Regional Elective Day Procedure Centre Pilot- the solution to waiting lists and trainee deficit in the reshaping of services following COVID-19?

Background: Consequences from the COVID-19 pandemic have resulted in the secondary impact of cessation of elective surgical services, amplifying the waiting list problem with devastating patient and surgical training repercussions. With the introduction of the first regional inter-trust daycase elective care centre pilot in Northern Ireland, we aim to assess the impact of this pathway on elective inguinal hernia waiting lists, patient outcomes, and influence on surgical training. Methods: Data was collected prospectively over a 10-week pilot of consecutive elective day case hernia lists at a newly established regional day surgery centre. Key operative time points for each patient were collated via the Theatre Management System (TMS). Retrospective patient feedback was collected from participating patients via 26-question telephone survey at 6 weeks post-operatively. Trainees allocated to the participating units during this pilot received a retrospective electronic survey. Results: Fifty-five patients underwent open unilateral elective inguinal hernia repair, 54% of cases were trainee led. Median trainee operating time of 53 minutes compared with 51 minutes for consultant led procedures, with no significant difference consultant vs non-consultant as primary operator (p>0.05). On completion of the pilot, waiting list numbers were reduced by a third, 75% of trainees feedback reported increased confidence with surgical operative exposure, and high levels of patient satisfaction reported. Conclusion: Inter-trust day surgery at a dedicated green site could successfully contribute to resuming and reforming surgical services, addressing the impact on mounting waiting lists with positive patient impact as well as providing an excellent training opportunity to narrow the observed training deficit.

A qualitative evaluation of a multi-modal cancer prehabilitation programme for colorectal, head and neck and lung cancers patients.

BACKGROUND: Growing evidence indicates patients' survivorship outcomes can be enhanced through active engagement in a multi-modal cancer prehabilitation programme (MCPP), although this intervention is not uniformly embedded as a standard of care. MCPP aims to optimise patients physiologically and psychologically for cancer treatments, shorten recovery time, reduce complications, promote healthier lifestyles and improve quality of life. South Eastern Health and Social Care Trust (SET) developed and evaluated a system-wide collaborative approach to MMCP across three tumour groups (colorectal, lung, head and neck cancer). Addressing the lack of qualitative evaluation of MCPPs, this novel paper explores mechanisms promoting feasibility and acceptability of MCPP from patients' and interdisciplinary professionals' perspectives. METHODS: Semi-structured virtual one-to-one interviews were conducted with 24 interdisciplinary professionals and nine patients. Transcripts were recorded, transcribed verbatim and themes developed using Framework Analysis. RESULTS: Analysis of findings identified three themes providing an in-depth understanding of key elements required to develop and promote system-wide delivery of a MCPP: 1) Equipping the team: Capability and capacity, 2) Timing of intervention and delivery timeframe and 3) Systems and processes. CONCLUSION: The system-wide collaborative approach to developing a MCPP was deemed both feasible and acceptable. Success was attributed to visionary leadership, alongside a diverse group of interdisciplinary professionals being engaged, motivated and committed to intervention delivery in an effort to improve patient outcomes. Iterative, responsive troubleshooting during initial delivery is required to facilitate successful implementation. Further training is required for greater adherence to provision of prescriptive high intensity exercise within the programme, which may further promote enhanced patient outcomes. To enable sustainability of MCPP, ongoing training for professionals and funding is required.

A Six Year Experience of a National Leadership Fellowship in Northern Ireland: Achieve, Develop, Explore Programme for Trainees (ADEPT).

Introduction: The Achieve, Develop, Explore Programme for Trainees (ADEPT) Clinical Leadership Fellowship Programme was established in response to growing recommendations to underpin healthcare reconfiguration in Northern Ireland with a collective leadership strategy. The fellowship combines a leadership development programme with a project carried out within a host organisation. With the fellowship now in its sixth year, a need was identified to assess its impact on the fellows' leadership skills, career choices, achievements, and views on both the fellowship and how to develop future leaders. Methods: Demographic data for all ADEPT fellows was held centrally through Northern Ireland Medical and Dental Training Agency (NIMDTA) and assessed anonymously. A mixed-methods questionnaire was composed using Smart Survey. Likert scale questions were designed to determine the extent to which participants believed ADEPT supported their development of strong and exemplary elements of the nine dimensions of the NHS Healthcare Leadership Model. The questionnaire was distributed electronically to all ADEPT alumni in November 2021 and remained open for 4 weeks. Results: There have been 46 ADEPT fellows to date (72% female; all fellows were white). ADEPT fellows were most commonly from Psychiatry (33%), Paediatrics (17%) and Obstetrics and Gynaecology (15%). There were 19 responses from the alumni cohort of 46 (41%). 75% of respondents reported that their project resulted in publication, presentation or award. Leadership skill development was identified as best in "Evaluating Information" and "Engaging the Team", whereas skills in "Sharing the Vision" and "Developing Capability" saw less improvement. The majority felt that the fellowship had been useful in securing their position as a consultant or general practitioner and 50% went on to pursue senior leadership positions. Conclusion: The ADEPT Clinical Leadership Fellowship delivers effective leadership training as measured by the nine domains of the NHS Healthcare Leadership Model. It provides value for host organisations through the projects undertaken and by developing doctors who are more likely to engage in future formal leadership roles. ADEPT alumni saw the value in their leadership experience and felt it should be embedded in standard postgraduate training schemes to reach a wider audience.

Implementation of ESC QI Initiative in Neonatal Unit Setting and Adaptation During the Pandemic.

OBJECTIVES: To improve outcomes in infants with neonatal opioid withdrawal syndrome (NOWS) admitted to NICU by implementing a quality improvement (QI) initiative incorporating "eat, sleep, console" (ESC) as a withdrawal evaluation tool and promotion of nonpharmacological interventions. Secondarily, we evaluated the impact of the coronavirus disease 2019 pandemic on QI initiative and outcomes. METHODS: We included infants born ≥ 36 weeks gestation and admitted to NICU with a primary diagnosis of NOWS between December 2017 and February 2021. (preintervention; December 2017-January 2019, postintervention; February 2019-February 2021). We compared cumulative dose, duration of opioid treatment, and length of stay (LOS) as our primary outcomes. RESULTS: The average duration of opioid treatment decreased from 18.6 days in the preimplementation cohort (n = 36) to 1.5 days in the first-year postimplementation (n = 44) with a reduction in cumulative opioid dose from 5.8 mg/kg to 0.6 mg/kg and decrease in the proportion of infants treated with opioids from 94.2% to 41.1%. Similarly, the average LOS decreased from 26.6 to 7.6 days. In the second-year postimplementation during the coronavirus disease 2019 pandemic (n = 24), there was an increase in average opioid treatment duration and LOS to 5.1 and 12.3 days respectively, but cumulative opioid dose (0.8 mg/kg) remained significantly lower than the preimplementation cohort. CONCLUSIONS: ESC-based quality improvement initiative led to a significant decrease in LOS and opioid pharmacotherapy in infants with NOWS in NICU setting. Despite the impact of the pandemic, some of the gains were sustained with adaptation to ESC QI initiative.

'No-Barriers' tobacco product? Selling smokeless tobacco to women, people of colour and the LGBTQ+ community in the USA.

BACKGROUND: In both Sweden and the USA, smokeless tobacco (ST) is legal and used predominantly by men. Starting in the 1970s, US tobacco companies attempted to expand the ST market to women, African Americans, Hispanic Americans and lesbian, gay, bisexual, transgender, queer and other sexual orientation (LGBTQ+) people. DESIGN: We analysed industry documents from the Truth Tobacco Industry Documents Library triangulating findings with recent ST advertising and publicly available literature. FINDINGS: We found tobacco companies used design innovations such as pouched moist snuff, snus and dissolvable products to expand the market. In addition, diverse advertising campaigns targeted women, people of colour (Hispanic, African American) and LGBTQ+ communities with identity-targeted messages emphasising novelty, convenience, cleanliness and use in smoke-free environments. However, stereotypes of ST users as rural white males endured, perpetuated by continued marketing aimed at this customer base, which created cognitive dissonance and stymied marketer's hopes that pouch products would 'democratize' ST. CONCLUSION: These failed campaigns suggest novel products such as nicotine pouch products may provide a 'clean slate' to similarly target women and other low-ST-using groups. Based on this history, the risk of new tobacco and nicotine products to increase health disparities should be closely monitored.

Imaging of Light-Enhanced Extracellular Vesicle-Mediated Delivery of Oxaliplatin to Colorectal Cancer Cells via Laser Ablation, Inductively Coupled Plasma Mass Spectrometry.

Extracellular vesicles (EVs) are lipid bilayer structures released by all cells that mediate cell-to-cell communication via the transfer of bioactive cargo. Because of the natural origin of EVs, their efficient uptake by recipient cells, capacity to stabilize and transport biomolecules and their potential for cell/tissue targeting and preferential uptake by cancer cells, they have enormous potential for bioengineering into improved and targeted drug delivery systems. In this work, we investigated the use of laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) as a tool to measure the loading of platinum-based chemotherapeutic agents. The EV loading of oxaliplatin via co-incubation was demonstrated, and LA-ICP-MS imaging showed greater efficiency of delivery to colorectal cancer cells compared to free oxaliplatin, leading to enhanced cytotoxic effect. Further, the impact of EV co-loading with a porphyrin (C5SHU, known as 'C5') photosensitizer on oxaliplatin delivery was assessed. Fluorescence analysis using nano-flow cytometry showed dose-dependent EV loading as well as a trend towards the loading of larger particles. Exposure of OXA-C5-EV-treated colorectal cancer cells to light indicated that delivery was enhanced by both light exposure and porphyrins, with a synergistic effect on cell viability observed between oxaliplatin, EVs and light exposure after the delivery of the co-loaded EVs. In summary, this work demonstrates the utility of LA-ICP-MS and mass spectrometry imaging in assessing the loading efficiency and cellular delivery of platinum-based therapeutics, which would also be suitable for agents containing other elements, confirms that EVs are more efficient at delivery compared to free drugs, and describes the use of light exposure in optimizing delivery and therapeutic effects of EV-mediated drug delivery both in combination and independently of porphyrin-based photosensitizers.

Water-Soluble Truncated Fatty Acid-Porphyrin Conjugates Provide Photo-Sensitizer Activity for Photodynamic Therapy in Malignant Mesothelioma.

Clinical trials evaluating intrapleural photodynamic therapy (PDT) are ongoing for mesothelioma. Several issues still hinder the development of PDT, such as those related to the inherent properties of photosensitizers. Herein, we report the synthesis, photophysical, and photobiological properties of three porphyrin-based photosensitizers conjugated to truncated fatty acids (C5SHU to C7SHU). Our photosensitizers exhibited excellent water solubility and high PDT efficiency in mesothelioma. As expected, absorption spectroscopy confirmed an increased aggregation as a consequence of extending the fatty acid chain length. In vitro PDT activity was studied using human mesothelioma cell lines (biphasic MSTO-211H cells and epithelioid NCI-H28 cells) alongside a non-malignant mesothelial cell line (MET-5A). The PDT effect of these photosensitizers was initially assessed using the colorimetric WST-8 cell viability assay and the mode of cell death was determined via flow cytometry of Annexin V-FITC/PI-stained cells. Photosensitizers appeared to selectively localize within the non-nuclear compartments of cells before exhibiting high phototoxicity. Both apoptosis and necrosis were induced at 24 and 48 h. As our pentanoic acid-derivatized porphyrin (C5SHU) induced the largest anti-tumor effect in this study, we put this forward as an anti-tumor drug candidate in PDT and photo-imaging diagnosis in mesothelioma.

Is qFIT a useful tool in prioritising symptomatic patients referred with suspect colorectal cancer in the COVID-19 era?

Background: The COVID-19 pandemic is an evolving healthcare challenge causing secondary disruption of cancer services. Quantitative Faecal Immunochemical Testing (qFIT) has been established as a screening method in asymptomatic patients. We aim to assess its utility as a triage tool to prioritise investigations in symptomatic patients with suspected colorectal cancer. Methods: At the commencement of the COVID-19 pandemic a database was established to include patients awaiting red flag outpatient consultation or colonic investigations and new red flag referrals from March to June 2020. Patients were supplied with qFIT kits and returned results categorised into 3 priority groups according to the qFIT value. Group 1 >150µg Hb/g, Group 2 ≥10 to ≤150µg Hb/g and Group 3 <10µg Hb/g. Subsequent colonic evaluation was offered by colonoscopy or cross-sectional imaging with urgency determined by qFIT priority group. When identified colorectal cancer, inflammatory bowel disease or high-risk polyps were recorded as "significant colorectal pathology." Findings: Three hundred and seventeen patients were identified with data analysed on 290 patients. Colorectal malignancy was identified in 17 patients; 94% of these patients were in Group 1. A qFIT result >150 µg Hb/g had a sensitivity and specificity for colorectal cancer of 94.12% (95% CI 71.31-99.85) and 91.21% (95% CI 87.20-94.29) respectively. No malignancy was detected in Priority Group 3; negative predictive value of 100% (95% CI 98.06-100). Conclusions: In symptomatic, suspect lower GI cancer patients qFIT is a useful adjunct for prioritising patients and can be used to determine the urgency of colorectal investigations.

Elemental Mapping of Human Malignant Mesothelioma Tissue Samples Using High-Speed LA-ICP-TOFMS Imaging.

This is the first report of the use of laser ablation-inductively coupled plasma time-of-flight mass spectrometry (LA-ICP-TOFMS) to analyze human malignant pleural mesothelioma (MPM) samples at the cellular level. MPM is an aggressive, incurable cancer associated with asbestos exposure, with a long latency and poor overall survival. Following careful optimization of the laser fluence, the simultaneous ablation of soft biological tissue and hard mineral fibers was possible, allowing the spatial detection of elements such as Si, Mg, Ca, and Fe, which are also present in the glass substrate. A low-dispersion LA setup was employed, which provided the high spatial resolution necessary to identify the asbestos fibers and fiber fragments in the tissue and to characterize the metallome at the cellular level (a pixel size of 2 µm), with a high speed (at 250 Hz). The multielement LA-ICP-TOFMS imaging approach enabled (i) the detection of asbestos fibers/mineral impurities within the MPM tissue samples of patients, (ii) the visualization of the tissue structure with the endogenous elemental pattern at high spatial resolution, and (iii) obtaining insights into the metallome of MPM patients with different pathologies in a single analysis run. Asbestos and other mineral fibers were detected in the lung and pleura tissue of MPM patients, respectively, based on their multielement pattern (Si, Mg, Ca, Fe, and Sr). Interestingly, strontium was detected in asbestos fibers, suggesting a link between this potential toxic element and MPM pathogenesis. Furthermore, monitoring the metallome around the talc deposit regions (characterized by elevated levels of Al, Mg, and Si) revealed significant tissue damage and inflammation caused by talc pleurodesis. LA-ICP-TOFMS results correlated to Perls' Prussian blue and histological staining of the corresponding serial sections. Ultimately, the ultra-high-speed and high-spatial-resolution capabilities of this novel LA-ICP-TOFMS setup may become an important clinical tool for simultaneous asbestos detection, metallome monitoring, and biomarker identification.

Scorpion Venom Antimicrobial Peptides Induce Caspase-1 Dependant Pyroptotic Cell Death.

Within the last decade, several peptides have been identified according to their ability to inhibit the growth of microbial pathogens. These antimicrobial peptides (AMPs) are a part of the innate immune system of all living organisms. Many studies on their effects on prokaryotic microorganisms have been reported; some of these peptides have cytotoxic properties although the molecular mechanisms underlying their activity on eukaryotic cells remain poorly understood. Smp24 and Smp43 are novel cationic AMPs which were identified from the venom of the Egyptian scorpion Scorpio maurus palmatus. Smp24 and Smp43 showed potent activity against both Gram-positive and Gram-negative bacteria as well as fungi. Here we describe cytotoxicity of these peptides towards two acute leukaemia cell lines (myeloid (KG1-a) and lymphoid (CCRF-CEM) leukaemia cell lines) and three non-tumour cell lines CD34+ (hematopoietic stem progenitor from cord blood), HRECs (human renal epithelial cells) and HaCaT (human skin keratinocytes). Smp24 and Smp43 (4-256 µg/ml) decreased the viability of all cell lines, although HaCaT cells were markedly less sensitive. With the exception HaCaT cells, the caspase-1 gene was uniquely up-regulated in all cell lines studied. However, all cell lines showed an increase in downstream interleukin-1ß (IL-1ß) expression. Transmission electron microscope studies revealed the formation of cell membrane blebs and the appearance of autolysosomes and lipid droplets in all cell lines; KG1-a leukemia cells also showed the unique appearance of glycogen deposits. Our results reveal a novel mechanism of action for scorpion venom AMPs, activating a cascade of events leading to cell death through a programmed pyroptotic mechanism.

Comorbid Conditions, Mental Health and Cognitive Functions in Adults with Fibromyalgia.

This study examined age group differences across adulthood in comorbid conditions, mental health, and cognitive function in people with fibromyalgia. Participants completed an online survey about how fibromyalgia affects their everyday life. Chi square analyses were conducted to examine associations between age groups and (a) comorbid conditions and (b) severity of anxiety and depression. ANOVA analyses examined age group differences on aspects of self-report cognitive function. The greatest prevalence of comorbid conditions was found in middle adulthood. Early adulthood was associated with more cases of severe anxiety with the lowest number of cases being in the oldest age group. Middle adulthood was associated with worse self-report pain compared to the youngest age group. Older adults showed better self-report cognitive function compared to younger adults. Distinct age profiles based on comorbid conditions, mental health, and symptom severity across adulthood in fibromyalgia have been demonstrated.

Genetic or pharmacologic Nrf2 activation increases proteinuria in chronic kidney disease in mice.

The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway upregulates key cellular defenses. Clinical trials are utilizing pharmacologic Nrf2 inducers such as bardoxolone methyl to treat chronic kidney disease, but Nrf2 activation has been linked to a paradoxical increase in proteinuria. To understand this effect, we examined genetically engineered mice with elevated Nrf2 signaling due to reduced expression of the Nrf2 inhibitor, Kelch-like ECH-associated protein 1 (Keap1). These Keap1FA/FA mice lacked baseline proteinuria but exhibited increased proteinuria in experimental models evoked by adriamycin, angiotensin II, or protein overload. After injury, Keap1FA/FA mice had increased glomerulosclerosis, nephrin disruption and shedding, podocyte injury, foot process effacement, and interstitial fibrosis. Keap1FA/FA mice also had higher daytime blood pressures and lower heart rates measured by radiotelemetry. Conversely, Nrf2 knockout mice were protected from proteinuria. We also examined the pharmacologic Nrf2 inducer CDDO-Im. Compared to angiotensin II alone, the combination of angiotensin II and CDDO-Im significantly increased proteinuria, a phenomenon not observed in Nrf2 knockout mice. This effect was not accompanied by additional increases in blood pressure. Finally, Nrf2 was found to be upregulated in the glomeruli of patients with focal segmental glomerulosclerosis, diabetic nephropathy, fibrillary glomerulonephritis, and membranous nephropathy. Thus, our studies demonstrate that Nrf2 induction in mice may exacerbate proteinuria in chronic kidney disease.

Laser ablation inductively coupled plasma mass spectrometry as a novel clinical imaging tool to detect asbestos fibres in malignant mesothelioma.

RATIONALE: Malignant pleural mesothelioma is an extremely aggressive and incurable malignancy associated with prior exposure to asbestos fibres. Difficulties remain in relation to early diagnosis, notably due to impeded identification of asbestos in lung tissue. This study describes a novel laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) imaging approach to identify asbestos within mesothelioma models with clinical significance. METHODS: Human mesothelioma cells were exposed to different types of asbestos fibres and prepared on plastic slides for LA-ICP-MS analysis. No further sample preparation was required prior to analysis, which was performed using an NWR Image 266 nm laser ablation system coupled to an Element XR sector-field ICP mass spectrometer, with a lateral resolution of 2 µm. Data was processed using LA-ICP-MS ImageTool v1.7 with the final graphic production made using DPlot software. RESULTS: Four different mineral fibres were successfully identified within the mesothelioma samples based on some of the most abundant elements that make up these fibres (Si, Mg and Fe). Using LA-ICP-MS as an imaging tool provided information on the spatial distribution of the fibres at cellular level, which is essential in asbestos detection within tissue samples. Based on the metal counts generated by the different types of asbestos, different fibres can be identified based on shape, size, and elemental composition. Detection of Ca was attempted but requires further optimisation. CONCLUSIONS: Detection of asbestos fibres in lung tissues is very useful, if not necessary, to complete the pathological dt9iagnosis of asbestos-related malignancies in the medicolegal field. For the first time, this study demonstrates the successful application of LA-ICP-MS imaging to identify asbestos fibres and other mineral fibres within mesothelioma samples. Ultimately, high-resolution, fast-speed LA-ICP-MS analysis has the potential to be integrated into clinical workflow to aid earlier detection and stratification of mesothelioma patient samples.

Headspace analysis of mesothelioma cell lines differentiates biphasic and epithelioid sub-types.

Malignant mesothelioma (MM) is an incurable cancer. MM is often misdiagnosed, with a poor 5-year survival and limited treatment options. The discovery of endogenous volatile organic compounds (VOCs) is required in order to accelerate the development of a breath test as an alternative to conventional MM diagnosis. For the first time, this study used solid-phase microextraction and gas chromatography-mass spectrometry to identify VOCs released directly from the biphasic MM cell line MSTO-211H and the epithelioid MM cell line NCI-H28 as well as the non-malignant mesothelial cell line MET-5A. Multivariate statistical analysis showed separation between MSTO-211H, NCI-H28 and MET-5A results. 2-ethyl-1-hexanol was significantly increased in both MSTO-211H and NCI-H28 cells compared to MET-5A controls. In addition, ethyl propionate and cyclohexanol were significantly increased in MSTO-211H cells and dodecane was significantly increased in NCI-H28 cells. This is the first study reporting headspace analysis of these MM cell lines and the first to consider the effects of mesothelioma sub-type on VOC profile. Current results further highlight the potential for a diagnostic mesothelioma breath test as well as providing proof of concept for the differentiation between biphasic and epithelioid mesothelioma based on VOC profiles.

Polyphenols enhance the activity of alkylating agents in leukaemia cell lines.

Polyphenols have been shown to sensitize solid tumours to alkylating agents such as cisplatin, and induce apoptosis and/or cell-cycle arrest. Here, we assess the effects of five polyphenols alone and in combination with three alkylating agents: cisplatin, cyclophosphamide and chlorambucil in lymphoid and myeloid leukaemia cells lines, and non-tumour control cells. In lymphoid leukaemia cell lines there was a synergistic reduction in ATP and glutathione levels, an induction of cell cycle arrest, DNA damage and apoptosis when quercetin, apigenin, emodin and rhein were combined with cisplatin and cyclophosphamide; and when apigenin and rhein were combined with chlorambucil. In myeloid leukaemia cells quercetin, apigenin and emodin showed a similar synergistic effect with all alkylating agents; however antagonistic effects were observed with some or all alkylating agents when combined with emodin, rhein and cis-stilbene. All synergistic effects were associated with reduced glutathione levels, DNA damage and apoptosis; whilst during antagonism the reverse effects were observed. The combination of alkylating agents, particularly cisplatin with polyphenols could be promising for the treatment of lymphoid leukaemias, with apigenin showing the greatest effects. Likewise in myeloid cells apigenin also synergised the action of all alkylating agents, suggesting that apigenin may also be beneficial in myeloid leukaemias.

Patients' perspective of the effectiveness and acceptability of pharmacological and non-pharmacological treatments of fibromyalgia.

Background and aims Fibromyalgia is a complex condition characterised by widespread pain, sleep disturbance, fatigue and cognitive impairment, with a global mean prevalence estimated at 2.7%. There are inconsistencies in guidelines on the treatment of fibromyalgia leading to dissatisfaction from patients and healthcare professionals. This study investigated patient-reported outcomes of pharmacological and non-pharmacological treatment usage and effectiveness with an assessment of acceptability. Methods Nine hundred and forty-one participants completed a self-administered anonymous questionnaire giving quantitative data of demographics, treatment usage and treatment outcomes. Participant-reported effectiveness and side effects were compared in the following treatment classes: analgesics, antidepressants, gabapentinoids, gastrointestinal treatments, activity interventions, dietary-based treatments, and psychological, physical and alternative therapies. Participants also reported whether they knew about or had tried different treatments. Results The results from the online survey indicated that the range of mean effectiveness ratings were similar for pharmacological and non-pharmacological treatments, whereas non-pharmacological treatments had lower side effects ratings and higher acceptability relative to pharmacological treatments. Participants were not aware of some treatment options. Conclusions The results show lower side effects ratings and higher acceptability for non-pharmacological treatments compared to pharmacological treatments despite similar effectiveness ratings. Implications This article presents results from a large online survey on fibromyalgia patient perspectives of pharmacological and non-pharmacological treatments. Results will inform healthcare professionals and patients about optimal treatments based on ratings of effectiveness, side effects and acceptability that are tailored to patient symptom profiles. Some participants were unaware of treatment options highlighting the importance of patient education allowing collaboration between patients and healthcare professionals to find optimal treatments.

An Efficient Sieving Method to Isolate Intact Glomeruli from Adult Rat Kidney.

Preservation of glomerular structure and function is pivotal in the prevention of glomerulonephritis, a category of kidney disease characterized by proteinuria which can eventually lead to chronic and end-stage renal disease. The glomerulus is a complex apparatus responsible for the filtration of plasma from the body. In disease, structural integrity is lost and allows for the abnormal leakage of plasma contents into the urine. A method to isolate and examine glomeruli in culture is critical for the study of these diseases. In this protocol, an efficient method of retrieving intact glomeruli from adult rat kidneys while conserving structural and morphological characteristics is described. This process is capable of generating high yields of glomeruli per kidney with minimal contamination from other nephron segments. With these glomeruli, injury conditions can be mimicked by incubating them with a variety of chemical toxins, including protamine sulfate, which causes foot process effacement and proteinuria in animal models. Degree of injury can be assessed using transmission electron microscopy, immunofluorescence staining, and western blotting. Nephrin and Wilms Tumor 1 (WT1) levels can also be assessed from these cultures. Due to the ease and flexibility of this protocol, the isolated glomeruli can be utilized as described or in a way that best suits the needs of the researcher to help better study glomerular health and structure in diseased states.

What causes fibromyalgia? An online survey of patient perspectives.

Fibromyalgia is a severe chronic pain condition that affects every aspect of life. Causes of the condition remain unclear, and quantitative research cannot account for patients' personal illness narratives and perceptions. This online survey gathered qualitative accounts of the perceived causes of their condition from 596 people with fibromyalgia, which were analyzed thematically. Themes were "Bodily assault, ill-health, and change"; "Emotional trauma and distress"; "Stress and vulnerability"; and "Explaining and authenticating fibromyalgia." Discussion focuses on the complexity of causation, the importance of understanding and having symptoms validated, and the potential for benefiting from patient expertise in building better practitioner-client relationships.

Dietary polyphenols influence antimetabolite agents: methotrexate, 6-mercaptopurine and 5-fluorouracil in leukemia cell lines.

Polyphenols have been previously shown to sensitize leukemia cell lines to topoisomerase inhibitors. Here, we assess the effects of five polyphenols when used alone and in combination with antimetabolites: methotrexate, 6-mercaptopurine and 5-fluorouracil; in lymphoid and myeloid leukemia cells lines, and non-tumor control cells. The effects of combined treatments were investigated on ATP and glutathione levels, cell-cycle progression, DNA damage and apoptosis. Polyphenols antagonized methotrexate and 6-mercaptopurine induced cell-cycle arrest and apoptosis in most leukemia cell lines. This was associated with reduced DNA damage and increased glutathione levels, greater than that seen following individual treatments alone. In contrast, 5-fluorouracil when combined with quercetin, apigenin and rhein caused synergistic decrease in ATP levels, induction of cell-cycle arrest and apoptosis in some leukemia cell lines. However, antagonistic effects were observed when 5-fluorouracil was combined with rhein and cis-stilbene in myeloid cell lines. The effects were dependant on polyphenol type and chemotherapy agent investigated, and cell type treated. Interestingly treatment of non-tumor control cells with polyphenols protected cells from antimetabolite treatments. This suggests that polyphenols modulate the action of antimetabolite agents; more importantly they antagonized methotrexate and 6-mercaptopurine actions, thus suggesting the requirement of polyphenol-exclusion during their use.

FGF21 resistance is not mediated by downregulation of beta-klotho expression in white adipose tissue.

OBJECTIVE: Fibroblast growth factor 21 (FGF21) is an endocrine hormone that regulates metabolic homeostasis. Previous work has suggested that impairment of FGF21 signaling in adipose tissue may occur through downregulation of the obligate FGF21 co-receptor, ß-klotho, which leads to "FGF21 resistance" during the onset of diet-induced obesity. Here, we sought to determine whether maintenance of ß-klotho expression in adipose tissue prevents FGF21 resistance and whether other mechanisms also contribute to FGF21 resistance in vivo. METHODS: We generated adipose-specific ß-klotho transgenic mice to determine whether maintenance of ß-klotho expression in adipose tissue prevents FGF21 resistance in vivo. RESULTS: ß-klotho protein levels are markedly decreased in white adipose tissue, but not liver or brown adipose tissue, during diet-induced obesity. Maintenance of ß-klotho protein expression in adipose tissue does not alleviate impaired FGF21 signaling in white adipose or increase FGF21 sensitivity in vivo. CONCLUSIONS: In white adipose tissue, downregulation of ß-klotho expression is not the major mechanism contributing to impaired FGF21 signaling in white adipose tissue.