We describe the novel use of oral chloramphenicol for treatment-resistant
) infection in a 20-year-old heterosexual cisgender male presenting with recurrent symptomatic non-gonococcal urethritis.
...urethritis is an increasingly common clinical conundrum in sexual health clinics and in cases of second-line treatment failure (such as moxifloxacin), UK and international guidelines struggle to make recommendations for third-line treatments. As shown in our case, the evidence base for third-line treatments is lacking, with poor success rates, and may be poorly tolerated. Here we demonstrate the novel use of a well-tolerated oral antimicrobial, chloramphenicol, resulting in rapid microbiological and clinical cure in treatment-resistant
urethritis.
The phenotypic diagnosis of von Willebrand disease (VWD) is a multistep process with classification dependent on the quantification of von Willebrand factor (VWF) multimeric structure. VWF multimer ...analysis is a technically challenging, lengthy and non‐standardised assay, usually performed in specialist laboratories. Recently, a new semi‐automated multimer assay, the Hydragel 5 von Willebrand multimers (H5VWM) has become available.
This study, performed in two European centres, compared existing in‐house multimer assays to the H5VWM in individuals with and without VWD.
Overall agreement of 91.1% was observed in 74 individuals with normal VWF levels, 57 patients grouped as type 1 VWD, 33 type 2A, 16 type 2B, 28 type 2M, 11 type 2N. Patients tested following Desmopressin or VWF concentrate, with thrombotic thrombocytopenic purpura and acquired von Willebrand syndrome were also evaluated. Many of the discrepancies between methods were in patients with genetic mutations linked to more than one type of VWD including p.R1374C/H and p.R1315C. Quantifiable multimer results were available within one working day. Densitometry improved the interpretation of the multimers with slight structural variations that were not apparent by visual inspection of the in‐house method.
5VWM was a rapid, sensitive, standardised assay which used existing technology and could be included as an initial screen of VWF multimers in a VWD diagnostic algorithm in conjunction with traditional multimer analysis.
The ability to stratify a patient's risk of metastasis and survival permits more refined care. A proof of principle study was undertaken to investigate the relationship between single nucleotide ...polymorphisms (SNPs) in literature based candidate cancer genes and the risk of nodal metastasis and clinical outcome in endometrioid endometrial cancer (EEC) patients.
Surgically-staged EEC patients from the Gynecologic Oncology Group or Washington University School of Medicine with germline DNA available were eligible. Fifty-four genes represented by 384 SNPs, were evaluated by Illumina Custom GoldenGate array. Association with lymph node metastases was the primary outcome. Progression-free survival (PFS) and overall survival (OS) was also evaluated.
361 SNPs with high quality genotype data were evaluated in 337 patients with outcome data. Five SNPs in CXCR2 had an odds ratio (OR) between 0.68 and 0.70 (p-value ≤ 0.025). The A allele rs946486 in ABL had an OR of 1.5 (p-value = 0.01) for metastasis. The G allele in rs7795743 in EGFR had an OR for metastasis of 0.68 (p-value = 0.02) and hazard ratio (HR) for progression of 0.66 (p-value = 0.004). Importantly, no SNP met genome wide significance after adjusting for multiple test correcting and clinical covariates. The A allele in rs2159359 SNP in NME1 and the G allele in rs13222385 in EGFR were associated with worse OS. Both exhibited genome wide significance; rs13222385 remained significant after adjusting for prognostic clinical variables.
SNPs in cancer genes including rs2159359 SNP in NME1 and rs13222385 in EGFR may stratify risk in EEC and are prioritized for further investigation.
•NME1 and EGFR were the candidate genes most strongly associated with progression in this endometrial cancer patient cohort.•SNP rs13222385 in EGFR also remained significant after adjusting for prognostic clinical variables.•Although hypothesis generating, further work is needed to validate these findings and assess for other predictive SNPs.
Abstract
Aims
Systemic inflammation and increased activity of atrial NOX2-containing NADPH oxidases have been associated with the new onset of atrial fibrillation (AF) after cardiac surgery. In ...addition to lowering LDL-cholesterol, statins exert rapid anti-inflammatory and antioxidant effects, the clinical significance of which remains controversial.
Methods and results
We first assessed the impact of cardiac surgery and cardiopulmonary bypass (CPB) on atrial nitroso-redox balance by measuring NO synthase (NOS) and GTP cyclohydrolase-1 (GCH-1) activity, biopterin content, and superoxide production in paired samples of the right atrial appendage obtained before (PRE) and after CPB and reperfusion (POST) in 116 patients. The effect of perioperative treatment with atorvastatin (80 mg once daily) on these parameters, blood biomarkers, and the post-operative atrial effective refractory period (AERP) was then evaluated in a randomized, double-blind, placebo-controlled study in 80 patients undergoing cardiac surgery on CPB. CPB and reperfusion led to a significant increase in atrial superoxide production (74% CI 71–76%, n = 46 paired samples, P < 0.0001) and a reduction in atrial tetrahydrobiopterin (BH4) (34% CI 33–35%, n = 36 paired samples, P < 0.01), and in GCH-1 (56% CI 55–58%, n = 26 paired samples, P < 0.001) and NOS activity (58% CI 52–67%, n = 20 paired samples, P < 0.001). Perioperative atorvastatin treatment prevented the effect of CPB and reperfusion on all parameters but had no significant effect on the postoperative right AERP, troponin release, or NT-proBNP after cardiac surgery.
Conclusion
Perioperative statin therapy prevents post-reperfusion atrial nitroso-redox imbalance in patients undergoing on-pump cardiac surgery but has no significant impact on postoperative atrial refractoriness, perioperative myocardial injury, or markers of postoperative LV function.
Clinical Trial Registration
https://clinicaltrials.gov/ct2/show/NCT01780740
Graphical Abstract
This article presents a comprehensive and multistage approach to the development of the user experience (UX) for an mHealth application targeting older adult patients with chronic diseases, ...specifically chronic heart failure and chronic obstructive pulmonary disease. The study adopts a mixed methods approach, incorporating both quantitative and qualitative components. The underlying hypothesis posits that baseline medicine adherence knowledge (measured by the MARS questionnaire), beliefs about medicines (measured by the BMQ questionnaire), and level of user experience (measured by the SUS and UEQ questionnaires) act as predictors of adherence change after a period of usage of the mHealth application. However, contrary to our expectations, the results did not demonstrate the anticipated relationship between the variables examined. Nevertheless, the qualitative component of the research revealed that patients, in general, expressed satisfaction with the application. It is important to note that the pilot testing phase revealed a notable prevalence of technical issues, which may have influenced participants’ perception of the overall UX. These findings contribute to the understanding of UX development in the context of mHealth applications for older adults with chronic diseases and emphasise the importance of addressing technical challenges to enhance user satisfaction and engagement.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
We have previously shown that the recurrent endometrial cancer MAX p.His28Arg mutation (MAXH28R) is associated with a proangiogenesis phenotype in both in vitro and xenograft models. The ...purpose of this study is to characterize the MAXH28R secretome to identify the proangiogenic and other paracrine factors contributing to MAXH28R associated tumorigenesis. Bottom-up high-resolution liquid chromatography tandem mass spectrometry (LC-MS/MS) of secreted proteins coupled with microarray analysis of global gene expression was performed in AN3CA endometrial cancer cell lines that stably express the long isoform of MAX-wild type (MAXWT) or MAXH28R. Orthogonal validation of differentially expressed proteins was performed by Western blot (WB) and enzyme-linked immunosorbent assay (ELISA) using MAXWT- or MAXH28R-expressing AN3CA cell lines. Bioinformatic analysis of the proteins secreted into conditioned media (secretome) identified 114 proteins differentially expressed by MAXH28R compared to MAXWT-expressing AN3CA cells (P < 0.05). Differential expression of proteins was highly correlated with mRNA expression (Pearson r = 0.75, P < 0.001), indicating that a subset of the differentially expressed proteins are potential direct transcriptional targets of MAX. Secretome analysis revealed that Laminin-β1 expression in MAXH28R was reduced more than 100-fold compared to MAXWT (P < 0.001), while ALCAM (CD166) expression was increased 3.5-fold (P < 0.001). Decreased expression of TGFβ1 (5.9-fold decrease, P = 0.023) and TGFβ2 (3-fold decrease, P = 0.009) was seen for MAXH28R cells compared to MAXWT. Differential expression of Laminin-β1 and ALCAM was confirmed by WB analysis and TGFβ1 and TGFβ2 by ELISA. Our analyses revealed extensive changes in the MAXH28R secretome, as exemplified above. Reduced Laminin-β1 highlights alteration in the extracellular matrix with implications for cell adhesion and integrin signaling. Increased ALCAM expression indicates changes to cell-cell adhesion. Elevated levels of ALCAM in conditioned media are consistent with increased ALCAM shedding, which is a marker of more aggressive tumors in a variety of malignancies. Reduced TGFβ ligand levels suggest potential alterations in paracrine and autocrine TGFβ signaling. However, the impact on canonical and noncanonical TGFβ signaling in MAX mutant endometrial cancers remains unknown. ChIP-qPCR experiments are ongoing to assess MAXH28R binding at the promoters of differentially expressed genes. Biologic validation of MAXH28R effects on differential expression of secreted proteins is being performed in the Ishikawa and RL95-2 endometrial cancer cell lines that stably express MAXH28R and MAXWT. The effects of reduced Laminin-β1 on integrin signaling and anchorage independent growth will be reported, as will effects of altered TGFβ expression on canonical and noncanonical TGFβ signaling.
Citation Format: Craig M. Rush, Miranda L. Gardner, Caroline E. Sapp, Michael A. Freitas, Paul J. Goodfellow. Characterizing the MAXH28R secretome in endometrial cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3335.
Behavior change apps have the potential to provide individual support on a population scale at low cost, but they face numerous barriers to implementation. Electronic health records (EHRs) in acute ...care hospitals provide a valuable resource for identifying patients at risk, who may benefit from behavior change apps. A novel, emerging implementation strategy is to use digital technologies not only for providing support to help-seeking individuals but also for signposting patients at risk to support services (also called proactive referral in the United States).
The OptiMine study aimed to increase the reach of behavior change apps by implementing electronic signposting for smoking cessation and alcohol reduction in a large, at-risk population that was identified through an acute care hospital EHR.
This 3-phase, mixed methods implementation study assessed the acceptability, feasibility, and reach of electronic signposting to behavior change apps by using a hospital's EHR system to identify patients who are at risk. Phase 1 explored the acceptability of the implementation strategy among the patients and staff through focus groups. Phase 2 investigated the feasibility of using the hospital EHR to identify patients with target risk behaviors and contact them via SMS text message, email, or patient portal. Phase 3 assessed the impact of SMS text messages sent to patients who were identified as smokers or risky drinkers, which signposted them to behavior change apps. The primary outcome was the proportion of participants who clicked on the embedded link in the SMS text message to access information about the apps. The acceptability of the SMS text messages among the patients who had received them was also explored in a web-based survey.
Our electronic signposting strategy-using SMS text messages to promote health behavior change apps to patients at risk-was found to be acceptable and feasible and had good reach. The hospital sent 1526 SMS text messages, signposting patients to either the National Health Service Smokefree or Drink Free Days apps. A total of 13.56% (207/1526) of the patients clicked on the embedded link to the apps, which exceeded our 5% a priori success criterion. Patients and staff contributed to the SMS text message content and delivery approach, which were perceived as acceptable before and after the delivery of the SMS text messages. The feasibility of the SMS text message format was determined and the target population was identified by mining the EHR.
The OptiMine study demonstrated the proof of concept for this novel implementation strategy, which used SMS text messages to signpost at-risk individuals to behavior change apps at scale. The level of reach exceeded our a priori success criterion in a non-help-seeking population of patients receiving unsolicited SMS text messages, disconnected from hospital visits.
RR2-10.2196/23669.
As mortality rates from COVID-19 disease fall, the high prevalence of long-term sequelae (Long COVID) is becoming increasingly widespread, challenging healthcare systems globally. Traditional ...pathways of care for Long Term Conditions (LTCs) have tended to be managed by disease-specific specialties, an approach that has been ineffective in delivering care for patients with multi-morbidity. The multi-system nature of Long COVID and its impact on physical and psychological health demands a more effective model of holistic, integrated care. The evolution of integrated care systems (ICSs) in the UK presents an important opportunity to explore areas of mutual benefit to LTC, multi-morbidity and Long COVID care. There may be benefits in comparing and contrasting ICPs for Long COVID with ICPs for other LTCs.
This study aims to evaluate health services requirements for ICPs for Long COVID and their applicability to other LTCs including multi-morbidity and the overlap with medically not yet explained symptoms (MNYES). The study will follow a Delphi design and involve an expert panel of stakeholders including people with lived experience, as well as clinicians with expertise in Long COVID and other LTCs. Study processes will include expert panel and moderator panel meetings, surveys, and interviews. The Delphi process is part of the overall STIMULATE-ICP programme, aimed at improving integrated care for people with Long COVID.
Ethical approval for this Delphi study has been obtained (Research Governance Board of the University of York) as have approvals for the other STIMULATE-ICP studies. Study outcomes are likely to inform policy for ICPs across LTCs. Results will be disseminated through scientific publication, conference presentation and communications with patients and stakeholders involved in care of other LTCs and Long COVID.
Researchregistry: https://www.researchregistry.com/browse-the-registry#home/registrationdetails/6246bfeeeaaed6001f08dadc/.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In radiation hybrid mapping, chromosomes in human-rodent hybrid cells are fragmented by X-rays and fragments rescued by fusion of the donor cell to a recipient rodent cell. The co-retention ...frequencies of markers in 100-200 hybrids are used to map individual chromosomes, but mapping the whole genome in this way is impractical. We have reverted to the original protocols of Goss and Harris and have produced a panel of 44 hybrids using irradiated human fibroblasts as donors. This panel has been used to make a map of human chromosome 14 containing 40 ordered markers. The map integrates previously published maps and localizes nine new markers. We suggest that the construction of a high resolution map of the whole human genome is feasible with a single panel of 100-200 hybrids.
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