2021

Assembly of alternative prothrombinase by extracellular histones initiate and disseminate intravascular coagulation (2021)

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Type of publication:
Journal article

Author(s):
Abrams, Simon Timothy; Su, Dunhao; Sahraoui, Yasmina; Lin, Ziqi; Cheng, Zhenxing; Nesbitt, Kate; *Alhamdi, Yasir; Harrasser, Micaela; Du, Min; Foley, Jonathan; Lillicrap, David; Wang, Guozheng; Toh, Cheng-Hock

Citation:
Blood; 2021 Jan 7;137(1):103-114

Abstract:
Thrombin generation is pivotal to both physiological blood clot formation and pathological development of disseminated intravascular coagulation (DIC). In critical illness, extensive cell damage can release histones into the circulation, which can increase thrombin generation and cause DIC, but the molecular mechanism is not clear. Typically, thrombin is generated by the prothrombinase complex, comprising activated factor X (FXa), activated co-factor V (FVa) and phospholipids to cleave prothrombin in the presence of calcium. In this study, we found that in the presence of extracellular histones, an alternative prothrombinase could form without FVa and phospholipids. Histones directly bind to prothrombin fragments F1 and F2 specifically, to facilitate FXa cleavage of prothrombin to release active thrombin, unlike FVa which requires phospholipid surfaces to anchor the classical prothrombinase complex. In vivo, histone infusion into mice induced DIC, which was significantly abrogated when prothrombin fragments F1+F2 were infused prior to histones, to act as decoy. In a cohort of intensive care unit (ICU) patients with sepsis (n=144), circulating histone levels were significantly elevated in patients with DIC. These data suggest that histone-induced alternative prothrombinase without phospholipid anchorage may disseminate intravascular coagulation, and reveal a new molecular mechanism of thrombin generation and DIC development. In addition, histones significantly reduced the requirement for FXa in the coagulation cascade to enable clot formation in Factor VIII and IX-deficient plasma, as well as in Factor VIII-deficient mice. In conclusion, this study highlights a novel mechanism in coagulation with therapeutic potential in both targeting systemic coagulation activation as well as in correcting coagulation factor deficiency.

Randomized Trial of Ciprofloxacin Doxycycline and Hydroxychloroquine Versus Budesonide in Active Crohn's Disease (2021)

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Type of publication:
Randomised controlled trial

Author(s):
Rhodes J.M.; Subramanian S.; Martin K.; Probert C.; Flanagan P.K.; Horgan G.W.; Mansfield J.; Parkes M.; Hart A.; Dallal H.; Iqbal T.; *Butterworth J.; Culshaw K.

Citation:
Digestive Diseases and Sciences; Aug 2021; vol. 66 (no. 8); p. 2700-2711

Abstract:
Background: Increased mucosa-associated E. coli are present in Crohn's disease, but their role in pathogenesis is uncertain. Aim(s): To assess efficacy and safety of an antibiotic/hydroxychloroquine combination effective against E. coli inside macrophages. Method(s): Adults with moderately active disease (CDAI > 220-450 plus C reactive protein >= 5 mg/l and/or fecal calprotectin > 250 mug/g) were randomized to receive (open-label) oral budesonide (Entocort CR 9 mg/day 8 weeks, 6 mg/day 2 weeks, 3 mg/day 2 weeks) or oral ciprofloxacin 500 mg bd, doxycycline 100 mg bd, hydroxychloroquine 200 mg tds for 4 weeks, followed by doxycycline 100 mg bd and hydroxychloroquine 200 mg tds for 20 weeks. Primary endpoints were remission (CDAI <= 150) at 10 weeks, remission maintained to 24 weeks, and remission maintained to 52 weeks. Patients not responding (CDAI fall by > 70) by 10 weeks were invited to crossover onto the alternative therapy. Result(s): Fifty-nine patients were recruited across 8 sites. Including crossover, 39 patients received antibiotics/hydroxychloroquine and 39 received budesonide. At 10 weeks, 24 weeks, and 52 weeks on initial therapy, only 2/27, 2/27, and 1/27 were in remission on antibiotics/hydroxychloroquine compared with 8/32, 1/32, and 1/32 on budesonide (P = 0.092 at 10 weeks). Withdrawals by 10 weeks due to adverse events were seen in 15 receiving antibiotics/hydroxychloroquine and 6 budesonide. Results including crossover were more promising with 9/24 patients receiving antibiotics/hydroxychloroquine per protocol in remission by 24 weeks. No correlation was seen between response to antibiotics/hydroxychloroquine and ASCA/OmpC antibody status or disease location. Conclusion(s): Overall results with this antibiotic/hydroxychloroquine combination were unimpressive, but long-term remission is seen in some patients and justifies further study.

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Routine Use of Swallowing Outcome Measures Following Head and Neck Cancer in a Multidisciplinary Clinic Setting (2021)

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Type of publication:
Journal article

Author(s):
*Annette C. Zuydam, Simon N. Rogers, Kate Grayson, *Clare F. Probert

Citation:
International Archives of Otorhinolaryngology, 2021; 25(02): e185-e192

Abstract:
Introduction: Chemoradiotherapy treatment for head and neck cancer (HNC) can have a major impact on swallowing function and health-related quality of life. The use of outcome measures in early detection of patients with swallowing problems provides the opportunity for targeting speech and language therapy (SLT) interventions to aid adaption and promote better clinical outcomes.
Objective: The purpose of the present study was to assess relationships between four outcomes measures over time, in a cohort of HNC patients, treated by (chemo-) radiotherapy.
Methods: Data were collected at 3 months and 12 months, on 49 consecutive patients with primary squamous cell cancer of the oropharynx, nasopharynx or hypopharynx stage T1–4, N0–2b, M0 disease.
Results: Out of 49 eligible patients, 45 completed assessment at 3 months and 20 at 12 months. The 3-month outcomes gave a strong indication of performance at 1 year. There were several strong correlations found between measures. The strongest was between the 3-month Performance Status Scale for Head and Neck Cancer (PSSHN) and the 12-month PSSHN (rs ¼ 0.761, n ¼ 17), the 12-month PSSHN and the 12-month
Functional Oral Intake Scale (FOIS) (rs ¼ 0.823, n ¼ 20), and the 12-month University of Washington Head and Neck Quality of Life (UWQoL) swallow and the 12-month Water Swallow Test (WST) capacity (rs ¼ 0.759, n ¼ 17).
Conclusion: The UW-QoL swallow item and WST are easy to incorporate into routine care and should be used as part of a standard assessment of swallow outcome. These measures can serve to help screen patients for dysfunction and focus allocation of resources for those who would benefit from more comprehensive assessment and intervention by SLT.

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Optimising patients with long-term spinal cord injury for nephrectomy: A review of pre-, peri- and post-operative factors to safeguard outcomes (2021)

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Type of publication:
Journal article

Author(s):
*Donati-Bourne J.; *Mohamed W.G.E.; *Pillai P.; *O'Dair J.; Kasmani Z.; Bhatt R.I.

Citation:
Journal of Clinical Urology; 2021, Volume: 14 issue: 2, page(s): 78-84

Abstract:
Objectives: To review the potential challenges a urologist may encounter when embarking on simple/partial/radical nephrectomy in patients with long-term spinal cord injury and propose strategies to pre-empt and manage these.
Material(s) and Method(s): Comprehensive literature review via PubMed, MEDLINE and Google Scholar searching for relevant scientific articles published to date in English. Recommendations for strategies to safeguard surgical outcomes discussed with a panel of experienced upper-tract urologists.
Result(s): Pre-operative considerations: – urethral assessment via flexible cystoscopy due to higher incidence of urethral pathology in spinal cord injury; – assessing for chronic constipation and distended bowel; and – considering glomerular filtration rate assessment by radio-isotope techniques, such as 51chromium-EDTA Perioperative considerations: – adequate theatre staffing for safe patient transfer; and – planned choice of incision, due to higher incidence of previous abdominal surgery, stoma bags and/or foreign body devices. Post-operative considerations: – ensuring attending medical staff are trained to recognise autonomic dysreflexia; – early remobilisation with physiotherapists experienced in treating spinal cord injury; and – attentive antibiotic stewardship due to higher risk of hospital-acquired or urinary infections
Conclusion(s): Patients with long-term spinal cord injury pose significant potential challenges in the pre-, periand post-operative stages of nephrectomy. Familiarisation and optimisation of such factors is recommended to safeguard outcomes.
Level of Evidence: Not applicable for this multicentre audit.

Thyrotoxicosis and the consumption of bovine thyroid tissue (2021)

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Type of publication:
Journal article

Author(s):
S Senthilkumaran, *F Benita, P Thirumalaikolundusubramanian, K Swaminathan

Citation:
QJM : monthly journal of the Association of Physicians; Jul 2021; vol. 114 (no. 4); p. 253-254

Abstract:
Thyrotoxicosis due to consumption of bovine thyroid tissue is called hamburger thyroiditis. Despite bovine meat consumption in India and Asia, it is surprising to note that very few thyrotoxicosis from food contamination has been reported from Asia. We report a case of exogenous thyrotoxicosis due to bovine thyroid tissue consumption probably for the first time from Asia, to create an awareness of this entity among physicians and practitioners and others to consider this entity while handling patients with features of thyrotoxicosis of recent onset.