Predictive performance of the common red flags in emergency department headache patients: a HEAD and HEAD-Colombia study.

OBJECTIVES: Only a small proportion of patients presenting to an ED with headache have a serious cause. The SNNOOP10 criteria, which incorporates red and orange flags for serious causes, has been proposed but not well studied. This project aims to compare the proportion of patients with 10 commonly accepted red flag criteria (singly and in combination) between patients with and without a diagnosis of serious secondary headache in a large, multinational cohort of ED patients presenting with headache. METHODS: Secondary analysis of data obtained in the HEAD and HEAD-Colombia studies. The outcome of interest was serious secondary headache. The predictive performance of 10 red flag criteria from the SNNOOP10 criteria list was estimated individually and in combination. RESULTS: 5293 patients were included, of whom 6.1% (95% CI 5.5% to 6.8%) had a defined serious cause identified. New neurological deficit, history of neoplasm, older age (>50 years) and recent head trauma (2-7 days prior) were independent predictors of a serious secondary headache diagnosis. After adjusting for other predictors, sudden onset, onset during exertion, pregnancy and immune suppression were not associated with a serious headache diagnosis. The combined sensitivity of the red flag criteria overall was 96.5% (95% CI 93.2% to 98.3%) but specificity was low, 5.1% (95% CI 4.3% to 6.0%). Positive predictive value was 9.3% (95% CI 8.2% to 10.5%) with negative predictive value of 93.5% (95% CI 87.6% to 96.8%). CONCLUSION: The sensitivity and specificity of the red flag criteria in this study were lower than previously reported. Regarding clinical practice, this suggests that red flag criteria may be useful to identify patients at higher risk of a serious secondary headache cause, but their low specificity could result in increased rates of CT scanning. TRIAL REGISTRATION NUMBER: ANZCTR376695.

Clinical presentation and assessment of older patients presenting with headache to emergency departments: A multicentre observational study.

OBJECTIVE: To describe the characteristics, assessment and management of older emergency department (ED) patients with non-traumatic headache. METHODS: Planned sub-study of a prospective, multicentre, international, observational study, which included adult patients presenting to ED with non-traumatic headache. Patients aged ≥75 years were compared to those aged <75 years. Outcomes of interest were epidemiology, investigations, serious headache diagnosis and outcome. RESULTS: A total of 298 patients (7%) in the parent study were aged ≥75 years. Older patients were less likely to report severe headache pain or subjective fever (both P < 0.001). On examination, older patients were more likely to be confused, have lower Glasgow Coma Scores and to have new neurological deficits (all P < 0.001). Serious secondary headache disorder (composite of headache due to subarachnoid haemorrhage (SAH), intracranial haemorrhage, meningitis, encephalitis, cerebral abscess, neoplasm, hydrocephalus, vascular dissection, stroke, hypertensive crisis, temporal arteritis, idiopathic intracranial hypertension or ventriculoperitoneal shunt complications) was diagnosed in 18% of older patients compared to 6% of younger patients (P < 0.001). Computed tomography brain imaging was performed in 66% of patients ≥75 years compared to 35% of younger patients (P < 0.001). Older patients were less likely to be discharged (43% vs 63%, P < 0.001). CONCLUSIONS: Older patients with headache had different clinical features to the younger cohort and were more likely to have a serious secondary cause of headache than younger adults. There should be a low threshold for investigation in older patients attending ED with non-traumatic headache.

Epidemiology, investigation, management, and outcome of headache in emergency departments (HEAD study)-A multinational observational study.

OBJECTIVE: To describe the epidemiology of nontraumatic headache in adults presenting to emergency departments (EDs). BACKGROUND: Headache is a common reason for presentation to EDs. Little is known about the epidemiology, investigation, and treatment of nontraumatic headache in patients attending EDs internationally. METHODS: An international, multicenter, observational, cross-sectional study was conducted over one calendar month in 2019. Participants were adults (≥18 years) with nontraumatic headache as the main presenting complaint. Exclusion criteria were recent head trauma, missing records, interhospital transfers, re-presentation with same headache as a recent visit, and headache as an associated symptom. Data collected included demographics, clinical assessment, investigation, treatment, and outcome. RESULTS: We enrolled 4536 patients (67 hospitals, 10 countries). "Thunderclap" onset was noted in 14.2% of cases (644/4536). Headache was rated as severe in 27.2% (1235/4536). New neurological examination findings were uncommon (3.2%; 147/4536). Head computed tomography (CT) was performed in 36.6% of patients (1661/4536), of which 9.9% showed clinically important pathology (165/1661). There was substantial variation in CT scan utilization between countries (15.9%-75.0%). More than 30 different diagnoses were made. Presumed nonmigraine benign headache accounted for 45.4% of cases (2058/4536) with another 24.3% classified as migraine (1101/4536). A small subgroup of patients have a serious secondary cause for their headache (7.1%; 323/4536) with subarachnoid hemorrhage (SAH), stroke, neoplasm, non-SAH intracranial hemorrhage/hematoma, and meningitis accounting for about 1% each. Most patients were treated with simple analgesics (paracetamol, aspirin, or nonsteroidal anti-inflammatory agents). Most patients were discharged home (83.8%; 3792/4526). In-hospital mortality was 0.3% (11/4526). CONCLUSION: Diagnosis and management of headache in the ED is challenging. A small group of patients have a serious secondary cause for their symptoms. There is wide variation in the use of neuroimaging and treatments. Further work is needed to understand the variation in practice and to better inform international guidelines regarding emergent neuroimaging and treatment.

Determinants of ovarian function after response-adapted therapy in patients with advanced Hodgkin's lymphoma (RATHL): a secondary analysis of a randomised phase 3 trial.

BACKGROUND: Adverse effects on reproductive function are a key concern in young women treated with chemotherapy for advanced Hodgkin's lymphoma. We aimed to identify risk factors for the extent of ovarian damage in women with Hodgkin's lymphoma treated with different chemotherapy regimens to inform accurate advice on options for fertility preservation. METHODS: We recruited female participants from the randomised phase 3 RATHL trial, aged 18-45 years, based on availability of participants at recruiting sites in the UK. The RATHL trial key inclusion criteria were histologically confirmed classic Hodgkin's lymphoma, stage IIB-IV or IIA with adverse features (bulky disease or more than two sites of involvement), no previous treatments, and a performance status of 0-3. As part of RATHL, participants were treated with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or AVD followed by an interim PET-CT scan. Participants who had negative interim scans (PET score of 1 to 3 according to the Lugano classification) were randomly assigned (1:1) by use of minimisation, stratified by interim PET score and study centre, to continue ABVD or AVD for four more cycles. Participants with positive scans (PET score of 4 or 5) were escalated to treatment with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone (BEACOPP-14 or escalated BEACOPP) for four cycles. For the protocol-driven prospective cohort substudy, ovarian function was assessed before treatment, during chemotherapy, and then annually for 3 years by use of serum antimüllerian hormone and follicle-stimulating hormone measurements. The RATHL study is registered with ClinicalTrials.gov, number NCT00678327. FINDINGS: Between Dec 13, 2010, and Dec 19, 2012, 67 eligible participants were recruited for this prospective cohort study; 57 had received ABVD or AVD (ABVD-AVD group) and ten BEACOPP-14 or escalated BEACOPP (BEACOPP group). Follow-up was fixed at 3 years. Antimüllerian hormone concentrations decreased during both chemotherapy regimens. At 1 year after chemotherapy, antimüllerian hormone concentrations recovered to a median of 10·5 pmol/L (IQR 4·3-17·3) in the ABVD-AVD group, but little recovery was seen after BEACOPP (median 0·11 pmol/L [0·07-0·20]). Age also affected the extent of ovarian function recovery, with antimüllerian hormone recovery in participants aged 35 years or older in the ABVD-AVD group to 37% (SD 10) of their before treatment concentrations, compared with full recovery to 127% (SD 12) in those younger than 35 years (p<0·0001). Follicle-stimulating hormone recovery to less than 25 IU/L occurred for 95% of women younger than 35 years in the ABVD-AVD group by 2 years and was also dependent on age (hazard ratio 0·49, 95% CI 0·37-0·65; p<0·0001). INTERPRETATION: Reduced recovery of ovarian function observed in women older than 35 years treated with ABVD or AVD compared with younger women indicates that treatment could reduce their reproductive lifespan and supports discussion of fertility preservation before treatment. Women treated with BEACOPP should be informed of its potential high gonadotoxicity. These findings warrant further investigation in large, prospective studies with fertility and reproductive lifespan as outcomes. FUNDING: Medical Research Foundation and Cancer Research UK.

Loss of Prox1 in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy.

Correct regulation of troponin and myosin contractile protein gene isoforms is a critical determinant of cardiac and skeletal striated muscle development and function, with misexpression frequently associated with impaired contractility or disease. Here we reveal a novel requirement for Prospero-related homeobox factor 1 (Prox1) during mouse heart development in the direct transcriptional repression of the fast-twitch skeletal muscle genes troponin T3, troponin I2, and myosin light chain 1. A proportion of cardiac-specific Prox1 knockout mice survive beyond birth with hearts characterized by marked overexpression of fast-twitch genes and postnatal development of a fatal dilated cardiomyopathy. Through conditional knockout of Prox1 from skeletal muscle, we demonstrate a conserved requirement for Prox1 in the repression of troponin T3, troponin I2, and myosin light chain 1 between cardiac and slow-twitch skeletal muscle and establish Prox1 ablation as sufficient to cause a switch from a slow- to fast-twitch muscle phenotype. Our study identifies conserved roles for Prox1 between cardiac and skeletal muscle, specifically implicated in slow-twitch fiber-type specification, function, and cardiomyopathic disease.

Novel exomphalos genetic mouse model: the importance of accurate phenotypic classification.

BACKGROUND: Rodent models of abdominal wall defects (AWD) may provide insight into the pathophysiology of these conditions including gut dysfunction in gastroschisis, or pulmonary hypoplasia in exomphalos. Previously, a Scribble mutant mouse model (circletail) was reported to exhibit gastroschisis. We further characterise this AWD in Scribble knockout mice. METHOD: Homozygous Scrib knockout mice were obtained from heterozygote matings. Fetuses were collected at E17.5-18.5 with intact amniotic membranes. Three mutants and two control fetuses were imaged by in amnio micro-MRI. Remaining fetuses were dissected, photographed and gut length/weight measured. Ileal specimens were stained for interstitial cells of Cajal (ICC), imaged using confocal microscopy and ICC quantified. RESULTS: 127 fetuses were collected, 15 (12%) exhibited AWD. Microdissection revealed 3 mutants had characteristic exomphalos phenotype with membrane-covered gut/liver herniation into the umbilical cord. A further 12 exhibited extensive AWD, with eviscerated abdominal organs and thin covering membrane (intact or ruptured). Micro-MRI confirmed these phenotypes. Gut was shorter and heavier in AWD group compared to controls but morphology/number of ICC was not different. DISCUSSION: The Scribble knockout fetus exhibits exomphalos (intact and ruptured), in contrast to the original published phenotype of gastroschisis. Detailed dissection of fetuses is essential ensuring accurate phenotyping and result reporting.