The incidence of psychotic disorders in the Republic of Ireland: a systematic review.

OBJECTIVES: Despite a substantial epidemiological literature on the incidence of psychotic disorders in Ireland, no systematic review has previously been undertaken. Such evidence can help inform understanding of need for psychosis care. METHODS: We conducted a prospectively registered systematic review (PROSPERO: CRD42021245891) following PRISMA guidelines. We searched four databases (Medline, PsycInfo, Web of Science, Embase) for papers containing incidence data on non-organic psychotic disorders, in people 16-64 years, published between 1950 and 2021 in the general adult population. We conducted duplicate screening, risk of bias assessments, and extracted data to a standardised template. We undertook a narrative synthesis for each major diagnostic outcome. Random effects meta-analyses were conducted for comparisons with ≥5 incidence rates. RESULTS: Our search yielded 1975 non-duplicate citations, of which 23 met inclusion criteria, containing incidence data ascertained between 1974 and 2016 (median study quality: 5/8; interquartile range: 4-6). Incidence of all psychotic disorders (N = 4 studies) varied from 22.0 (95%CI: 17.3-28.0) in Dublin to 34.1 per 100,000 person-years (95%CI: 31.0-37.5) in Cavan and Monaghan. The pooled incidence of schizophrenia (N = 6 studies, N = 8 settings) was 20.0 per 100,000 person-years, though with imprecision around this estimate (95%CI: 10.6-37.5; I2: 97.6%). Higher rates of most outcomes were observed in men. There was consistent evidence of raised rates in more deprived and fragmented social environments, but no clear pattern by rural-urban status. CONCLUSIONS: Patterns of incidence of psychotic disorders in Ireland are broadly consistent with the wider literature from the Global North. Findings could help identify populations at higher risk of psychosis in Ireland.

Use of Advanced Flexible Modeling Approaches for Survival Extrapolation from Early Follow-up Data in two Nivolumab Trials in Advanced NSCLC with Extended Follow-up.

OBJECTIVES: Immuno-oncology (IO) therapies are often associated with delayed responses that are deep and durable, manifesting as long-term survival benefits in patients with metastatic cancer. Complex hazard functions arising from IO treatments may limit the accuracy of extrapolations from standard parametric models (SPMs). We evaluated the ability of flexible parametric models (FPMs) to improve survival extrapolations using data from 2 trials involving patients with non-small-cell lung cancer (NSCLC). METHODS: Our analyses used consecutive database locks (DBLs) at 2-, 3-, and 5-y minimum follow-up from trials evaluating nivolumab versus docetaxel in patients with pretreated metastatic squamous (CheckMate-017) and nonsquamous (CheckMate-057) NSCLC. For each DBL, SPMs, as well as 3 FPMs-landmark response models (LRMs), mixture cure models (MCMs), and Bayesian multiparameter evidence synthesis (B-MPES)-were estimated on nivolumab overall survival (OS). The performance of each parametric model was assessed by comparing milestone restricted mean survival times (RMSTs) and survival probabilities with results obtained from externally validated SPMs. RESULTS: For the 2- and 3-y DBLs of both trials, all models tended to underestimate 5-y OS. Predictions from nonvalidated SPMs fitted to the 2-y DBLs were highly unreliable, whereas extrapolations from FPMs were much more consistent between models fitted to successive DBLs. For CheckMate-017, in which an apparent survival plateau emerges in the 3-y DBL, MCMs fitted to this DBL estimated 5-y OS most accurately (11.6% v. 12.3% observed), and long-term predictions were similar to those from the 5-y validated SPM (20-y RMST: 30.2 v. 30.5 mo). For CheckMate-057, where there is no clear evidence of a survival plateau in the early DBLs, only B-MPES was able to accurately predict 5-y OS (14.1% v. 14.0% observed [3-y DBL]). CONCLUSIONS: We demonstrate that the use of FPMs for modeling OS in NSCLC patients from early follow-up data can yield accurate estimates for RMST observed with longer follow-up and provide similar long-term extrapolations to externally validated SPMs based on later data cuts. B-MPES generated reasonable predictions even when fitted to the 2-y DBLs of the studies, whereas MCMs were more reliant on longer-term data to estimate a plateau and therefore performed better from 3 y. Generally, LRM extrapolations were less reliable than those from alternative FPMs and validated SPMs but remained superior to nonvalidated SPMs. Our work demonstrates the potential benefits of using advanced parametric models that incorporate external data sources, such as B-MPES and MCMs, to allow for accurate evaluation of treatment clinical and cost-effectiveness from trial data with limited follow-up. HIGHLIGHTS: Flexible advanced parametric modeling methods can provide improved survival extrapolations for immuno-oncology cost-effectiveness in health technology assessments from early clinical trial data that better anticipate extended follow-up.Advantages include leveraging additional observable trial data, the systematic integration of external data, and more detailed modeling of underlying processes.Bayesian multiparameter evidence synthesis performed particularly well, with well-matched external data.Mixture cure models also performed well but may require relatively longer follow-up to identify an emergent plateau, depending on the specific setting.Landmark response models offered marginal benefits in this scenario and may require greater numbers in each response group and/or increased follow-up to support improved extrapolation within each subgroup.

Socioeconomic variation in uptake of colonoscopy following a positive faecal occult blood test result: a retrospective analysis of the NHS Bowel Cancer Screening Programme.

BACKGROUND: Bowel cancer is a serious health burden and its early diagnosis improves survival. The Bowel Cancer Screening Programme (BCSP) in England screens with the Faecal Occult Blood test (FOBt), followed by colonoscopy for individuals with a positive test result. Socioeconomic inequalities have been demonstrated for FOBt uptake, but it is not known whether they persist at the next stage of the screening pathway. The aim of this study was to assess the association between colonoscopy uptake and area socioeconomic deprivation, controlling for individual age and sex, and area ethnic diversity, population density, poor self-assessed health, and region. METHODS: Logistic regression analysis of colonoscopy uptake using BCSP data for England between 2006 and 2009 for 24 180 adults aged between 60 and 69 years. RESULTS: Overall colonoscopy uptake was 88.4%. Statistically significant variation in uptake is found between quintiles of area deprivation (ranging from 86.4 to 89.5%), as well as age and sex groups (87.9-89.1%), quintiles of poor self-assessed health (87.5-89.5%), non-white ethnicity (84.6-90.6%) and population density (87.9-89.3%), and geographical regions (86.4-90%). CONCLUSION: Colonoscopy uptake is high. The variation in uptake by socioeconomic deprivation is small, as is variation by subgroups of age and sex, poor self-assessed health, ethnic diversity, population density, and region.

Effects of miRNA-15 and miRNA-16 expression replacement in chronic lymphocytic leukemia: implication for therapy.

Chronic lymphocytic leukemia (CLL) clones are characterized by loss of a critical region in 13q14.3, (del(13)(q14)) involving the microRNA (miRNA) cluster miR-15a and miR-16-1. We have investigated the effects of replacement of miR-15a and miR-16-1. CLL cells transfected with these miRNA mimics exhibited a decrease in cell viability in vitro and impaired capacity for engraftment and growth in NOD/Shi-scid,γcnull (NSG) mice. No synergistic effects were observed when the two miRNA mimics were combined. The phenomena were not restricted to CLL with the del(13)(q14) lesion. Similar effects induced by miRNA mimics were seen in cells with additional chromosomal abnormalities with the exception of certain CLL clones harboring TP53 alterations. Administration of miRNA mimics to NSG mice previously engrafted with CLL clones resulted in substantial tumor regression. CLL cell transfection with miR-15a and miR-16-1-specific inhibitors resulted in increased cell viability in vitro and in an enhanced capacity of the engrafted cells to grow in NSG mice generating larger splenic nodules. These data demonstrate that the strong control by miR-15a and miR-16-1 on CLL clonal expansion is exerted also at the level of full-blown leukemia and provide indications for a miRNA-based therapeutic strategy.

Health Data Entanglement and artificial intelligence-based analysis: a brand new methodology to improve the effectiveness of healthcare services.

Healthcare expenses will be the most relevant policy issue for most governments in the EU and in the USA. This expenditure can be associated with two major key categories: demographic and economic drivers. Factors driving healthcare expenditure were rarely recognised, measured and comprehended. An improvement of health data generation and analysis is mandatory, and in order to tackle healthcare spending growth, it may be useful to design and implement an effective, advanced system to generate and analyse these data. A methodological approach relied upon the Health Data Entanglement (HDE) can be a suitable option. By definition, in the HDE a large amount of data sets having several sources are functionally interconnected and computed through learning machines that generate patterns of highly probable future health conditions of a population. Entanglement concept is borrowed from quantum physics and means that multiple particles (information) are linked together in a way such that the measurement of one particle's quantum state (individual health conditions and related economic requirements) determines the possible quantum states of other particles (population health forecasts to predict their impact). The value created by the HDE is based on the combined evaluation of clinical, economic and social effects generated by health interventions. To predict the future health conditions of a population, analyses of data are performed using self-learning AI, in which sequential decisions are based on Bayesian algorithmic probabilities. HDE and AI-based analysis can be adopted to improve the effectiveness of the health governance system in ways that also lead to better quality of care.

Cognitive processes in insulin-dependent diabetes.

Cognitive processes in a group of neurologically asymptomatic patients with relatively severe but uncomplicated insulin-dependent diabetes mellitus (IDDM) were studied. In comparison with a homogeneous group of normoglycemic controls, the diabetic group performed significantly worse in global memory, abstract reasoning, and eye-hand coordination tests. The two groups scored similarly in intelligence, concentration and attention, spatial, visual, and psychomotor tests. The neuropsychological deficits did not correlate with the duration or the severity of the disease. Whether these mild neuropsychological deficits are transient or stable or whether they are caused by central nervous system vascular or metabolic dysfunctions or by the emotional influence of the chronic illness on the intellectual and educational development of patients remains unclear. Our findings need to be cautiously interpreted and perhaps could not be extended to diabetic patients with better metabolic control.

Effects of naloxone on prolactin, luteinizing hormone, and cortisol responses to surgical stress in humans.

To evaluate the possible involvement of endogenous opioid peptides in the responses of PRL, LH, and cortisol to surgical stress, we have studied the effect of naloxone on these hormones in otherwise normal subjects of both sexes undergoing cholecystectomy for gallstones. In 24 subjects (12 males and 12 females), premedication consisted of atropine sulfate (0.007 mg/kg BW); general anesthesia (30 min later) was induced by thiopental (7 mg/kg) and maintained constant by 1% ethrane in a 70%:30% nitrous oxide-oxygen mixture. In 6 males and 6 females, naloxone (0.4 mg) was injected iv before anesthesia induction. After skin incision, a clear PRL release was observed in all subjects; this was more evident in females than in males. PRL release was significantly lower in naloxone-pretreated subjects. LH release was observed only in males and was significantly higher in naloxone-pretreated subjects. Cortisol release occurred in both sexes in a similar way and was not significantly different in naloxone-pretreated subjects. Cortisol release occurred in both sexes in a similar way and was not significantly different in naloxone-pretreated subjects. These results indicate that endogenous opioid peptides are involved in stress-induced PRL and LH release in humans.

The effect of histamine and H1 and H2 receptors on prolactin and luteinizing hormone release in humans: sex differences and the role of stress.

The present experiments were performed to investigate the possible role of histamine and its receptors, H1 and H2, in the control of PRL and LH release in normal adult humans of both sexes. Histamine infusion (200 microgram, iv, in 15 min) induced PRL and LH release in men; in women, histamine inhibited LH release without affecting PRL release. Two H1 antagonists, dexchlorpheniramine (10 mg, iv) and promethazine (50 mg, im), reduced PRL release in both sexes, stimulated LH release in men, and inhibited LH release in women. Cimetidine, an H2 antagonist (400 mg, iv), elicited PRL release in both sexes, more consistently in females than in males, and was without effect on LH release in either sex. These data suggest that in humans, the effect of histamine on PRL release is linked to H1 and H2 receptors, which respectively stimulate and inhibit PRL release independently of sex. The effect of histamine on LH release appears to depend on sex and to be mediated only by H1 receptors. To rule out the possibility that the effects of histamine are merely due to a nonspecific stress reaction, we have evaluated PRL and LH release in otherwise normal men and women undergoing surgery for gallstones. Surgery was accompanied by PRL release in both sexes, more evident in women, and by LH release only in men. These results indicate that the effect of histamine on PRL and LH release in humans is linked to sex and H1 and H2 receptors and is not due to stress; further studies are required to clarify the possible mechanism and site of action of histamine in modifying PRL and LH release in humans.

Glucose metabolism alterations in Friedreich's ataxia.

We have characterized the abnormalities of glucose metabolism associated with Friedreich's ataxia (FA) by studying plasma glucose, insulin, growth hormone (GH), and glucagon before and after an oral glucose tolerance test (OGTT), an IV glucose load, and an IV arginine load, in 21 patients and in controls. Twelve patients were normotolerant (NT) to glucose, five glucose-intolerant (IT), and four diabetic (DM). Insulin secretion of IT patients was increased and delayed during OGTT. Interestingly, the insulin release during arginine load was significantly decreased in NT and IT as well as in DM patients. The GH response to OGTT was altered in IT patients. Plasma glucagon after an arginine load was significantly higher in patients than in controls. The results indicate that FA is associated with insulin resistance, beta-cell deficiency, and type I diabetes. These alterations might be genetically linked or metabolically related to the primary defect in FA. Their interplay or independent effects are responsible for abnormalities of glucose metabolism in FA.

Long-term persistence with antihypertensive drugs in new patients.

The objective of this study was to investigate stay-on-therapy patterns over 3 years among patients prescribed different classes of antihypertensive drugs for the first time. A retrospective analysis of information recorded in the drugs database of the Local Health Unit of Ravenna (Italy) was carried out on 7312 subjects receiving a first prescription for diuretics, beta-blockers, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II antagonists between 1 January and 31 December 1997. Patients were followed up for 3 years. All prescriptions of antihypertensive drugs filled during the follow-up periods were considered. The patients continuing or discontinuing the initial treatment, the duration of treatment, and the doses taken were all calculated, as well as main factors influencing the persistence rate. The drugs prescribed were predominantly ACE-inhibitors, followed by calcium channel blockers, diuretics, beta-blockers and angiotensin II antagonists. A total of 57.9% of patients continued their initial treatment during the 3-year follow-up period, 34.5% discontinued the treatment, whilst 7.6% were restarted on a treatment in the third year. Persistence with treatment was influenced by: age of patient (persistence rate increasing proportionately with advancing years), type of drug first prescribed (persistence rate higher with angiotensin II antagonists, progressively lower with ACE-inhibitors, beta-blockers, calcium channel blockers and diuretics), gender of patient (persistence was better in males), age of general practitioner (GP) (the younger the GP, the better the persistence rate) and gender of GP (better stay-on-therapy rate with male GP prescribing). In the case of patients treated continuously, mean daily dose increased progressively over the 3 years. With adequate markers, helpful data can be collected from prescription claims databases for the purpose of monitoring the persistence of patients in continuing their medication, and the quality of antihypertensive treatment in a general practice setting.

[Evaluation model of the effect of Rofecoxib on the co-prescription of gastroprotective agents observed during the treatment of osteoarthritis]. / Modello valutativo dell'effetto sulla co-prescrizione di gastroprotettori osservato durante il trattamento dell'artrosi con Rofecoxib.

OBJECTIVE: This study was conducted to define an evaluation model to estimate changes in the co-prescription of gastroprotective agents (GPAs) induced by rofecoxib in the treatment of osteoarthritis (OA). METHODS: On the basis of a cross-linking information, which were stored in different administrative and clinical databases, a multivariate regression analysis was used to develop the model. Data were collected by 30 general practitioners of the Local Health Unit of Ravenna (middle-north of Italy). RESULTS: The study population consisted of 2,944 patients treated with non-steroidal anti-inflammatory drugs (NSAIDs) and 487 treated with rofecoxib. Patients treated with rofecoxib generally presented a higher number of gastrointestinal damage risk factors and also a lower level of GPAs co-prescription compared to those treated with NSAIDs. Including in the model variables such as type of anti-inflammatory treatment (NSAIDs or rofecoxib), gender, age by class, previous hospital admissions due to gastrointestinal complications, number of different NSAIDs used, and prescription of corticosteroids, the regression equation and its coefficients were identified. A non-linear relationship between the percentage of patients treated with rofecoxib and the relative reduction of GPAs co-prescription was found. It has been estimated the basis of the registered percentage of patients treated with rofecoxib (17,6%) adjusting for gastrointestinal damage risk factors, and on a 63% (CI95%: 55%-70%) relative reduction of GPA use with rofecoxib with respect to NSAIDs was estimated. CONCLUSIONS: Based on data collected in the clinical practice after the introduction of rofecoxib, a model evaluating the relationship between the frequency of its use in the OA population and the expected reduction of GPAs, has been developed.

Strategy for power calculation for interactions: application to a trial of interventions to improve uptake of bowel cancer screening.

Poorer postcodes within 5 regions in England have a lower response to bowel-cancer screening invitations than do richer postcodes. An extension of the sample-size formula for two proportions is used to determine that needed to detect an increase in response rate that varies by deprivation quintile. The proportions plugged into the formula are weighted averages based on the relationship between response and deprivation; the response rate is adjusted to be constant across deprivation quintiles. From a baseline period between October 2006 and January 2009, detection of an absolute or relative increase of at least 1,2,3,4 and 5% in response rate is required for the richest to poorest quintiles respectively because the interventions were chosen as those most likely to have an effect in the lower socioeconomic groups. A computer simulation experiment shows that the approach is more conservative than a likelihood-ratio calculation, and it appears sensible when compared with repeated application of a two-sample calculation at each quintile.

Brachial plexus assessment with three-dimensional isotropic resolution fast spin echo MRI: comparison with conventional MRI at 3.0 T.

OBJECTIVE: The purpose of our study was to determine whether a three-dimensional (3D) isotropic resolution fast spin echo sequence (FSE-cube) has similar image quality and diagnostic performance to a routine MRI protocol for brachial plexus evaluation in volunteers and symptomatic patients at 3.0 T. Institutional review board approval and written informed consent were guaranteed. METHODS: In this prospective study FSE-cube was added to the standard brachial plexus examination protocol in eight patients (mean age, 50.2 years) with brachial plexus pathologies and in six volunteers (mean age, 54 years). Nerve visibility, tissue contrast, edge sharpness, image blurring, motion artefact and acquisition time were calculated for FSE-cube sequences and for the standard protocol on a standardised five-point scale. The visibility of brachial plexus nerve and surrounding tissues at four levels (roots, interscalene area, costoclavicular space and axillary level) was assessed. RESULTS: Image quality and nerve visibility did not significantly differ between FSE-cube and the standard protocol (p>0.05). Acquisition time was statistically and clinically significantly shorter with FSE-cube (p<0.05). Pathological findings were seen equally well with FSE-cube and the standard protocol. CONCLUSION: 3D FSE-cube provided similar image quality in a shorter acquisition time and enabled excellent visualisation of brachial plexus anatomy and pathology in any orientation, regardless of the original scanning plane.

Magnetic resonance imaging at 1.5 T with immunospecific contrast agent in vitro and in vivo in a xenotransplant model.

OBJECT: Demonstrating the feasibility of magnetic resonance imaging (MRI) at 1.5 T of ultrasmall particle iron oxide (USPIO)-antibody bound to tumor cells in vitro and in a murine xenotransplant model. METHODS: Human D430B cells or Raji Burkitt lymphoma cells were incubated in vitro with different amounts of commercially available USPIO-anti-CD20 antibodies and cell pellets were stratified in a test tube. For in vivo studies, D430B cells and Raji lymphoma cells were inoculated subcutaneously in immunodeficient mice. MRI at 1.5 T was performed with T1-weighted three-dimensional fast field echo sequences (17/4.6/13 degrees ) and T2-weighted three-dimensional fast-field echo sequences (50/12/7 degrees ). For in vivo studies MRI was performed before and 24 h after USPIO-anti-CD20 administration. RESULTS: USPIO-anti-CD20-treated D430B cells, showed a dose-dependent decrease in signal intensity (SI) on T2*-weighted images and SI enhancement on T1-weighted images in vitro. Raji cells showed lower SI changes, in accordance to the fivefold lower expression of CD20 on Raji with respect to D430B cells. In vivo 24 h after USPIO-anti-CD20 administration, both tumors showed an inhomogeneous decrease of SI on T2*-weighted images and SI enhancement on T1-weighted images. CONCLUSIONS: MRI at 1.5 T is able to detect USPIO-antibody conjugates targeting a tumor-associated antigen in vitro and in vivo.

Retinal laser photocoagulation in diabetic patients causes prolactin, growth hormone and cortisol release.

Stress of many kinds (psychological, physical, metabolic) is able to induce endocrine modifications in humans, such as growth hormone (GH), prolactin (PRL), luteinizing hormone (LH), glucagon and cortisol release. Argon laser photocoagulation of the retina (RP), the treatment of choice for diabetic retinopathy, is a painful and stressful maneuvre and represents a direct injury onto a nervous tissue. Therefore it was decided to evaluate the possible endocrine modifications induced by RP in diabetic patients affected by retinopathy. In 19 insulin-dependent diabetic patients (12 men and 7 women), RP induced cortisol release in all cases, GH and PRL release in men, but not in women, and no modification of LH and glucagon plasma levels; in 12 similar patients receiving saline infusions without RP, no endocrine modifications were observed. It is concluded that RP elicits GH, PRL and cortisol release in diabetic patients.

Sulfonylureas enhance in vivo the effectiveness of insulin in type 1 (insulin dependent) diabetes mellitus.

Indirect evidence suggests that sulfonylureas, in addition to stimulating insulin release, exert additional effects at extrapancreatic levels which are of value in the management of type 2 diabetes. In order to characterize in vivo some of these effects, insulin sensitivity was studied in 9 type 1 diabetics with no residual insulin secretory activity, during treatment with chlorpropamide (250 mg b.i.d. for 8 days) and with glipizide (5 mg t.i.d. for 8 days). Employing the glucose clamp technique with the aid of an artificial pancreas (Biostator), glucose disposal during insulin infusion (0.1 U/kg in 60 min) was calculated by the amount of glucose required to keep the blood glucose at preinfusion levels. Chlorpropamide and glipizide administration was accompanied by a significant increase of the amount of glucose required to clamp blood glucose levels, while serum (free) insulin levels were superimposable during the different clamping studies. In the absence of endogenous insulin release, these data strongly suggest that the two sulfonylureas employed enhance in vivo the peripheral sensitivity to insulin. Further studies are required to indicate a preferential site of action (liver, muscle, adipose tissue) of sulfonylureas.

Pharmacoutilization and costs of osteoarthritis: changes induced by the introduction of a cyclooxygenase-2 inhibitor into clinical practice.

OBJECTIVE: To establish whether the introduction of a cyclooxygenase-2 inhibitor has led to changes in pharmacoutilization in the treatment of osteoarthritis (OA) in clinical practice. METHODS: Administrative and general practice databases were cross-linked to analyse the use of non-steroidal anti-inflammatory drugs (NSAIDs) and gastroprotective agents (GPAs) before and after the introduction of rofecoxib. Costs of treatment and costs of hospitalization for gastrointestinal events were also considered. RESULTS: A total of 3090 patients were evaluated. A significant reduction in the use of GPAs in the rofecoxib group was observed, corresponding to reductions of 64 and 59.7% compared to NSAIDs among patients in incident and prevalent cases respectively. The weighted mean daily cost of therapy with rofecoxib in incident cases was 1.88 euro, 7.4% lower than that of NSAIDs (2.03), and in prevalent cases it was 1.87 euro, 28.1% higher than that of NSAIDs (1.46). Although the rate of hospitalization was similar, there was an additional daily cost per patient of 186.6 for patients being treated with NSAIDs and 21.6 euro for those being treated with rofecoxib. CONCLUSIONS: The cyclooxygenase-2 inhibitor rofecoxib determined substantial changes in the pharmacoutilization and costs of OA.