Prescribed safer supply during dual public health emergencies: a qualitative study examining service providers perspectives on early implementation.

BACKGROUND: Within North America and worldwide, drug related overdoses have increased dramatically over the past decade. COVID-19 escalated the need for a safer supply to replace unregulated substances and to reduce toxicity and overdoses. Service providers play an integral role in the delivery of safer supply but there is little empirical evidence that conceptualizes effective safer supply from their perspectives. This study explored early implementation and impacts of a safer supply program, capturing the perspectives of an interdisciplinary team of service providers on tensions and issues encountered in the development of the SAFER program. METHODS: Using a community-based participatory approach, we conducted individual interviews with program providers (n = 9). The research team was composed of researchers from a local drug user organization, a local harm reduction organization, and academic researchers. The Consolidated Framework for Implementation Research (CFIR) informed the interview guide. Data was analyzed using thematic analysis. RESULTS: There are six themes describing early implementation: (1) risk mitigation prescribing as context for early implementation; (2) developing SAFER specific clinical protocols; (3) accessibility challenges and program innovations; (4) interdisciplinary team and wraparound care; (5) program tensions between addiction medicine and harm reduction; (6) the successes of safer supply and future visions. CONCLUSION: Early implementation issues and tensions included prescriber concerns about safer supply prescribing in a highly politicized environment, accessibility challenges for service users such as stigma, encampment displacement, OAT requirements, program capacity and costs, and tensions between addiction medicine and harm reduction. Navigating these tensions included development of clinical protocols, innovations to reduce accessibility challenges such as outreach, wraparound care, program coverage of medication costs and prescribing safer supply with/without OAT. These findings contribute important insights for the development of prescribed safer supply programs.

Clinical and laboratory features of seventy-eight UK patients with Good's syndrome (thymoma and hypogammaglobulinaemia).

Good's syndrome (thymoma and hypogammaglobulinaemia) is a rare secondary immunodeficiency disease, previously reported in the published literature as mainly individual cases or small case series. We use the national UK-Primary Immune Deficiency (UKPID) registry to identify a large cohort of patients in the UK with this PID to review its clinical course, natural history and prognosis. Clinical information, laboratory data, treatment and outcome were collated and analysed. Seventy-eight patients with a median age of 64 years, 59% of whom were female, were reviewed. Median age of presentation was 54 years. Absolute B cell numbers and serum immunoglobulins were very low in all patients and all received immunoglobulin replacement therapy. All patients had undergone thymectomy and nine (12%) had thymic carcinoma (four locally invasive and five had disseminated disease) requiring adjuvant radiotherapy and/or chemotherapy. CD4 T cells were significantly lower in these patients with malignant thymoma. Seventy-four (95%) presented with infections, 35 (45%) had bronchiectasis, seven (9%) chronic sinusitis, but only eight (10%) had serious invasive fungal or viral infections. Patients with AB-type thymomas were more likely to have bronchiectasis. Twenty (26%) suffered from autoimmune diseases (pure red cell aplasia, hypothyroidism, arthritis, myasthenia gravis, systemic lupus erythematosus, Sjögren's syndrome). There was no association between thymoma type and autoimmunity. Seven (9%) patients had died. Good's syndrome is associated with significant morbidity relating to infectious and autoimmune complications. Prospective studies are required to understand why some patients with thymoma develop persistent hypogammaglobulinaemia.

The United Kingdom Primary Immune Deficiency (UKPID) registry 2012 to 2017.

This is the second report of the United Kingdom Primary Immunodeficiency (UKPID) registry. The registry will be a decade old in 2018 and, as of August 2017, had recruited 4758 patients encompassing 97% of immunology centres within the United Kingdom. This represents a doubling of recruitment into the registry since we reported on 2229 patients included in our first report of 2013. Minimum PID prevalence in the United Kingdom is currently 5·90/100 000 and an average incidence of PID between 1980 and 2000 of 7·6 cases per 100 000 UK live births. Data are presented on the frequency of diseases recorded, disease prevalence, diagnostic delay and treatment modality, including haematopoietic stem cell transplantation (HSCT) and gene therapy. The registry provides valuable information to clinicians, researchers, service commissioners and industry alike on PID within the United Kingdom, which may not otherwise be available without the existence of a well-established registry.

Bronchiectasis and deteriorating lung function in agammaglobulinaemia despite immunoglobulin replacement therapy.

Immunoglobulin replacement therapy enhances survival and reduces infection risk in patients with agammaglobulinaemia. We hypothesized that despite regular immunoglobulin therapy, some patients will experience ongoing respiratory infections and develop progressive bronchiectasis with deteriorating lung function. One hundred and thirty-nine (70%) of 199 patients aged 1-80 years from nine cities in the United Kingdom with agammaglobulinaemia currently listed on the UK Primary Immune Deficiency (UKPID) registry were recruited into this retrospective case study and their clinical and laboratory features analysed; 94% were male, 78% of whom had Bruton tyrosine kinase (BTK) gene mutations. All patients were on immunoglobulin replacement therapy and 52% had commenced therapy by the time they were 2 years old. Sixty per cent were also taking prophylactic oral antibiotics; 56% of patients had radiological evidence of bronchiectasis, which developed between the ages of 7 and 45 years. Multivariate analysis showed that three factors were associated significantly with bronchiectasis: reaching 18 years old [relative risk (RR) = 14·2, 95% confidence interval (CI) = 2·7-74·6], history of pneumonia (RR = 3·9, 95% CI = 1·1-13·8) and intravenous immunoglobulin (IVIG) rather than subcutaneous immunoglobulin (SCIG) = (RR = 3·5, 95% CI = 1·2-10·1), while starting immunoglobulin replacement after reaching 2 years of age, gender and recent serum IgG concentration were not associated significantly. Independent of age, patients with bronchiectasis had significantly poorer lung function [predicted forced expiratory volume in 1 s 74% (50-91)] than those without this complication [92% (84-101)] (P < 0·001). We conclude that despite immunoglobulin replacement therapy, many patients with agammaglobulinaemia can develop chronic lung disease and progressive impairment of lung function.

Antibody deficiency in Rubinstein-Taybi syndrome.

The developmental disorder Rubinstein-Taybi syndrome (RTS) is frequently complicated by recurrent respiratory infections. In many cases this is likely to be the result of microaspiration or gastro-oesophageal reflux but, in a proportion, underlying antibody deficiency is a potentially modifiable susceptibility factor for infection. Relatively subtle, specific defects of pneumococcal antibody production have previously been described in the context of RTS. Here, we report a rare association between the syndrome and an overt, major primary antibody deficiency disorder (common variable immune deficiency) which was successfully managed with immunoglobulin replacement therapy. Early recognition and investigation for antibody deficiency associated with RTS allied to effective and optimized treatment are essential to minimize morbidity and mortality and improve quality and duration of life.

T cell participation in autoreactivity to NC16a epitopes in bullous pemphigoid.

Bullous pemphigoid is a blistering skin disease characterized by autoantibodies against the NC16a domain of bullous pemphigoid 180. This study was performed to characterize and map the fine specificity of T cell responses to NC16a. Peripheral blood mononuclear cells (PBMC) from a total of 28 bullous pemphigoid patients and 14 matched controls were tested for proliferative and cytokine responses to recombinant NC16a and a complete panel of 21 overlapping peptides spanning this region of BP180. Proliferative responses to NC16A and the peptide panel in the patients with active disease were similar in frequency and magnitude to those in healthy donors, and included late responses typical of naive cells in approximately 60% of each group. Interleukin (IL)-4 responses were slightly stronger for six peptides, and significantly stronger for Nc16a, in patients than in controls. Factor analysis identified factors that separate responses to the peptide panel discretely into IL-4, T helper type 2 (Th2) pattern, interferon (IFN)-γ, Th1 pattern and IL-10 or transforming growth factor [TGF-ß, regulatory T cell (Treg )] pattern. Factors segregating IL-10 versus IFN-γ were predicted by active blistering or remission, and TGF-ß or IL-10 versus IFN-γ by age. Finally, we confirmed a significant up-regulation of IgE responses to BP180 in the patients with pemphigoid. This shows the complexity of T cell phenotype and fine autoreactive specificity in responses to NC16A, in patients and in normal controls. Important disease-associated factors determine the balance of cytokine responses. Of these, specific IL-4 and IgE responses show the strongest associations with pemphigoid, pointing to an important contribution by Th2 cytokines to pathogenesis.

The United Kingdom Primary Immune Deficiency (UKPID) Registry: report of the first 4 years' activity 2008-2012.

This report summarizes the establishment of the first national online registry of primary immune deficency in the United Kingdom, the United Kingdom Primary Immunodeficiency (UKPID Registry). This UKPID Registry is based on the European Society for Immune Deficiency (ESID) registry platform, hosted on servers at the Royal Free site of University College, London. It is accessible to users through the website of the United Kingdom Primary Immunodeficiency Network (www.ukpin.org.uk). Twenty-seven centres in the United Kingdom are actively contributing data, with an additional nine centres completing their ethical and governance approvals to participate. This indicates that 36 of 38 (95%) of recognized centres in the United Kingdom have engaged with this project. To date, 2229 patients have been enrolled, with a notable increasing rate of recruitment in the past 12 months. Data are presented on the range of diagnoses recorded, estimated minimum disease prevalence, geographical distribution of patients across the United Kingdom, age at presentation, diagnostic delay, treatment modalities used and evidence of their monitoring and effectiveness.

Antibody deficiency.

Antibody deficiencies may arise as primary disorders or secondary to a variety of diseases, drugs and other environmental/iatrogenic factors. Significant primary antibody deficiencies are relatively rare but, collectively, account for the majority of primary immunodeficiency syndromes encountered in clinical practice. The genetic basis of a number of primary deficiencies has been clarified, although there is considerable genotype/phenotype heterogeneity and the role of gene/environment interactions has yet to be fully elucidated. Primary antibody deficiency can present at any age. The hallmark clinical presentation is recurrent bacterial infection, but these disorders are also associated with a wide variety of other infectious and non-infectious complications and with a high incidence of chronic, structural tissue damage, particularly in the respiratory tract. Clinical recognition of primary antibody deficiency is frequently delayed with consequent increased morbidity, diminished quality of life and early mortality. Clinical laboratories can contribute to improved and timely detection through awareness of routine test results which may be overtly or indirectly suggestive of antibody deficiency. Secondary deficiency is associated with increased awareness, better recognition and earlier diagnosis than in primary disorders. Early liaison and referral of patients with suspected antibody deficiency for specialist opinion and prompt, appropriate therapy is central to the achievement of good clinical outcomes.

Best practice in primary care pathology: review 6.

This sixth best practice review examines four series of common primary care questions in laboratory medicine: (1) laboratory monitoring in hypertension and heart failure abnormalities; (2) markers of inflammatory joint disease; (3) laboratory investigation of chronic diarrhoea; and (4) mumps and chickenpox. The review is presented in question-answer format, referenced for each question series. The recommendations represent a precis of guidance found using a standardised literature search of national and international guidance notes, consensus statements, health policy documents and evidence-based medicine reviews, supplemented by Medline Embase searches to identify relevant primary research documents. They are not standards but form a guide to be set in the clinical context. Most are consensus based rather than evidence based. They will be updated periodically to take account of new information.

Survey of clinical allergy services provided by clinical immunologists in the UK.

BACKGROUND: The UK National Health Service is failing to meet the need for diagnosis and treatment of allergic disorders, which are common and increasing in prevalence. The House of Commons select committee report on allergy services highlighted the inequalities and urgent need for investment. AIM: To survey the allergy workload provided by clinical immunologists to inform service planning and resource allocation. METHODS: The allergy services performed by clinical immunologists during a 12 month period from 1 April 2003 to 31 March 2004 were surveyed by means of a questionnaire via supra-regional audit groups. RESULTS: The immunology centres surveyed serve 32 million people and offer almost the complete repertoire of a specialised allergy service. There were large variations in clinic capacity, new referrals, appointment duration, and service configuration. Services were largely consultant delivered, but availability of joint clinics with paediatricians and anaesthetists was locally variable. Novel service delivery models utilising nurses and clinical assistants have been developed and merit further investigation. CONCLUSION: Consultant immunologists and trainees currently make a major contribution to the development and provision of specialised allergy services. Consultant immunologists will probably remain key providers of tertiary level allergy care in the UK in the long term (in line with other countries) and will be pivotal in supporting and developing the provision of equitable national access to specialist allergy services in a timely manner. Rapid progress in developing the new specialty of allergy and securing better access to services for patients in the short term will be best served by strengthening the collaborative relationship between allergists and clinical immunologists.

Annual incidence and mortality of bullous pemphigoid in the Grampian Region of North-east Scotland.

BACKGROUND: Data on the annual incidence of bullous pemphigoid (BP) in the U.K. are scarce. OBJECTIVES: To estimate the annual incidence of BP in Grampian Region (North-east Scotland) and to assess the causes of mortality in this cohort of patients. METHODS: Details were obtained of all patients with a diagnosis of BP recorded in the database of the Pathology Department, Aberdeen Royal Infirmary between January 1991 and December 2001. Community Health Index population data were obtained from the Grampian Health Board and the annual incidence and age- and sex-specific incidence were calculated. Mortality data were obtained from the Patient Administration System and causes of death obtained from the Office of the Registrar for Births and Deaths for Scotland. RESULTS: Eighty-three patients met criteria for diagnosis of BP. The annual incidence of BP in Grampian region was estimated to be 14 cases per million per year. There was a clear and marked rise in the incidence in patients over the age of 80 years. Forty-eight per cent of patients with BP died within 2 years of diagnosis. The all-cause age-standardized mortality ratio was 576%. When compared with cause-specific mortality in the Grampian population over 60 years of age, respiratory disease accounted for a higher than expected number of deaths in our cohort of patients with BP (odds ratio 5.3, 95% confidence interval 3.0-9.4). CONCLUSIONS: North-east Scotland appears to have a relatively high incidence of BP when compared with incidence rates in continental Europe. The mortality rate in patients with BP is considerable, especially within the first 2 years of diagnosis.

Subacute cutaneous lupus erythematosus associated with phenytoin.

Subacute cutaneous lupus erythematosus is a well recognized subset of systemic lupus erythematosus. It is characterized by a nonscarring, papulosquamous or annular eruption in a photosensitive distribution. Several cases, thought to be caused by drugs, have been reported. We report a case of subacute cutaneous lupus erythematosus caused by phenytoin, which has not previously been associated with this condition.

Humoral immunity and bronchiectasis.

Bronchiectasis is a common complication of primary antibody deficiency but the incidence of antibody deficiency as an underlying cause of bronchiectasis is largely undefined. In this study the humoral immune status of a cohort of bronchiectatic patients was investigated to detect the frequency of significant antibody deficiency and to determine the extent of immunological investigation which is appropriate for routine assessment of bronchiectasis patients. Fifty-six out-patients (with a mean age of 59.6 years) had serum immunoglobulins, IgG subclasses and specific antibodies to capsular polysaccharides of Haemophilus influenzae and Streptococcus pneumoniae measured. Where specific antibody -levels were low, where possible, appropriate immunization with pneumococcal or conjugated Haemophilus polysaccharide vaccines was offered and the responses quantified. Three of 56 patients had low total serum IgG levels. Thirteen of 56 had deficiencies of either a single IgG subclass or combinations of two or more subclasses, with IgG4 being most frequently implicated (9/56). Twenty-nine of 56 had low basal specific polysaccharide antibody levels. Test immunization, where performed, produced satisfactory responses in all cases except one, where a specific defect of responsiveness to pneumococcal polysaccharide was identified. This study indicates that antibody deficiency is an uncommon aetiological/underlying factor in the causation of bronchiectasis beyond the fourth decade and that detailed investigation of humoral immune status as a routine in bronchiectasis patients, at least at this age, is not generally justified.

Effect of combination therapy on immunologic progression of human immunodeficiency virus at a population level.

There is accumulating evidence from clinical trials and cohort studies that highly active antiretroviral combination therapy is effective at halting immunologic and clinical progression of human immunodeficiency virus (HIV). Its impact at a population level is less well known because the regimes may be difficult to tolerate and compliance poorer. The authors make use of population data for almost all of the HIV-infected people in Scotland in 1997 who were under clinical care and monitor their response to therapy during the first year when these effective treatments became widely available. More than two thirds of the HIV-positive patients were on some form of antiretroviral therapy during the year. The authors show that all treated groups, even those who were on changing regimes, showed net improvement in immunologic status during the year. For the group of patients on triple or quadruple therapy, there was an average increase of more than 100 CD4 cells/mm(3) over the year, with other treatment groups showing more modest, but significant, increases.

Bilateral hand oedema related to acupuncture.

We report the case of bilateral hand swelling following acupuncture therapy for chronic low back pain. Despite thorough history, examination and laboratory testing no systemic cause for the swelling could be elicited. This case highlights the incomplete knowledge of acupuncture mechanisms and that limited acupuncture therapy can have significant adverse effects.

Fine needle aspiration cytology in the investigation on non-Hodgkin's lymphoma.

AIMS: To assess the value of flow cytometry (FCM) in the diagnosis and classification of reactive lymphoid hyperplasia and malignant lymphoma by fine needle aspiration (FNA) cytology. METHODS: Forty six fine needle aspirates of lymphoproliferative disorders were examined by FCM as well as routine cytological assessment. An immunoglobulin light chain ratio (LCR) was calculated for clonality analysis. Additional immunophenotyping was performed in 15 cases. RESULTS: All 25 cases of reactive lymphoid hyperplasia were polyclonal by FCM (LCR < 2/1); 17 of 20 cases of B cell non-Hodgkin's lymphoma were monoclonal (LCR > 3/1). Analysis of cells based on size facilitated detection of small populations of clonal neoplastic cells. Analysis of CD5, CD10, and CD23 expression by FCM facilitated subclassification of mantle cell lymphoma, small lymphocytic lymphoma, and some lymphomas of follicle centre cell origin. One case of T cell non-Hodgkin's lymphoma was correctly classified by FCM. CONCLUSIONS: FNA cytology is a reliable method for investigation of lymphoproliferative disorders. Although excision biopsy and histopathological examination remain the gold standard for primary diagnosis and classification of non-Hodgkin's lymphoma, FNA cytology with clonality analysis and immunophenotyping by FCM is useful for distinguishing reactive from neoplastic lymphoid populations, and can facilitate lymphoma classification.

Detection of nitric oxide and nitric oxide synthases in psoriasis.

Biopsies from psoriasis lesions and clinically uninvolved skin of eight patients and five normal subjects were studied by immunocytochemistry with computerized image analysis for the presence of endothelial, neuronal and inducible isoforms of nitric oxide synthase. Endothelial nitric oxide synthase was expressed in the endothelium and weakly in some keratinoctyes. Its expression was not significantly different in psoriasis. Inducible nitric oxide synthase, however, was absent from normal skin but was significantly upregulated in psoriatic lesional skin, focally in keratinocytes but to the greatest extent in the papillary dermis and to a lesser extent in clinically uninvolved psoriatic skin. Inducible nitric oxide synthase staining was greatest in the more severe lesions and correlated with the inflammatory infiltrate (CD3-positive cells) and with keratinocyte proliferation (Ki-67-positive cells). In normal skin, neuronal nitric oxide synthase was expressed only in keratinocytes in the granular layer and eccrine sweat glands. However, in psoriasis and clinically uninvolved skin the neuronal form was present through all levels of the epidermis. Direct measurement of nitric oxide production from the skin surface revealed a tenfold increase in the lesions of 16 psoriatic patients compared with their nonlesional skin, and this nitric oxide production was inhibited by topical betamethasone.