," which shapes observers' impressions of the leaders and the organizations they represent. A first set of studies (Studies 1-4) detail the variety of factors that lead observers to conclude their leader has fallen for flattery and the resulting impacts to the leaders' reputation and their organization (e.g., competence, warmth, commitment to the leader, organizational fairness). The second set of studies look at the contextual factors that impact what costs leaders pay for being perceived to have fallen for flattery, including the type of flattery (Study 5), who is harmed by the favor (Study 6), and the leader's apparent awareness of the motives underlying flattery (Study 7). Whereas previous research highlights positive consequences of flattery for the flatterer, we find that flattery comes with costs for leaders and their organizations. We discuss theoretical and practical implications for leaders who are frequently flattered. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Outpatient parenteral antibiotic therapy (OPAT) for the management of bronchiectasis.

Background: Patients with bronchiectasis often require hospitalisation for the administration of intravenous antibiotics for the management of acute exacerbations. Increasingly, Outpatient Parenteral Antibiotic Therapy (OPAT) services have become available as a potential alternative for domiciliary management. Aims: This study assessed outcomes in both cystic fibrosis (CF) and non-CF bronchiectasis patients who received OPAT for the management of an acute exacerbation of bronchiectasis. Methods: A retrospective study of consecutive subjects was done in both CF and non-CF groups in a large metropolitan Health Service in Australia from 2016 to 2022. Results: There were 51 episodes of care in the non-CF group (22 subjects) and 73 episodes in the CF group (13 subjects). The non-CF group were nearly all treated with once daily domiciliary intravenous (IV) ceftriaxone (49/51 episodes) for a duration of 9.1 ± 3.0 days (mean and standard deviation (SD)) via a peripherally inserted venous canula (84% of episodes). In contrast, the CF group generally received dual IV antibiotics (64% of episodes), with an average duration of 16.8 ± 6.3 days via central venous access (100%). In the non-CF group, the admission rate to hospital after 1 month was 9.6% and in the CF group was 0%. At 3 and 6 months the readmission rate for the non-CF group was 15.7% and 19.6% and CF group was 21.9% and 31.5%. There was a low rate of complications for the OPAT admissions (2% for the non-CF group and 7% for CF group). Conclusions: OPAT is a viable alternative for the management of bronchiectasis exacerbations.

Exploring the advancements of Australian OPAT.

Outpatient parenteral antimicrobial therapy (OPAT) in Australia has evolved from modest beginnings to a well-established health service with proven benefits in patient outcomes. This is a comprehensive review of the current state of art Australian OPAT with vignettes of the types of OPAT models of care, antimicrobial prescribing and antimicrobial use. In addition, we highlight the similarities and differences between OPAT to other countries and describe Australian OPAT experiences with COVID-19 and paediatrics. Australian OPAT continues to advance with OPAT antifungals, novel treatment options and upcoming high-impact research.

Longer-term Mortality and Kidney Outcomes of Participants in the Combination Antibiotics for Methicillin-Resistant Staphylococcus aureus (CAMERA2) Trial: A Post Hoc Analysis.

Background: The Combination Antibiotic Therapy for Methicillin-Resistant Staphylococcus aureus (CAMERA2) trial ceased recruitment in July 2018, noting that a higher proportion of patients in the intervention arm (combination therapy) developed acute kidney injury (AKI) compared to the standard therapy (monotherapy) arm. We analyzed the long-term outcomes of participants in CAMERA2 to understand the impact of combination antibiotic therapy and AKI. Methods: Trial sites obtained additional follow-up data. The primary outcome was all-cause mortality, censored at death or the date of last known follow-up. Secondary outcomes included kidney failure or a reduction in kidney function (a 40% reduction in estimated glomerular filtration rate to <60 mL/minute/1.73 m2). To determine independent predictors of mortality in this cohort, adjusted hazard ratios were calculated using a Cox proportional hazards regression model. Results: This post hoc analysis included extended follow-up data for 260 patients. Overall, 123 of 260 (47%) of participants died, with a median population survival estimate of 3.4 years (235 deaths per 1000 person-years). Fifty-five patients died within 90 days after CAMERA2 trial randomization; another 68 deaths occurred after day 90. Using univariable Cox proportional hazards regression, mortality was not associated with either the assigned treatment arm in CAMERA2 (hazard ratio [HR], 0.84 [95% confidence interval [CI], .59-1.19]; P = .33) or experiencing an AKI (HR at 1 year, 1.04 [95% CI, .64-1.68]; P = .88). Conclusions: In this cohort of patients hospitalized with methicillin-resistant S aureus bacteremia, we found no association between either treatment arm of the CAMERA2 trial or AKI (using CAMERA2 trial definition) and longer-term mortality.

Proximal Gastric Pressurization After Sleeve Gastrectomy Associates With Gastroesophageal Reflux.

INTRODUCTION: Sleeve gastrectomy (SG) results in persistent or de novo reflux more often than Roux-en-Y gastric bypass (RYGB). We investigated pressurization patterns in the proximal stomach on high-resolution manometry (HRM) to determine associations with reflux after SG. METHODS: Patients undergoing HRM and ambulatory pH-impedance monitoring after SG and RYGB over a 2-year period (2019-2020) were included. For each included patient, 2 symptomatic control patients with HRM and pH-impedance monitoring for reflux symptoms were identified within the same time frame; 15 asymptomatic healthy controls with HRM studies were also studied. Concurrent myotomy and preoperative diagnosis of obstructive motor disorders were exclusions. Conventional HRM metrics, esophagogastric junction (EGJ) pressures, contractile integral (EGJ-CI), acid exposure time (AET), and reflux episode numbers were extracted. Intragastric pressure was sampled at baseline, during swallows, and with straight leg raise maneuver, and compared with intraesophageal pressure and reflux burden. RESULTS: Patient cohorts included 36 SG patients, 23 RYGB patients, 113 symptomatic controls, and 15 asymptomatic controls. While both SG and RYGB patients pressurized the stomach during swallows and straight leg raise, SG patients had higher AET (median 6.0% vs 0.2%), reflux episode numbers (median 63.0 vs 37.5), and baseline intragastric pressure (median 17.3 mm Hg vs 13.1 mm Hg) ( P < 0.001). SG patients also had lower trans-EGJ pressure gradients when reflux episodes were >80 or AET was >6.0% ( P = 0.018 and 0.08, respectively, compared with no pathologic reflux). On multivariable analysis, SG status and low EGJ-CI independently associated with AET and reflux episode numbers ( P ≤ 0.04). DISCUSSION: Impaired EGJ barrier function and proximal gastric pressurization after SG are associated with gastroesophageal reflux, especially during strain maneuvers.

Intermittent Hiatus Hernia on High-Resolution Manometry Associates With Abnormal Reflux Burden Similar to Persistent Hiatus Hernia.

INTRODUCTION: Hiatus hernia is characterized by axial separation between the lower esophageal sphincter and the crural diaphragm, and higher reflux burden. Impact on reflux is unclear if such separation is intermittent rather than persistent. METHODS: Reflux burden off antisecretory therapy was compared between no hernia (n = 357), intermittent hernia (n = 42), and persistent hernia (n = 155) after review of consecutive high-resolution manometry and reflux monitoring studies. RESULTS: Proportions with pathologic acid exposure was similar between intermittent and persistent hernia (45.2% vs 46.5%, respectively), and both were significantly different from no hernia (28.7%, P ≤ 0.002). DISCUSSION: Intermittent hiatus hernias are clinically relevant in gastroesophageal reflux pathophysiology.

Molecular epidemiology, clinical features and significance of Shiga toxin detection from routine testing of gastroenteritis specimens.

After introduction of faecal multiplex PCR that includes targets for stx1 and stx2 genes, we found stx genes were detected in 120 specimens from 111 patients over a 31-month period from 2018-2020 from a total of 14,179 separate tests performed. The proportion of stx1 only vs stx2 only vs stx1 and stx2 was 35%, 22% and 42%, respectively. There were 54 specimens which were culture positive, with 33 different serotypes identified, the predominant serotype being O157:H7 (19%). Eighty-two patients had clinical data available; we found a high rate of fever (35%), bloody diarrhoea (34%), acute kidney injury (27%), hospital admission (80%) and detection of faecal co-pathogens (23%). Only one patient developed haemolytic uraemic syndrome. We found no significant association with stx genotype and any particular symptom or complication. We found a significant association of serotypes O157:H7 and O26:H11 with bloody stool, but no significant association with any other symptom or complication.

Non-inferiority trial of a shorter (7 days) compared with a longer (14 days) duration of antimicrobial therapy for the treatment of bacteraemic urinary sepsis, measured by microbiological success after the completion of therapy: a substudy protocol for the Bacteraemia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) multicentre randomised controlled trial.

INTRODUCTION: The BALANCE study is a randomised clinical trial (3626 participants) designed to assess the non-inferiority of 7 days (short-course) antibiotic therapy compared with 14 days of therapy for bacteraemia using the pragmatic endpoint of 90-day survival. Based on pilot study data, approximately 30% of enrolees will have a urinary tract infection (UTI) as the source of bacteraemia. METHODS AND ANALYSIS: We aim to assess the non-inferiority of short-course antibiotic therapy for patients with bacteraemia UTIs.Participating sites in four countries will be invited to join this substudy. All participants of this substudy will be enrolled in the main BALANCE study. The intervention will be assigned and treatment administered as specified in the main protocol.We will include participants in this substudy if the probable source of their infection is a UTI, as judged by the site principal investigator, and they have a urine microscopy and culture indicative of a UTI. Participants will be excluded if they have an ileal loop, vesicoureteric reflux or suspected or confirmed prostatitis.The primary outcome is the absence of a positive culture on a test-of-cure urine sample collected 6-12 days after cessation of antimicrobials, with a non-inferiority margin of 15%. Secondary outcomes include the clinical resolution of infection symptoms at test-of-cure. ETHICS AND DISSEMINATION: The study has been approved in conjunction with the main BALANCE study through the relevant ethics review process at each participating site. We will disseminate the results through the Australasian Society for Infectious Diseases, Canadian Critical Care Trials Group, the Association for Medical Microbiology and Infectious Diseases Canada Clinical Research Network (AMMI Canada CRN) and other collaborators. UNIVERSAL TRIAL NUMBER: U1111-1256-0874. MAIN BALANCE TRIAL REGISTRATION: NCT03005145. TRIAL REGISTRATION NUMBER: Australian Clinical Trial Register: ACTRN12620001108909.

Seeing your life story as a Hero's Journey increases meaning in life.

Meaning in life is tied to the stories people tell about their lives. We explore whether one timeless story-the Hero's Journey-might make people's lives feel more meaningful. This enduring story appears across history and cultures and provides a template for ancient myths (e.g., Beowulf) and blockbuster books and movies (e.g., Harry Potter). Eight studies reveal that the Hero's Journey predicts and can causally increase people's experience of meaning in life. We first distill the Hero's Journey into seven key elements-protagonist, shift, quest, allies, challenge, transformation, legacy-and then develop a new measure that assesses the perceived presence of the Hero's Journey narrative in people's life stories: the Hero's Journey Scale. Using this scale, we find a positive relationship between the Hero's Journey and meaning in life with both online participants (Studies 1-2) and older adults in a community sample (Study 3). We then develop a restorying intervention that leads people to see the events of their life as a Hero's Journey (Study 4). This intervention causally increases meaning in life (Study 5) by prompting people to reflect on important elements of their lives and connecting them into a coherent and compelling narrative (Study 6). This Hero's Journey restorying intervention also increases the extent to which people perceive meaning in an ambiguous grammar task (Study 7) and increases their resilience to life's challenges (Study 8). These results provide initial evidence that enduring cultural narratives like the Hero's Journey both reflect meaningful lives and can help to create them. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Application of Artificial Intelligence in Measuring Novel pH-Impedance Metrics for Optimal Diagnosis of GERD.

Novel metrics extracted from pH-impedance monitoring can augment the diagnosis of gastroesophageal reflux disease (GERD). Artificial intelligence (AI) is being widely used to improve the diagnostic capabilities of various diseases. In this review, we update the current literature regarding applications of artificial intelligence in measuring novel pH-impedance metrics. AI demonstrates high performance in the measurement of impedance metrics, including numbers of reflux episodes and post-reflux swallow-induced peristaltic wave index and, furthermore, extracts baseline impedance from the entire pH-impedance study. AI is expected to play a reliable role in facilitating measuring novel impedance metrics in patients with GERD in the near future.

A systematic review of optimal pharmacokinetic/pharmacodynamic parameters for beta-lactam therapy in infective endocarditis.

BACKGROUND: Beta-lactam antibiotics are the mainstay of therapy for most bacterial causes of infective endocarditis (IE). Traditionally considered as agents with a broad therapeutic index, there is increasing recognition that standard doses may be subtherapeutic or toxic in critically ill patients. Optimizing therapy for efficacy requires a defined pharmacokinetic (PK)/pharmacodynamic (PD) target associated with clinical and microbiological cure. OBJECTIVES: To elucidate the factors that influence beta-lactam PK and PD variability in IE and to examine optimal PK/PD target parameters for therapy. METHODS: The review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Clinical and laboratory in vivo animal or human studies examining PK and/or PD of beta-lactam antibiotics in IE were eligible. Ovid MEDLINE, Embase and Cochrane Central Registry were searched using defined terms. The Office of Health Assessment and Translation (OHAT) tool was used for assessing risk of bias. RESULTS: From 2677 abstracts, 62 articles were selected for review and synthesis, comprising: 45 animal studies investigating the broad categories of beta-lactam diffusion into vegetations, PK/PD determinants of outcome, mode of antibiotic delivery and synergistic impact of agents; and 17 human studies totalling 347 participants. Findings supported the importance of time-dependent killing for beta-lactams but heterogeneous data limited the determination of an optimal PK/PD target for IE treatment. CONCLUSION: Beta-lactam PK and PD in endocarditis are variable and specific to the particular antibiotic-organism combination. Time-dependent killing is important, consistent with non-endocarditis studies, but there is little agreement on optimal drug exposure. Clinical studies examining PK/PD targets in endocarditis are required to further inform drug selection and dosing.