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NK cells in pancreatic cancer demonstrate impaired cytotoxicity and a regulatory IL-10 phenotype.
No full textPancreatic ductal adenocarcinoma (PDAC) is one of the most common tumor subtypes and remains associated with very poor survival. T cell infiltration into tumor tissue is associated with improved clinical outcome but little is known regarding the potential role of NK cells in disease control. Here we analyze the phenotype and function of NK cells in the blood and tumor tissue from patients with PDAC. Peripheral NK cells are present in normal numbers but display a CD16CD57 phenotype with marked downregulation of NKG2D. Importantly, these cells demonstrate reduced cytotoxic activity and low levels of IFN-γ expression but instead produce high levels of intracellular IL-10, an immunoregulatory cytokine found at increased levels in the blood of PDAC patients. In contrast, NK cells are largely excluded from tumor tissue where they display strong downregulation of both CD16 and CD57, a phenotype that was recapitulated in primary NK cells following co-culture with PDAC organoids. Moreover, expression of activatory proteins, including DNAM-1 and NKP30, was markedly suppressed and the DNAM-1 ligand PVR was strongly expressed on tumor cells. As such, and peripheral NK cells display differential features in patients with PDAC and indicate local and systemic mechanisms by which the tumor can evade immune control. These findings offer a number of potential options for NK-based immunotherapy in the management of patients with PDAC
Congenital intrahepatic aorto-portal fistula presenting with cardiac failure.
No full textCongenital intrahepatic arterio-portal fistulae (cIAPF) are rare, high-flow vascular malformations that usually present with portal hypertension. They almost never cause heart failure, unless there is associated congenital heart disease or the ductus venosus in patent. We present an unusual case of IAPF in an 11-day-old boy, who presented with features of cardiac failure associated with increased N-terminal pro-brain natriuretic peptide (NT pro-BNP). The IAPF arose directly from the aorta, separated from the hepatic artery and divided to separately supply both left and right portal veins. The ductus venosus was occluded. The IAPF was treated with embolization of the aorto-portal fistula, accessed through a direct percutaneous puncture of the fistula. Embolization was associated with an immediate clinical improvement and a rapid and sustained normalization of the NT pro-BNP level. A similar re-presentation was noted and treated with repeat embolization. The child is well on follow-up. To our knowledge, this is the first case of cIAPF, which was presented with cardiac failure when the ductus venosus has closed and has been treated successfully with direct, percutaneous transhepatic embolization of the fistula, twice. Serial clinical follow-up and ultrasonographical examinations have proven to be an effective strategy to detect recurrent fistulae
Evaluation of Smoking as a Modifying Factor in Chronic Rhinosinusitis.
No full textImportance
The negative association of smoking with the respiratory tract is well known; however, the association between smoking and chronic rhinosinusitis (CRS) has not been well characterized.
Objective
To analyze whether active smoking was a risk factor for CRS development, smoking was associated with disease-specific quality of life, and smokers experience an increased symptom burden than nonsmokers.
Design, Setting, and Participants
This subanalysis of the Chronic Rhinosinusitis Epidemiology Study (CRES), a prospective, questionnaire-based case-control study conducted between October 2007 and September 2013 was conducted across 30 UK tertiary/secondary care sites. Participants were identified at ear, nose, and throat outpatient clinics and classified into CRS phenotypes as per European Position Paper on Rhinosinusitis and Nasal Polyps 2012 criteria. The overall response rate of those identified to take part in the study was 66%. A total of 1535 questionnaires were returned, with 1470 considered eligible for inclusion. Data analysis was conducted in January 2020.
Main Outcomes and Measures
The CRES was designed to distinguish differences in socioeconomic status, geography, medical comorbidities, lifestyle, and quality of life between patients with CRS and healthy controls.
Results
A total of 1450 patients completed the smoking question, comprising 219 controls (15.1%; mean [SD] age, 47.3 [14.9] years; 143 women [68%]), 546 participants with CRS (37.7%; mean [SD] age, 51.8 [15.3] years; 259 women [53%]) without nasal polyps (CRSsNPs), and 685 participants (47.2%; mean [SD] age, 56.0 [14.5] years; 204 women [33%]) with CRS and nasal polyps/allergic fungal rhinosinusitis (CRSwNPs+). The mean age was similar, with a greater female preponderance in the control group and male in the CRSwNP group. The greatest number of active smokers was found among control participants (33 [15%]), with a lower rate of smokers in the patients with CRSwNPs+ (9.9%) and CRSsNPs (13.9%), respectively. We found a clinically significant difference in the mean difference in Sino-nasal Outcome Test (SNOT-22) scores between active smokers and nonsmokers for both CRS phenotypes (4.49, 12.25). In both CRS subgroups active smokers had significantly worse SNOT-22 scores than nonsmokers by a mean (SD) magnitude of 10 (18.99, 24.14) points. Nonsmokers also demonstrated a higher percentage of surgical procedures (1 or more), although this was not clinically or statistically different (0.34, 1.10).
Conclusions and Relevance
This questionnaire-based case-control study demonstrated a clinically significant symptom burden associated with active cigarette smoking, with worse SNOT-22 scores in the smoking cohort by a mean magnitude of 10 points. We could find no demonstrable evidence that smoking increases the likelihood of need for revision sinus surgery. Clinicians should encourage smoking cessation alongside general CRS medical management
Obstacles to Early Diagnosis and Treatment of Alpha-1 Antitrypsin Deficiency: Current Perspectives.
No full textThis review summarizes the current research and outlooks regarding the obstacles to diagnosing and treating early alpha-1-antitrypsin deficiency (AATD). It draws on prior systematic reviews and expert surveys to discover precisely what difficulties exist in early diagnosis and treatment of AATD and elucidate potential solutions to ease these difficulties. The perceived rarity of AATD may translate to a condition poorly understood by primary care physicians, and even many respiratory physicians, which results in opportunities for diagnosis being missed, especially in mild or asymptomatic patients. There are diagnostic techniques involving biomarkers and home testing methods which could improve the rate of early diagnosis. With respect to treatment, AATD involves treating two separate pathologies, lung disease and liver disease. The only specific AATD treatment, augmentation therapy, has proven ability in treating lung disease but not liver disease. Alpha-1-antitrypsin (AAT) synthesized in the liver can form damaging polymers that also result in reduced circulating AAT levels and, whilst liver transplantation is used to effectively treat AATD, it is inappropriate in early disease. Novel therapeutic areas such as gene editing and increasing autophagy are therefore being researched as future treatments. Ultimately, diagnosis and treatment are intrinsically linked in AATD, with earlier diagnosis leading to better treatment options and thus better patient outcomes
Emergency preparedness, resilience and response to a biological outbreak.
No full textMajor disease outbreaks continue to be a significant risk to public health, with pandemic influenza or an emerging infectious disease outbreak at the top of the UK National Risk Register. The risk of deliberate release of a biological agent is lower but remains possible and may only be recognised after casualties seek medical attention. In this context the emergency preparedness, resilience and response (EPRR) process protects the public from high consequence infectious diseases, other infectious disease outbreaks and biological agent release. The core elements of the EPRR response are recognition of an outbreak, isolation of patients, appropriate personal protective equipment for medical staff and actions to minimise further disease spread. The paper discusses how high-threat agents may be recognised by clinicians, the initial actions to be taken on presentation and how the public health system is notified and responds. It draws on the national pandemic influenza plans to describe the wider response to a major disease outbreak and discusses training requirements and the potential role of the military
Influence of Different Partial Pressures of Oxygen During Continuous Hypothermic Machine Perfusion in a Pig Kidney Ischemia-reperfusion Autotransplant Model.
No full textBACKGROUND
The optimal perfusate partial pressure of oxygen (PO2) during hypothermic machine perfusion (HMP) is unknown. The aims of the study were to determine the functional, metabolic, structural, and flow dynamic effects of low and high perfusate PO2 during continuous HMP in a pig kidney ischemia-reperfusion autotransplant model.
METHODS
The left kidneys of a ±40 kg pigs were exposed to 30 minutes of warm ischemia and randomized to receive 22-hour HMP with either low perfusate PO2 (30% oxygen, low oxygenated HMP [HMPO2]) (n = 8) or high perfusate PO2 (90% oxygen, HMPO2high) (n = 8), before autotransplantation. Kidneys stored in 22-hour standard HMP (n = 6) and 22-hour static cold storage (n = 6) conditions served as controls. The follow-up after autotransplantation was 13 days.
RESULTS
High PO2 resulted in a 3- and 10-fold increase in perfusate PO2 compared with low HMPO2 and standard HMP, respectively. Both HMPO2 groups were associated with superior graft recovery compared with the control groups. Oxygenation was associated with a more rapid and sustained decrease in renal resistance. While there was no difference in functional outcomes between both HMPO2 groups, there were clear metabolic differences with an inverse correlation between oxygen provision and the concentration of major central metabolites in the perfusion fluid but no differences were observed by oxidative stress and metabolic evaluation on preimplantation biopsies.
CONCLUSIONS
While this animal study does not demonstrate any advantages for early graft function for high perfusate PO2, compared with low perfusate PO2, perfusate metabolic profile analysis suggests that aerobic mechanism is better supported under high perfusate PO2 conditions
Histopathology during the COVID-19 pandemic: resilience through adaptation and innovation.
No full textHistopathology departments have adapted to the challenges posed by the COVID-19 pandemic by a variety of changes including working pattern alterations, technology adoptions and incorporation of techniques. This article summarizes these adaptations and provides references to guide pathologists through the continuing pandemic
Effect of Digoxin vs Bisoprolol for Heart Rate Control in Atrial Fibrillation on Patient-Reported Quality of Life: The RATE-AF Randomized Clinical Trial.
No full textImportance
There is little evidence to support selection of heart rate control therapy in patients with permanent atrial fibrillation, in particular those with coexisting heart failure.
Objective
To compare low-dose digoxin with bisoprolol (a β-blocker).
Design, Setting, and Participants
Randomized, open-label, blinded end-point clinical trial including 160 patients aged 60 years or older with permanent atrial fibrillation (defined as no plan to restore sinus rhythm) and dyspnea classified as New York Heart Association class II or higher. Patients were recruited from 3 hospitals and primary care practices in England from 2016 through 2018; last follow-up occurred in October 2019.
Interventions
Digoxin (n = 80; dose range, 62.5-250 μg/d; mean dose, 161 μg/d) or bisoprolol (n = 80; dose range, 1.25-15 mg/d; mean dose, 3.2 mg/d).
Main Outcomes and Measures
The primary end point was patient-reported quality of life using the 36-Item Short Form Health Survey physical component summary score (SF-36 PCS) at 6 months (higher scores are better; range, 0-100), with a minimal clinically important difference of 0.5 SD. There were 17 secondary end points (including resting heart rate, modified European Heart Rhythm Association [EHRA] symptom classification, and N-terminal pro-brain natriuretic peptide [NT-proBNP] level) at 6 months, 20 end points at 12 months, and adverse event (AE) reporting.
Results
Among 160 patients (mean age, 76 [SD, 8] years; 74 [46%] women; mean baseline heart rate, 100/min [SD, 18/min]), 145 (91%) completed the trial and 150 (94%) were included in the analysis for the primary outcome. There was no significant difference in the primary outcome of normalized SF-36 PCS at 6 months (mean, 31.9 [SD, 11.7] for digoxin vs 29.7 [11.4] for bisoprolol; adjusted mean difference, 1.4 [95% CI, -1.1 to 3.8]; P = .28). Of the 17 secondary outcomes at 6 months, there were no significant between-group differences for 16 outcomes, including resting heart rate (a mean of 76.9/min [SD, 12.1/min] with digoxin vs a mean of 74.8/min [SD, 11.6/min] with bisoprolol; difference, 1.5/min [95% CI, -2.0 to 5.1/min]; P = .40). The modified EHRA class was significantly different between groups at 6 months; 53% of patients in the digoxin group reported a 2-class improvement vs 9% of patients in the bisoprolol group (adjusted odds ratio, 10.3 [95% CI, 4.0 to 26.6]; P < .001). At 12 months, 8 of 20 outcomes were significantly different (all favoring digoxin), with a median NT-proBNP level of 960 pg/mL (interquartile range, 626 to 1531 pg/mL) in the digoxin group vs 1250 pg/mL (interquartile range, 847 to 1890 pg/mL) in the bisoprolol group (ratio of geometric means, 0.77 [95% CI, 0.64 to 0.92]; P = .005). Adverse events were less common with digoxin; 20 patients (25%) in the digoxin group had at least 1 AE vs 51 patients (64%) in the bisoprolol group (P < .001). There were 29 treatment-related AEs and 16 serious AEs in the digoxin group vs 142 and 37, respectively, in the bisoprolol group.
Conclusions and Relevance
Among patients with permanent atrial fibrillation and symptoms of heart failure treated with low-dose digoxin or bisoprolol, there was no statistically significant difference in quality of life at 6 months. These findings support potentially basing decisions about treatment on other end points.
Trial Registration
ClinicalTrials.gov Identifier: NCT02391337 and clinicaltrialsregister.eu Identifier: 2015-005043-13
Management of acute and chronic iliofemoral venous outflow obstruction: a multidisciplinary team consensus.
No full textThe aim of this manuscript was to establish a consensus for the management of acute and chronic venous obstruction among specialists in the UK. Specialist physicians representing vascular surgery, interventional radiology and hematology were invited to 3 meetings to discuss management of acute and chronic iliofemoral obstruction. The meetings outlined controversial areas, included a topic-by-topic review; and on completion reached a consensus when greater than 80% agreement was reached on each topic. Physicians from 19 UK hospitals agreed on treatment protocols and highlighted areas that need development. Potential standard treatment algorithms were created. It was decided to establish a national registry of venous patients led by representatives from the treating multidisciplinary teams. Technical improvements have facilitated invasive treatment of patients with acute and chronic venous obstruction; however, the evidence guiding treatment is weak. Treatment should be conducted in centers with multi-disciplinary input; robust, coordinated data collection; and regular outcome analysis to ensure safe and effective treatment and a basis for future evolvement
Independent Prescribing Pharmacists Supporting the Early Discharge of Patients Through Completion of Medical Discharge Summaries.
No full textPURPOSE
Independent prescribing pharmacists are able to independently prescribe medications following additional postgraduate training. This study examined their use in completing medical discharge summaries, normally completed by junior doctors, in order to assess their impact on expedited hospital discharge times.
METHODS
In total, 163 patients were studied through a 2-stage audit. The first cycle evaluated junior doctors completing medical discharge summaries (as is normal practice). Three independent prescribing pharmacists were then trained to complete discharge summaries, and a second cycle was completed.
RESULTS
Following implementation of independent prescribing pharmacists to complete medical discharge summaries, the time from medical decision to discharge to summary completion dropped significantly (mean of 2:42 hours to 1:35 hours, < .001). The time from medical decision to discharge to actual hospital discharge also dropped significantly (mean of 5:21 hours to 3:58 hours, < .01). The number of discharge summary medication errors dropped significantly ( < .05) between audit cycles.
CONCLUSION
The introduction of independent prescribing pharmacists to complete medical discharge summaries has significantly reduced the time to summary completion, discharge time, and the number of medication errors. In a time of limited medical resources and bed shortages, the use of allied health professionals to improve service delivery is of paramount importance. This project is the first of its kind within the literature