ICPC-2--international classification of primary health care and its application in Croatian health care

A consensus reached by the medical profession, Croatian Institute of Health Insurance, Croatian Institute of Public Health, and Ministry of Health constitutes a solution to the problem of a data standard required in building an information system for primary health care. This consists of accepting ICPC-2 as a data standard for our Family Medicine, Pediatrics and Women's Health. The classification structure of the International Classification of Primary Care allows, recommends and urges that special codes be established by individual states or local authorities when registering patients' reasons for seeking medical aid or medical procedures. Namely, it urges the authorities to set the codes for such reasons about which a state or local agreement or determination has been made. This is the first public presentation of the proposal Croatia's Additions to the International Classification of Primary Care. They are essential to its implementation in our health insurance, health statistics and medical informatics.     

SARS-CoV-2 Vaccine Responses in Individuals with Antibody Deficiency: Findings from the COV-AD Study

Background

Vaccination prevents severe morbidity and mortality from COVID-19 in the general population. The immunogenicity and efficacy of SARS-CoV-2 vaccines in patients with antibody deficiency is poorly understood.

Objectives

COVID-19 in patients with antibody deficiency (COV-AD) is a multi-site UK study that aims to determine the immune response to SARS-CoV-2 infection and vaccination in patients with primary or secondary antibody deficiency, a population that suffers from severe and recurrent infection and does not respond well to vaccination.

Methods

Individuals on immunoglobulin replacement therapy or with an IgG less than 4 g/L receiving antibiotic prophylaxis were recruited from April 2021. Serological and cellular responses were determined using ELISA, live-virus neutralisation and interferon gamma release assays. SARS-CoV-2 infection and clearance were determined by PCR from serial nasopharyngeal swabs.

Results

A total of 5.6% (n?=?320) of the cohort reported prior SARS-CoV-2 infection, but only 0.3% remained PCR positive on study entry. Seropositivity, following two doses of SARS-CoV-2 vaccination, was 54.8% (n?=?168) compared with 100% of healthy controls (n?=?205). The magnitude of the antibody response and its neutralising capacity were both significantly reduced compared to controls. Participants vaccinated with the Pfizer/BioNTech vaccine were more likely to be seropositive (65.7% vs. 48.0%, p?=?0.03) and have higher antibody levels compared with the AstraZeneca vaccine (IgGAM ratio 3.73 vs. 2.39, p?=?0.0003). T cell responses post vaccination was demonstrable in 46.2% of participants and were associated with better antibody responses but there was no difference between the two vaccines. Eleven vaccine-breakthrough infections have occurred to date, 10 of them in recipients of the AstraZeneca vaccine.

Conclusion

SARS-CoV-2 vaccines demonstrate reduced immunogenicity in patients with antibody deficiency with evidence of vaccine breakthrough infection.

     

The NLR network and the immunological disease continuum of adaptive and innate immune-mediated inflammation against self

The nucleotide-binding domain, leucine-rich repeat containing family (NLR) network has provided pivotal genetic and molecular insights into diseases that were hitherto regarded as autoimmune. The NLR-related disorders include rare monogenic autoinflammatory diseases collectively termed cryopyrin-associated periodic syndromes, Crohn's disease which is a common polygenic disease and also an association at the mechanistic level with gout and pseudogout. Unlike the classical autoimmune diseases where disease immunopathogenesis is played out primarily in the primary and secondary lymphoid organs, the immunopathogenesis of the NLR-related disorders is played out in the tissues where inflammation arises. As the genetic mutations or molecular cascades associated with the NLR-related disorders have a widespread cellular distribution, it has been somewhat enigmatic why these disorders attack certain territories, but not others. This implies that tissue-specific factors in the target organs themselves contribute to disease expression. Such examples include the high abundance of NOD2 expressing cells in the part of the gut most typically afflicted by Crohn's disease and the preferential deposition of crystals in the joints to where inflammation localises in gout and pseudogout. The NLR network is associated principally with increases in TNF or IL-1 production, both of which are key players in innate immunity. Therefore, the NLR network identifies at the genetic and molecular level a robust paradigm for innate immune activation against self. This tissue-specific-factor-associated inflammation is the diametric opposite of classical autoimmunity. Of note, the MHC class-I-associated diseases including psoriasis (HLA-Cw6) and ankylosing spondylitis (HLA-B27) show striking clinical overlaps with Crohn's disease and also some rare monogenic diseases. Thus, the NLR innate immune pathway allows the full spectrum of inflammation against self to be viewed along an immunological disease continuum with autoantibody-associated disease at one end, innate immune diseases at the other and MHC class-1-related disorders as an intermediate.     

Assessment of reliability endometrial brush cytology in detection etiology of late postmenopausal bleedings

We evaluated the possibility of discovering bleeding causes in late postmenopausal period with cytological examination of material received by endometrial brush in comparison with Pap test and fractionated curettage. Sixty-two women in late postmenopausal period with cervical canal bleeding, treated in gynecological department of clinical hospital in Osijek, were cytological and histological processed. Final diagnosis in 29 from 62 (46.8%) women with late postmenopausal bleeding was cancer. 25 (40.3%) women had endometrial adenocarcinoma and 4 (6.5%) of them had squamous endocervical carcinoma. Two women had endometrial precancerous (3.2%). With Pap test accurate diagnosis was set up in 13 from 25 (52.0%) women with endometrial adenocarcinoma and in all of them with squamous endocervical carcinoma. With endometrial brush accurate diagnosis was set up in 14 from 25 (56.0%) women with endometrial adenocarcinoma and in 3 from 4 (75.0%) women with squamous endocervical carcinoma. With fractional curettage the diagnosis of endometrial adenocarcinoma was accurately correct in 21 from 25 (84.0%) women and in all of them with squamous endocervical carcinoma. Cytological examination of material derived with endometrial brush, alike vaginal cytology, is not enough reliable method in our conditions for discovering bleeding causes in late postmenopausal period. Diagnostic exactness of procedure could be increased by histopathological examination of material from endometrial brush procedure and with ultrasound evaluation of endometrium thickness.An erratum to this article can be found at     

17O magnetic resonance imaging of the human brain

Here we show the first example of in vivo oxygen-17 (17O) magnetic resonance imaging of the human in natural abundance. Two-dimensional fast multi-planar gradient recalled 90 deg echo (FMPGR/90) pulse sequence and three-dimensional projection reconstruction pulse sequence methods were used.     

Laser-induced mouse model of chronic ocular hypertension

PURPOSE. To develop an inducible mouse model of glaucoma. METHODS. An obstruction of aqueous humor outflow in adult C57BL6/J mice was induced by combined injection of indocyanine green (ICG) dye into the anterior chamber and diode laser treatment. To evaluate intraocular pressure (IOP), tonometry was performed with a modified Goldmann tonometer. The function of the retina was evaluated with electroretinography (ERG). RESULTS. IOP was significantly elevated in surgical eyes compared with control eyes: before surgery, 15.2 +/- 0.6 mm Hg; 10 days after surgery, 33.6 +/- 1.5 mm Hg (P < 0.001); and 30 days after surgery, 27.4 +/- 1.2 mm Hg (P < 0.001). However, 60 days after surgery, IOP in the surgical eyes decreased to 19.5 +/- 0.9 mm Hg and was not significantly different compared with control eyes (control, 17.3 +/- 0.7 mm Hg; P = 0.053). ERG amplitudes, expressed as a ratio (surgical/control), were decreased in surgical eyes. The amplitudes for b-wave were: before surgery, 107.6% +/- 4.6%; 28 days after surgery, 61% +/- 4% (P < 0.001); and 56 days after surgery, 62% +/- 5.6% (P < 0.001). Oscillatory potentials were the most dramatically affected: before surgery, 108.6% +/- 6.7%; 28 days after surgery, 57.5% +/- 5% (P < 0.01); and 56 days after surgery, 57% +/- 8.5% (P < 0.001). Amplitudes of the a-waves had relatively smaller but still significant deficits: before surgery, 105.8% +/- 6.9%; 28 days after surgery, 72.2% +/- 5.4% (P < 0.01); and 56 days after surgery, 79.8% +/- 11.0% (P < 0.01). Histologic analysis of the surgical eyes revealed development of anterior synechia, loss of retinal ganglion cells (RGCs), and thinning of all retinal layers. Electron microscopy of optic nerve cross sections revealed swelling and degeneration of the large diameter axons and gliosis. CONCLUSIONS. Diode laser treatment of ICG saturated episcleral veins causes a chronic elevation of IOP and sustained ERG deficits.     

Hyperbaric oxygen in the treatment of sudden hearing loss

Treatment of idiopathic sudden hearing loss (SHL) is still a great problem for the physicians, due to the still unexplained etiopathogenesis of the disease. This retrospective study includes 115 patients with idiopathic SHL and compares two therapy regimens. Of the total number of patients, 51 had been primarily treated by hyperbaric oxygen (HBO) at 2.8 bar. The remaining 64 patients had been treated by pentoxifylline infusions in increasing and decreasing doses. Hearing thresholds were ascertained at the frequencies of 250, 500, 1,000, 2,000 and 4,000 Hz using pure-tone audiometry. The results after treatment showed a statistically significant improvement of hearing by 46.35 (SD +/-18.58) dB hearing level (HL) in the group of patients treated with HBO, compared with an improvement of hearing by 21.48 dB HL (SD +/-13.5) in the group of patients treated with pentoxifylline infusions (p < 0.001). Furthermore, hearing recovered to physiological values in 24 of 51 (47.1%) HBO-treated patients, compared to only 4 of 64 (6.2%) of the pentoxifylline-treated patients. Furthermore, after pentoxifylline treatment only 8/64 (12.5%) patients showed partial recovery, whereas after HBO therapy 21/51 (41.2%) patients improved up to a mild persistent hearing loss. This indicates strong evidence that HBO therapy is more effective in the treatment of idiopathic SHL than conventional rheological treatment. However, more prospective clinical trials should confirm the efficiency of HBO therapy and lead to its wider application.     

The calcified ascending aorta in aortocoronary bypass

Heavily calcified ascending aorta significantly increased morbidity and lethality during open-heart surgery. Cannulation and clamping (partial or total) of severely atherosclerotic ascending aorta can easily cause damage and rupture of aortic wall, with consequential distal (often fatal) embolization with atheromatous debris (brain, myocardium). From June 1998. until June 2000, 11 of 2,136 (0.5%) patients who underwent coronary artery bypass grafting were with the severe atheromatous ascending aorta. The site of cannulation was in the aortic arch in three patients (aorta was occluded with Foley catheter in one case, and single clamp technique was used in the other two cases). The femoral artery was the cannulation site in other five cases. Profound hypothermia, ventricular fibrillation, and circulatory arrest, with no cross-clamping or cardioplegia, were used in three patients. Two patients were operated on with extracorporeal circulation, one in normothermia, on the beating heart, the other in moderate hypothermia, on fibrillating heart. In three patients myocardial revascularization was performed on the beating heart, in normothermia, without extracorporeal circulation. Postoperative course was uneventful in all 11 patients. Neither atheroembolism in the peripheral organs, nor atheroembolism of the extremities occurred. The proposed surgical approaches have the potential to reduce the prevalence of stroke and systemic embolization associated with coronary artery bypass grafting in patients with heavily calcified ascending aorta. This result was achieved due to the applied modifications of standard cardiosurgical technique.     

A High-Throughput Amplicon Screen for Somatic UBA1 Variants in Cytopenic and Giant Cell Arteritis Cohorts

Journal of Clinical Immunology -     

Mechanistic immunological based classification of rheumatoid arthritis

The classical autoimmunity paradigm in rheumatoid arthritis (RA) is strongly supported by immunogenetics suggesting follicular helper T-cell responses driving high titre specific autoantibodies that pre-dates disease onset. Using the immunological disease continuum model of inflammation against self with “pure” adaptive and innate immune disease at opposite boundaries, we propose a novel immune mechanistic classification describing the heterogeneity within RA. Mutations or SNPs in autoinflammatory genes including MEFV and NOD2 are linked to seronegative RA phenotypes including some so called palindromic RA cases. However, just as innate and adaptive immunity are closely functionally integrated, some ACPA+ RA cases have superimposed “autoinflammatory” features including abrupt onset attacks, severe attacks, self-limiting attacks, relevant autoinflammatory mutations or SNPs and therapeutic responses to autoinflammatory pathway therapies including colchicine and IL-1 pathway blockade. An emergent feature from this classification that non-destructive RA phenotypes, both innate and adaptive, have disease epicentres situated in the extracapsular tissues. This mixed innate and adaptive immunopathogenesis may be the key to understanding severe disease flares, resistant disease subsets that are unresponsive to standard therapy and for therapies that target the autoinflammatory component of disease that are not currently considered by expert therapeutic recommendations.