Cardiovascular risk factors following renal transplant

Kidney transplantation is the gold-standard treatment for many patients with end-stage renal disease. Renal transplant recipients(RTRs) remain at an increased risk of fatal and non-fatal cardiovascular(CV) events compared to the general population, although rates are lower than those patients on maintenance haemodialysis. Death with a functioning graft is most commonly due to cardiovascular disease(CVD) and therefore this remains an important therapeutic target to prevent graft failure. Conventional CV risk factors such as diabetes, hypertension and renal dysfunction remain a major influence on CVD in RTRs. However it is now recognised that the morbidity and mortality from CVD are not entirely accounted for by these traditional risk-factors. Immunosuppression medications exert a deleterious effect on many of these well-recognised contributors to CVD and are known to exacerbate the probability of developing diabetes, graft dysfunction and hypertension which can all lead on to CVD. Nontraditional CV risk factors such as inflammation and anaemia have been strongly linked to increased CV events in RTRs and should be considered alongside those which are classified as conventional. This review summarises what is known about risk-factors for CVD in RTRs and how, through identification of those which are modifiable, outcomes can be improved. The overall CV risk in RTRs is likely to be multifactorial and a complex interaction between the multiple traditional and non-traditional factors; further studies are required to determine how these may be modified to enhance survival and quality of life in this unique population.

1400W reduces ischemia reperfusion injury in an ex-vivo porcine model of the donation after circulatory death kidney donor

AIM: To investigate the effects of 1400W-a selective inducible nitric oxide synthase(iN OS) inhibitor in a model of donation after circulatory death(DCD) kidneys. METHODS: Porcine kidneys were retrieved after 25 min warm ischemia. They were then stored on ice for 18 h before being reperfused ex vivo with oxygenated autologous blood on an isolated organ perfusion system. The selective i NOS inhibitor 1400W(10 mg/kg) was administered before reperfusion(n = 6) vs control group(n = 7). Creatinine(1000 μmol/L) was added to the system, renal and tubular cell function and the level of ischemia reperfusion injury were assessed over 3 h of reperfusion using plasma, urine and tissue samples. RESULTS: Kidneys treated with 1400 W had a higher level of creatinine clearance(CrC l) [area under the curve(AUC) CrC l: 2.37 ± 0.97 mL /min per 100 g vs 0.96 ± 0.32 mL /min per 100 g, P = 0.004] and urine output [Total: 320 ± 96 mL vs 156 ± 82 mL, P = 0.008]. There was no significant difference in levels of fractional excretion of sodium(AUC, Fr ex Na+: Control, 186.3% ± 81.7%.h vs 1400 W, 153.4% ± 12.1%.h, P = 0.429). Levels of total protein creatinine ratio were significantly lower in the 1400 W group after 1 h of reperfusion(1h Pr/Cr: 1400 W 9068 ± 6910 mg/L/mmol/L vs Control 21586 ± 5464 mg/L/mmol/L, P = 0.026). Levels of 8-isoprostane were significantly lower in the 1400 W group [8-iso/creatinine ratio: Control 239 ± 136 pg/L/mmol/L vs 1400 W 139 ± 47 pg/L/mmol/L, P = 0.041].CONCLUSION: This study demonstrated that 1400 W reduced ischaemia reperfusion injury in this porcine kidney model of DCD donor. Kidneys had improved renal function and reduced oxidative stress.

Duration of treatment with 5-aminosalicylic acid compounds

The development of 5-aminosalicylic acid (5-ASA) therapy as a life long treatment for ulcerative colitis is reviewed from its origins in the 1940s to the present day. The drug was designed to treat rheumatoid arthritis,but was found helpful in the management of nine patients with ulcerative colitis. This discovery preceded the emergence of the clinical trial as a tool for assessing a new drug's efficacy; as a result it lacked scientific rigour and was selective in its presentation of results. Nevertheless it identified the future cornerstone of therapy in ulcerative colitis. In 1962,the first double blind controlled trial of sulphasalazine was conducted on 40 patients. Outcome measures were subjective and included symptoms and an assessment of the rectal mucosa. In 1973,the first two papers on the role of sulphasalazine in maintenance of remission were published. Both used placebo controls and had a stratified design. Outcomes were measured using "an intention to treat" approach. The British study of 64 patients used both subjective and objective criteria to assess outcomes. Patients on placebo had a relapse rate four times patients on active treatment and this founded the basis for a life long approach to therapy with 5-ASA compounds in ulcerative colitis. However,in 1985,a small "on demand" study of 32 patients suggested this approach might be as effective as continuous treatment. Some support for this view came from an Italian study which showed no benefit to continued treatment for those in remission for two years or more. The central problem these studies identify is that of adherence to treatment in the long-term. Few studies have considered patients' attitudes to continuous therapy and it is an area that needs further investigation.

Age at diagnosis of type 2 diabetes and cardiovascular risk factor profile:A pooled analysis

BACKGROUND The diagnosis of type 2 diabetes(T2D)in younger adults,an increasingly common public health issue,is associated with a higher risk of cardiovascular complications and mortality,which may be due to a more adverse cardiovascular risk profile in individuals diagnosed at a younger age.AIM To investigate the association between age at diagnosis and the cardiovascular risk profile in adults with T2D.METHODS A pooled dataset was used,comprised of data from five previous studies of adults with T2D,including 1409 participants of whom 196 were diagnosed with T2D under the age of 40 years.Anthropometric and blood biomarker measurements included body weight,body mass index(BMI),waist circumference,body fat percentage,glycaemic control(HbA1c),lipid profile and blood pressure.Univariable and multivariable linear regression models,adjusted for diabetes duration,sex,ethnicity and smoking status,were used to investigate the association between age at diagnosis and each cardiovascular risk factor.RESULTS A higher proportion of participants diagnosed with T2D under the age of 40 were female,current smokers and treated with glucose-lowering medications,compared to participants diagnosed later in life.Participants diagnosed with T2D under the age of 40 also had higher body weight,BMI,waist circumference and body fat percentage,in addition to a more adverse lipid profile,compared to participants diagnosed at an older age.Modelling results showed that each one year reduction in age at diagnosis was significantly associated with 0.67 kg higher body weight[95%confidence interval(CI):0.52-0.82 kg],0.18 kg/m^(2) higher BMI(95%CI:0.10-0.25)and 0.32 cm higher waist circumference(95%CI:0.14-0.49),after adjustment for duration of diabetes and other confounders.Younger age at diagnosis was also significantly associated with higher HbA1c,total cholesterol,low-density lipoprotein cholesterol and triglycerides.CONCLUSION The diagnosis of T2D earlier in life is associated with a worse cardiovascular risk factor profile,compared to those diagnosed later in life.

Management of early rectal cancer;current surgical options and future direction

Rectal cancer is the second commonest cause of cancer death within the United Kingdom.Utilization of national screening programmes have resulted in a greater proportion of patients presenting with early-stage disease.The technique of transanal endoscopic microsurgery was first described in 1984 following which further options for local excision have emerged with transanal endoscopic operation and,more recently,transanal minimally invasive surgery.Owing to the risks of local recurrence,the current role of minimally invasive techniques for local excision in the management of rectal cancer is limited to the treatment of pre-invasive disease and low risk early-stage rectal cancer(T1N0M0 disease).The roles of chemotherapy and radiotherapy for the management of early rectal cancer are yet to be fully established.However,results of high-quality research such as the GRECCAR II,TESAR and STAR-TREC randomised control trials may highlight a wider role for local excision surgery in the future,when used in combination with oncological therapies.The aim of our review is to provide an overview in the current management of early rectal cancer,the surgical options available for local excision and the future multimodal direction of early rectal cancer treatment.

Considerations when using the activPAL monitor in field-based research with adult populations

Research indicates that high levels of sedentary behavior(sitting or lying with low energy expenditure) are adversely associated with health. A key factor in improving our understanding of the impact of sedentary behavior(and patterns of sedentary time accumulation) on health is the use of objective measurement tools that collect date and time-stamped activity information. One such tool is the activP AL monitor. This thigh-worn device uses accelerometer-derived information about thigh position to determine the start and end of each period spent sitting/lying, standing, and stepping, as well as stepping speed, step counts, and postural transitions. The activP AL is increasingly being used within field-based research for its ability to measure sitting/lying via posture. We summarise key issues to consider when using the activP AL in physical activity and sedentary behavior field-based research with adult populations. It is intended that the findings and discussion points be informative for researchers who are currently using activP AL monitors or are intending to use them. Pre-data collection decisions, monitor preparation and distribution, data collection considerations, and manual and automated data processing possibilities are presented using examples from current literature and experiences from 2 research groups from the UK and Australia.

Acute kidney injury in China:A neglected truth and perspective

Acute kidney injury(AKI)affects approximately 13.3 million individuals and contributes to about 1.7 million deaths globally per year.As estimated 85% of those affected live in the developing world[1].Although there are various measures to prevent or treat AKI,including renal protective drugs and continuous renal replacement therapy,most of them have limited success or are still in their infancy[2,3].

History,ethics,advantages and limitations of experimental models for hepatic ablation

Numerous techniques developed in medicine require careful evaluation to determine their indications,limitations and potential side effects prior to their clinical use.At present this generally involves the use of animal models which is undesirable from an ethical standpoint,requires complex and time-consuming authorization,and is very expensive.This process is exemplified in the development of hepatic ablation techniques,starting experiments on explanted livers and progressing to safety and efficacy studies in living animals prior to clinical studies.The two main approaches used are ex vivo isolated non-perfused liver models and in vivo animal models.Ex vivo non perfused models are less expensive,easier to obtain but not suitable to study the heat sink effect or experiments requiring several hours.In vivo animal models closely resemble clinical subjects but often are expensive and have small sample sizes due to ethical guidelines.Isolated perfused ex vivo liver models have been used to study drug toxicity,liver failure,organ transplantation and hepatic ablation and combine advantages of both previous models.

Is there a role for fish oil in inflammatory bowel disease?

A number of animal and human studies suggest omega3-fatty acids are anti-inflammatory. As a result they may have a therapeutic role in inflammatory bowel disease(IBD). The aim of this review is to briefly assess the literature about the utility of poly-unsaturated fatty acids(PUFAs) in the management of IBD. Taken together, almost all studies suggest some beneficial effects of n-3 PUFAs in IBD but the mechanism remains controversial. In addition, clinical benefit seems to be largely confined to ulcerative colitis. However all studies have concluded that these compounds have no potential for a steroid/aminosalicylic acid sparing effect or to maintain remission. Now the question arises as to whether this treatment is of real value to IBD patients?Clearly they have some therapeutic potential but further work is needed.

When is a bone scan study appropriate in asymptomatic men diagnosed with prostate cancer？

Aims： To determine when a bone scan investigation is appropriate in asymptomatic men diagnosed with prostate cancer. Methods： Between November 2005 and July 2006, 317 men with prostate cancer underwent a bone scan study; 176 men fulfilled the inclusion criteria. Prostate-specific antigen （PSA） cut-offs as well as univariate and multivariate logistic regression analyses using digital rectal examination finding, biopsy Gleason scores and age were performed to determine when a bone scan study is likely to be of value. Results： Only 1/61 men （1.6%） with a serum PSA 〈 20 ng/mL had a positive bone scan. However, 2/38 men （4.7%） with a serum PSA 20.1-40.0 ng/mL, 3/20 men （15%） with a serum PSA 40.1-60.0 ng/mL, 7/19 men （36.8%） with a serum PSA 60.1-100.0 ng/mL and 19/38 men （50%） with a serum PSA 〉 100.0 ng/mL had positive bone scans. Univariate and multivariate logistic regression analyses were uninformative in these groups. Conclusion： Based on our findings, a bone scan is of limited value in asymptomatic prostate cancer patients presenting PSA 〈 20 ng/mL. Therefore, this investigation can be eliminated unless a curative treatment is contemplated. Furthermore, digital rectal examination finding, biopsy Gleason score and age are unhelpful in predicting those who might harbor bone metastasis.

Thermal ablation for unresectable liver tumours,time to move forward?

Even with the advent of laparoscopic techniques for liver tumours,classic resections still represent a major undertaking for numerous liver lesions.The avoidance of surgery using ablative techniques has been the aim for over 20 years.Large volumes can now be rapidly treated with low morbidity with the many technical developments and modifications of the delivery probes.Despite these advances recurrences rates remain high with all of the presently available techniques.The biological and pathophysiological basis underlying may help explain their limitations and are important in understanding where they may be appropriately applied and ways in which they may be improved in the future.

Molecular advances in pancreatic cancer:A genomic,proteomic and metabolomic approach

Pancreatic ductal adenocarcinoma(PDAC)represents a challenging pathology with very poor outcomes and is increasing in incidence within the general population.The majority of patients are diagnosed incidentally with insidious symptoms and hence present late in the disease process.This significantly affects patient outcomes:the only cure is surgical resection but only up to 20%of patients present with resectable disease at the time of clinical presentation.The use of“omic”technology is expanding rapidly in the field of personalised medicine-using genomic,proteomic and metabolomic approaches allows researchers and clinicians to delve deep into the core molecular processes of this difficult disease.This review gives an overview of the current findings in PDAC using these“omic”approaches and summarises useful markers in aiding clinicians treating PDAC.Future strategies incorporating these findings and potential application of these methods are presented in this review article.

Communication after cancellations in orthopaedics: The patient perspective

AIM: To examine patients' perceptions on communication surrounding the cancellation of orthopaedic operations and to identify areas for improvement in communication.METHODS: A prospective survey was undertaken at a university teaching hospital within the department of Trauma and Orthopaedics. Patients admitted to an acute orthopaedic unit, whose operations were cancelled, were surveyed to assess patient satisfaction and preferences for notification of cancellation of their operations. Patients with an abbreviated mental test score of < 9, patients unable to complete the survey independently, those under 16 years of age, and any patient notified of the cancellation by any of the authors were excluded from this study. Patients were surveyed themorning after their operation had been cancelled thus ensuring that every opportunity was given for the medical staff to discuss the cancellation with the patient. The survey included questions on whether or not patients were notified of the cancellation of their surgery, the qualifications of the person discussing the cancellation, and patient preferences on the process. Satisfaction was assessed via 5-point Likert scale questions.RESULTS: Sixty-five consecutive patients had their operations cancelled on 75 occasions. Fifty-four point seven percent of the patients who had cancellations were notified by a nurse and 32% by a doctor. No formal communication occurred for 13.3% cancellations and no explanation was provided for a further 16%. Patients reported that they were dissatisfied with the explanation provided for 36 of the 75(48%) cancellations. Of those patients who were dissatisfied, 25(69.4%) were notified by a nurse. Twenty-three of the 24(96%) patients notified by a doctor were satisfied with the explanation and that communication. Of those patients who were notified by a nurse 83% patients reported that they would have preferred it if a doctor had discussed the cancellation with them. There was a significant difference in satisfaction between those counselled by a nurse and those notified by a doctor(P < 0.0001).CONCLUSION: Communication surrounding cancellations does not meet patient expectations. Patients prefer to be notified by a doctor, illustrating the importance of communication in the doctor-patient relationship.

Outcomes of Pringle maneuver in patients undergoing hepatic resection for colorectal liver metastases

To the Editor:The Pringle maneuver(PM)was initially described more than a century ago to control bleeding associated with hepatic trauma and it remains the most common method to block hepatic inflow and minimize blood loss during hepatic resections[1].

Utilising the impact of COVID-19 on trauma throughput to adapt elective care models for more efficient trauma care

BACKGROUND Coronavirus disease 2019(COVID-19)has necessitated adaptations in local trauma services,with implementation of novel methods of practice,strategic adaptations,and shifting of resource management.Many of these may serve the driver for landmark changes to future healthcare provision.AIM To analyse the impact of COVID-19 on service provision by comparing throughput and productivity metrics with preceding years to identify differences in practice that were successful,cost-effective,and sustainable.METHODS We quantified orthopaedic trauma care provision at a single University Teaching Hospital over a three consecutive year period,from 1st January 2018 to 31st December 2020.Each year was split into four phases based on the 2020 national COVID-19 pandemic periods.We quantitatively analysed change in rates of inpatient trauma operative case load,sub-specialty variation,theatre throughput,and changes in management strategy.Qualitative analysis was based on multidisciplinary team interviews to highlight changes to care pathways.RESULTS Of 1704 cases were admitted in 2020,11.9%and 12.4%fewer than 2019 and 2018,respectively.During phase 1,hip fractures encompassed the majority(48.8%)of trauma throughput,with all other subspecialties seeing a reduction.Mean length of stay was shorter during phase 1(5.7 d);however,the time in theatre was longer(144.3 min).Both,Charlson(0.90)and Elixhauser(1.55)Comorbidity Indices indicated the most co-morbid admissions during 2020 phase 1.CONCLUSION COVID-19 has resulted in a paradigm shift in how care is accessed and delivered,with many evolving changes and adaptations likely to leave an impression upon healthcare provision in the future.

Reversal of Tetracycline Resistance by Cepharanthine,Cinchonidine,Ellagic Acid and Propyl Gallate in a Multi-drug Resistant Escherichia coli

Bacterial resistance to antibiotics is an increasing threat to global healthcare systems.We therefore sought compounds with potential to reverse antibiotic resistance in a clinically relevant multi-drug resistant isolate of Escherichia coli(NCTC 13400).200 natural compounds with a history of either safe oral use in man,or as a component of a traditional herb or medicine,were screened.Four compounds;ellagic acid,propyl gallate,cinchonidine and cepharanthine,lowered the minimum inhibi-tory concentrations(MICs)of tetracycline,chloramphenicol and tobramycin by up to fourfold,and when combined up to eightfold.These compounds had no impact on the MICs of ampicillin,erythromycin or trimethoprim.Mechanistic studies revealed that while cepharanthine potently suppressed efflux of the marker Nile red from bacterial cells,the other hit com-pounds slowed cellular accumulation of this marker,and/or slowed bacterial growth in the absence of antibiotic.Although cepharanthine showed some toxicity in a cultured HEK-293 mammalian cell-line model,the other hit compounds exhibited no toxicity at concentrations where they are active against E.coli NCTC 13400.The results suggest that phytochemicals with capacity to reverse antibiotic resistance may be more common in traditional medicines than previously appreciated,and may offer useful scaffolds for the development of antibiotic-sensitising drugs.

Nephrectomy Avoided in a Patient with Lipid Poor Angiomylipoma with Radiological Features Suspicious for Renal Cell Carcinoma: A Case Report

Angiomyolipoma (AML) is a benign neoplasm that is easily mistaken for renal cell carcinoma (RCC) upon radiological investigation. The management of the two pathologies is significantly different, and so accurate diagnosis is vital. We report a case in which ultrasound guided biopsy saved the patient from an unnecessary nephrectomy when an AML had radiological appearances consistent with RCC. This case report also discusses the literature surrounding radiological features and novel imaging techniques of minimal-fat AML and RCC.

Assessment of long-term graft function following total pancreatectomy and autologous islet transplantation:the Leicester experience

Background:Total pancreatectomy and islet autotransplantation(TPIAT)is a recognised treatment for chronic pancreatitis(CP)with the potential to mitigate or prevent pancreatogenic diabetes.We present our 10-year follow-up of TPIAT patients.Methods:The University Hospitals of Leicester performed 60 TPIAT procedures from September 1994 to May 2011.Seventeen patients completed their 10-year assessment and were grouped using the modified Auto-Igls criteria;good response,n=5(insulin-independent for first 5 years post-TPIAT);partial response,n=6(insulin requirements<20 iU/day post-TPIAT)and poor response,n=6(insulin requirements≥20 iU/day post-TPIAT).C-peptide,haemoglobin A1c(HbA1c)and oral glucose tolerance test(OGTT)were undertaken preoperatively(baseline),then at 3,6 months and then yearly for 10 years.Data was analysed using analysis of variance(ANOVA).Results:Median C-peptide levels were significantly higher,120 minutes following OGTT,in the“good response”compared to“partial”and“poor”groups(two-way ANOVA test,P<0.0001).All groups demonstrated preservation of C-peptide release.HbA1c levels were significantly lower in the“good response”compared to“partial”and“poor”groups(two-way ANOVA test,P<0.0003 and P<0.0001).Median fasting glucose levels at 30 and 120 min following OGTT,were significantly lower in the“good response”compared to“partial”and“poor”groups(two-way ANOVA test,P<0.0001 and P<0.0001).Conclusions:TPIAT preserves long-term islet graft functions in 10-year follow up.Even in patients in the poor response group,there is evidence of C-peptide release(>0.5 ng/mL)after OGTT stimulation potentially preventing long-term diabetes-related complications.

Sexual and Reproductive Service Interventions for Menstrual Regulation,Safe Abortion,and Post-abortion Care and Their Effectiveness During Disaster Response:A Global Systematic Review

Sexual and reproductive health(SRH)services are crucial for women especially during disasters,to reduce maternal mortality and morbidity from miscarriages,unsafe abortions,and post-abortion complications.This study explored the SRH interventions provided during disaster response.A systematic review was conducted to identify what menstrual regulation(MR),safe abortion(SA),and post-abortion care(PAC)approaches/interventions exist to promote resilience in the health system in disaster settings;what intervention components were most eff ective;and challenges and opportunities to meeting SRH rights.Five electronic databases were searched,resulting in 4194 records.Following the screening process,seven publications were included.The intervention-related information in each publication was assessed based on availability,accessibility,acceptability,and quality.Two SRH approaches/interventions were found.The eff ectiveness of intervention components could not be conducted due to the limited number of relevant studies.Challenges were found at facility and community levels,and opportunities included overcoming them,making MR,SA,and PAC integral to the mitigation phase,and policy change to overcome barriers related to unaff ordability and inaccessibility.Recommendations are provided to encourage research and policy towards improving neglected SRH in disaster settings to realize Sustainable Development Goal 3 and the Global Strategy and Sendai Framework's priority to promote disaster-resilient health systems.

The integration of artificial intelligence models to augment imaging modalities in pancreatic cancer

Pancreatic ductal adenocarcinoma(PDAC)is an aggressive malignancy with a limited number of effective treatments.Using emerging technologies such as artificial intelligence(AI)to facilitate the earlier diagnosis and decision-making process represents one of the most promising areas for investigation.The integration of AI models to augment imaging modalities in PDAC has made great progression in the past 5 years,especially in organ segmentation,AI-aided diagnosis,and radiomics based individualized medicine.In this article,we review the developments of AI in the field of PDAC and the present clinical position.We also examine the barriers to future development and more widespread application which will require increased familiarity of the underlying technology among clinicians to promote the necessary enthusiasm and collaboration with computer professionals.