Key Points We report rare monoallelic variants of THPO that alter intracellular trafficking and diminish thrombopoietin secretion. Affected cases have autosomal-dominant thrombocytopenia but no other hematological features.

While it is widely recognised that communication and handover are a fundamental component in providing safe clinical care for hospital patients (1,2.3). The Royal College of Physicians found that the majority of hospital doctors are dissatisfied with the standard of their handovers (4). These findings were mirrored by the junior staff at the Royal United Hospital, who felt that the weekend handover was inadequate, and detrimental to patient safety.A group of eight junior doctors at the Royal United Hospital, Bath utilised The Model For Improvement to systematically analyse and improve various aspects of the weekend handover system. Handover sheets from a subset of wards were assessed to observe direct effects of staged interventions over a nine month period, allowing small-scale testing prior to widespread implementation of a standardised intranet-based weekend handover. The effects of interventions were evaluated using a predesigned scoring system and data was collected continuously throughout the project.Over a nine month period the quality of handovers improved significantly from 76% to 93% (p <0.01): a success which was supported by a 100% improvement in formal feedback collected from hospital doctors and highlighted by the desire of senior staff and directors to implement the system throughout the trust. Using The Model For Improvement a group of junior doctors were able to introduce and develop a standardised weekend handover system that met their requirements. A structured, efficient and auditable system has been successfully produced which improves the quality and safety of patient care. ProblemWeekend handover of ward based patients at the Royal United Hospital (RUH), Bath, lacked structure and organisation. Under the original system it was the role of the junior doctors working on each ward to generate a list of jobs to be completed over the course of the weekend -ranging from routine blood tests to patient reviews. These lists would be left in the medical or surgical admissions unit on a Friday evening, ready for the doctor covering the wards to collect on Saturday morning. There was neither a standardised form to be completed or guidance on what details to provide, nor was there any backup or record of the jobs to be completed. As a result handovers varied significantly in format, detail, appropriateness and ultimately safety.Every weekend junior doctors working on ward cover were met with the same problems: lack of patient identifiers, insufficient detail to allow appropriate prioritisation, illegible handwriting, poor description of the job to be executed, inadequate guidance on how to act upon certain findings, incorrect location of the patient and excessive pieces of paper to carry (Fig. 4). As a consequence, doctors were finding that they had insufficient time to review all their patients and complete all their jobs. Many critical jobs were missed causing the doctors a great deal of stress and putting patients' safety at risk.

A 66-year-old man presented with fevers, myalgia, weight loss and an urticarial rash. A full blood count showed haemoglobin concentration 70 g/l and white cell count 1Á7 9 10 9 /l with rouleaux and lymphoplasmacytoid lymphocytes seen in the blood film. He was positive for anti-neutrophil cytoplasmic antibodies (cANCA) and anti-proteinase 3 (weakly). Parvovirus immunoglobulin (Ig) M and IgG antibodies were detected, but polymerase chain reaction (PCR) for parvovirus DNA was negative. A computed tomography (CT) scan demonstrated widespread lymphadenopathy and hepatosplenomegaly (top left). A lymph node biopsy showed proliferation of capillaries with an infiltrate of small to medium sized atypical lymphocytes admixed with eosinophils, plasma cells and large blasts (bottom left). These lymphocytes were CD2 + CD3 + CD5 + with the blasts being CD10 + on immunohistochemistry, confirming a diagnosis of angioimmunoblastic T-cell lymphoma (AITL). Prior to starting treatment, the symptoms improved spontaneously with normalisation of his full blood count. Repeat CT imaging 5 months after the initial presentation confirmed complete remission (top centre).He remained well for 52 months before re-presenting with a similar symptom complex, including rash, sweats and weight loss, with widespread lymphadenopathy and splenomegaly on CT imaging (top right). Serological tests for human immunodeficiency virus (HIV) and human T-cell lymphotropic virus 1 (HTLV1) were positive, but an HIV line immunoassay and HTLV1 PCR confirmed neither infection was present. A lymph node biopsy showed increased blood vessels with a polymorphous lymphoid infiltrate, including some blasts, and numerous eosinophils (bottom right). The blasts co-expressed CD10 and PD-1 (also termed PDCD1) on immunohistochemistry, consistent with relapsed AITL. The patient was subsequently commenced on combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) achieving a very good partial response after four cycles.AITL is frequently associated with abnormal immune phenomena, such as inflammatory rashes and false positive serology results. Spontaneous remissions are rare and usually short-lived, with a median of 9 months (Pangalis et al, 1983) but, as shown in our patient, can be more sustained.

Background: People with cancer experience high rates of venous thromboembolism (VTE). Additionally, risk of subsequent cancer is increased in people experiencing their first VTE. The causal mechanisms underlying this association are not completely understood, and it is unknown whether VTE is itself a risk factor for cancer. Methods: We used data from large genome-wide association study meta-analyses to perform bi-directional Mendelian randomisation analyses to estimate causal associations between genetically-proxied lifetime risk of VTE and risk of 18 different cancers. Results: We found no conclusive evidence that genetically-proxied lifetime risk of VTE was causally associated with an increased incidence of cancer, or vice-versa. We observed an association between VTE and pancreatic cancer risk (odds ratio for pancreatic cancer 1.23 (95% confidence interval 1.08 - 1.40) per log-odds increase in risk of VTE, P = 0.002). However, sensitivity analyses revealed this association was predominantly driven by a variant proxying non-O blood group, with inadequate evidence from Mendelian randomisation to suggest a causal relationship. Conclusions: These findings do not support the hypothesis that genetically-proxied lifetime risk of VTE is a cause of cancer. Existing observational epidemiological associations between VTE and cancer are therefore more likely to be driven by pathophysiological changes which occur in the setting of active cancer and anti-cancer treatments. Further work is required to explore and synthesise evidence for these mechanisms.