Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial.

BACKGROUND: Studies have suggested that evening dosing with antihypertensive therapy might have better outcomes than morning dosing. The Treatment in Morning versus Evening (TIME) study aimed to investigate whether evening dosing of usual antihypertensive medication improves major cardiovascular outcomes compared with morning dosing in patients with hypertension. METHODS: The TIME study is a prospective, pragmatic, decentralised, parallel-group study in the UK, that recruited adults (aged ≥18 years) with hypertension and taking at least one antihypertensive medication. Eligible participants were randomly assigned (1:1), without restriction, stratification, or minimisation, to take all of their usual antihypertensive medications in either the morning (0600-1000 h) or in the evening (2000-0000 h). Participants were followed up for the composite primary endpoint of vascular death or hospitalisation for non-fatal myocardial infarction or non-fatal stroke. Endpoints were identified by participant report or record linkage to National Health Service datasets and were adjudicated by a committee masked to treatment allocation. The primary endpoint was assessed as the time to first occurrence of an event in the intention-to-treat population (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants who submitted at least one follow-up questionnaire. The study is registered with EudraCT (2011-001968-21) and ISRCTN (18157641), and is now complete. FINDINGS: Between Dec 17, 2011, and June 5, 2018, 24 610 individuals were screened and 21 104 were randomly assigned to evening (n=10 503) or morning (n=10 601) dosing groups. Mean age at study entry was 65·1 years (SD 9·3); 12 136 (57·5%) participants were men; 8968 (42·5%) were women; 19 101 (90·5%) were White; 98 (0·5%) were Black, African, Caribbean, or Black British (ethnicity was not reported by 1637 [7·8%] participants); and 2725 (13·0%) had a previous cardiovascular disease. By the end of study follow-up (March 31, 2021), median follow-up was 5·2 years (IQR 4·9-5·7), and 529 (5·0%) of 10 503 participants assigned to evening treatment and 318 (3·0%) of 10 601 assigned to morning treatment had withdrawn from all follow-up. A primary endpoint event occurred in 362 (3·4%) participants assigned to evening treatment (0·69 events [95% CI 0·62-0·76] per 100 patient-years) and 390 (3·7%) assigned to morning treatment (0·72 events [95% CI 0·65-0·79] per 100 patient-years; unadjusted hazard ratio 0·95 [95% CI 0·83-1·10]; p=0·53). No safety concerns were identified. INTERPRETATION: Evening dosing of usual antihypertensive medication was not different from morning dosing in terms of major cardiovascular outcomes. Patients can be advised that they can take their regular antihypertensive medications at a convenient time that minimises any undesirable effects. FUNDING: British Heart Foundation.

IgG4-related hypophysitis: a retrospective cohort study.

PURPOSE: IgG4-related hypophysitis (IgG4-RH) is a rare chronic inflammatory condition of the pituitary gland. This study reports the presentation, management and outcomes for patients with histologically proven IgG4-related hypophysitis. METHODS: A prospectively maintained electronic database was searched over a 14-year period from 1 January 2007 to 31 December 2020 at a single academic centre to identify all patients with a histological diagnosis of IgG4-RH. A retrospective case note review from electronic health records was conducted for each case to extract data on their presentation, management and outcomes. RESULTS: A total of 8 patients (5 male) with a median age of 51 years were identified. The most common presenting symptoms were headache (4/8; 50%), fatigue (3/8; 37.5%) and visual impairment (2/8; 25%). Three patients were initially treated with high-dose steroids aiming for reduction of the pituitary mass. However, ultimately all patients underwent transsphenoidal surgery. Post-operative changes included radiological reduction in pituitary mass in all patients that had imaging (7/7; 100%), improvement in vision (1/2; 50%), residual thick pituitary stalk (5/7; 71.4%), persistent anterior hypopituitarism (4/8; 50%) and panhypopopituitarism including diabetes insipidus (3/8; 37.5%). CONCLUSIONS: IgG4-RH is an increasingly recognised entity presenting with a variety of symptoms and signs. Clinical presentation is similar to other forms of hypophysitis. It is therefore important to consider IgG4-RH as a differential and to have a low threshold for pituitary biopsy, the diagnostic gold standard. The diagnosis of IgG4-RH will guide decisions for additional workup for IgG4-related disease, multi-disciplinary team involvement and follow-up.

Phenotype-driven molecular autopsy for sudden cardiac death.

A phenotype-driven approach to molecular autopsy based in a multidisciplinary team comprising clinical and laboratory genetics, forensic medicine and cardiology is described. Over a 13 year period, molecular autopsy was undertaken in 96 sudden cardiac death cases. A total of 46 cases aged 1-40 years had normal hearts and suspected arrhythmic death. Seven (15%) had likely pathogenic variants in ion channelopathy genes [KCNQ1 (1), KCNH2 (4), SCN5A (1), RyR2(1)]. Fifty cases aged between 2 and 67 had a cardiomyopathy. Twenty-five had arrhythmogenic right ventricular cardiomyopathy (ARVC), 10 dilated cardiomyopathy (DCM) and 15 hypertrophic cardiomyopathy (HCM). Likely pathogenic variants were found in three ARVC cases (12%) in PKP2, DSC2 or DSP, two DCM cases (20%) in MYH7, and four HCM cases (27%) in MYBPC3 (3) or MYH7 (1). Uptake of cascade screening in relatives was higher when a molecular diagnosis was made at autopsy. In three families, variants previously published as pathogenic were detected, but clinical investigation revealed no abnormalities in carrier relatives. With a conservative approach to defining pathogenicity of sequence variants incorporating family phenotype information and population genomic data, a molecular diagnosis was made in 15% of sudden arrhythmic deaths and 18% of cardiomyopathy deaths.

Correcting for accidental correlations in saturated avalanche photodiodes.

In this paper we present a general method for estimating rates of accidental coincidence between a pair of single photon detectors operated within their saturation regimes. By folding the effects of recovery time of both detectors and the detection circuit into an "effective duty cycle" we are able to accomodate complex recovery behaviour at high event rates. As an example, we provide a detailed high-level model for the behaviour of passively quenched avalanche photodiodes, and demonstrate effective background subtraction at rates commonly associated with detector saturation. We show that by post-processing using the updated model, we observe an improvement in polarization correlation visibility from 88.7% to 96.9% in our experimental dataset. This technique will be useful in improving the signal-to-noise ratio in applications which depend on coincidence measurements, especially in situations where rapid changes in flux may cause detector saturation.

Management strategy for treatment of vasospasm following transsphenoidal excision of craniopharyngioma.

We describe two cases of clinical and radiographic vasospasm after transsphenoidal resection of a craniopharyngioma. We review the literature on the association of vasospasm and craniopharyngioma and examine management options. Given the lack of evidence for the optimal management of these patients, treatment in concordance with protocols for vasospasm due to subarachnoid haemorrhage is recommended.

Measuring nanoscale forces with living probes.

Optical trapping techniques have been used to investigate fundamental biological processes ranging from the identification of the processive mechanisms of kinesin and myosin to understanding the mechanics of DNA. To date, these investigations have relied almost exclusively on the use of isotropic probes based on colloidal microspheres. However, there are many potential advantages in utilizing more complex probe morphologies: use of multiple trapping points enables control of the interaction volume; increasing the distance between the optical trap and the sample minimizes photodamage in sensitive biological materials; and geometric anisotropy introduces the potential for asymmetric surface chemistry and multifunctional probes. Here we demonstrate that living cells of the freshwater diatom Nitzschia subacicularis Hustedt can be exploited as advanced probes for holographic optical tweezing applications. We characterize the optical and material properties associated with the high shape anisotropy of the silica frustule, examine the trapping behavior of the living algal cells, and demonstrate how the diatoms can be calibrated for use as force sensors and as force probes in the presence of rat B-cell hybridoma (11B11) cells.

Factors influencing home blood pressure monitor ownership in a large clinical trial.

Home blood pressure monitor (HBPM) ownership prevalence and the factors that influence it are unclear. This study aimed to investigate factors associated with HBPM ownership among participants in the Treatment in Morning versus Evening (TIME) hypertension study. This study is a sub-analysis of the TIME study, a randomised trial investigating the effect of day-time versus night-time dosing of antihypertensive medication on cardiovascular outcomes in adults with hypertension. As part of the TIME study online registration process, participants were asked to indicate whether they owned an HBPM. A multivariable logistic regression model was constructed to determine factors associated with HBPM ownership. Of 21,104 randomised participants, 11,434 (54.2%) reported owning an HBPM. The mean age of all participants at enrolment was 67.7 ± 9.3 years, 12,134 (57.5%) were male, and 8892 (42.1%) reported a current or previous history of smoking. Factors associated with an increased likelihood of reporting HBPM owned include being male (OR:1.47; 95% CI 1.39-1.56) or residing in a less deprived socioeconomic region (IMD Decile 6-10) (OR:1.31; 95% CI 1.23-1.40). Participants with a history of diabetes mellitus (OR:0.74; 95% CI:0.64-0.86) or current smokers, compared to non-smokers, (OR:0.71; 95% CI:0.62-0.82) were less likely to report owning an HBPM. This study has identified important patient factors influencing HBPM ownership. Further qualitative research would be valuable to identify and explore potential patient-level barriers to engagement with self-monitoring of blood pressure.

Home blood pressure monitors owned by participants in a large decentralised clinical trial in hypertension: the Treatment In Morning versus Evening (TIME) study.

Various home blood pressure monitors (HBPMs) are available to the public for purchase but only some are validated against standardised protocols. This study aimed to assess whether HBPMs owned by participants taking part in a clinical trial were validated models. The TIME study is a decentralised randomised trial investigating the effect of antihypertensive medication dosing time on cardiovascular outcomes in adults with hypertension. No HBPMs were provided to participants in this trial but patients were asked to report if they already owned one. We identified the model of HBPM reported by participants, then cross-referenced this against lists of validated HBPMs produced by dabl Educational Trust and the British and Irish Hypertension Society (BIHS). Of 21,104 participants, 10,464 (49.6%) reported their model of HBPM. 7464 (71.3%) of these participants owned a monitor that could be identified from the participants' entry. Of these, 6066 (81.3%) participants owned a monitor listed as validated by either dabl (n = 5903) or BIHS (n = 5491). Some were listed as validated by both. 1398 (18.7%) participants owned an identifiable HBPM that lacked clear evidence of validation. 6963 (93.3%) participants owned an upper arm HBPM and 501 (6.7%) owned a wrist HBPM. Validated HBPMs had a higher median online retail price of £45.00 compared to £20.00 for HBPMs lacking clear evidence of validation. A significant number of participants own HBPMs lacking evidence of validation.

Position clamping of optically trapped microscopic non-spherical probes.

We investigate the degree of control that can be exercised over an optically trapped microscopic non-spherical force probe. By position clamping translational and rotational modes in different ways, we are able to dramatically improve the position resolution of our probe with no reduction in sensitivity. We also demonstrate control over rotational-translational coupling, and exhibit a mechanism whereby the average centre of rotation of the probe can be displaced away from its centre.

Surface imaging using holographic optical tweezers.

We present an imaging technique using an optically trapped cigar-shaped probe controlled using holographic optical tweezers. The probe is raster scanned over a surface, allowing an image to be taken in a manner analogous to scanning probe microscopy (SPM), with automatic closed loop feedback control provided by analysis of the probe position recorded using a high speed CMOS camera. The probe is held using two optical traps centred at least 10 µm from the ends, minimizing laser illumination of the tip, so reducing the chance of optical damage to delicate samples. The technique imparts less force on samples than contact SPM techniques, and allows highly curved and strongly scattering samples to be imaged, which present difficulties for imaging using photonic force microscopy. To calibrate our technique, we first image a known sample--the interface between two 8 µm polystyrene beads. We then demonstrate the advantages of this technique by imaging the surface of the soft alga Pseudopediastrum. The scattering force of our laser applied directly onto this sample is enough to remove it from the surface, but we can use our technique to image the algal surface with minimal disruption while it is alive, not adhered and in physiological conditions. The resolution is currently equivalent to confocal microscopy, but as our technique is not diffraction limited, there is scope for significant improvement by reducing the tip diameter and limiting the thermal motion of the probe.

Calibration of optically trapped nanotools.

Holographically trapped nanotools can be used in a novel form of force microscopy. By measuring the displacement of the tool in the optical traps, the contact force experienced by the probe can be inferred. In the following paper we experimentally demonstrate the calibration of such a device and show that its behaviour is independent of small changes in the relative position of the optical traps. Furthermore, we explore more general aspects of the thermal motion of the tool.

Hands-on with optical tweezers: a multitouch interface for holographic optical trapping.

We report the implementation of a multitouch console for control of a holographic optical tweezers system. This innovative interface enables the independent but simultaneous interactive control of numerous optical traps by multiple users, overcoming the limitations of traditional interfaces and placing the full power of holographic optical tweezing into the operators' hands.

Rapid fixation of brains: a viable alternative?

AIM: Recent events surrounding postmortem practices have necessitated several changes in the way necropsies are conducted both within the medicolegal and hospital settings. These changes have resulted in a striking reduction in the frequency of brain retention for neuropathological examination. Aberdeen Royal Infirmary, responding quickly to rising concerns among bereaved relatives regarding organ retention, instituted a change in practice regarding the examination of brains at necropsy as early as 2001. The new protocol involved subjecting the brain to rapid fixation using combined immersion and perfusion techniques. This allows return of the organ to the body without unreasonable delay to the funeral. In this article, we present the results of a retrospective audit comparing the efficacy of the new method against the conventional fixation protocol. METHODS: An equal number of postmortem brains were selected randomly from the year 1998 (following the usual fixation protocol), and from the year 2001 (following the new method). A three tier scoring system was devised to assess section and staining quality, and a single observer scored all the cases. RESULTS: No statistical difference was noted in the quality of sections prepared by rapid fixation those by conventional fixation. Furthermore, the rapid method was more frequently adequate for diagnosis (considering scores of 2 and 3 together) than the conventional method. CONCLUSION: Rapid fixation offers a viable alternative for detailed examination of brains at necropsy, without necessarily prolonging the retention of the organ.

A systematic review of loss of independence in Parkinson's disease.

Functional dependency (needing help with basic ADLs) is an important outcome in Parkinson's disease (PD). "Death or dependency", as opposed to being alive and independent, is a useful dichotomous indicator of poor outcome. We aimed to systematically review the progression to dependency in PD and what factors predicted development of dependency. Comprehensive searches were performed to identify observational studies of dependency in PD with follow-up of at least 3 years. Other forms of parkinsonism and highly selected cohorts were excluded. Descriptive analysis of included studies was performed and outcomes over time were plotted by type of cohort (inception/non-inception). Independent prognostic factors were identified. There were insufficient data for meta-analysis. Of 15,154 unique references identified, 14 studies were included. Most studies were of low quality. There was heterogeneity in definitions of dependency and the measured risk of dependency at similar time-points. Risk of dependency in inception studies was about 10-25 % at 5 years and about 20-50 % at 10 years; and risk of "death or dependency" in the inception studies was about 15-40 % at 5 years and about 35-70 % at ten years. More bradykinesia and older age were associated with more dependency, but there was little evidence for other prognostic factors. Few high-quality data on dependency are available. Heterogeneity in study populations, methodology and outcome reporting made data synthesis difficult. Few prognostic factors have been identified. Further data from representative inception studies are necessary to better understand the progression of dependency in PD.

Contrast-enhanced MR angiography of intracranial giant aneurysms.

BACKGROUND AND PURPOSE: Intravoxel phase dispersion and flow saturation often prevent adequate depiction of intracranial giant aneurysms on 3D time-of-flight (3D-TOF) MR angiography (MRA). Additional diagnostic difficulties may arise from T1 contamination artifact of an associated blood clot. Our aim was to assess whether contrast-enhanced MRA could improve the evaluation of giant aneurysms and to compare two different types of contrast-enhanced MRA. METHODS: We studied 11 aneurysms in 10 patients (age range, 31-77 years) with giant aneurysms of the anterior (n = 9) and posterior (n = 2) cerebral circulation by comparing 3D-TOF, first-pass dynamic contrast-enhanced MRA, and steady-state contrast-enhanced 3D-TOF sequences. Additional comparison with digital subtraction angiography (DSA) was performed in eight aneurysms. RESULTS: In nine of 11 aneurysms, 3D-TOF did not adequately show the lumen and exiting vessels. Contrast-enhanced 3D-TOF and dynamic contrast-enhanced MRA showed the aneurysm sac and exiting vessels in all of these cases. Dynamic contrast-enhanced MRA showed a better intravascular contrast than did contrast-enhanced 3D-TOF, which led to better delineation of the aneurysms. T1 contamination artifact from intra- or extraluminal blood clot was evident on the 3D-TOF images in four cases. The artifact was less marked on the contrast-enhanced 3D-TOF image and was completely eliminated on the dynamic contrast-enhanced MRA image by subtraction of precontrast images. The diagnostic information provided by dynamic contrast-enhanced MRA was comparable to that provided by DSA. CONCLUSION: Precontrast 3D-TOF is inadequate for the assessment of giant cerebral aneurysms. Both contrast-enhanced 3D-TOF and dynamic contrast-enhanced MRA reliably show the aneurysm sac and connected vessels. Dynamic MRA provides a superior contrast between flow and background and eliminates T1 contamination artifact. It should therefore be considered as the MRA sequence of choice.

Risk factors for the formation of multiple intracranial aneurysms.

OBJECT: Several factors are known to increase the risk of subarachnoid hemorrhage (SAH) and spontaneous intracerebral hematoma. However, information on the roles of these same factors in the formation of multiple aneurysms is less well defined. The purpose of this study was to examine factors associated with an increased risk of multiple aneurysm formation. METHODS: A retrospective review of the medical records of all patients with a diagnosis of SAH and intracranial aneurysms who were admitted to a single institution between 1985 and 1997 was undertaken. The authors examined associations between risk factors (patient age and sex, menopausal state of female patients, hypertension, cigarette smoking, alcohol consumption, history of cardiovascular disease or diabetes mellitus, and family history of cerebrovascular disease) and the presence of multiple aneurysms by using the Fisher exact test and logistic regression analysis. Of 400 patients admitted with a diagnosis of cerebral aneurysms, 392 were included in the study (287 women and 105 men). Two hundred eighty-four patients harbored a single aneurysm and 108 harbored multiple aneurysms (2 aneurysms in 68 patients, three aneurysms in 22 patients, four aneurysms in 13 patients, and five aneurysms in five patients). CONCLUSIONS: Statistical analysis revealed that, as opposed to the occurrence of a single aneurysm, there was a significant association between the presence of multiple aneurysms and hypertension (p < 0.001), cigarette smoking (p < 0.001), family history of cerebrovascular disease (p < 0.001), female sex (p < 0.001), and postmenopausal state in female patients (p < 0.001).

Giant temporo-occipital sinus pericranii. A case report.

A rare case of a giant, temporo-occipital sinus pericranii is presented. A 38-year-old male presented with minor symptoms of headache and heaviness over an enlarging temporo-occipital bone defect. Within the defect a soft, compressible, mass lesion was observed, which varied in size with changes in intracranial pressure. Radiological imaging demonstrated bone erosion around a fluid filled mass, which on angiography communicated via a series of channels with the transverse sinus. A diagnosis of sinus pericranii was made. Due to the risk of future complication the patient elected to undergo surgery, which successfully resected the mass and obliterated the venous communications with the diploic veins and transverse sinus. The classification, aetiology, differential diagnosis, radiological characteristics and management options relating to sinus pericranii are discussed.

Palatal trauma: an unusual cause of a parotid sinus.

A case is described of a 3-year-old boy who presented with a seemingly trivial injury to his soft palate, who went on to develop a parotid sinus as a result of a retained foreign body. This is a rare clinical problem and it highlights the difficulty in the clinical assessment of a palatal injury--especially in children. The child had the foreign body removed successfully 5 months after the initial injury and made an uneventful recovery.

Advances in non-invasive imaging of intracranial vascular disease.

Intra-arterial catheter angiography has, in the past, been the mainstay for the investigation of intracranial vascular disease. It is, however, invasive, usually requires in-patients admission, and is associated with a rate of neurological complications between 1% and 3%. In recent years, magnetic resonance angiography (MRA) and CT angiography (CTA) have emerged as non-invasive alternatives for imaging blood vessels and have made a significant impact on neuroradiological investigations. It is the purpose of this article to explain the basic technical principles of these two methods and to give an overview of their current clinical applications.

Drug-related deaths in Grampian, Scotland.

AIMS: To analyse the demographic data from fatalities arising directly from illicit drug abuse in the Grampian area and compare the findings with trends in drug seizures in Grampian to ascertain if these reflect the recorded deaths, and to attempt to identify a subgroup of the abusing population which might be at greater danger from overdose of controlled substances. METHODS: Cases in which the cause of death was directly attributed to illicit drugs from the beginning of January 1995 until the end of December 1999 were identified, and their epidemiological and toxicological data were analysed. The information regarding drug seizures was gained from Home Office publications for the same time period. RESULTS: One hundred and thirteen cases were retrieved consisting of 93 males and 20 females, aged 16 to 43 years (Median 25). The most commonly isolated substance was morphine followed by benzodiazepines. In 97 cases two or more drugs were involved with five cases showing positive toxicology for four or more drugs. Of the female deaths 75% fell into the 16-25 year age range. Drug seizures rose by 49% from 1995 to 1998 with both heroin and benzodiazepine seizures increasing by more than five fold in the same period. CONCLUSIONS: Deaths directly due to illicit drugs showed a significant increase over the study period and were concentrated in the young male population. The drug seizures increased but the extent of this was not mirrored in the deaths. A shift in emphasis to an older age group is also indicated; drug misuse educational programmes should continue to be targeted at all populations but information may also be targeted at the older age groups and at females under 25 years of age.