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The emergence of a transferable colistin resistance gene (mcr-1) is of global concern. The insertion sequence ISApl1 is a key component in the mobilization of this gene, but its role remains poorly understood. Six Escherichia coli isolates were cultured from the same patient over the course of 1 month in Germany and the United States after a brief hospitalization in Bahrain for an unconnected illness. Four carried mcr-1 as determined by real-time PCR, but two were negative. Two additional mcr-1-negative E. coli isolates were collected during follow-up surveillance 9 months later. All isolates were analyzed by whole-genome sequencing (WGS). WGS revealed that the six initial isolates were composed of two distinct strains: an initial ST-617 E. coli strain harboring mcr-1 and a second, unrelated, mcr-1-negative ST-32 E. coli strain that emerged 2 weeks after hospitalization. Follow-up swabs taken 9 months later were negative for the ST-617 strain, but the mcr-1-negative ST-32 strain was still present. mcr-1 was associated with a single copy of ISApl1, located on a 64.5-kb IncI2 plasmid that shared >95% homology with other mcr-1 IncI2 plasmids. ISApl1 copy numbers ranged from 2 for the first isolate to 6 for the final isolate, but ISApl1 movement was independent of mcr-1. Some movement was accompanied by gene disruption, including the loss of genes encoding proteins involved in stress responses, arginine catabolism, and l-arabinose utilization. These data represent the first comprehensive analysis of ISApl1 movement in serial clinical isolates and reveal that, under certain conditions, ISApl1 is a highly active IS element whose movement may be detrimental to the host cell.

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Stress conditions, such as a block in fatty acid synthesis, signal bacterial cells to exit the cell cycle. Caulobacter crescentus FabH is a cell-cycle-regulated b-ketoacyl-acyl carrier protein synthase that initiates lipid biosynthesis and is essential for growth in rich media. To explore how C. crescentus responds to a block in lipid biosynthesis, we created a FabH-depletion strain. We found that FabH depletion blocks lipid biosynthesis in rich media and causes a cell cycle arrest that requires the alarmone (p)ppGpp for adaptation. Notably, basal levels of (p)ppGpp coordinate both a reduction in cell volume and a block in the over-initiation of DNA replication in response to FabH depletion. The gene ctrA encodes a master transcription factor that directly regulates 95 cell-cycle-controlled genes while also functioning to inhibit the initiation of DNA replication. Here, we demonstrate that ctrA transcription is (p)ppGpp-dependent during fatty acid starvation. CtrA fails to accumulate when FabH is depleted in the absence of (p)ppGpp due to a substantial reduction in ctrA transcription. The (p)ppGpp-dependent maintenance of ctrA transcription during fatty acid starvation initiated from only one of the two ctrA promoters. In the absence of (p)ppGpp, the majority of FabH-depleted cells enter a viable but non-culturable state, with multiple chromosomes, and are unable to recover from the miscoordination of cell cycle events. Thus, basal levels of (p)ppGpp facilitate C. crescentus' re-entry into the cell cycle after termination of fatty acid starvation.

Background: Lateral epicondylitis is a common overuse injury affecting approximately 1 to 3 percent of the population. Although symptoms may disappear spontaneously within 1 year, the clinical guidelines for conservative treatment are not clear. The authors’ objective was to examine the outcomes of nonsurgical treatments for lateral epicondylitis through a meta-analysis and provide a treatment recommendation using the available evidence. Methods: The authors searched the PubMed, EMBASE, Scopus, and Web of Science databases to identify primary research articles studying conservative treatments (electrophysiotherapy, physical therapy, and injections) for lateral epicondylitis. The authors included randomized controlled trials published in peer-reviewed journals. Data related to outcomes (pain, grip strength, Patient-Rated Tennis Elbow Evaluation score, and Disabilities of the Arm, Shoulder and Hand score) and complications were extracted. Results: Fifty-eight randomized controlled trials were included in the meta-analysis. Electrophysiotherapy was effective in improving pain [mean difference, −10.0 (95 percent CI, −13.8 to −6.1)], Patient-Rated Tennis Elbow Evaluation score [mean difference, −10.7 (95 percent CI, −16.3 to −5.0)], and Disabilities of the Arm, Shoulder and Hand score [mean difference, −11.9 (95 percent CI, −15.8 to −7.9)]; and physical therapy improved pain [mean difference, −6.0 (95 percent CI, −9.7 to −2.3)] and Patient-Rated Tennis Elbow Evaluation scores [mean difference, −7.5 (95 percent CI, −11.8 to −3.2)] compared to placebo. Injections did not improve any outcome measures. Patients who received electrophysiotherapy and injections reported higher adverse effects than physical therapy patients. Conclusions: Patients who received electrophysiotherapy and physical therapy reported statistically and clinically improved scores in pain and function compared to placebo. Injections may put patients at higher risk for adverse effects compared to other conservative treatments. When managing lateral epicondylitis conservatively, electrophysiotherapy and physical therapy should be prioritized before other interventions. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I.

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Purpose We sought to evaluate how often physicians who perform carpal tunnel release (CTR) in the State of Michigan routinely request electrodiagnostic studies (EDS) or other diagnostic tests prior to an initial consultation, and whether provider or practice characteristics had an influence on requirements for pre-consultation diagnostic tests. Methods Through online data sources, we identified 356 providers in 261 practices throughout the State of Michigan with profiles confirming hand surgery practice or surgical treatment of carpal tunnel syndrome (CTS). We recorded American Society for Surgery of the Hand (ASSH) membership, teaching facility status, practice size, and primary specialty for each provider. Using a standardized telephone script, 219 providers were contacted by telephone to determine whether any diagnostic tests were needed before an appointment. Using multivariable logistic regression, we evaluated the relationship between the requirement for pre-consultation testing and surgeon and practice characteristics. Results Among the 134 providers who were confirmed to perform CTR, 57% (n=76) required and 9% (n=12) recommended a diagnostic test prior to the initial consultation. Of the 88 physicians who required/recommended testing, 85% (n=75) requested EDS, 22% (n=19) requested an MRI, 13% (n=11) requested a CT scan, and 9% (n=8) requested an X-ray. Patients were asked to have multiple studies by 19 (22%) of the 88 surgeons who requested/recommended testing. In the multivariable analysis, ASSH membership, size of practice and teaching facility status did not have a significant relationship with the requirement for pre-consultation testing. Conclusions Most surgeons who treat CTS in the State of Michigan routinely request EDS before evaluation, rather than reserving the test for cases where the diagnosis is unclear.

Background As morbidity due to viral co-infections declines among HIV-infected persons, changes in liver related morbidity are anticipated. We examined data from the US Military HIV Natural History Study (NHS), a cohort of military beneficiaries, to evaluate incidence and risk factors associated with chronic liver enzyme elevation (cLEE) in HIV mono-infected patients in the combination antiretroviral therapy (cART) era. Methods Participants who were HBV and HCV seronegative with follow-up after 1996 were included. We defined chronic liver enzyme elevation (cLEE) as alanine aminotransferase (ALT) elevations ≥ 1.25 times the upper limit of normal on at least two visits, for a duration of six months or more within 2 years. We used multivariate Cox proportional hazards models to examine risk factors for cLEE. Results Of 2,779 participants, 309 (11%) met criteria for cLEE for an incidence of 1.28/100 PYFU (1.28 – 1.29). In an adjusted model, cLEE was associated with Hispanic/other ethnicity [Reference Caucasian: HR 1.744 (1.270 – 2.395)], non–nucleoside reverse transcriptase (NNRTI) based cART [Reference boosted protease inhibitors: HR 2.232 (1.378 – 3.616)], being cART naïve [HR 6.046 (3.686 – 9.915)] or having cART interruptions [HR 8.671 (4.651 – 16.164)]. African American race [HR 0.669 (0.510 – 0.877)] and integrase strand transfer inhibitor (INSTI) based cART [HR 0.222 (0.104 – 0.474)] were protective. Conclusions Our findings demonstrate initiation and continued use of cART is protective against cLEE and supports the hypothesis HIV infection directly impacts the liver. INSTI based regimens were protective and could be considered in persons with cLEE.