Comparison of mathematically arterialised venous blood gas sampling with arterial, capillary, and venous sampling in adult patients with hypercapnic respiratory failure: a single-centre longitudinal cohort study.

BACKGROUND: Accurate arterial blood gas (ABG) analysis is essential in the management of patients with hypercapnic respiratory failure, but repeated sampling requires technical expertise and is painful. Missed sampling is common and has a negative impact on patient care. A newer venous to arterial conversion method (v-TAC, Roche) uses mathematical models of acid-base chemistry, a venous blood gas sample and peripheral blood oxygen saturation to calculate arterial acid-base status. It has the potential to replace routine ABG sampling for selected patient cohorts. The aim of this study was to compare v-TAC with ABG, capillary and venous sampling in a patient cohort referred to start non-invasive ventilation (NIV). METHODS: Recruited patients underwent near simultaneous ABG, capillary blood gas (CBG) and venous blood gas (VBG) sampling at day 0, and up to two further occasions (day 1 NIV and discharge). The primary outcome was the reliability of v-TAC sampling compared with ABG, via Bland-Altman analysis, to identify respiratory failure (via PaCO2) and to detect changes in PaCO2 in response to NIV. Secondary outcomes included agreements with pH, sampling success rates and pain. RESULTS: The agreement between ABG and v-TAC/venous PaCO2 was assessed for 119 matched sampling episodes and 105 between ABG and CBG. Close agreement was shown for v-TAC (mean difference (SD) 0.01 (0.5) kPa), but not for CBG (-0.75 (0.69) kPa) or VBG (+1.00 (0.90) kPa). Longitudinal data for 32 patients started on NIV showed the closest agreement for ABG and v-TAC (R2=0.61). v-TAC sampling had the highest first-time success rate (88%) and was less painful than arterial (p<0.0001). CONCLUSION: Mathematical arterialisation of venous samples was easier to obtain and less painful than ABG sampling. Results showed close agreement for PaCO2 and pH and tracked well longitudinally such that the v-TAC method could replace routine ABG testing to recognise and monitor patients with hypercapnic respiratory failure. TRIAL REGISTRATION NUMBER: NCT04072848; www. CLINICALTRIALS: gov.

Administration of BDNF in the ventral tegmental area produces a switch from a nicotine-non-dependent D1R-mediated motivational state to a nicotine-dependent-like D2R-mediated motivational state.

Brain-derived neurotrophic factor (BDNF) has been implicated in the transition from a non-dependent motivational state to a drug-dependent and drug-withdrawn motivational state. Chronic nicotine can increase BDNF in the rodent brain and is associated with smoking severity in humans; however, it is unknown whether this increased BDNF is linked functionally to the switch from a nicotine-non-dependent to a nicotine-dependent state. We used a place conditioning paradigm to measure the conditioned responses to nicotine, showing that a dose of acute nicotine that non-dependent male mice find aversive is found rewarding in chronic nicotine-treated mice experiencing withdrawal. A single BDNF injection in the ventral tegmental area (in the absence of chronic nicotine treatment) caused mice to behave as if they were nicotine dependent and in withdrawal, switching the neurobiological substrate mediating the conditioned motivational effects from dopamine D1 receptors to D2 receptors. Quantification of gene expression of BDNF and its receptor, tropomyosin-receptor-kinase B (TrkB), revealed an increase in TrkB mRNA but not BDNF mRNA in the VTA in nicotine-dependent and nicotine-withdrawn mice. These results suggest that BDNF signalling in the VTA is a critical neurobiological substrate for the transition to nicotine dependence. The modulation of BDNF signalling may be a promising new pharmacological avenue for the treatment of addictive behaviour.

To study the contributing factors and outcomes of Clostridioides difficile infection in patients with solid tumors.

BACKGROUND: Clostridioides difficile infection (CDI) is a considerable healthcare burden, and now identified as the leading cause of acquired diarrheal illness in patients receiving antibiotics. Patients with malignancies are more prone to acquire CDI, owing to their frequent exposure to risk factors. OBJECTIVE: This study aims to investigate the factors affecting the outcome of Clostridioides Difficile Infection in patients with solid tumors at our community healthcare center. METHODS: This is a retrospective study that included a total of 59 patients with solid tumors who were hospitalized for Clostridioides difficile infection. RESULTS: The median age of the study population was 79 years with 39 males and 20 females. The patients had a diagnosis of a malignancy involving the following sites: prostate (25), lung (19), colon (7), bladder (4), breast (3), and renal (1). There were 52 cases of first time and 7 cases of recurrent CDI admissions. 40 patients were detected to have CDI at presentation while 19 patients were diagnosed with CDI after admission. CDI was categorized as follows: non-severe (29), severe (28), and very severe (2). There were 33 patients on chemotherapy and 20 patients undergoing radiotherapy. Twenty-seven patients had a recent history of cancer care-related procedures or interventions. Twenty-nine patients were from either a rehabilitation center or a long-term nursing care facility. There were 39 recent hospitalizations with 29 patients receiving antibiotics. Almost half of the patients were on proton pump inhibitors (29) and 12 were on steroids (20.3%) at the time of developing CDI. Patients with a high-risk qSOFA score of 2 or more (p-value = 0.008) or a high white blood cell count of >15 × 109/L (p-value = 0.016) at the time of admission were found to have higher in-hospital mortality. Critical care data suggested that 9 patients required intensive care, 7 patients required vasopressor support, and 6 needed mechanical ventilation. Patients were treated with either vancomycin alone (13), or metronidazole alone (25), or combination therapy with vancomycin + metronidazole (21). The median duration of hospital stay was 6 days with 11 fatalities (18.64%). CONCLUSIONS: CDI causes significant morbidity in patients with malignancies. A high qSOFA score and leukocytosis are significantly associated with high morbidity and thus should be used to prioritize and intensify inpatient care of these patients.

Neck Disability and Swallowing Function in Posttreatment Head and Neck Cancer Patients.

OBJECTIVE: To examine the relationship between symptoms of neck disability and swallowing dysfunction among head and neck cancer (HNC) survivors. STUDY DESIGN: Cross-sectional analysis. SETTING: Single-center, university-affiliated HNC survivorship clinic. SUBJECTS AND METHODS: Survivors' patient-reported symptoms of neck disability and swallowing dysfunction were prospectively collected from March 2017 to May 2018. Neck disability and swallowing dysfunction were measured using the Neck Disability Index and Eating Assessment Tool (EAT-10), respectively. Linear regression was used to analyze the association between neck disability and swallowing dysfunction. RESULTS: A total of 179 survivors, predominantly male (n = 130, 72.6%) with an average age of 64.64 ± 9.91 years, were included in the analysis. Primary cancer sites were oropharynx (n = 85, 47.5%), oral cavity (n = 59, 33.0%), and larynx/hypopharynx (n = 35, 19.5%). Mean EAT-10 score was 10.07 ± 10.89 (range = 0-40; >2 indicative of swallowing dysfunction). Survivors treated for early stage cancer had lower EAT-10 scores than those with advanced stage (early = 3.55 ± 7.46; advanced = 11.95 ± 11.02, P < .001). After controlling for age, time since treatment, American Joint Committee on Cancer stage, and treatment modality, the EAT-10 score for patients with mild neck disability was 6.88 (95% confidence interval [CI], 3.71-10.06; P < .001) points higher than those without neck disability, and the score for those with moderate-complete neck disability was 13.65 (95% CI, 9.47-17.83; P < .001) points higher than those without neck disability. CONCLUSIONS: Swallowing dysfunction is a commonly recognized effect of HNC treatment. The prevalence and burden of neck disability are shown to be highly correlated with swallowing dysfunction. These results support the need for comprehensive, multidisciplinary rehabilitation interventions for patients with HNC.

Clinical spectrum, risk factors, management and outcome of patients with retroperitoneal hematoma: a retrospective analysis of 3-year experience.

Objective: Retroperitoneal Hematoma (RPH) is an underdiagnosed and overlooked disease entity and has a high mortality rate if not diagnosed in a timely manner. This study aims to analyze the clinical characteristics, risk factors, treatment and the outcome of RPH cases at our medical center.Methods: In this retrospective study, all cases who presented to the emergency room (ER) and/or admitted to our center with the diagnosis of RPH from Jan 2016 to Dec 2018 were included (3-year data).Results: A total number of 78 RPH cases were included including both the traumatic and spontaneous bleed. The most common setting was spontaneous bleeding with no concurrent use of anti-thrombotic agents. Zone 3 (pelvic hematoma) bleed was the most common type of RPH. Most patients were successfully managed medically alone (59%). Others required surgical intervention, either laparoscopy, laparotomy or through the interventional radiological approach. There was a significant association between the need for vasopressors (OR-5.65, P-value of 0.039), spontaneous bleed (P-value of 0.001), bleed without antithrombotic agents (P-value of 0.002) with prolonged hospital stay (> 5 days). On follow-up, 83% of cases were reported to be alive. Only 2 patients died secondary to hemorrhagic shock.Conclusion: Most cases of RPH had an excellent outcome with conservative management alone.

Sex difference in dopamine D1-D2 receptor complex expression and signaling affects depression- and anxiety-like behaviors.

Depression and anxiety are more common among females than males and represent a leading cause of disease-related disability in women. Since the dopamine D1-D2 heteromer is involved in depression- and anxiety-like behavior, the possibility that the receptor complex may have a role in mediating sex differences in such behaviors and related biochemical signaling was explored.In non-human primate caudate nucleus and in rat striatum, females expressed higher density of D1-D2 heteromer complexes and a greater number of D1-D2 expressing neurons compared to males. In rat, the sex difference in D1-D2 expression levels occurred even though D1 receptor expression was lower in female than in male with no difference in D2 receptor expression. In behavioral tests, female rats showed faster latency to depressive-like behavior and a greater susceptibility to the pro-depressive and anxiogenic-like effects of D1-D2 heteromer activation by low doses of SKF 83959, all of which were ameliorated by the selective heteromer disrupting peptide, TAT-D1. The sex difference observed in the anxiety test correlated with differences in low-frequency delta and theta oscillations in the nucleus accumbens. Analysis of signaling pathways revealed that the sex difference in D1-D2 heteromer expression led to differences in basal and heteromer-stimulated activities of two important signaling pathways, BDNF/TrkB and Akt/GSK3/ß-catenin.These results suggest that the higher D1-D2 heteromer expression in female may significantly increase predisposition to depressive-like and anxiety-like behavior in female animals.

Impact of Neck Disability on Health-Related Quality of Life among Head and Neck Cancer Survivors.

OBJECTIVE: Although neck impairment has been described following surgical resection, limited studies have investigated its prevalence in nonsurgical treatment. The purpose of this study is to determine the prevalence and predictors of neck disability following head and neck cancer (HNC) treatment and to explore its association with quality of life (QOL). STUDY DESIGN: Cross-sectional study. SETTING: HNC survivorship clinic. SUBJECTS AND METHODS: We identified 214 survivors who completed treatment ≥1 year prior to evaluation in the clinic. Self-reported neck impairment was measured using the Neck Disability Index. QOL was measured using the University of Washington QOL Questionnaire, with physical and social subscale scores calculated. Regression analysis and trend tests were employed to explore associations. RESULTS: Over half of survivors (54.2%) reported neck disability. The odds of neck disability in survivors who received nonsurgical treatment and those who received surgery plus adjuvant treatment were 3.46 and 4.98 times higher compared to surgery alone (P = .008, P = .004). Survivors who underwent surgery only had higher physical and social QOL than those who received nonsurgical treatment (physical QOL: P < .001, social QOL: P = .023) and those who received surgery plus adjuvant treatment (physical QOL: P < .001, social QOL: P = .039). CONCLUSION: This study revealed a high prevalence of neck disability following nonsurgical treatment. While neck disability is an established sequela of surgical resection, the impact of nonsurgical treatment has gone unrecognized. Early identification and intervention to prevent progression of neck disability are crucial to optimize QOL.

Disruption of a dopamine receptor complex amplifies the actions of cocaine.

Cocaine-induced increases in dopamine signaling in nucleus accumbens (NAc) play a significant role in cocaine seeking behavior. The majority of cocaine addiction research has focused on neuroanatomically segregated dopamine D1 and D2 receptor-expressing neurons, yet an involvement for those NAc neurons coexpressing D1 and D2 receptors in cocaine addiction has never been explored. In situ proximity ligation assay, confocal fluorescence resonance energy transfer and coimmunoprecipitation were used to show native D1 and D2 receptors formed a heteromeric complex in D1/D2 receptor-coexpressing neurons in rat and non-human primate NAc. D1-D2 heteromer expression was lower in NAc of adolescent rats compared to their adult counterparts. Functional disruption of the dopamine D1-D2 receptor heteromer, using a peptide targeting the site of interaction between the D1 and D2 receptor, induced conditioned place preference and increased NAc expression of ∆FosB. D1-D2 heteromer disruption also resulted in the promotion, exacerbation and acceleration of the locomotor activating and incentive motivational effects of cocaine in the self-administration paradigm. These findings support a model for tonic inhibition of basal and cocaine-induced reward processes by the D1-D2 heteromer thus highlighting its potential value as a novel target for drug discovery in cocaine addiction. Given that adolescents show increased drug abuse susceptibility, an involvement for reduced D1-D2 heteromer function in the heightened sensitivity to the rewarding effects of cocaine in adolescence is also implicated.

Effectiveness of Decolonization With Chlorhexidine and Mupirocin in Reducing Surgical Site Infections: A Systematic Review.

BACKGROUND: Surgical site infections (SSI) are a serious complication of surgery. Staphylococcus aureus (S aureus) is 1 of the most common causative organisms responsible for SSI. Patients who are carriers of methicillin-resistant S aureus and methicillin-sensitive S aureus are at increased risk of developing S aureus-associated SSIs. Decolonization of skin with chlorhexidine and nares with mupirocin may reduce the risk of SSI. OBJECTIVE: The primary object of this systematic review is to examine the effectiveness of preoperative universal decolonization of skin with chlorhexidine and nares with intranasal mupirocin in preventing SSIs. METHODS: The following databases were searched: Ovid Medline (from 1946 to September week 3, 2015), Embase (1947 to 2015, week 38), EBSCO CINHAL (1980-2015), Cochrane Collaboration for Systematic Reviews, EBM Reviews, and Google Scholar. STUDY SELECTION: All experimental and nonexperimental studies that evaluated the effect of chlorhexidine in combination with intranasal mupirocin for decolonization were included. Inclusion was limited to published studies written in English. A total of 19 studies were included in this review. One study was deleted from final analysis as other agents were used for skin decolonization. DATA EXTRACTION: Data were extracted independently by 2 members of the study team. Discrepancies were resolved through discussion. RESULTS: Decolonization with topical chlorhexidine and intranasal mupirocin resulted in reduction of S aureus SSI and methicillin-resistant S aureus nosocomial infection and eradication of S aureus nasal carriage. Incidence of SSIs was significantly reduced in 10 studies, which was the primary outcome. Four of the 10 studies used preoperative universal decolonization and significant reduction in SSI was observed in cardiac and orthopedic patients. CONCLUSION: The results of this review indicate the combination of topical chlorhexidine and intranasal mupirocin is effective in reducing S aureus-associated SSIs.

Application of Transformational Leadership Principles in the Development and Integration of Palliative Care Within an Advanced Heart Failure Program.

Heart failure (HF) is a major health problem in United States, and it has reached epidemic proportions. Heart failure is associated with significant morbidity, mortality, and cost. Although the prognosis of HF is worse than many forms of cancer, many patients, families, and clinicians are unaware of the dire prognosis. As the disease progress to advanced HF, patients are faced with many challenges, such as poor quality of life due to worsening symptoms and frequent hospitalizations. Heart failure management adds significant financial burden to the health care system. Palliative care can be integrated into HF care to improve quality of life and symptom management and to address physical, spiritual, and psychosocial needs of patients and families. Palliative care can be used concurrently with or independent of curative or life-prolonging HF therapies. Transformational leadership principles were used to guide the development of a plan to enhance integration of palliative care within traditional advanced HF care.

National Breast and Cervical Cancer Early Detection Program partnerships in action.

Since the inception of the Centers for Disease Control and Prevention (CDC) National Breast and Cervical Cancer Early Detection Program (NBCCEDP) in 1990, partnerships have played a significant role in providing breast and cervical cancer screening and early detection to uninsured and underinsured women. The state, tribal, and territorial NBCCEDP grantees have shared resources and responsibilities with a variety of partners (eg, community-based organizations, government agencies, tribes, health care systems, companies, professional organizations) to achieve common goals. National partners, such as the American Cancer Society, Susan G. Komen for the Cure, and the Avon Foundation for Women, have provided funding, lobbied for national and state funding, supported outreach and education activities, and provided treatment referral services for the programs. This article provides an overview of grantee partnerships to illustrate the effects, successes, and challenges of these partnerships and how they have affected the populations served by the program.

A peptide targeting an interaction interface disrupts the dopamine D1-D2 receptor heteromer to block signaling and function in vitro and in vivo: effective selective antagonism.

Although the dopamine D1-D2 receptor heteromer has emerging physiological relevance and a postulated role in different neuropsychiatric disorders, such as drug addiction, depression, and schizophrenia, there is a need for pharmacological tools that selectively target such receptor complexes in order to analyze their biological and pathophysiological functions. Since no selective antagonists for the D1-D2 heteromer are available, serial deletions and point mutations were used to precisely identify the amino acids involved in an interaction interface between the receptors, residing within the carboxyl tail of the D1 receptor that interacted with the D2 receptor to form the D1-D2 receptor heteromer. It was determined that D1 receptor carboxyl tail residues (404)Glu and (405)Glu were critical in mediating the interaction with the D2 receptor. Isolated mutation of these residues in the D1 receptor resulted in the loss of agonist activation of the calcium signaling pathway mediated through the D1-D2 receptor heteromer. The physical interaction between the D1 and D2 receptor could be disrupted, as shown by coimmunoprecipitation and BRET analysis, by a small peptide generated from the D1 receptor sequence that contained these amino acids, leading to a switch in G-protein affinities and loss of calcium signaling, resulting in the inhibition of D1-D2 heteromer function. The use of the D1-D2 heteromer-disrupting peptide in vivo revealed a pathophysiological role for the D1-D2 heteromer in the modulation of behavioral despair. This peptide may represent a novel pharmacological tool with potential therapeutic benefits in depression treatment.

Dopamine receptor heteromeric complexes and their emerging functions.

Dopamine neurotransmission is traditionally accepted as occurring through the five dopamine receptors that transduce its signal. Recent evidence has demonstrated that the range of physiologically relevant dopamine signaling complexes is greatly expanded by the ability of dopamine receptors to interact with other dopamine receptors and with receptors of other endogenous signaling ligands. These novel heteromeric complexes have functional properties distinct from the component receptors or are able to modulate the canonical signaling and function of the cognate receptors. These dopamine receptor heteromers provide new insight into physiological mechanisms and pathophysiological processes involving dopamine.

Heteromeric dopamine receptor signaling complexes: emerging neurobiology and disease relevance.

The pharmacological modification of dopamine transmission has long been employed as a therapeutic tool in the treatment of many mental health disorders. However, as many of the pharmacotherapies today are not without significant side effects, or they alleviate only a particular subset of symptoms, the identification of novel therapeutic targets is imperative. In light of these challenges, the recognition that dopamine receptors can form heteromers has significantly expanded the range of physiologically relevant signaling complexes as well as potential drug targets. Furthermore, as the physiology and disease relevance of these receptor heteromers is further understood, their ability to exhibit pharmacological and functional properties distinct from their constituent receptors, or modulate the function of endogenous homomeric receptor complexes, may allow for the development of alternate therapeutic strategies and provide new avenues for drug design. In this review, we describe the emerging neurobiology of the known dopamine receptor heteromers, their physiological relevance in brain, and discuss the potential role of these receptor complexes in neuropsychiatric disease. We highlight their value as targets for future drug development and discuss innovative research strategies designed to selectively target these dopamine receptor heteromers in the search for novel and clinically efficacious pharmacotherapies.

Functional characterization of recombinant bromelain of Ananas comosus expressed in a prokaryotic system.

Bromelain (BRM) is a defense protein present in the fruit and stem of pineapple (Ananas comosus) and it is grouped as a cysteine protease enzyme with diversified medicinal uses. Based on its therapeutic applications, bromelain has got sufficient attention in pharmaceutical industries. In the present study, the full coding gene of bromelain in pineapple stem (1,093 bp) was amplified by RT-PCR. The PCR product was cloned, sequenced, and characterized. The sequence analysis of the gene revealed the single nucleotide polymorphism and its phylogenetic relatedness. The peptide sequence deduced from the gene showed the amino acid variations, physicochemical properties and secondary and tertiary structural features of the protein. The full BRM gene was transformed to prokaryotic vector pET32b and expressed in Escherichia coli BL21 DE3pLysS host cells successfully. The identity of the recombinant bromelain (rBRM) protein was confirmed by Western blot analysis using anti-BRM-rabbit IgG antibody. The activity of recombinant bromelain compared with purified native bromelain was determined by protease assay. The inhibitory effect of rBRM compared with native BRM in the growth of Gram-positive and Gram-negative strains of Streptococcus agalactiae and Escherichia coli O111 was evident from the antibacterial sensitivity test. To the best of our knowledge, this is the first report showing the bactericidal property of rBRM expressed in a prokaryotic system.

Reconstruction of the distal humerus and elbow joint using a pedicled scapular flap: case report.

Loss of elbow function resulting from major bone loss negatively affects quality of life and leaves limited options for reconstruction and restoration of function. To overcome this disabling problem, we reconstructed the distal humerus of a child in a single stage using a scapular flap based on the angular branch of the thoracodorsal artery as a pedicled flap. We also reconstructed the proximal ulna using an iliac crest bone graft with dermal graft interposition arthroplasty, which enabled the restoration of useful elbow function.