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Resident cardiac macrophages are critical mediators of cardiac function. Despite their known importance to cardiac electrophysiology and tissue maintenance, there are currently no stem-cell-derived models of human engineered cardiac tissues (hECTs) that include resident macrophages. In this study, we made an induced pluripotent stem cell (iPSC)-derived hECT model with a resident population of macrophages (iM0) to better recapitulate the native myocardium and characterized their impact on tissue function. Macrophage retention within the hECTs was confirmed via immunofluorescence after 28 days of cultivation. The inclusion of iM0s significantly impacted hECT function, increasing contractile force production. A potential mechanism underlying these changes was revealed by the interrogation of calcium signaling, which demonstrated the modulation of β-adrenergic signaling in +iM0 hECTs. Collectively, these findings demonstrate that macrophages significantly enhance cardiac function in iPSC-derived hECT models, emphasizing the need to further explore their contributions not only in healthy hECT models but also in the contexts of disease and injury. [Display omitted] • Engineered cardiac tissues can maintain an iPSC-macrophage (iM0) population for 28 days • iM0s in engineered cardiac tissues take on a tissue-resident-like phenotype • iM0s alter cardiac tissue function, increasing contractile force production • Observed functional changes may be due to iM0 stimulation of the β-adrenergic pathway in iCMs Lock and Graney et al. develop a human engineered cardiac tissue with an incorporated iPSC-derived macrophage population to better mimic the complex cell landscape of the native myocardium. Macrophage inclusion leads to increased contractile function of the tissue, which is attributed to macrophage stimulation of the cardiomyocyte β-adrenergic signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Site-based cardiac rehabilitation (CR) provides supervised exercise, education and motivation for patients. Graduates of CR have improved exercise tolerance. However, when participation in CR ceases, adherence to regular physical activity often declines, consequently leading to worsening risk factors and clinical events. Therefore, the purpose of this pilot study was to evaluate if a mHealth program could sustain the fitness and physical activity levels gained during CR.Methods and Results: A 12-week mHealth program was implemented using physical activity trackers and health coaching. Twenty-five patients were randomized into mHealth or usual care after completing CR. The combination of a 4.7±13.8% increase in the mHealth and a 8.5±11.5% decrease in the usual care group resulted in a difference between groups (P≤.05) for absolute peak VO2. Usual care decreased the amount of moderate-low physical activity minutes per week (117±78 vs 50±53; P<.05) as well as moderate-high (111±87 vs 65±64; P<.05). mHealth increased moderate-high physical activity (138±113 vs 159±156; NS). The divergent changes between mHealth and usual care in moderate-high physical activity minutes/week resulted in a difference between groups (21±103 vs - 46±36; P<.05).Conclusions: A 12-week mHealth program of physical activity trackers and health coaching following CR graduation can sustain the gains in peak VO2 and physical activity achieved by site-based CR. [ABSTRACT FROM AUTHOR]

Abstract: It has been over a century since Perls described the first case of choroidal metastasis. For the next six decades only 230 cases were described in the literature. Today, however, ocular metastasis is recognized as the most common intraocular malignancy. Thanks to recent advances in treatment options for metastatic disease, patients are living longer, and choroidal metastases will become an increasingly important issue for oncologists and ophthalmologists alike. We summarize the current knowledge of choroidal metastases and examine their emerging systemic and local therapies. Targeted therapies for metastatic lung, breast, and colon cancer—the most common causes of choroidal metastases—are reviewed in detail with the goal of identifying the most effective treatment strategies. [Copyright &y& Elsevier]

We have shown that branching morphogenesis of mammary ductal structures requires the action of the morphogen epimorphin/syntaxin-2. Epimorphin, originally identified as an extracellular molecule, is identical to syntaxin-2, an intracellular molecule that is a member of the extensively investigated syntaxin family of proteins that mediate vesicle trafficking. We show here that, although epimorphin/syntaxin-2 is highly homologous to syntaxin-la, only epimorphin/syntaxin-2 can stimulate mammary branching morphogenesis. We construct a homology model of epimorphin/syntaxin-2 based on the published structure of syntaxin-1a, and we use this model to identify the structural motif responsible for the morphogenic activity. We identify four residues located within the cleft between helices B and C that differ between syntaxin-1a and epimorphin/syntaxin-2; through site-directed mutagenesis of these four amino acids, we confer the properties of epimorphin for cell adhesion, gene activation, and branching morphogenesis onto the inactive syntaxin-la template. These results provide a dramatic demonstration of the use of structural information about one molecule to define a functional motif of a second molecule that is related at the sequence level but highly divergent functionally. [ABSTRACT FROM AUTHOR]

: Study objectiveTo determine the significance of pain and other symptoms on the recovery process after ambulatory surgery, by surveying pain, analgesic use, and related aspects of recovery in the first 48 hours after discharge from an ambulatory surgery unit.: DesignProspective, observational, surveillance survey.: PatientsA total of 175 patients were studied, 25 in each of 6 surgical groups including knee arthroscopy, hernia repair, pelvic laparoscopy, transvaginal surgery, surgery for breast disease, and plastic surgery.: InterventionsPatients were treated in a manner considered normal or “usual” for the surgeon and the institution.: MeasurementsPain scores (0 to 10), analgesic use, symptom frequency, symptom distress scores, activity level (% of normal), and satisfaction scores were obtained by telephone interview 24 and 48 hours after discharge. Group means (±SE), proportions and correlations between predictor variables were determined in relevant groups.: Main resultsThe response rate to postoperative telephone calls was 89% at 24 hours, and 82% at 48 hours. At 24 hours, maximum pain was >3/10 in 60%, or >7/10 in 20% of patients. Pain prevented or disrupted sleep in 46% of patients. Activity level was reduced to 33% of normal at 24 hours; pain was reported as the primary or secondary reason for limiting activity by 54% of patients. At 24 hours, average pain scores correlated inversely with activity (r = −0.49, p = < 0.0001); least pain score correlated best with satisfaction (r = 0.03, p = 0.0005).: ConclusionsImprovements in pain therapy after discharge appear warranted to provide more consistent pain relief, and hasten return to normal activity. [Copyright &y& Elsevier]

Corneal techniques for enhancing near and intermediate vision to correct presbyopia include surgical and contact lens treatment modalities. Broad approaches used independently or in combination include correcting one eye for distant and the other for near or intermediate vision, (termed monovision or mini-monovision depending on the degree of anisometropia) and/or extending the eye's depth of focus [1]. This report reviews the evidence for the treatment profile, safety, and efficacy of the current range of corneal techniques for managing presbyopia. The visual needs and expectations of the patient, their ocular characteristics, and prior history of surgery are critical considerations for patient selection and preoperative evaluation. Contraindications to refractive surgery include unstable refraction, corneal abnormalities, inadequate corneal thickness for the proposed ablation depth, ocular and systemic co-morbidities, uncontrolled mental health issues and unrealistic patient expectations. Laser refractive options for monovision include surface/stromal ablation techniques and keratorefractive lenticule extraction. Alteration of spherical aberration and multifocal ablation profiles are the primary means for increasing ocular depth of focus, using surface and non-surface laser refractive techniques. Corneal inlays use either small aperture optics to increase depth of field or modify the anterior corneal curvature to induce corneal multifocality. In presbyopia correction by conductive keratoplasty, radiofrequency energy is applied to the mid-peripheral corneal stroma, leading to mid-peripheral corneal shrinkage and central corneal steepening. Hyperopic orthokeratology lens fitting can induce spherical aberration and correct some level of presbyopia. Postoperative management, and consideration of potential complications, varies according to technique applied and the time to restore corneal stability, but a minimum of 3 months of follow-up is recommended after corneal refractive procedures. Ongoing follow-up is important in orthokeratology and longer-term follow-up may be required in the event of late complications following corneal inlay surgery. [ABSTRACT FROM AUTHOR]

Abstract: Objective: An exploratory version of the Modified Brief Pain Inventory (mBPI-e) to measure acute post-operative pain, with new items on coughing, breathing, and concentration, was examined for their measurement properties. Study Design: This is a secondary study using data from two randomized clinical trials: general surgery trial (N=1050) and coronary artery bypass graft (CABG) surgery trial (N=1636). The measurements used in the two trials were: 1) mBPI-e; 2) clinician and patient global evaluations of medications; and 3) pain intensity diary. The mBPI-e and pain intensity were collected for 10 days. Clinician and patient global evaluations of medication were collected twice. The analyses conducted were: 1) exploratory factor analysis (EFA); 2) confirmatory factor analysis (CFA); 3) item response theory (IRT); 4) internal consistency; 5) test-retest reliability; 6) concurrent validity; 7) known-group validity; and 8) responsiveness. Results: Pain severity, pain interference, and coughing and breathing factors were identified. Pain severity and pain interference subscale scores were constructed for mBPI-e. IRT analyses showed all items exhibited good item characteristics. Internal consistency was 0.85 for severity and 0.87 for interference. Test-retest reliability was 0.81 for severity and 0.71 for interference. Both severity and interference scores were correlated with diary-based pain intensity ratings (P <.0001). Mean severity and interference scores varied by physician and patient global ratings (P <.05). Severity and interference scores were responsive to changes in pain diary scores and physician global ratings (P <.001). There were no substantive differences in reliability or validity for sub-samples of surgery patients. Conclusions: The original BPI has been used in clinical studies, and the mBPI has demonstrated good reliability and validity in CABG patients. Based on this study, the mBPI-e has also demonstrated good reliability and validity for assessing postoperative acute pain in CABG and general surgery patients. [Copyright &y& Elsevier]

To examine the safety and efficacy of soft multifocal contact lenses on slowing the rate of myopia progression. A prospective, randomized, double-masked clinical trial was conducted including 115 children (55 boys and 60 girls) aged 8 to 15 years. Children were assigned to wear one of two daily disposable soft contact lens designs; a multifocal design (Pegavision) or a dual-focus design (MiSight, Coopervision) in both eyes for at least 8 h per day for one year. All contact lenses were replaced on a daily basis. Measurements were obtained using a logMAR vision meter, including objective refraction, handheld retinoscopy, high (96 %) and low (12 %) contrast sensitivity, and distance and near visual acuity. Axial length was measured every 6 months. After one year, the spherical equivalent refractive error and axial length of the experimental group (Pegavision) increased by −0.50 ± 0.48 D and 0.24 ± 0.16 mm, respectively, in the right eye and −0.47 ± 0.37 D and 0.23 ± 0.16 mm, respectively, in the left eye. The spherical equivalent refractive error and axial length of the control group (MiSight) increased by −0.48 ± 0.47 D and 0.22 ± 0.13 mm, respectively, in the right eye and by −0.50 ± 0.44 D and 0.23 ± 0.14 mm, respectively, in the left eye, with no significant differences observed between the two lens types. The one-year results from this clinical trial show that the multifocal soft contact lenses used in the experimental group have a similar myopia control efficacy with respect to spherical equivalent refraction and axial length elongation as a commercially available dual focus soft contact lens design. [ABSTRACT FROM AUTHOR]

Purpose: To explore the journey taken by patients in a range of different countries to manage their dry eye symptoms.Method: Members of the general public who responded positively to the question "Do your eyes ever feel dry?" completed a questionnaire describing their demographics, the impact of their symptomology, the advice they have received and the management options they have tried. The Ocular Surface Disease Index (OSDI) questionnaire was also completed.Results: A total of 916 individuals (Canada = 235, Mexico = 127, New Zealand = 157, Taiwan = 246, UK = 151) of similar age distribution (median 38 years, IQR: 27-50) completed the survey. The reported duration of symptoms was longest in Canada (median 4 years, range 2-10) and least in Taiwan (2 years, range 1-3; p < 0.001), and similar trends were observed for symptom severity (p = 0.001). However, there was no statistically significant difference between countries with respect to the impact of symptoms on quality of life (median 3/10; p = 0.08). Less than half of the individuals in any country had consulted with a health professional. About half had tried a treatment for their dry eye symptoms, with artificial tears being the most common treatment, followed by warm compresses, and both therapies were rated as reasonably effective (median 5-7/10).Conclusion: Many people with dry eye symptoms are not consulting health care professionals who can confirm the diagnosis, exclude differential diagnoses, and offer a wide range of treatments targeted at the dry eye subtype. [ABSTRACT FROM AUTHOR]

Objectives: Indications for the use of stents are evolving and their optimal place in therapy remains to be defined. The objective was to compare the 1-year clinical and economic outcomes of percutaneous transluminal coronary agioplasty (PTCA) with and without the use of stents. Methods: This retrospective database analysis was conducted using data from 60 US academic medical centers in 1996 and 1997. Outcomes of interest included in-hospital mortality (both on sentinel and readmission visits), readmission rates, revascularization procedures, length of stay, and the cost of sentinel and readmission hospitalization. Results: A total of 27,020 patients either did (n = 13,254) or did not (n = 13,766) receive coronary stents in conjunction with PTCA. The median cost of hospitalization for the stent group was about $1,409 higher (mean, $1,200) than the no-stent group and the length of stay was similar (4.3 days vs. 4.5 days, respectively, P = .2628). Mortality rates on readmission (0.9% stent vs. 0.8% no-stent, P = NS) did not differ. However, patients in the stent group had better mortality rates compared to the no-stent group during the sentinel visit (1.7% vs. 2.7%, P < .001). Stent use was not associated with a significantly lower risk of a revascularization procedure on readmission to the same institution (OR 0.95, 95% CI 0.87–1.04, P = .28). Conclusions: Stents were associated with a 1% decrease of inpatient mortality during the sentinel visit without impacting length of stay or readmission rates. This advantage was associated with a $1,409 higher median cost of hospitalization in the stent group. [ABSTRACT FROM AUTHOR]

Highlights • Classification and labeling of chemicals as hazards is occurring at an increasing pace in Europe as laws regulating chemicals are implemented. • It is important to use best practices in order to appropriately interpret developmental toxicity data. • Recommendations are made concerning data quality, improved study designs, the proper interpretation of maternal toxicity data, interpretation of mechanistic data, and defining the limits of chemical classes are presented. Abstract Many chemicals are going through a hazard-based classification and labeling process in Europe. Because of the significant public health implications, the best science must be applied in assessing developmental toxicity data. The European Teratology Society and Health and Environmental Sciences Institute co-organized a workshop to consider best practices, including data quality and consistency, interpretation of developmental effects in the presence of maternal toxicity, human relevance of animal data, and limits of chemical classes. Recommendations included larger historical control databases, more pharmacokinetic studies in pregnant animals for dose setting and study interpretation, generation of mechanistic data to resolve questions about whether maternal toxicity is causative of developmental toxicity, and more rigorous specifications for what constitutes a chemical class. It is our hope that these recommendations will form the basis for subsequent consensus workshops and other scientific activities designed to improve the scientific robustness of data interpretation for classification and labeling. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of focal (hemiablation) or total cryotherapy and minimum tumor temperature on patient-reported quality of life (QoL) in patients with prostate cancer.Methods: An Institutional Review Board-approved database was reviewed for patients who underwent cryotherapy or active surveillance (AS). QoL questionnaire responses were collected and scores were analyzed for differences between focal and total cryotherapy and between very cold (<-76°C) and moderate-cold (≥-76°C) minimum tumor temperatures.Results: A total of 197 patients responded to a total of 547 questionnaires. Focal and total cryotherapy patients had initially lower sexual function scores relative to AS (year 1 mean difference focal: -31.7, P <.001; total: -48.1, P <.001). Focal cryotherapy was associated with a more rapid improvement in sexual function. Both focal and total cryotherapy sexual function scores were not statistically significantly different from the AS cohort by postprocedural year 4. Very cold and moderate-cold temperatures led to initially lower sexual function scores relative to AS (year 1 very cold: -38.1, P <.001; moderate-cold: -30.7, P <.001). Moderate-cold temperature scores improved more rapidly than those of very cold temperature. Neither very cold nor moderate-cold temperatures had a statistically significant difference in sexual function scores relative to AS by postprocedural year 4. Urinary function and bowel habits were not significantly different between focal and total cryotherapy and between very cold and moderate-cold temperature groups.Conclusion: Focal cryotherapy and moderate-cold (≥-76°C) temperature were associated with favorable sexual function relative to total cryotherapy and very cold temperature, respectively. No significant differences in urinary function or bowel habits were observed between groups. [ABSTRACT FROM AUTHOR]

Small molecule pharmaceutical products are assumed to reach concentrations in semen similar to those in blood plasma. Exposure modeling for these small-molecule products in humans assumes a daily dose of 5 mL of semen and 100% absorption from the vagina with distribution to the conceptus through the maternal systemic circulation. Monoclonal antibody drugs are present in semen at concentrations about 2% or less of those in blood, and the modeling used for small molecules will over-estimate the possibility of conceptus exposure to immunoglobulins. It is not known whether peptide products reach semen, but in general peptide medications are destroyed by vaginal peptidases, and conceptus exposure is predicted to be minimal. Theoretical exposure routes to pharmaceuticals that might result in exposure of the conceptus greater than that of maternal systemic exposures include direct access through the cervical canal, adsorption to sperm for carriage into the oocyte, and direct delivery from the vaginal veins or lymphatics to the uterine artery. There is some evidence for direct access to the uterus for progesterone, terbutaline, and danazol, but the evidence does not involve exposures during pregnancy in most instances. Studies in mice, rats, rabbits, and monkeys do not suggest that exposure to small molecule pharmaceuticals in semen imposes risks to the conceptus beyond those that can be predicted using modeling of systemic maternal exposure. Monoclonal antibody and peptide exposure in semen does not pose a significant risk to the conceptus. [ABSTRACT FROM AUTHOR]

Small molecule pharmaceutical products are assumed to reach concentrations in semen similar to those in blood plasma. Exposure modeling for these small-molecule products in humans assumes a daily dose of 5 mL of semen and 100% absorption from the vagina with distribution to the conceptus through the maternal systemic circulation. Monoclonal antibody drugs are present in semen at concentrations about 2% or less of those in blood, and the modeling used for small molecules will over-estimate the possibility of conceptus exposure to immunoglobulins. It is not known whether peptide products reach semen, but in general peptide medications are destroyed by vaginal peptidases, and conceptus exposure is predicted to be minimal. Theoretical exposure routes to pharmaceuticals that might result in exposure of the conceptus greater than that of maternal systemic exposures include direct access through the cervical canal, adsorption to sperm for carriage into the oocyte, and direct delivery from the vaginal veins or lymphatics to the uterine artery. There is some evidence for direct access to the uterus for progesterone, terbutaline, and danazol, but the evidence does not involve exposures during pregnancy in most instances. Studies in mice, rats, rabbits, and monkeys do not suggest that exposure to small molecule pharmaceuticals in semen imposes risks to the conceptus beyond those that can be predicted using modeling of systemic maternal exposure. Monoclonal antibody and peptide exposure in semen does not pose a significant risk to the conceptus. [ABSTRACT FROM AUTHOR]

Summary: Background: In previous clinical trials of patients with metastatic renal-cell carcinoma, patients treated with axitinib as second-line therapy had longer median progression-free survival than those treated with sorafenib. We therefore undertook a phase 3 trial comparing axitinib with sorafenib in patients with treatment-naive metastatic renal-cell carcinoma. Methods: In this randomised, open-label, phase 3 trial, patients with treatment-naive, measurable, clear-cell metastatic renal-cell carcinoma from 13 countries were stratified by Eastern Cooperative Oncology Group performance status, and then randomly assigned (2:1) by a centralised registration system to receive axitinib 5 mg twice daily, or sorafenib 400 mg twice daily. The primary endpoint was progression-free survival, assessed by masked independent review committee in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT00920816. Findings: Between June 14, 2010, and April 21, 2011, we randomly assigned 192 patients to receive axitinib, and 96 patients to receive sorafenib. The cutoff date for this analysis was July 27, 2012, when 171 (59%) of 288 patients died or had disease progression, as assessed by the independent review committee. There was no significant difference in median progression-free survival between patients treated with axitinib or sorafenib (10·1 months [95% CI 7·2–12·1] vs 6·5 months [4·7–8·3], respectively; stratified hazard ratio 0·77, 95% CI 0·56–1·05). Any-grade adverse events that were more common (≥10% difference) with axitinib than with sorafenib were diarrhoea (94 [50%] of 189 patients vs 38 [40%] of 96 patients), hypertension (92 [49%] vs 28 [29%]), weight decrease (69 [37%] vs 23 [24%]), decreased appetite (54 [29%] vs 18 [19%]), dysphonia (44 [23%] vs ten [10%]), hypothyroidism (39 [21%] vs seven [7%]), and upper abdominal pain (31 [16%] vs six [6%]); those more common with sorafenib than with axitinib included palmar-plantar erythrodysaesthesia (PPE; 37 [39%] of 96 patients vs 50 [26%] of 189), rash (19 [20%] vs 18 [10%]), alopecia (18 [19%] vs eight [4%]), and erythema (18 [19%] vs five [3%]). The most common grade 3 or 4 adverse events in patients treated with axitinib included hypertension (26 [14%] of 189 patients), diarrhoea (17 [9%]), asthenia (16 [8%]), weight decrease (16 [8%]), and PPE (14 [7%]); common grade 3 or 4 adverse events in patients treated with sorafenib included PPE (15 [16%] of 96 patients), diarrhoea (five [5%]), and asthenia (five [5%]). Serious adverse events were reported in 64 (34%) of 189 patients receiving axitinib, and 24 (25%) of 96 patients receiving sorafenib. Interpretation: Axitinib did not significantly increase progression-free survival in patients with treatment-naive metastatic renal-cell carcinoma compared with those treated with sorafenib, but did demonstrate clinical activity and an acceptable safety profile. Funding: Pfizer Inc. [ABSTRACT FROM AUTHOR]

Summary: Background: In a phase 3 trial comparing the efficacy and safety of axitinib versus sorafenib as second-line treatment for metastatic renal cell carcinoma, patients given axitinib had a longer progression-free survival (PFS). Here, we report overall survival and updated efficacy, quality of life, and safety results. Methods: Eligible patients had clear cell metastatic renal cell carcinoma, progressive disease after one approved systemic treatment, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1. 723 patients were stratified by ECOG PS and previous treatment and randomly allocated (1:1) to receive axitinib (5 mg twice daily; n=361) or sorafenib (400 mg twice daily; n=362). The primary endpoint was PFS assessed by a masked, independent radiology review committee. We assessed patient-reported outcomes using validated questionnaires. Baseline characteristics and development of hypertension on treatment were studied as prognostic factors. Efficacy was assessed in the intention-to-treat population, and safety was assessed in patients who received at least one dose of the study drug. This ongoing trial is registered on ClinicalTrials.gov, number NCT00678392. Findings: Median overall survival was 20·1 months (95% CI 16·7–23·4) with axitinib and 19·2 months (17·5–22·3) with sorafenib (hazard ratio [HR] 0·969, 95% CI 0·800–1·174; one-sided p=0·3744). Median investigator-assessed PFS was 8·3 months (95% CI 6·7–9·2) with axitinib and 5·7 months (4·7–6·5) with sorafenib (HR 0·656, 95% CI 0·552–0·779; one-sided p<0·0001). Patient-reported outcomes scores were similar in the treatment groups at baseline, were maintained during treatment, but decreased at end-of-treatment. Common grade 3 or higher treatment-related adverse events were hypertension (60 [17%]), diarrhoea (40 [11%]), and fatigue (37 [10%]) in 359 axitinib-treated patients and hand–foot syndrome (61 [17%]), hypertension (43 [12%]), and diarrhoea (27 [8%]) in 355 sorafenib-treated patients. In a post-hoc 12-week landmark analysis, median overall survival was longer in patients with a diastolic blood pressure of 90 mm Hg or greater than in those with a diastolic blood pressure of less than 90 mm Hg: 20·7 months (95% CI 18·4–24·6) versus 12·9 months (10·1–20·4) in the axitinib group (p=0·0116), and 20·2 months (17·1–32·0) versus 14·8 months (12·0–17·7) in the sorafenib group (one-sided p=0·0020). Interpretation: Although overall survival, a secondary endpoint for the study, did not differ between the two groups, investigator-assessed PFS remained longer in the axitinib group compared with the sorafenib group. These results establish axitinib as a second-line treatment option for patients with metastatic renal cell carcinoma. Funding: Pfizer Inc. [ABSTRACT FROM AUTHOR]

Abstract: The chemistry of trifluoromethyl ketones has been studied. The work examines the condensation reactions of trifluoromethyl ketones with arenes in the superacid, including both synthetic and mechanistic aspects. [ABSTRACT FROM AUTHOR]

SsgA-like proteins (SALPs) are a family of homologous cell division-related proteins that occur exclusively in morphologically complex actinomycetes. We show that SsgB, a subfamily of SALPs, is the archetypal SALP that is functionally conserved in all sporulating actinomycetes. Sporulation-specific cell division of Streptomyces coelicolor ssgB mutants is restored by introduction of distant ssgB orthologues from other actinomycetes. Interestingly, the number of septa (and spores) of the complemented null mutants is dictated by the specific ssgB orthologue that is expressed. The crystal structure of the SsgB from Thermobifida fusca was determined at 2.6 Å resolution and represents the first structure for this family. The structure revealed similarities to a class of eukaryotic "whirly" single-stranded DNA/RNA-binding proteins. However, the electro-negative surface of the SALPs suggests that neither SsgB nor any of the other SALPs are likely to interact with nucleotide substrates. Instead, we show that a conserved hydrophobic surface is likely to be important for SALP function and suggest that proteins are the likely binding partners. [ABSTRACT FROM AUTHOR]

This health outcomes analysis based on data from a randomized, double-blind, placebo-controlled trial determined dose-response relationship between opioid use and related symptoms. All patients received intravenous fentanyl on demand for pain predischarge, and oral acetaminophen 500 mg/hydrocodone 5 mg every 4–6 hours as needed postdischarge for up to 7 days postsurgery. Patients completed an opioid-related Symptom Distress Scale (SDS) questionnaire every 24 hours postdischarge for 7 days, which assessed 12 opioid-related symptoms by 3 ordinal measures: frequency, severity, and bothersomeness. Clinically meaningful events (CMEs) were defined based on the responses to this questionnaire. Opioid use was converted to morphine equivalent dose (MED). The dose-response relationship between composite SDS scores and MED on Day 1, on Days 0 and 1, and on Days 1–4, was assessed. SDS scores for all 12 symptoms within the 3 dimensions were significantly associated with MED on Day 1 (F-value = 1.56; P = 0.04), as well as cumulative MED used on Days 0 and 1 (F-value = 1.85; P<0.01). Patients with a specific CME used a higher MED than those without a CME on Day 1 (P<0.001). Between Days 1 and 4, patients with a higher number of patient-CME-days used a significantly higher MED. Regression analyses suggested that once the MED reached a threshold, approximately every 4 mg increase in MED was related to 1 additional patient-CME-day (P<0.01). A dose-response relationship empirically exists between MED and directly assessed opioid-related CMEs after ambulatory laparoscopic cholecystectomy. Once daily MED reaches a threshold, every 3–4 mg increase will be associated with 1 additional clinically meaningful opioid-related symptom, or 1 additional patient-day with an opioid-related CME. [Copyright &y& Elsevier]

Opioids have demonstrated efficacy and often are drugs of choice in the management of postoperative pain. However, their use is often limited by adverse drug events (ADEs). The objective of this study was to determine the ADE rate in adult surgical patients who received opioids and the impact of opioid ADEs on length of stay (LOS), costs, and mortality. A hospital-based computerized system detected potential ADEs. Adult patients were selected if they received at least one dose of opioid medication during a surgical hospitalization between 1 January 1990 and 31 December 1999. Control patients were matched based on matching length of stay ([LOS] at least as long as time to ADE), age (within 10 years), sex, admission year, major disease category (MDC), and without an ADE. Linear regression models were used to determine the predictors of increased LOS, total hospital costs, and log-transformed total hospital costs. 60,722 patients received opioid medication during their surgical hospitalization and 2.7% experienced an opioid-related ADE. The most common clinical manifestations were nausea and vomiting (67%), and rash, hives, or itching (33.5%). No statistically significant difference was seen in mortality between ADE/non-ADE patients. ADE patients had statistically significant increases in LOS (0.53 days) and in log-transformed cost (16%). The estimated log cost difference of 16%, if applied to the median cost patient in the non-ADE group, averaged US$ 840. Opioid-related ADEs are common in hospitalized patients and increase LOS and total hospital costs. [ABSTRACT FROM AUTHOR]

Study Objective: To determine the rate of unanticipated admissions and readmissions, and to characterize the associated reasons and costs.Design: Retrospective medical records database analysis.Setting: University teaching hospital.Patients: Any patient undergoing same day surgery (SDS) during a 12-month period.Measurements: All nonelective return visits to the hospital within 30 days and the reasons for return were identified.Main Results: There were a total of 20,817 patients who underwent SDS in 1999; 1,195 (5.7%) of these returned to the hospital within 30 days or were admitted directly after surgery. Of those unanticipated admissions and readmissions, 313 (1.5%) were directly related to the original SDS procedure. The mean age of these patients was 51 years, 164 (52%) were female, and 266 (85%) were Caucasian. Pain was the most commonly reported reason for return, occurring in 120 (38%) patients who had an unanticipated admission or readmission. After controlling for SDS volume, the general surgery service had the highest rate of unanticipated admissions or readmissions (3.2%), followed by otolaryngology (3.1%) and urology (2.9%). Of the 120 patients returning with unanticipated admissions and readmissions due to pain, 46 (38%) had orthopedic procedures during their index SDS. Mean charges for patients with unanticipated admissions and readmission due to pain were $1,869 ± $4,553 per visit, whereas charges for nonpain related readmissions were $12,000 ± $36,886.Conclusion: At our teaching institution, approximately 1.5% of patients undergoing outpatient ambulatory surgery return within 30 days due to problems directly related to the original surgical procedure. Pain accounted for more than one third of return visits, incurring significant costs. Efforts to manage pain should focus not only on pain in the hospital but also anticipation of pain-related issues on discharge. [Copyright &y& Elsevier]