Neutrophils infiltrate sensory ganglia and mediate chronic widespread pain in fibromyalgia.

Fibromyalgia is a debilitating widespread chronic pain syndrome that occurs in 2 to 4% of the population. The prevailing view that fibromyalgia results from central nervous system dysfunction has recently been challenged with data showing changes in peripheral nervous system activity. Using a mouse model of chronic widespread pain through hyperalgesic priming of muscle, we show that neutrophils invade sensory ganglia and confer mechanical hypersensitivity on recipient mice, while adoptive transfer of immunoglobulin, serum, lymphocytes, or monocytes has no effect on pain behavior. Neutrophil depletion abolishes the establishment of chronic widespread pain in mice. Neutrophils from patients with fibromyalgia also confer pain on mice. A link between neutrophil-derived mediators and peripheral nerve sensitization is already established. Our observations suggest approaches for targeting fibromyalgia pain via mechanisms that cause altered neutrophil activity and interactions with sensory neurons.

Gate control of sensory neurotransmission in peripheral ganglia by proprioceptive sensory neurons.

Melzak and Wall's gate control theory proposed that innocuous input into the dorsal horn of the spinal cord represses pain-inducing nociceptive input. Here we show that input from proprioceptive parvalbumin-expressing sensory neurons tonically represses nociceptor activation within dorsal root ganglia. Deletion of parvalbumin-positive sensory neurons leads to enhanced nociceptor activity measured with GCaMP3, increased input into wide dynamic range neurons of the spinal cord and increased acute and spontaneous pain behaviour, as well as potentiated innocuous sensation. Parvalbumin-positive sensory neurons express the enzymes and transporters necessary to produce vesicular GABA that is known to be released from depolarized somata. These observations support the view that gate control mechanisms occur peripherally within dorsal root ganglia.

Transfusion of leukoreduced blood products and risk of antibody-mediated rejection of renal allografts.

BACKGROUND: Antibody-mediated rejection (AMR) is a major barrier to the long-term function of renal allografts. White blood cells, which may be present in red blood cell (RBC) units, and platelets (PLTs) express HLA antigens that may increase the risk of AMR by inducing or increasing humoral sensitization to HLA. STUDY DESIGN AND METHODS: A retrospective cohort study of HLA-incompatible (HLAi) renal transplant recipients between 2004 and 2015 was conducted. Data on apheresis PLT and leukoreduced RBC transfusions within 4 weeks of transplantation, demographic information, and biopsy-proven AMR were collected from medical records and the Scientific Registry of Transplant Recipients. Patients were evaluated until they showed evidence of AMR or until 1 year posttransplant, whichever came first. Multivariable analysis with Cox modeling was performed. RESULTS: Of 244 individuals, 182 (74.6%) received RBCs and 20 (8.2%) of those also received PLTs. During the first year posttransplant, 97 (39.8%) had AMR. RBC-alone or RBC and PLT transfusions were not associated with increased risk of AMR after adjustment for panel-reactive antibody, years on dialysis, HLA antibody strength, and number of therapeutic plasma exchange treatments (adjusted hazard ratio [adjHR] 1.00, 95% confidence interval [95% CI] 0.59-1.69; and adjHR 0.68, 95% CI 0.28-1.68, respectively). For each 1-unit increase in RBC transfusions, there was no association with AMR (adjHR 0.94, 95% CI 0.85-1.05). Only HLA antibody strength before transplantation was associated with AMR (adjHR 2.23, 95% CI 1.10-4.52; cytotoxic crossmatch compared to crossmatch negative but detectable donor-specific HLA antibodies). CONCLUSIONS: Patients who receive an HLAi transplant who are transfused with leukoreduced RBCs or PLTs in the peritransplant period are at no higher risk of AMR than nontransfused patients.

Relative toxicity of mood stabilisers and antipsychotics: case fatality and fatal toxicity associated with self-poisoning.

BACKGROUND: Bipolar and other psychiatric disorders are associated with considerably increased risk of suicidal behaviour, which may include self-poisoning with medication used to treat the disorder. Therefore, choice of medication for treatment should include consideration of toxicity, especially for patients at risk. The aim of this study was to estimate the relative toxicity of specific drugs within two drug categories, antipsychotics and mood stabilizers, using large-scale databases to provide evidence that could assist clinicians in making decisions about prescribing, especially for patients at risk of suicidal behaviour. METHOD: Two indices were used to assess relative toxicity of mood stabilisers and antipsychotics: case fatality (the ratio between rates of fatal and non-fatal self-poisoning) and fatal toxicity (the ratio between rates of fatal self-poisoning and prescription). Mood stabilisers assessed included lithium [reference], sodium valproate, carbamazepine, and lamotrigine, while antipsychotics included chlorpromazine [reference], clozapine, olanzapine, quetiapine and risperidone. Fatal self-poisoning (suicide) data were provided by the Office for National Statistics (ONS), non-fatal self-poisoning data by the Multicentre Study of Self-harm in England, and information on prescriptions by the Clinical Practice Research Datalink. The primary analysis focussed on deaths due to a single drug. Cases where the drug of interest was listed as the likely primary toxic agent in multiple drug overdoses were also analysed. The study period was 2005-2012. RESULTS: There appeared to be little difference in toxicity between the mood stabilisers, except that based on case fatality where multiple drug poisonings were considered, carbamazepine was over twice as likely to result in death relative to lithium (OR 2.37 95% CI 1.16-4.85). Of the antipsychotics, clozapine was approximately18 times more likely to result in death when taken in overdose than chlorpromazine (single drug case fatality: OR 18.53 95% CI 8.69-39.52). Otherwise, only risperidone differed from chlorpromazine, being less toxic (OR 0.06 95% CI 0.01-0.47). CONCLUSIONS: There was little difference in toxicity of the individual mood stabilisers. Clozapine was far more toxic than the other antipsychotics. The findings are relevant to prescribing policy, especially for patients at particular risk of suicidal behaviour.

Site and Stage of Colorectal Cancer Influence the Likelihood and Distribution of Disease Recurrence and Postrecurrence Survival: Data From the FACS Randomized Controlled Trial.

OBJECTIVES: To describe patterns of recurrence and postrecurrence survival in a large cohort of accurately staged patients with Dukes' A-C colorectal cancer. BACKGROUND: Recurrence remains a frequent cause of mortality after the treatment of colorectal cancer with curative intent. Understanding the likelihood and site of recurrence informs adjuvant treatment and follow-up. METHODS: Retrospective cohort analysis of data from the FACS (follow-up after colorectal cancer surgery) trial after a median 4.4 years of follow-up; postrecurrence survival was calculated using the Kaplan-Meier method. RESULTS: Complete data were available for 94% of patients; 189 (17%) patients had experienced recurrence. Incidence of recurrence varied according to the site of the primary (right colon: 51/379, 14%; left colon: 68/421, 16%; rectum: 70/332, 21%; P = 0.023) and initial stage (Dukes' A: 26/249, 10%; Dukes' B: 81/537, 15%; Dukes' C: 82/346, 24%; P < 0.0001). Pulmonary recurrence was most frequently associated with rectal tumors, and multisite/other recurrence with right-sided colonic tumors. Recurrences from lower-stage tumors were more likely to be treatable with curative intent (Dukes' A: 13/26, 50%; Dukes' B: 32/81, 40%; Dukes' C: 20/82, 24%; P = 0.03). Those with rectal tumors benefited most from follow-up (proportion with treatable recurrence: rectum 30/332, 9%; left colon 23/421, 6%; right colon 12/379, 3%; P = 0.003). Both initial stage (log rank P = 0.005) and site of primary (log rank P = 0.01) influenced postrecurrence survival. CONCLUSIONS: The likelihood and site of recurrence, and survival, are influenced by the site and stage of the primary tumor. Those with rectal cancers benefited most from follow-up.ISRCTN 41458548.

Platelet corrected count increments by apheresis platform.

BACKGROUND: Automated blood collection platforms use different technological systems to isolate and collect individual blood components. These unique systems could potentially result in differences in platelet in vivo viability, as measured by the corrected count increment (CCI). STUDY DESIGN AND METHODS: This retrospective study evaluated CCI data of platelet transfusions among oncology patients who received multiple unmanipulated apheresis platelets between January 1, 2006 and December 31, 2009. Apheresis platelets were collected from our community blood center by standard procedures using two different collection systems and were transfused to patients in a blinded manner. RESULTS: The CCI of the platelet recipient was significantly higher at 0-2 hours post-transfusion among the individuals who received platelets collected on Trima Accel (Terumo BCT) (mean = 6281, standard deviation = 3650) compared to the platelets collected by the Amicus system (Fresenius Kabi) (mean = 5251, standard deviation = 3311, p = 0.004). CONCLUSIONS: These hypothesis-generating data suggesting improved recovery and survival of Trima Accel platelets demonstrate the need for the investigation and implementation of the best collection methods to provide better platelet transfusion support.

The impact of platelet additive solution apheresis platelets on allergic transfusion reactions and corrected count increment (CME).

BACKGROUND: Allergic transfusion reaction (ATR) incidence ranges from 1% to 3% of all transfusions. We evaluated the impact of InterSol platelet additive solution (PAS) apheresis platelets (APs) on the incidence of ATRs and the posttransfusion platelet (PLT) increment. STUDY DESIGN AND METHODS: This retrospective study evaluated all ATRs among patients at a university hospital that maintained a mixed inventory of PAS APs and non-PAS APs (standard plasma-suspended PLTs). Corrected count increments (CCIs) were calculated for AP transfusions of individuals who received both a PAS and a non-PAS AP transfusion within a 7-day period. Hypothesis testing was performed with chi-square test for dichotomous variables and t tests for continuous variables. RESULTS: The incidence of ATRs among the non-PAS APs was 1.85% (72 ATRs/3884 transfusions) and 1.01% (12 ATRs/1194 transfusions) for PAS APs (risk ratio [RR], 0.54; 95% confidence interval [CI]=0.30-0.99; p=0.04). However, there was no difference in the incidence of febrile nonhemolytic transfusion reactions between non-PAS APs (incidence, 0.70%; 27/3884) compared to PAS APs (incidence, 0.59%; 7/1194; p=0.69). Among 223 individuals with paired non-PAS and PAS AP transfusions, the mean CCI at 1 to 4 hours after transfusion was 4932 (95% CI, 4452-5412) for non-PAS APs and was lower for PAS APs (CCI, 3766; 95% CI, 3375-4158; p ≤ 0.001). However, there was no significant difference in mean CCI at 12 to 24 hours between non-PAS (CCI, 2135; 95% CI, 1696-2573) and PAS APs (CCI, 1745; 95% CI, 1272-2217; p=0.14). CONCLUSIONS: PAS APs substantially reduce the number of ATRs. CCIs for PAS APs were lower immediately after transfusion, but not significantly different at 12 to 24 hours.

Effect of 3 to 5 years of scheduled CEA and CT follow-up to detect recurrence of colorectal cancer: the FACS randomized clinical trial.

IMPORTANCE: Intensive follow-up after surgery for colorectal cancer is common practice but is based on limited evidence. OBJECTIVE: To assess the effect of scheduled blood measurement of carcinoembryonic antigen (CEA) and computed tomography (CT) as follow-up to detect recurrent colorectal cancer treatable with curative intent. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial in 39 National Health Service hospitals in the United Kingdom; 1202 eligible participants were recruited between January 2003 and August 2009 who had undergone curative surgery for primary colorectal cancer, including adjuvant treatment if indicated, with no evidence of residual disease on investigation. INTERVENTIONS: Participants were randomly assigned to 1 of 4 groups: CEA only (n = 300), CT only (n = 299), CEA+CT (n = 302), or minimum follow-up (n = 301). Blood CEA was measured every 3 months for 2 years, then every 6 months for 3 years; CT scans of the chest, abdomen, and pelvis were performed every 6 months for 2 years, then annually for 3 years; and the minimum follow-up group received follow-up if symptoms occurred. MAIN OUTCOMES AND MEASURES: The primary outcome was surgical treatment of recurrence with curative intent; secondary outcomes were mortality (total and colorectal cancer), time to detection of recurrence, and survival after treatment of recurrence with curative intent. RESULTS: After a mean 4.4 (SD, 0.8) years of observation, cancer recurrence was detected in 199 participants (16.6%; 95% CI, 14.5%-18.7%) overall; 71 of 1202 participants (5.9%; 95% CI, 4.6%-7.2%) were treated for recurrence with curative intent, with little difference according to Dukes staging (stage A, 5.1% [13/254]; stage B, 6.1% [34/553]; stage C, 6.2% [22/354]). Surgical treatment of recurrence with curative intent was 2.3% (7/301) in the minimum follow-up group, 6.7% (20/300) in the CEA group, 8% (24/299) in the CT group, and 6.6% (20/302) in the CEA+CT group. Compared with minimum follow-up, the absolute difference in the percentage of patients treated with curative intent in the CEA group was 4.4% (95% CI, 1.0%-7.9%; adjusted odds ratio [OR], 3.00; 95% CI, 1.23-7.33), in the CT group was 5.7% (95% CI, 2.2%-9.5%; adjusted OR, 3.63; 95% CI, 1.51-8.69), and in the CEA+CT group was 4.3% (95% CI, 1.0%-7.9%; adjusted OR, 3.10; 95% CI, 1.10-8.71). The number of deaths was not significantly different in the combined intensive monitoring groups (CEA, CT, and CEA+CT; 18.2% [164/901]) vs the minimum follow-up group (15.9% [48/301]; difference, 2.3%; 95% CI, -2.6% to 7.1%). CONCLUSIONS AND RELEVANCE: Among patients who had undergone curative surgery for primary colorectal cancer, intensive imaging or CEA screening each provided an increased rate of surgical treatment of recurrence with curative intent compared with minimal follow-up; there was no advantage in combining CEA and CT. If there is a survival advantage to any strategy, it is likely to be small. TRIAL REGISTRATION: isrctn.org Identifier: 41458548.

Self-monitoring of oral anticoagulation: systematic review and meta-analysis of individual patient data.

BACKGROUND: Uptake of self-testing and self-management of oral anticoagulation [corrected] has remained inconsistent, despite good evidence of their effectiveness. To clarify the value of self-monitoring of oral anticoagulation, we did a meta-analysis of individual patient data addressing several important gaps in the evidence, including an estimate of the effect on time to death, first major haemorrhage, and thromboembolism. METHODS: We searched Ovid versions of Embase (1980-2009) and Medline (1966-2009), limiting searches to randomised trials with a maximally sensitive strategy. We approached all authors of included trials and requested individual patient data: primary outcomes were time to death, first major haemorrhage, and first thromboembolic event. We did prespecified subgroup analyses according to age, type of control-group care (anticoagulation-clinic care vs primary care), self-testing alone versus self-management, and sex. We analysed patients with mechanical heart valves or atrial fibrillation separately. We used a random-effect model method to calculate pooled hazard ratios and did tests for interaction and heterogeneity, and calculated a time-specific number needed to treat. FINDINGS: Of 1357 abstracts, we included 11 trials with data for 6417 participants and 12,800 person-years of follow-up. We reported a significant reduction in thromboembolic events in the self-monitoring group (hazard ratio 0·51; 95% CI 0·31-0·85) but not for major haemorrhagic events (0·88, 0·74-1·06) or death (0·82, 0·62-1·09). Participants younger than 55 years showed a striking reduction in thrombotic events (hazard ratio 0·33, 95% CI 0·17-0·66), as did participants with mechanical heart valve (0·52, 0·35-0·77). Analysis of major outcomes in the very elderly (age ≥85 years, n=99) showed no significant adverse effects of the intervention for all outcomes. INTERPRETATION: Our analysis showed that self-monitoring and self-management of oral coagulation is a safe option for suitable patients of all ages. Patients should also be offered the option to self-manage their disease with suitable health-care support as back-up. FUNDING: UK National Institute for Health Research (NIHR) Technology Assessment Programme, UK NIHR National School for Primary Care Research.

The mechanisms and management of persistent postsurgical pain.

An estimated 10%-50% of patients undergoing a surgical intervention will develop persistent postsurgical pain (PPP) lasting more than 3 months despite adequate acute pain management and the availability of minimally invasive procedures. The link between early and late pain outcomes for surgical procedures remains unclear-some patients improve while others develop persistent pain. The elective nature of a surgical procedure offers a unique opportunity for prophylactic or early intervention to prevent the development of PPP and improve our understanding of its associated risk factors, such as pre-operative anxiety and the duration of severe acute postoperative pain. Current perioperative pain management strategies often include opioids, but long-term consumption can lead to tolerance, addiction, opioid-induced hyperalgesia, and death. Pre-clinical models provide the opportunity to dissect mechanisms underpinning the transition from acute to chronic, or persistent, postsurgical pain. This review highlights putative mechanisms of PPP, including sensitisation of peripheral sensory neurons, neuroplasticity in the central nervous system and nociceptive signalling along the neuro-immune axis.

The impact of apheresis platelet manipulation on corrected count increment.

BACKGROUND: Concentrating and washing apheresis platelets (APs) substantially reduce the number of allergic transfusion reactions likely due to removal of plasma. However, these processes may damage platelets (PLTs). This study evaluated whether concentrating or washing APs decrease the corrected count increment (CCI). STUDY DESIGN AND METHODS: This retrospective study evaluated individuals who initially received unmanipulated APs and subsequently received concentrated and/or washed APs at a large university hospital between 1998 and 2009. Concentrated units were prepared by reducing the plasma volume of APs by a goal of more than 67%. Washed units were prepared by washing the APs with 1 L of normal saline. The CCI (PLTs [×10(6)] × m(2)/L) for all transfusions was calculated. Hypothesis testing was performed with t tests for continuous variables and chi-square tests for dichotomous variables. RESULTS: We evaluated 121 individuals: 46 patients who received unmanipulated, concentrated, and then washed APs; 59 patients who received unmanipulated and then concentrated APs; and 16 patients who received unmanipulated and then washed APs. Patient demographics were similar among the three groups. The mean CCI for unmanipulated AP transfusions at 0 to 2 hours posttransfusion was significantly higher than concentrated and washed PLT transfusions (p<0.001). When accounting for PLT loss due to manipulation, concentrating APs did not impact the CCI. However, the CCI remained significantly lower for washed products at all time points after transfusion (40.7% mean reduction at 20-24 hr, p<0.001). CONCLUSIONS: Washing APs significantly reduces PLT count recovery and survival, as demonstrated by a significantly reduced CCI.

Incidence of fractures in people with intellectual disabilities over the life course: a retrospective matched cohort study.

Background: Current osteoporosis guidelines do not identify individuals with intellectual disabilities (ID) as at risk of fracture, potentially missing opportunities for prevention. We aimed to assess the incidence of fractures in people with ID over the life course. Methods: Descriptive analysis of open cohort study using anonymised electronic health records from the UK Clinical Practice Research Datalink, linked to the Hospital Episode Statistics database (Jan 1, 1998-Dec 31, 2017). All individuals with ID were matched on age and sex to five individuals without ID.  We calculated the incidence rate (95% CI) per 10000 person-years (py) and incidence rate ratio (IRR, 95% CI) to compare fractures between individuals with and without ID (age 1-17 and ≥18 years) for any fracture, and in those aged 18-49 and ≥ 50 years for major osteoporotic fracture (vertebra, shoulder, wrist, hip), and for hip fracture. Findings: 43176 individuals with ID (15470 children aged 1-17 years; 27706 adults aged ≥ 18 years) were identified and included (40.4% females) along with 215733 matched control individuals.  The median age at study entry was 24 (10th-90th centiles 3-54) years. Over a median (10th-90th centile) follow-up of 7.1 (0.9-17.6) and 6.5 (0.8-17.6) years, there were 5941 and 24363 incident fractures in the ID and non ID groups respectively. Incidence of any fracture was 143.5 (131.8-156.3) vs 120.7 (115.4-126.4)/10000 py (children), 174.2 (166.4-182.4)/10000 py vs 118.2 (115.3-121.2)/10000 py (adults) in females. In males it was 192.5 (182.4-203.2) vs 228.5 (223.0-234.1)/10000 py (children), 155.6 (149.3-162.1)/10000 py vs 128.4 (125.9-131.0)/10000 py (adults). IRR for major osteoporotic fracture was 1.81 (1.50-2.18) age 18-49 years, 1.69 (1.53-1.87) age ≥ 50 years in women. In men it was 1.56 (1.36-1.79) age 18-49 years, 2.45 (2.13-2.81) age ≥ 50 years. IRR for hip fracture was 7.79 (4.14-14.65) age 18-49 years, 2.28 (1.91-2.71) age ≥ 50 years in women. In men it was 6.04 (4.18-8.73) age 18-49 years, 3.91 (3.17-4.82) age ≥ 50 years. Comparable rates of major osteoporotic fracture and of hip fracture occurred approximately 15 and 20 years earlier respectively in women and 20 and 30 years earlier respectively in men with ID than without ID. Fracture distribution differed profoundly, hip fracture 9.9% vs 5.0% of any fracture in adults with ID vs without ID. Interpretation: The incidence, type, and distribution of fractures in people with intellectual disabilities suggest early onset osteoporosis. Prevention and management strategies are urgently required, particularly to reduce the incidence of hip fracture. Funding: National Institute for Health and Care Research.

A comprehensive program to minimize platelet outdating.

BACKGROUND: Platelet (PLT) transfusions are essential for patients who are bleeding or have an increased risk of bleeding due to a decreased number or abnormal function of circulating PLTs. A shelf life of 5 days for PLT products presents an inventory management challenge. In 2006, greater than 10% of apheresis PLTs made in the United States outdated. It is imperative to have a sufficient number of products for patients requiring transfusion, but outdating PLTs is a financial burden and a waste of a resource. STUDY DESIGN AND METHODS: We present the approach used in our institution to anticipate inventory needs based on current patient census and usage. Strategies to predict usage and to identify changes in anticipated usage are examined. Annual outdating is reviewed for a 10-year period from 2000 through 2009. RESULTS: From January 1, 2000, through December 2009, there were 128,207 PLT transfusions given to 15,265 patients. The methods used to anticipate usage and adjust inventory resulted in an annual outdate rate of approximately 1% for the 10-year period reviewed. In addition we have not faced situations where inventory was inadequate to meet the needs of the patients requiring transfusions. CONCLUSION: We have identified three elements of our transfusion service that can minimize outdate: a knowledgeable proactive staff dedicated to PLT management, a comprehensive computer-based transfusion history for each patient, and a strong two-way relationship with the primary product supplier. Through our comprehensive program, based on the principles of providing optimal patient care, we have minimized PLT outdating for more than 10 years.

Allergic transfusion reactions to platelets are associated more with recipient and donor factors than with product attributes.

BACKGROUND: Mechanisms of allergic transfusion reactions (ATRs) are not well understood. The aim of this study was to distinguish recipient-, donor-, and product-specific factors associated with ATRs. STUDY DESIGN AND METHODS: We conducted a retrospective cohort study of apheresis platelet (AP) products transfused from April 2000 through March 2010. The concordance rate of ATRs when split AP products were transfused to at least two individuals was compared to the overall ATR rate among all AP products. Per-person ATR rates also were compared to the overall ATR rate. RESULTS: We observed 1616 ATRs among 93,737 transfusions, for an overall incidence of 1.72% (95% confidence interval [CI], 1.64%-1.81%). Of the 1616 ATRs, 630 occurred when split AP products were transfused to at least two recipients. Of these 630 AP products, ATRs were observed in at least two different recipients of the same AP collection only 6 of 630 times, for a concordant incidence of 0.95% (95% CI, 0.35%-2.06%), which is similar to the overall ATR rate (p = 0.17). On an individual level, 30.0% of recipients had ATR rates of more than 5%, and these 30.0% accounted for 62.1% of ATRs. Donors of AP products associated with concordant ATRs donated AP products that had an ATR rate of 5.8% (95% CI, 3.1%-9.7%), which is higher than the overall ATR rate (p < 0.001). CONCLUSIONS: An observed ATR does not predict an ATR in a different recipient of a split AP product. A minority of platelet recipients accounts for the majority of ATRs. Some donors are strongly associated with ATRs. Consequently, recipient and donor factors are implicated in the mechanism of ATRs.

Measuring the complexity of general practice consultations: a Delphi and cross-sectional study in English primary care.

BACKGROUND: The complexity of general practice consultations may be increasing and varies in different settings. A measure of complexity is required to test these hypotheses. AIM: To develop a valid measure of general practice consultation complexity applicable to routine medical records. DESIGN AND SETTING: Delphi study to select potential indicators of complexity followed by a cross-sectional study in English general practices to develop and validate a complexity measure. METHOD: The online Delphi study over two rounds identified potential indicators of consultation complexity. The cross-sectional study used an age-sex stratified random sample of patients and general practice face-to-face consultations from 2013/2014 in the Clinical Practice Research Datalink. The authors explored independent relationships between each indicator and consultation duration using mixed-effects regression models, and revalidated findings using data from 2017/2018. The proportion of complex consultations in different age-sex groups was assessed. RESULTS: A total of 32 GPs participated in the Delphi study. The Delphi panel endorsed 34 of 45 possible complexity indicators after two rounds. After excluding factors because of low prevalence or confounding, 17 indicators were retained in the cross-sectional study. The study used data from 173 130 patients and 725 616 face-to-face GP consultations. On defining complexity as the presence of any of these 17 factors, 308 370 consultations (42.5%) were found to be complex. Mean duration of complex consultations was 10.49 minutes, compared to 9.64 minutes for non-complex consultations. The proportion of complex consultations was similar in males and females but increased with age. CONCLUSION: The present consultation complexity measure has face and construct validity. It may be useful for research, management and policy, and for informing decisions about the range of resources needed in different practices.

Bacterial culture reduces but does not eliminate the risk of septic transfusion reactions to single-donor platelets.

BACKGROUND: Transfusion-associated bacterial sepsis is a significant risk of morbidity and mortality related to platelet (PLT) transfusions. Previously the rate of septic PLT transfusion reactions (SPTRs) to single-donor PLTs (SDPs) in our hospital was determined to be 1 in 15,098 (6.6 per 100,000; 95% confidence interval [CI], 0.17-36.9 per 100,000) transfusions. The goal of this study was to determine if bacterial testing of SDPs reduced the rate of SPTRs in our hospital. STUDY DESIGN AND METHODS: An automated microbial detection system was implemented by our blood supplier in February 2004. A retrospective examination of the number of SPTRs that have occurred to SDPs at our hospital since that time was performed, using the same criteria used before bacterial screening. Transfusions over a 3.5-year period were examined. Clinical and laboratory data were gathered and correlated from transfusion reaction files and three independent computer systems. RESULTS: From March 1, 2004, through August 31, 2007, there were 49,625 transfusions of SDPs with 1096 transfusion reactions reported. Only one reaction detected the same organism in two of three sites, meeting our criteria for a SPTR. The rate of SPTRs in SDPs was identified as 1 in 49,625 (2.0 per 100,000; 95% CI, 0.05-11.2 per 100,000). This represents a 69.7% reduction in the incidence of SPTRs (p = 0.41). CONCLUSION: With the implementation of bacterial testing, a decrease in the rate of SPTRs to SDPs from 6.6 per 100,000 to 2.0 per 100,000 transfusions was observed. Although not significant, these findings suggest a trend.

Antibiotic exposure and 'response failure' for subsequent respiratory tract infections: an observational cohort study of UK preschool children in primary care.

BACKGROUND: Childhood antibiotic exposure has important clinically relevant implications. These include disruption to the microbiome, antibiotic resistance, and clinical workload manifesting as treatment 'failure'. AIM: To examine the relationship between the number of antibiotic courses prescribed to preschool children for acute respiratory tract infections (RTI), in the preceding year, and subsequent RTIs that failed to respond to antibiotic treatment ('response failures'). DESIGN AND SETTING: A cohort study using UK primary care data from the Clinical Practice Research Datalink, 2009 to 2016. METHOD: Children aged 12 to 60 months (1 to 5 years) who were prescribed an antibiotic for an acute RTI (upper and lower RTI or otitis media) were included. One random index antibiotic course for RTI per child was selected. Exposure was the number of antibiotic prescriptions for acute RTI up to 12 months before the index antibiotic prescription. The outcome was 'response failure' up to 14 days after index antibiotic prescription, defined as: subsequent antibiotic prescription; referral; hospital admission; death; or emergency department attendance within 3 days. The authors used logistic regression models to estimate the odds between antibiotic exposure and response failure. RESULTS: Out of 114 329 children who were prescribed an antibiotic course for acute RTI, children who received ≥2 antibiotic courses for acute RTIs in the preceding year had greater odds of response failure; one antibiotic course: adjusted odds ratio (OR) 1.03 (95% confidence interval [CI] = 0.88 to 1.21), P = 0.67, n = 230 children; ≥2 antibiotic courses: adjusted OR 1.32 (CI = 1.04 to 1.66), P = 0.02, n = 97. CONCLUSION: Childhood antibiotic exposure for acute RTI may be a good predictor for subsequent response failure (but not necessarily because of antibiotic treatment failure). Further research is needed to improve understanding of the mechanisms underlying response failure.

Relative toxicity of analgesics commonly used for intentional self-poisoning: A study of case fatality based on fatal and non-fatal overdoses.

BACKGROUND: Analgesics are used most frequently in fatal and non-fatal medicinal self-poisonings. Knowledge about their relative toxicity in overdose is important for clinicians and regulatory agencies. METHODS: Using data for 2005-2012 we investigated case fatality (number of suicides relative to number of non-fatal self-poisonings) of paracetamol, aspirin, codeine, dihydrocodeine, tramadol, paracetamol with codeine (co-codamol), paracetamol with dihydrocodeine (co-dydramol), ibuprofen and co-proxamol (paracetamol plus dextropropoxyphene; withdrawn in the UK in 2008 due to high toxicity). Data on suicides obtained from the Office for National Statistics and on non-fatal self-poisonings from the Multicentre Study of Self-harm in England. Case fatality was estimated for each drug, using paracetamol as the reference category. RESULTS: Compared to paracetamol and based on single drug deaths the case fatality index of dihydrocodeine was considerably elevated (odds ratio (OR) 12.81, 95% Confidence Interval (CI) 10.19-16.12). Case fatality indices for tramadol (OR 4.05, 95% CI 3.38-4.85) and codeine (OR 2.21, 95% CI 1.81-2.70) were also significantly higher than for paracetamol. The results when multiple drug deaths were included produced similar results. The relative toxicity of co-proxamol far exceeded that of the other analgesics. LIMITATIONS: Data on fatal self-poisonings were based on national data, whereas those for non-fatal poisonings were based on local data. CONCLUSIONS: Dihydrocodeine and tramadol are particularly toxic in overdose and codeine is also relatively toxic. They should be prescribed with caution, particularly to individuals at risk of self-harm.

rpoB gene sequencing highlights the prevalence of an E. miricola cluster over other Elizabethkingia species among UK cystic fibrosis patients.

Difficulties in distinguishing species of the Elizabethkingia genus by MALDI-TOF prompted use of rpoB sequencing to investigate species distribution among 44 isolates from cystic fibrosis (CF) patients. Forty-three isolates from 38 patients formed a cluster comprising E. miricola and proposed novel species E. bruuniana sp. nov., the exception clustering with proposed species E. ursingii sp. nov., also part of this wider cluster. All 44 isolates were PCR-positive for urease gene ureG, whereas only one of 23 E. anophelis isolates from non-CF patients was positive, suggesting that this gene is largely associated with the E. miricola cluster. Antibiotic susceptibilities of 12 CF isolates revealed all were resistant to beta-lactams with the exception of piperacillin-tazobactam, and were only susceptible to minocycline and co-trimoxazole. Pulsed-field gel electrophoresis analysis revealed 4 shared strains among 17 CF patients in one pediatric clinic, but epidemiological investigations did not support patient-to-patient transmission except between one sibling pair.

Relative toxicity of benzodiazepines and hypnotics commonly used for self-poisoning: An epidemiological study of fatal toxicity and case fatality.

The relative toxicity of anxiolytic and hypnotic drugs commonly used for self-poisoning was assessed using data on suicides, prescriptions and non-fatal self-poisonings in England, 2005-2012. Data on suicide by self-poisoning were obtained from the Office for National Statistics, information on intentional non-fatal self-poisoning was derived from the Multicentre Study of Self-harm in England and data on prescriptions in general practice from the Clinical Practice Research Datalink. We used two indices of relative toxicity: fatal toxicity (the number of fatal self-poisonings relative to the number of individuals prescribed each drug) and case fatality (the number of fatal relative to non-fatal self-poisonings). Diazepam was the reference drug in all analyses. Temazepam was 10 times (95% confidence interval 5.48-18.99) and zopiclone/zolpidem nine times (95% confidence interval 5.01-16.65) more toxic in overdose than diazepam (fatal-toxicity index). Temazepam and zopiclone/zolpidem were 13 (95% confidence interval 6.97-24.41) and 12 (95% confidence interval 6.62-22.17) times more toxic than diazepam, respectively (case-fatality index). Differences in alcohol involvement between the drugs were unlikely to account for the findings. Overdoses of temazepam and zopiclone/zolpidem are considerably more likely to result in death than overdoses of diazepam. Practitioners need to exercise caution when prescribing these drugs, especially for individuals who may be at risk of self-harm, and also consider non-pharmacological options.