Links between the amount of antipsychotic medication prescribed per population at general practice level, local demographic factors and medication selection.

BACKGROUND: Antipsychotic medications are the first-line pharmacological intervention for severe mental illnesses (SMI) such as schizophrenia and other psychoses, while also being used to relieve distress and treat neuropsychiatric symptoms in dementia. Our aim was to examine the factors relating to antipsychotic prescribing in general practices across England and how cost changes in recent years have impacted on antipsychotic prescribing. METHODS: The study examined over time the prescribing volume and prices paid for antipsychotic medication by agent in primary care. Monthly prescribing in primary care was consolidated over 5 years (2013-2018) and DDD amount from WHO/ATC for each agent was used to convert the amount to total DDD/practice. The defined Daily Dose (DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults. RESULTS: We included 5750 general practices with practice population > 3000 and with > 30 people on their SMI register. In 2018/19 there were 10,360,865 prescriptions containing 136 million DDD with costs of £110 million at an average cost of £0.81/DDD issued in primary care. In 2017/18 there was a sharp increase in overall prices and they had not reduced to expected levels by the end of the 2018/19 evaluation year. There was a gradual increase in antipsychotic prescribing over 2013-2019 which was not perturbed by the increase in drug price in 2017/18. The strongest positive relation to increased prescribing of antipsychotics came from higher social disadvantage, higher population density (urban), and comorbidities e.g. chronic obstructive pulmonary disease (COPD). Higher % younger and % older populations, northerliness and non-white (Black and Minority Ethnic(BAME)) ethnicity were all independently associated with less antipsychotic prescribing. Higher DDD/general practice population was linked with higher proportion(%) injectable, higher %liquid, higher doses/prescription and higher %zuclopenthixol depot. Less DDD/population was linked with general practices using higher % risperidone and higher spending/dose of antipsychotic. CONCLUSIONS: The levels of antipsychotic prescribing at general practice level are driven by social factors/comorbidities. We found a link between depot prescriptions with higher antipsychotic DDD and risperidone prescriptions with lower antipsychotic DDD. It is important that all prescribers are aware of these drivers / links.

People with Type Diabetes Mellitus (T1DM) self-reported views on their own condition management reveal links to potentially improved outcomes and potential areas for service improvement.

BACKGROUND: The self-management of type 1 diabetes (T1DM) has moved forward in many areas over the last 40 years. Our study asked people with T1DM what is their experience of blood glucose (BG) monitoring day to day and how this influences decisions about insulin dosing. METHODS: An on-line self-reported questionnaire containing 44 questions prepared after consultation with clinicians and patients was circulated to people with T1DM 116 responders provided completed responses. Fixed responses were allocated specific values (e.g. not confident = 0 fairly confident = 1). Multivariate regression analysis was carried out. Only those 5 factors with p-value <0.05 were retained. RESULTS: 59% of respondents were >50 years old and 66% had diabetes for >20 years, with 63% of patients reporting HbA1c results ≤8% or 64 mmol/mol. Findings included; 75% used only 1 m; 56% had used the same meter for ≥3 years; 10% had tried flash monitors; 47% were concerned about current BG level; 85% were concerned about long-term impact of higher BG. 72% of respondents keep BG level high to avoid hypoglycaemia; 25% used ≥7 mmol/L as pre-meal BG target to calculate dose; 65% were concerned they might be over/under-dosing; 83% did not discuss accuracy when choosing meter. However 85% were confident in their meter's performance. The factors that linked to LOWER HbA1c included LESS units of basal insulin (p < 0.001), HIGHER number of daily BG tests (p = 0.008), LOWER bedtime blood glucose (p = 0.009), HIGHER patient's concern over long-term impact of high BG (BG) (p < 0.009 but LOWER patient's concern over current BG values (p = 0.009). The final statistical model could explain 41% of the observed variation in HbA1c. CONCLUSION: Many people still run their BG high to avoid hypoglycaemia. Concern about the longer-term consequences of suboptimal glycaemic control was associated with a lower HbA1c and is an area to explore in the future when considering how to help people with T1DM.

Route to improving Type 1 diabetes mellitus glycaemic outcomes: real-world evidence taken from the National Diabetes Audit.

AIM: To use general practice-level data for England, available through the National Diabetes Audit, and primary care prescribing data to identify prescription treatment factors associated with variations in achieved glucose control (HbA1c ). METHODS: General practice-level National Diabetes Audit data on Type 1 diabetes, including details of population characteristics, services, proportion of people achieving target glycaemic control [HbA1c ≤58 mmol/mol (7.5%)] and proportion of people at high glycaemic risk [HbA1c >86 mmol/ml (10%)], were linked to 2013-2016 primary care diabetes prescribing data on insulin types and blood glucose monitoring for all people with diabetes. RESULTS: A wide variation was found between the 10th percentile and the 90th percentile of general practices in both target glycaemic control (15.6% to 44.8%, respectively) and high glycaemic risk (4.8% to 28.6%, respectively). Our analysis suggests that, given the extrapolated total of 280 000 people with Type 1 diabetes in the UK, there may be the potential to increase the number of those within target glycaemic control from 80 000 to 101 000; 53% of this increase (11 000 people) would result from service improvements and 47% (10 000 people) from medication and technology changes. The same improvements would also provide the opportunity to reduce the number of people at high glycaemic risk from 42 000 to 26 500. A key factor associated with practice-level target HbA1c achievement would be greater use of insulin pumps for up to an additional 56 000 people. CONCLUSION: If the HbA1c achievement rates in service provision, medication and use of technology currently seen in practices in the 90th percentile were to be matched with regard to HbA1c achievement rates in all general practices, glycaemic control might be improved for 36 500 people, with all the attendant health benefits.

Higher levels of apomorphine and rotigotine prescribing reduce overall secondary healthcare costs in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) affects around 100,000 people in England. A number of non-oral therapies can improve both the quality of life and reduce patient needs for health and social care. However, these can be relatively expensive at £2000-£10,000 per year per patient. Our aim was to examine how prescribing of these agents relates to secondary care costs. METHODS: Using practice level primary care prescribing data and hospital episode statistical data in England, we investigated the relation between general practitioner prescriptions of apomorphine injections/rotigotine patches and the secondary care costs accrued for their diagnosed PD patients for 2011-2014. The median age of the PD patients was 78 years. RESULTS: In the period 2011-2014, 58% of the average annual £437 million secondary care costs for PD patients came from non-elective admissions. 80% of this came from seven Healthcare Resource Group Chapters linked to PD comorbidities. Compared with practices not using non-oral therapies, practices prescribing Apomorphine saved £897 per year per patient of secondary care costs to offset the average additional prescribing cost of £475 per overall patient per year. For Rotigotine, saving was £718 per year per patient of secondary care costs offsetting £137 prescribing cost. Practices in the highest quartile of non-oral prescribing were using non-oral agents in up to 28% of their PD patients. CONCLUSIONS: Those practices which used more non-oral therapies appear to incur less secondary care costs. A total of 70% of the advanced PD patients are not being given access to non-oral treatment. This is a challenge for all physicians looking after the older patient.

Comparative gastrointestinal safety of weekly oral bisphosphonates.

SUMMARY: Weekly bisphosphonates are the primary agents used to treat osteoporosis. Although these agents are generally well tolerated, serious gastrointestinal adverse events, including hospitalization for gastrointestinal bleed, may arise. We compared the gastrointestinal safety between weekly alendronate and weekly risedronate and found no important difference between new users of these agents. INTRODUCTION: Weekly bisphosphonates are the primary agents prescribed for osteoporosis. We examined the comparative gastrointestinal safety between weekly bisphosphonates. METHODS: We studied new users of weekly alendronate and weekly risedronate from June 2002 to August 2005 among enrollees in a state-wide pharmaceutical benefit program for seniors. Our primary outcome was hospitalization for upper gastrointestinal bleed. Secondary outcomes included outpatient diagnoses for upper gastrointestinal disease, symptoms, endoscopic procedures, use of gastroprotective agents, and switching between therapies. We used Cox proportional hazard models to compare outcomes between agents within 120 days of treatment initiation, adjusting for propensity score quintiles. We also examined composite safety outcomes and stratified results by age and prior gastrointestinal history. RESULTS: A total of 10,420 new users were studied, mean age = 79 years (SD, 6.9), and 95% women. We observed 31 hospitalizations for upper gastrointestinal bleed (0.91 per 100 person-years) within 120 days of treatment initiation. Adjusting for covariates, there was no difference in hospitalization for upper gastrointestinal bleed among those treated with risedronate compared with alendronate (HR, 1.12; 95%CI, 0.55 to 2.28). Risedronate switching rates were lower; otherwise, no differences were observed for secondary or composite outcomes. CONCLUSIONS: We found no important difference in gastrointestinal safety between weekly oral bisphosphonates.

Contribution of plasmid DNA to inflammation in the lung after administration of cationic lipid:pDNA complexes.

Cationic lipid-mediated gene transfer to the mouse lung induces a dose-dependent inflammatory response that is characterized by an influx of leukocytes and elevated levels of the cytokines interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma). We have examined the contribution of plasmid DNA (pDNA) to this observed toxicity, specifically the role of unmethylated CpG dinucleotides, which have been previously shown to be immunostimulatory. We report here that complexes of cationic lipid GL-67 and unmethylated pDNA (pCF1-CAT) instilled into the lungs of BALB/c mice induced highly elevated levels of the cytokines TNF-alpha, IFN-gamma, IL-6, and IL-12 in the bronchoalveolar lavage fluids (BALF). In contrast, BALF of animals administered either GL-67 alone or GL-67 complexed with SssI-methylated pDNA contained low levels of these cytokines. Similar results were observed using a plasmid (pCF1-null) that does not express a transgene, demonstrating that expression of chloramphenicol acetyltransferase (CAT) was not responsible for the observed inflammation. The response observed was dose dependent, with animals receiving increasingly higher amounts of unmethylated pDNA exhibiting progressively higher levels of the cytokines. Concomitant with this increase in cytokine levels were also elevated numbers of neutrophils in the BALF, suggesting a possible cause- and-effect relationship between neutrophil influx and generation of cytokines. Consistent with this proposal is the observation that reduction of neutrophils in the lung by administration of antibodies against Mac-1alpha and LFA-1 also diminished cytokine levels. This reduction in cytokine levels in the BALF was accompanied by an increase in transgene expression. In an attempt to abate the inflammatory response, sequences in the pDNA encoding the motif RRCGYY, shown to be most immunostimulatory, were selectively mutagenized. However, instillation of a plasmid in which 14 of the 17 CpG sites were altered into BALF/c mice did not reduce the levels of cytokines in the BALF compared with the unmodified vector. This suggests that other unmethylated motifs, in addition to RRCGYY, may also contribute to the inflammatory response. Together, these findings indicate that unmethylated CpG residues in pDNA are a major contributor to the induction of specific proinflammatory cytokines associated with instillation of cationic lipid:pDNA complexes into the lung. Strategies to abate this response are warranted to improve the efficacy of this nonviral gene delivery vector system for the treatment of chronic diseases.

Improving trauma care in Trinidad and Tobago.

Identification of trauma as a major cause of morbidity and mortality in Trinidad and Tobago prompted the establishment of a training programme aimed at improving trauma care in this developing country. An Advanced Trauma Life Support (ATLS) programme for physicians, funded through the Canadian International Development Agency resulted in a statistically significant improvement of in-hospital trauma patient outcome at the Port-of-Spain General Hospital (observed to expected mortality ratio of 3.16 pre-ATLS compared to 1.94 post-ATLS). A recent analysis of all motor vehicle injuries for a shorter period did not confirm this positive impact of the ATLS programme, primarily because a large number of these patients died in the pre-hospital period. Pre-hospital trauma care therefore required urgent attention to complement the positive in-hospital impact of the ATLS programme. A second training programme (the Pre-Hospital Trauma Life Support or PHTLS) for paramedical personnel was thus instituted in 1990. Over 250 physicians have been trained in the ATLS programme and to date over 100 paramedical personnel have been trained in the PHTLS programme. Attempts have also been made to equip the ambulances with more appropriate resuscitative devices in order to improve pre-hospital care. The combination of the PHTLS and the ATLS programme should result in further improvement in the care of patients sustaining major injuries in Trinidad and Tobago.

Improving trauma care in Trinidad and Tobago

Indentification of trauma as a major cause of morbidity and mortality in Trinidad and Tobago prompted the establishment of a training programme aimed at improving trauma care in this developing country. An Advanced Trauma Life Support (ATLS) programme for physicians, funded through the Canadian International Development Agency resulted in a statistically significant improvement of in-hospital trauma patient outcome at the Port-of-Spain General Hospital (observed to expected mortality ratio of 3.16 pre-ATLS compared to 1.94 post ATLS). A recent analysis of all motor vehicle injuries for a shorter period did not confirm this positive impact of the ATLS programme, primarily because a large number of these patients died in the pre-hospital period. Pre-hospital trauma care therefore required urgent attention to complement the positive in-hospital impact of the ATLS programme. A second training programme (the Pre-Hospital Trauma Life Support or PHTLS) for paramedical personnel was thus instituted in 1990. Over 250 physicians have been trained in the ATLS programme and to date over 100 paramedical personnel have been trained in the PHTLS programme. Attempts have also been made to equip the ambulances with more appropriate resuscitative devices in order to improve pre-hospital care. The combination of the PHTLS and the ATLS programme should result in further improvement in the care of patients sustaining major injuries in Trinidad and Tobago.

Cognitive and attitudinal impact of the Advanced Trauma Life Support program in a developing country.

Improvement in trauma patient outcome has been reported after Advanced Training Life Support training (ATLS) in the developing country of Trinidad and Tobago (T & T). The cognitive impact of ATLS training was assessed from pre-ATLS and post-ATLS performance of T & T physicians in multiple choice question tests and comparison with post-ATLS test performance among Nebraska physicians. Overall, improvement between the pre-test and post-test among the T & T physicians was 22.0% +/- 2.0%. All physicians including failures (199 out of 212 passed) improved in their post-test scores. Individual item analysis of the post-test, including the KR-20 determination, varied but the overall performance was similar for both physician groups with the T & T physicians performing slightly better in test 2 (6 of 16 vs. 25 of 100 failures, p < 0.05). Attitudinal impact was assessed through 87 questionnaires from 50 physicians (92% response) and 37 nurses (89% response). Physicians (97.8% compared with 69.7%) were more aware of the ATLS training, and both groups (physicians, 77.3%; nurses, 69.6%) differentiated ATLS-trained physicians based on better resuscitation, more timely and appropriate consultation, greater confidence in trauma management, and improvement in trauma mortality and morbidity; all respondents recommended ATLS training for all emergency room physicians. The demonstrated positive cognitive and attitudinal effects very likely contributed to the improved post-ATLS trauma patient outcome.

Advanced trauma life support program increases emergency room application of trauma resuscitative procedures in a developing country.

Over a 9-year period (July 1981-December 1985--pre-ATLS period; January 1986-June 1990--post-ATLS period), the hospital charts of 813 trauma patients with ISS > or = 16 were reviewed (n = 413, pre-ATLS and n = 400, post-ATLS) in order to assess the impact of the ATLS program. The frequency of endotracheal intubation (ET), nasogastric tube insertion (NG), intravenous access (i.v.), Foley catheterization of the bladder (Foley) and chest tube insertion (CT) were compared by Pearson Chi-square analysis. Overall, pre-ATLS vs. post-ATLS frequencies (%) were 83.5 vs. 65.3 for ET, 97.3 vs. 98.0 for i.v., 74.6 vs. 96.3 for Foley, 68.3 vs. 91.3 for NG, and 18.4 vs. 47.0 for CT. In the emergency room these frequencies (%) were 26.1 vs. 36.4 for ET, 98.8 vs. 98.7 for i.v., 11.0 vs. 97.1 for Foley, 3.2 vs. 95.9 for NG, and 3.9 vs. 95.2 for CT. The differences in the application of these life saving procedures between the pre-ATLS and post-ATLS periods were statistically significant (p < 0.05) except i.v. access, which showed no difference between the pre-ATLS and post-ATLS groups. Of the patients with severe chest injuries (AIS > or = 3) 87.7% had chest tubes post ATLS (94.4% in ER) compared with 48.1% pre ATLS (3.2% in ER). These differences were associated with significant improvement in trauma patient outcome post ATLS. We conclude that the frequency of lifesaving interventions, particularly in the ER, was increased post ATLS.(ABSTRACT TRUNCATED AT 250 WORDS)

Trauma outcome improves following the advanced trauma life support program in a developing country.

Trauma outcome variables before and after the institution of the Advanced Trauma Life Support (ATLS) program were compared for the largest hospital in Trinidad and Tobago from July 1981 through December 1985 (pre-ATLS) and from January 1986 to June 1990 (post-ATLS). A total of 199 physicians were ATLS trained by June 1990. Outcome data were analyzed for all dead or severely injured patients (ISS > or = 16; n = 413 pre-ATLS and n = 400 post-ATLS). Trauma mortality decreased post-ATLS (134 of 400 vs. 279 of 413) throughout the hospital, including the ICU (13.6% post-ATLS ICU mortality vs. 55.2% pre-ATLS). The odds of dying from trauma increased with age (1.02 for each year), ISS score (1.24 for each ISS increment), and blunt injury, both pre-ATLS and post-ATLS. Post-ATLS mortality was associated with a higher ISS (31.6 vs. 28.8). Although there was a higher percentage of blunt injury pre-ATLS (84.0%) versus post-ATLS (68.3%), the mortality rates for both blunt and penetrating injuries were higher in the pre-ATLS group (19.7% pre-ATLS vs. 6.3% post-ATLS for penetrating and 76.6% pre-ATLS versus 46.2% post-ATLS for blunt). For each ISS category, mortality was greater in the pre-ATLS group (ISS > or = 24 pre-ATLS mortality 47.9% vs. 16.7% post-ATLS; ISS 25-40 pre-ATLS mortality 91.0% vs. 71.0% post-ATLS). The overall ratio of observed to expected mortality based on the MTOS data base was lower for the post-ATLS period (pre-ATLS ratio 3.16; post-ATLS ratio 1.94).(ABSTRACT TRUNCATED AT 250 WORDS)

Trauma outcome improves following the advanced trauma life support program in a developing country

Trauma outcome variables before and after the institution of the Advanced Trauma Life Support (ATLS) program were compared for the largest hospital in Trinidad and Tobago from July 1981 through December 1985 (pre-ATLS) and from January 1986 to June 1990 (post-ATLS). A total of 199 physicians were ATLS trained by June 19990. Outcome data were analysed for all dead or severely injured patients (ISS greater than and equal to 16; n=413 pre-ATLAS and n=400 post ATLS). Trauma mortality decreased post ATLS (134 ICU mortality vs. 279 of 413) throughout the hospital, including the ICU (13.6 percent post-ATLS ICU mortality vs. 55.2 percent pre-ATLS). The odds of dying from trauma increased with age (1.02 for each year), ISS score (1.24 for each ISS increment), and blunt injury, both pre-ATLS and post-ATLS. Post-ATLS mortality was associated with a higher ISS (31.6 vs 28.8). Although there was a higher percentage of blunt injury pre-ATLS (84.0 percent) versus post-ATLS (68.3 percent), the mortality rates for both blunt and penetrating injuries were higher in the pre-ATLS group (19.7 percent pre-ATLS vs 6.3 percent post ATLS for penetrating and 76.6 percent pre-ATLS versus 46.2 percent post-ATLS for blunt). For each ISS category, mortalilty was greater in the pre-ATLS group (ISS greater than and equal to 24 pre-ATLS mortality 47;9 percent vs. 16.7 percent post-Atls; ISS 25-40 pre-ATLS mortality 91.0 percent vs. 71.0 percent post-ATLS). The overall ration of observed to expected mortality based on the MTOS data base was lower for the post-ATLS period (pre-ATLS ratio 3.16; post-ATLS ratio 1.94). Multiple logistic regression analysis indicated that although post-ATLS mortality was affected by the lower incidence of blunt injury and a lower overall ISS score, the ATLS program was a significant factor in determing the observed decrease in mortality. Postinjury functional status among survivors was improved post-ATLS (minor disabiltiy 88.3 percent post-ATLS vs. 22.4 percent pre-ATLS and major disability 1.9 percent post-ATLS vs. 6.7 percent pre-ATLS). Our data demonstrate that the ATLS program significantly improved trauma patient outcome in a developing country, thus supporting the concept of international promulgation of this program for physicians(AU)

Imaging of proteins by scanning tunnelling microscopy.

Scanning tunnelling microscopy has been used to examine the structure of proteins deposited on a graphite surface. Three molecules have been studied; immunoglobulin G (IgG), Complement component 1q (C1q) and ATP-citrate lyase (ACL). The images show IgG as a tri-lobed molecule, consistent with the known 3D structure as determined by X-ray crystallography. The C1q images differ from the well known "tulip bunch" model derived by electron microscopy, but are consistent with the model if it is assumed that the six globular heads have aggregated. Molecules of ACL are visible as discrete units, with some hints of substructure. These results highlight the potential of STM in studying protein structures, but also illustrate the difficulties of interpreting micrographs of proteins whose structure is currently unknown.

Structure of immunoglobulin G by scanning tunnelling microscopy.

Scanning tunnelling microscopy (STM) has been used to examine the shape of individual immunoglobulin G (IgG) molecules deposited onto a graphite surface. IgG was chosen for this study as it has a well-characterized and distinctive three-dimensional structure. The micrographs clearly reveal the IgG molecule as trilobed, corresponding with the known structural organization of IgG. Comparison of these images with the structure of IgG determined by X-ray crystallography shows that the STM images are consistent with the crystal structure. This illustrates that STM is a valuable technique for examining protein structure, allowing rapid determination of the overall molecular shape that is consistent with more established techniques.

Grazing incidence optics:amplitude-wavelength mapping as a unified approach to specification, theory, and metrology.

The concept of amplitude-wavelength space applied to the development of an x-ray optic provides a means of summarizing and unifying the complex data associated with each stage of its development: the specification; manufacturing tolerances; and etrology. The determination of manufacturing tolerances requires calculation of the image aberrations of perturbed optical systems and is most usefully carried out using a modified asymptotic Debye theory. Its range of applicability and that of other theories is illustrated in amplitude-wavelength space. Subnanometer perturbations are measured by mechanical or optical techniques, and the measuring instruments are calibrated by means of x-ray interferometry in terms of the primary standards of length.