Daily fosfomycin versus levofloxacin for complicated urinary tract infections.

IMPORTANCE: Concerns over resistance and safety have been identified in the current treatment regimen for complicated urinary tract infections. Fosfomycin is a drug that is routinely used for the treatment of uncomplicated cystitis. This study shows that fosfomycin could be an oral alternative as step-down therapy for the treatment of complicated urinary tract infections, with a clinical cure rate comparable to levofloxacin but a lower microbiological success rate 3 weeks from start of antibiotics.

Efficacy and safety of azithromycin versus placebo to treat lower respiratory tract infections associated with low procalcitonin: a randomised, placebo-controlled, double-blind, non-inferiority trial.

BACKGROUND: Lower respiratory tract infections are frequently treated with antibiotics, despite a viral cause in many cases. It remains unknown whether low procalcitonin concentrations can identify patients with lower respiratory tract infection who are unlikely to benefit from antibiotics. We aimed to compare the efficacy and safety of azithromycin versus placebo to treat lower respiratory tract infections in patients with low procalcitonin. METHODS: We conducted a randomised, placebo-controlled, double-blind, non-inferiority trial at five health centres in the USA. Adults aged 18 years or older with clinically suspected non-pneumonia lower respiratory tract infection and symptom duration from 24 h to 28 days were eligible for enrolment. Participants with a procalcitonin concentration of 0·25 ng/mL or less were randomly assigned (1:1), in blocks of four with stratification by site, to receive over-encapsulated oral azithromycin 250 mg or matching placebo (two capsules on day 1 followed by one capsule daily for 4 days). Participants, non-study clinical providers, investigators, and study coordinators were masked to treatment allocation. The primary outcome was efficacy of azithromycin versus placebo in terms of clinical improvement at day 5 in the intention-to-treat population. The non-inferiority margin was -12·5%. Solicited adverse events (abdominal pain, vomiting, diarrhoea, allergic reaction, or yeast infections) were recorded as a secondary outcome. This trial is registered with ClinicalTrials.gov, NCT03341273. FINDINGS: Between Dec 8, 2017, and March 9, 2020, 691 patients were assessed for eligibility and 499 were enrolled and randomly assigned to receive azithromycin (n=249) or placebo (n=250). Clinical improvement at day 5 was observed in 148 (63%, 95% CI 54 to 71) of 238 participants with full data in the placebo group and 155 (69%, 61 to 77) of 227 participants with full data in the azithromycin group in the intention-to-treat analysis (between-group difference -6%, 95% CI -15 to 2). The 95% CI for the difference did not meet the non-inferiority margin. Solicited adverse events and the severity of solicited adverse events were not significantly different between groups at day 5, except for increased abdominal pain associated with azithromycin (47 [23%, 95% CI 18 to 29] of 204 participants) compared with placebo (35 [16%, 12 to 21] of 221; between-group difference -7% [95% CI -15 to 0]; p=0·066). INTERPRETATION: Placebo was not non-inferior to azithromycin in terms of clinical improvement at day 5 in adults with lower respiratory tract infection and a low procalcitonin concentration. After accounting for both the rates of clinical improvement and solicited adverse events at day 5, it is unclear whether antibiotics are indicated for patients with lower respiratory tract infection and a low procalcitonin concentration. FUNDING: National Institute of Allergy and Infectious Diseases, bioMérieux.

Short- vs Standard-Course Outpatient Antibiotic Therapy for Community-Acquired Pneumonia in Children: The SCOUT-CAP Randomized Clinical Trial.

IMPORTANCE: Childhood community-acquired pneumonia (CAP) is usually treated with 10 days of antibiotics. Shorter courses may be effective with fewer adverse effects and decreased potential for antibiotic resistance. OBJECTIVE: To compare a short (5-day) vs standard (10-day) antibiotic treatment strategy for CAP in young children. DESIGN, SETTING, AND PARTICIPANTS: Randomized double-blind placebo-controlled clinical trial in outpatient clinic, urgent care, or emergency settings in 8 US cities. A total of 380 healthy children aged 6 to 71 months with nonsevere CAP demonstrating early clinical improvement were enrolled from December 2, 2016, to December 16, 2019. Data were analyzed from January to September 2020. INTERVENTION: On day 6 of their originally prescribed therapy, participants were randomized 1:1 to receive 5 days of matching placebo or 5 additional days of the same antibiotic. MAIN OUTCOMES AND MEASURES: The primary end point was the end-of-treatment response adjusted for duration of antibiotic risk (RADAR), a composite end point that ranks each child's clinical response, resolution of symptoms, and antibiotic-associated adverse effects in an ordinal desirability of outcome ranking (DOOR). Within each DOOR rank, participants were further ranked by the number of antibiotic days, assuming that shorter antibiotic durations were more desirable. Using RADAR, the probability of a more desirable outcome was estimated for the short- vs standard-course strategy. In a subset of children, throat swabs were collected between study days 19 and 25 to quantify antibiotic resistance genes in oropharyngeal flora. RESULTS: A total of 380 children (189 randomized to short course and 191 randomized to standard course) made up the study population. The mean (SD) age was 35.7 (17.2) months, and 194 participants (51%) were male. Of the included children, 8 were Asian, 99 were Black or African American, 234 were White, 32 were multiracial, and 7 were of unknown or unreported race; 33 were Hispanic or Latino, 344 were not Hispanic or Latino, and 3 were of unknown or unreported ethnicity. There were no differences between strategies in the DOOR or its individual components. Fewer than 10% of children in either strategy had an inadequate clinical response. The short-course strategy had a 69% (95% CI, 63-75) probability of a more desirable RADAR outcome compared with the standard-course strategy. A total of 171 children were included in the resistome analysis. The median (range) number of antibiotic resistance genes per prokaryotic cell (RGPC) was significantly lower in the short-course strategy compared with the standard-course strategy for total RGPC (1.17 [0.35-2.43] vs 1.33 [0.46-11.08]; P = .01) and ß-lactamase RGPC (0.55 [0.18-1.24] vs 0.60 [0.21-2.45]; P = .03). CONCLUSIONS AND RELEVANCE: In this study, among children responding to initial treatment for outpatient CAP, a 5-day antibiotic strategy was superior to a 10-day strategy. The shortened approach resulted in similar clinical response and antibiotic-associated adverse effects, while reducing antibiotic exposure and resistance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02891915.

Does a Premaxillary Setback and Lip Adhesion Have a Negative Impact on Lip Outcome in Bilateral Cleft Patients?

BACKGROUND: The early premaxillary setback and lip adhesion remains as a controversial maneuver in the treatment of bilateral cleft lip and palate patients. This study aimed to assess extent of preoperative deformity and lip outcomes during the first year after surgery in bilateral cleft patients who underwent premaxillary setback and lip adhesion and to compare to those with primary lip repair. METHODS: A retrospective observational study was conducted of 16 nonsyndromic consecutive bilateral complete cleft lip patients (with and without Simonart band), who underwent primary cleft lip repair. Patients were allocated in group 1 without premaxillary setback and group 2 with premaxillary setback and lip adhesion. Preoperative and postoperative linear measurements were used for intergroup and intragroup comparisons. RESULTS: Cutaneous lip height of patients in group 2 significantly (P < 0.05) improved after combined premaxillary setback and lip adhesion and primary cleft lip repair. There were no significant (all P > 0.05) differences in intragroup 1 comparisons, and in intergroup comparisons. CONCLUSION: Bilateral cleft patients with a protruded and deviated premaxilla over 10 mm discrepancy of the lateral maxillary achieved noninferior lip symmetry 1 year postoperatively compared with patients with less severe original deformity.

Patient satisfaction with procedural sedation in the emergency department.

OBJECTIVE: The aim of this study was to determine patient satisfaction with procedural sedation as a function of nature of the procedure and depth of sedation. METHOD: We undertook a prospective observational study of adult patients who received procedural sedation in two EDs (20 month period). The level of sedation was determined by an investigator, using the Observers Assessment of Anaesthesia/Sedation Scale (1 = awake to 6 = no response to noxious stimuli). Patient satisfaction was measured with the Iowa Satisfaction with Anaesthesia Scale after full recovery. This was self-administered, comprised 11 items (e.g. 'I felt pain') and has a score range of -3 (poor satisfaction) to +3 (very satisfied). RESULTS: A total of 163 patients were enrolled (51.2% men, mean age 50.7 years). The median (interquartile range) satisfaction score was 2.7 (0.7). Patient satisfaction was lower among patients who had orthopaedic procedures (median 2.6 vs 2.8, P < 0.01) and among patients who had a pre-sedation opioid (2.6 vs 2.8, P = 0.03). Satisfaction was positively correlated with deeper sedation (Spearman's correlation coefficient 0.49, P < 0.001). Satisfaction also differed significantly between the four most common sedation regimens (P < 0.001). It was greatest among those who were administered propofol with or without fentanyl and least among those who were administered nitrous oxide with or without opioid. Patients sedated with propofol with or without fentanyl had the greatest depths of sedation. There was no difference in satisfaction among patients who were and were not sedated by a consultant (median 2.6 and 2.7, respectively, P = 0.84). CONCLUSION: Generally, the level of patient satisfaction is high. Greater satisfaction is associated with deeper sedation, sedation with propofol and non-orthopaedic procedures.

Observational study of alternative therapies among paediatric emergency department patients.

OBJECTIVE: While complementary medicine use among ED paediatric patients is common, the use of alternative therapies (ATs; physical or spiritual therapies) is unknown. We aimed to determine the 12 month period prevalence and nature of AT use among paediatric patients and parent perceptions of AT use. METHODS: We undertook a cross-sectional survey of a convenience sample of parents of paediatric patients in three EDs in metropolitan Melbourne, Australia (January-June, 2015). Parents were invited to complete a validated, anonymous, self-administered questionnaire. The main outcomes were AT use by the patient and parent perceptions of ATs. RESULTS: A total of 806 parents were enrolled. In the previous 12 months, 393 (48.8%) patients had received at least one AT. There were no gender or ethnicity differences between AT users and non-users. AT use was more common among older patients (P < 0.05). Patients with chronic illness tended to use more ATs (P = 0.12). A total of 1091 courses of 43 different ATs had been provided. The most common were massage (16% of patients), chiropractic therapy (9.8%), relaxation (7.2%), meditation (6.2%) and aromatherapy (6.1%). ATs were generally used for musculoskeletal problems, health maintenance, stress and anxiety. Parents who arranged the ATs were significantly more likely to report that ATs are safe, prevent and treat illness, assist prescription medicines and offer a more holistic approach to healthcare (P < 0.001). CONCLUSION: AT use is common among paediatric ED patients. Parents who arrange AT have differing perceptions of AT usefulness and safety from those who do not.

Variables associated with administration of analgesia, nurse-initiated analgesia and early analgesia in the emergency department.

OBJECTIVE: To determine the patient and clinical variables associated with administration of any analgesia, nurse-initiated analgesia (NIA, prescribed and administered by a nurse) and early analgesia (within 30 min of presentation). METHODS: We undertook a retrospective cohort study of patients who presented to a metropolitan ED in Melbourne, Australia, during July and August, 2013. The ED has an established NIA programme. Patients were included if they were aged 18 years or more and presented with a painful complaint. The study sample was randomly selected from a list of all eligible patients. Data were extracted electronically from the ED records and by explicit extraction from the medical record. Logistic regression models were constructed to assess associations with the three binary study end points. RESULTS: 1289 patients were enrolled. Patients were less likely to receive any analgesia if they presented 08:00-15:59 hours (OR 0.67, 95% CI 0.46 to 0.98) or 16:00-24:00 hours (OR 0.55, 95% CI 0.37 to 0.80) were triage category 5 (OR 0.20, 95% CI 0.08 to 0.49) or required an interpreter (OR 0.34, 95% CI 0.14 to 0.86). Patients were less likely to receive NIA or early analgesia if they were aged 56 years or more (OR 0.70 and 0.63; OR 0.57 and 0.21, respectively) or if they had received ambulance analgesia (OR 0.59, 95% CI 0.36 to 0.95; OR 0.38, 95% CI 0.20 to 0.74, respectively). CONCLUSIONS: Patients who present during the daytime, have a triage category of 5 or require an interpreter are less likely to receive analgesia. Older patients and those who received ambulance analgesia are less likely to receive NIA or early analgesia.

The effect of provision of pain management advice on patient satisfaction with their pain management: a pilot, randomised, controlled trial (pain advice trial).

OBJECTIVE: We aimed to provide pain advice ('The treatment of pain is very important and be sure to tell the staff when you have pain') as an intervention and evaluate its effect upon patient satisfaction. The purpose of this pilot trial was to ensure the design and methods of a future trial are sound, practicable and feasible. METHOD: We undertook a pilot, randomised, controlled, clinical intervention trial in a single ED. The control arm received standard care. The intervention arm received standard care plus pain advice from an independent investigator. All patients and treating ED staff were blinded to patient enrolment. Patient satisfaction with their pain management (six-point ordinal scale) was measured 48 h post-ED discharge, by a blinded researcher. The primary outcome was satisfaction with pain management. RESULTS: Of the 280 and 275 patients randomised to the control and intervention arms, respectively, 196 and 215 had complete data, respectively. 77.6% (152/196) and 88.8% (191/215) of patients reported being provided with pain advice, respectively (difference 11.3% (95% CI 3.6 to 19.0)). The intervention was associated with absolute and relative increases in patient satisfaction of 6.3% and 14.2%, respectively. 91.3% (179/196) and 76.3% (164/215) of patients who were/were not very satisfied reported having received 'pain advice' (difference 15.0% (95% CI 7.6 to 22.5)). CONCLUSIONS: The intervention to provide pain advice resulted in a non-significant increase in patient satisfaction. A larger multicentre trial is feasible and is recommended to further explore the effects of provision of pain advice. TRIAL REGISTRATION NUMBER: ACTRN12615000097549.

Disruption of the folate pathway in zebrafish causes developmental defects.

BACKGROUND: Folic acid supplementation reduces the risk of neural tube defects and congenital heart defects. The biological mechanisms through which folate prevents birth defects are not well understood. We explore the use of zebrafish as a model system to investigate the role of folate metabolism during development. RESULTS: We first identified zebrafish orthologs of 12 human folate metabolic genes. RT-PCR and in situ analysis indicated maternal transcripts supply the embryo with mRNA so that the embryo has an intact folate pathway. To perturb folate metabolism we exposed zebrafish embryos to methotrexate (MTX), a potent inhibitor of dihydrofolate reductase (Dhfr) an essential enzyme in the folate metabolic pathway. Embryos exposed to high doses of MTX exhibited developmental arrest prior to early segmentation. Lower doses of MTX resulted in embryos with a shortened anterior-posterior axis and cardiac defects: linear heart tubes or incomplete cardiac looping. Inhibition of dhfr mRNA with antisense morpholino oligonucleotides resulted in embryonic lethality. One function of the folate pathway is to provide essential one-carbon units for dTMP synthesis, a rate-limiting step of DNA synthesis. After 24 hours of exposure to high levels of MTX, mutant embryos continue to incorporate the thymidine analog BrdU. However, additional experiments indicate that these embryos have fewer mitotic cells, as assayed with phospho-histone H3 antibodies, and that treated embryos have perturbed cell cycles. CONCLUSIONS: Our studies demonstrate that human and zebrafish utilize similar one-carbon pathways. Our data indicate that folate metabolism is essential for early zebrafish development. Zebrafish studies of the folate pathway and its deficiencies could provide insight into the underlying etiology of human birth defects and the natural role of folate in development.

A genomewide screen for petite-negative yeast strains yields a new subunit of the i-AAA protease complex.

Unlike many other organisms, the yeast Saccharomyces cerevisiae can tolerate the loss of mitochondrial DNA (mtDNA). Although a few proteins have been identified that are required for yeast cell viability without mtDNA, the mechanism of mtDNA-independent growth is not completely understood. To probe the relationship between the mitochondrial genome and cell viability, we conducted a microarray-based, genomewide screen for mitochondrial DNA-dependent yeast mutants. Among the several genes that we discovered is MGR1, which encodes a novel subunit of the i-AAA protease complex located in the mitochondrial inner membrane. mgr1Delta mutants retain some i-AAA protease activity, yet mitochondria lacking Mgr1p contain a misassembled i-AAA protease and are defective for turnover of mitochondrial inner membrane proteins. Our results highlight the importance of the i-AAA complex and proteolysis at the inner membrane in cells lacking mitochondrial DNA.

The C-terminal half of Saccharomyces cerevisiae Mad1p mediates spindle checkpoint function, chromosome transmission fidelity and CEN association.

The evolutionarily conserved spindle checkpoint is a key mechanism ensuring high-fidelity chromosome transmission. The checkpoint monitors attachment between kinetochores and mitotic spindles and the tension between sister kinetochores. In the absence of proper attachment or tension, the spindle checkpoint mediates cell cycle arrest prior to anaphase. Saccharomyces cerevisiae Mad1p is required for the spindle checkpoint and for chromosome transmission fidelity. Moreover, Mad1p associates with the nuclear pore complex (NPC) and is enriched at kinetochores upon checkpoint activation. Using partial mad1 deletion alleles we determined that the C-terminal half of Mad1p is necessary and sufficient for checkpoint activation in response to microtubule depolymerizing agents, high-fidelity transmission of a reporter chromosome fragment, and in vivo association with centromeres, but not for robust NPC association. Thus, spindle checkpoint activation and chromosome transmission fidelity correlate and these Mad1p functions likely involve kinetochore association but not robust NPC association. These studies are the basis for elucidating the role of protein complexes containing Mad1p in the spindle checkpoint pathway and in maintaining genome stability in S. cerevisiae and other systems.

Bipolar orientation of chromosomes in Saccharomyces cerevisiae is monitored by Mad1 and Mad2, but not by Mad3.

The spindle checkpoint governs the timing of anaphase separation of sister chromatids. In budding yeast, Mad1, Mad2, and Mad3 proteins are equally required for arrest in the presence of damage induced by antimicrotubule drugs or catastrophic loss of spindle structure. We find that the MAD genes are not equally required for robust growth in the presence of more subtle kinetochore and microtubule damage. A mad1Delta synthetic lethal screen identified 16 genes whose deletion in cells lacking MAD1 results in death or slow growth. Eleven of these mad1Delta genetic interaction partners encode proteins at the kinetochore-microtubule interface. Analysis of the entire panel revealed similar phenotypes in combination with mad2Delta. In contrast, 13 panel mutants exhibited a less severe phenotype in combination with mad3Delta. Checkpoint arrest in the absence of bipolar orientation and tension (induced by replication block in a cdc6 mutant) was lacking in cells without MAD1 or MAD2. Cells without MAD3 were checkpoint-proficient. We conclude that Mad1 and Mad2 are required to detect bipolar orientation and/or tension at kinetochores, whereas Mad3 is not.

S-phase checkpoint genes safeguard high-fidelity sister chromatid cohesion.

Cohesion establishment and maintenance are carried out by proteins that modify the activity of Cohesin, an essential complex that holds sister chromatids together. Constituents of the replication fork, such as the DNA polymerase alpha-binding protein Ctf4, contribute to cohesion in ways that are poorly understood. To identify additional cohesion components, we analyzed a ctf4Delta synthetic lethal screen performed on microarrays. We focused on a subset of ctf4Delta-interacting genes with genetic instability of their own. Our analyses revealed that 17 previously studied genes are also necessary for the maintenance of robust association of sisters in metaphase. Among these were subunits of the MRX complex, which forms a molecular structure similar to Cohesin. Further investigation indicated that the MRX complex did not contribute to metaphase cohesion independent of Cohesin, although an additional role may be contributed by XRS2. In general, results from the screen indicated a sister chromatid cohesion role for a specific subset of genes that function in DNA replication and repair. This subset is particularly enriched for genes that support the S-phase checkpoint. We suggest that these genes promote and protect a chromatin environment conducive to robust cohesion.