The association between mechanical temporal summation, state anxiety at baseline, and persistent low back pain: a 12-month prospective cohort study.

BACKGROUND: Persons with acute low back pain (LBP) have a good prognosis for regaining function, while pain often persists. Neurobiological and psychosocial factors are recognized to amplify pain responses, as reported for central sensitization. This study investigated the combination of mechanical temporal summation (TS) chosen to characterize central sensitization and state anxiety representing a psychological factor and their association with persistent pain. METHODS: A longitudinal prospective cohort study including 176 participants aged between 18 and 65 with acute LBP was performed. The following independent variables were analyzed at baseline: The mechanical TS at the lower back, of whom the Wind-up ratio (WUR) was calculated, and the state anxiety level measured with the State and Trait Anxiety Inventory (STAI-S). The outcome pain intensity was assessed at baseline and 2,3,6 and 12 months after the onset of acute LBP with the Numeric Rating Scale 0-10 (NRS). Linear mixed models (LMM) were used to analyze the association of the independent variables with pain intensity over time. RESULTS: The mean baseline WUR was 1.3 (SD 0.6) for the right and 1.5 (SD 1.0) for the left side. STAI-S revealed a mean score of 43.1 (SD 5.2). Pain intensity was, on average, 5.4 points (SD 1.6) on the NRS and decreased over one year to a mean of 2.2 (SD 2.4). After one year, 56% of the participants still experienced pain. The LMM revealed a considerable variation, as seen in large confidence intervals. Therefore, associations of the independent variables (WUR and STAI-S) with the course of the outcome pain intensity over one year were not established. CONCLUSION: This investigation did not reveal an association of mechanical TS and state anxiety at baseline with pain intensity during the one-year measurement period. Pain persistence, mediated by central sensitization, is a complex mechanism that single mechanical TS and state anxiety cannot capture.

A Non-Randomized Trial of In-Person Versus Text/Telephone Screening, Brief Intervention and Referral to Treatment for Pregnant and Postpartum Women.

Background: Systems of care that improve mental health and substance use disorder Screening, Brief Intervention and Referral to Treatment (SBIRT) for pregnant and postpartum women are needed. Aims: The aim of this study is to determine if women receiving prenatal care from January 2020 to April 2021 are more likely to be screened, screen positive, be referred for treatment and attend treatment with technology facilitated SBIRT, compared to women receiving prenatal care and in-person SBIRT January 2017 to December 2019. Materials & Methods: Technology facilitated SBIRT, designated Listening to Women (LTW), includes text message-based screening, phone-based brief intervention, and referral to treatment by a remote care coordinator. A total of 3535 pregnant and postpartum women were included in the quasi-experimental study and data were collected via text message and Electronic Health Record. Results: In-person SBIRT was completed by 65.2% (1947/2988) of women while 98.9% (547/553) of women approached agreed to take part in LTW and 71.9% (393/547) completed SBIRT via LTW. After controlling for potentially confounding variables, women enrolled in LTW were significantly more likely to be screened (relative risk [RR]: 1.10, 95% CI 1.03-1.16), screen positive (RR 1.91, 95% CI 1.72-2.10), referred to treatment (RR 1.55, 95% CI 1.43-1.69) and receive treatment (RR 4.95, 95% CI 3.93-6.23), compared to women receiving in-person SBIRT. Black women enrolled in LTW were significantly more likely to screen positive (RR 1.65, 95% CI 1.35-2.01), be referred to treatment (RR 1.54, 95% CI 1.35-1.76) and attend treatment (RR 5.49, 95% CI 3.69-8.17), compared to Black women receiving in-person SBIRT. Discussion: LTW appears to increase the proportion of pregnant and postpartum women receiving key elements of SBIRT.

Evaluation of Acute Postoperative Pain Management During an Injectable Opioid Shortage.

BACKGROUND: Drug product shortages, including injectable opioids, are common and have the potential to adversely affect patient care. OBJECTIVE: To evaluate the impact of an injectable opioid shortage for hospitalized adult patients in the acute postoperative setting. METHODS: A single-center, retrospective cohort study of noncritically ill hospitalized, postoperative patients requiring opioids for acute pain management was conducted. Patient cohorts were compared preshortage and postshortage for proportion of total intravenous (IV) opioids used, proportions of specific pain medications used, subjective pain scores, 30-day mortality, respiratory depression, need for opioid reversal, hospital length of stay, and opioid equivalent doses. RESULTS: A total of 275 patients were included, 130 patients in the preshortage cohort and 145 in the postshortage cohort. The proportion of total IV opioid doses was lower in the postshortage cohort versus the preshortage cohort (16.6% vs 20.5%; P < 0.01). Specific medications used were significantly different between the cohorts. The proportion of severe pain scores was lower in the postshortage cohort versus the preshortage cohort (55.6% vs 58.5%; P = 0.04). No significant differences were seen in the overall proportion of nonopioid analgesic use, 30-day mortality, respiratory depression, need for emergent opioid reversal, hospital length of stay, or opioid equivalent doses between cohorts. CONCLUSION AND RELEVANCE: In hospitalized, postoperative adults, an injectable opioid shortage was associated with significant decreases in IV opioid use and severe pain scores but no significant differences in nonopioid analgesic use, safety outcomes, or opioid equivalent doses. These results may assist clinicians in developing strategies for injectable opioid shortages and generating hypotheses for future studies.

Integration of Around-the-Clock Clinical Pharmacy Specialists Into the Critical Care Team Can Increase Safety of Hyperglycemic Crisis Management.

IN BRIEF "Quality Improvement Success Stories" are published by the American Diabetes Association in collaboration with the American College of Physicians, Inc., and the National Diabetes Education Program. This series is intended to highlight best practices and strategies from programs and clinics that have successfully improved the quality of care for people with diabetes or related conditions. Each article in the series is reviewed and follows a standard format developed by the editors of Clinical Diabetes. The following article describes an effort to improve the safety of hyperglycemic crisis management at a Veterans Affairs Medical Center by making clinical pharmacy specialists available to the critical care team 24 hours/day.

A Bedside Computerized Decision-Support Tool for Intravenous Insulin Infusion Management in Critically Ill Patients.

Intravenous (IV) insulin infusions using a validated protocol are the recommended method for blood glucose control in critically ill patients. Computerized decision-support tools improve quality over manual paper-based protocols. However, nonproprietary computerized tools targeting the recommended blood glucose range of 140-180 mg/dL are not readily available. A bedside computerized decision-support tool was developed at a US Department of Veterans Affairs health system to assist the nursing staff with the management of patients requiring IV insulin infusion. Initial evaluation showed that the tool was useful in the safe and effective management of an IV insulin infusion protocol for blood glucose control targeting the updated blood glucose range.

Impact of a Pharmacy-Cardiology Collaborative Practice on Dofetilide Safety Monitoring.

BACKGROUND: Limited studies have been published examining dofetilide's postmarketing use and its recommended monitoring. OBJECTIVE: To evaluate the impact of a collaborative pharmacy-cardiology antiarrhythmic drug (AAD) monitoring program on dofetilide monitoring. METHODS: This retrospective cohort study was performed to assess if a novel monitoring program improved compliance with dofetilide-specific monitoring parameters based on the Food and Drug Administration's Risk Evaluation and Mitigation Strategy. RESULTS: A total of 30 patients were included in the analysis. The monitoring parameters evaluated included electrocardiogram, serum potassium, serum magnesium, and kidney function. The primary outcome evaluated was the composite of these dofetilide monitoring parameters obtained in each cohort. In the standard cohort, 245 of 352 (69.6%) monitoring parameters were completed versus 134 of 136 (98.5%) in the intervention group ( P < 0.05). CONCLUSION: A collaborative pharmacy-cardiology AAD monitoring program was associated with a significant improvement in dofetilide monitoring. This improvement could potentially translate into enhanced patient safety outcomes, such as prevention of adverse drug reactions and decreased hospitalizations.

Murine toll-like receptor 2 activation induces type I interferon responses from endolysosomal compartments.

BACKGROUND: Toll-like receptors (TLRs) are among the first-line sentinels for immune detection and responsiveness to pathogens. The TLR2 subfamily of TLRs (TLR1, TLR2, TLR6) form heterodimers with each other and are thus able to recognize a broad range of components from several microbes such as yeast, Gram-positive bacteria and protozoa. Until now, TLR2 activation by bacterial ligands has long been associated with pro-inflammatory cytokines but not type I interferon responses. METHODOLOGY/PRINCIPAL FINDINGS: Using a variety of transgenic mice, here we provide in vivo and in vitro data showing that TLR2 activation does in fact induce interferon-beta and that this occurs via MyD88-IRF1 and -IRF7 pathways. Interestingly, by microscopy we demonstrate that although a cell surface receptor, TLR2 dependent induction of type I interferons occurs in endolysosomal compartments where it is translocated to upon ligand engagement. Furthermore, we could show that blocking receptor internalization or endolysosomal acidification inhibits the ability of TLR2 to trigger the induction type I interferon but not pro-inflammatory responses. CONCLUSION/SIGNIFICANCE: The results indicate that TLR2 activation induces pro-inflammatory and type I interferon responses from distinct subcellular sites: the plasma membrane and endolysosomal compartments respectively. Apart from identifying and characterizing a novel pathway for induction of type I interferons, the present study offers new insights into how TLR signaling discriminates and regulates the nature of responses to be elicited against extracellular and endocytosed microbes. These findings may also have clinical implication. Excessive production of pro-inflammatory cytokines and type I IFNs following activation of TLRs is a central pathologic event in several hyper-inflammatory conditions. The discovery that the induction of pro-inflammatory and type I IFN responses can be uncoupled through pharmacological manipulation of endolysosomal acidification suggests new avenues for potential therapeutic intervention against inflammations and sepsis.

Mast cells elicit proinflammatory but not type I interferon responses upon activation of TLRs by bacteria.

Balanced induction of proinflammatory and type I IFN responses upon activation of Toll-like receptors (TLRs) determines the outcome of microbial infections and the pathogenesis of autoimmune and other inflammatory diseases. Mast cells, key components of the innate immune system, are known for their debilitating role in allergy and autoimmunity. However, their role in antimicrobial host defenses is being acknowledged increasingly. How mast cells interact with microbes and the nature of responses triggered thereby is not well characterized. Here we show that in response to TLR activation by Gram-positive and -negative bacteria or their components, mast cells elicit proinflammatory but not type I IFN responses. We demonstrate that in mast cells, bound bacteria and TLR ligands remain trapped at the cell surface and do not undergo internalization, a prerequisite for type I IFN induction. Such cells, however, can elicit type I IFNs in response to vesicular stomatitis virus which accesses the cytosolic retinoic acid-inducible gene I receptor. Although important for antiviral immunity, a strong I IFN response is known to contribute to pathogenesis of several bacterial pathogens such as Listeria monocytogenes. Interestingly, we observed that the mast cell-dependent neutrophil mobilization upon L. monocytogenes infection is highly impaired by IFN-beta. Thus, the fact that mast cells, although endowed with the capacity to elicit type I IFNs in response to viral infection, elicit only proinflammatory responses upon bacterial infection shows that mast cells, key effector cells of the innate immune system, are well adjusted for optimal antibacterial and antiviral responses.

Tumor invasion of Salmonella enterica serovar Typhimurium is accompanied by strong hemorrhage promoted by TNF-alpha.

BACKGROUND: Several facultative anaerobic bacteria with potential therapeutic abilities are known to preferentially colonize solid tumors after systemic administration. How they efficiently find and invade the tumors is still unclear. However, this is an important issue to be clarified when bacteria should be tailored for application in cancer therapy. METHODOLOGY/PRINCIPAL FINDINGS: We describe the initial events of colonization of an ectopic transplantable tumor by Salmonella enterica serovar Typhimurium. Initially, after intravenous administration, bacteria were found in blood, spleen, and liver. Low numbers were also detected in tumors associated with blood vessels as could be observed by immunohistochemistry. A rapid increase of TNF-alpha in blood was observed at that time, in addition to other pro-inflammatory cytokines. This induced a tremendous influx of blood into the tumors by vascular disruption that could be visualized in H&E stainings and quantified by hemoglobin measurements of tumor homogenate. Most likely, together with the blood, bacteria were flushed into the tumor. In addition, blood influx was followed by necrosis formation, bacterial growth, and infiltration of neutrophilic granulocytes. Depletion of TNF-alpha retarded blood influx and delayed bacterial tumor-colonization. CONCLUSION: Our findings emphasize similarities between Gram-negative tumor-colonizing bacteria and tumor vascular disrupting agents and show the involvement of TNF-alpha in the initial phase of tumor-colonization by bacteria.

Signals triggered by a bacterial pore-forming toxin contribute to toll-like receptor redundancy in gram-positive bacterial recognition.

BACKGROUND: Toll-like receptor (TLR) 2 is the principal recognition receptor for gram-positive microbes. However, in some gram-positive bacterial infections, TLR2 is dispensable. One of the outstanding questions regarding host-bacteria interactions is why TLR2 is essential in some infections but dispensable in others. METHODS: We used a combination of bacterial plating, flow cytometry, enzyme-linked immunosorbent assay, and reverse-transcriptase polymerase chain reaction to analyze the inflammatory responses induced by Listeria monocytogenes and its toxin listeriolysin O (LLO) in vitro and in vivo. We analyzed wild-type, TLR2(-/-)-, TLR4(-/-)-, MyD88(-/-)-, interleukin (IL)-1beta(-/-)-, and IL-18(-/-)-deficient mice and the bone marrow-derived mast cells obtained from these respective groups. RESULTS: TLR2(-/-) mice had unaltered L. monocytogenes clearance and did not experience impairment of cytokine/chemokine induction and neutrophil mobilization by L. monocytogenes or purified LLO, but they were unresponsive to the LLO-deficient mutant L. monocytogenes (LmDeltahly). We show that L. monocytogenes and LLO mediate such responses in part via interleukin (IL)-1beta and IL-18-MyD88 pathways. CONCLUSIONS: The results illustrate that signals triggered by LLO contribute to TLR2 redundancy in recognition of L. monocytogenes. Under normal conditions, multiple and, sometimes, redundant pathways cooperate to induce a rapid antimicrobial defense. When one signaling pathway-in this case, TLR2-is removed from the system, the other pathways are still capable of mounting a sufficient response to ensure survival of the host.

Generation and comparative analysis of approximately 3.3 Mb of mouse genomic sequence orthologous to the region of human chromosome 7q11.23 implicated in Williams syndrome.

Williams syndrome is a complex developmental disorder that results from the heterozygous deletion of a approximately 1.6-Mb segment of human chromosome 7q11.23. These deletions are mediated by large (approximately 300 kb) duplicated blocks of DNA of near-identical sequence. Previously, we showed that the orthologous region of the mouse genome is devoid of such duplicated segments. Here, we extend our studies to include the generation of approximately 3.3 Mb of genomic sequence from the mouse Williams syndrome region, of which just over 1.4 Mb is finished to high accuracy. Comparative analyses of the mouse and human sequences within and immediately flanking the interval commonly deleted in Williams syndrome have facilitated the identification of nine previously unreported genes, provided detailed sequence-based information regarding 30 genes residing in the region, and revealed a number of potentially interesting conserved noncoding sequences. Finally, to facilitate comparative sequence analysis, we implemented several enhancements to the program, including the addition of links from annotated features within a generated percent-identity plot to specific records in public databases. Taken together, the results reported here provide an important comparative sequence resource that should catalyze additional studies of Williams syndrome, including those that aim to characterize genes within the commonly deleted interval and to develop mouse models of the disorder.