Quantifying the risk of SARS-CoV-2 reinfection over time.

Despite over 140 million SARS-CoV-2 infections worldwide since the beginning of the pandemic, relatively few confirmed cases of SARS-CoV-2 reinfection have been reported. While immunity from SARS-CoV-2 infection is probable, at least in the short term, few studies have quantified the reinfection risk. To our knowledge, this is the first systematic review to synthesise the evidence on the risk of SARS-CoV-2 reinfection over time. A standardised protocol was employed, based on Cochrane methodology. Electronic databases and preprint servers were searched from 1 January 2020 to 19 February 2021. Eleven large cohort studies were identified that estimated the risk of SARS-CoV-2 reinfection over time, including three that enrolled healthcare workers and two that enrolled residents and staff of elderly care homes. Across studies, the total number of PCR-positive or antibody-positive participants at baseline was 615,777, and the maximum duration of follow-up was more than 10 months in three studies. Reinfection was an uncommon event (absolute rate 0%-1.1%), with no study reporting an increase in the risk of reinfection over time. Only one study estimated the population-level risk of reinfection based on whole genome sequencing in a subset of patients; the estimated risk was low (0.1% [95% CI: 0.08-0.11%]) with no evidence of waning immunity for up to 7 months following primary infection. These data suggest that naturally acquired SARS-CoV-2 immunity does not wane for at least 10 months post-infection. However, the applicability of these studies to new variants or to vaccine-induced immunity remains uncertain.

Risk stratification through allergy history: single-centre experience of specialized COVID-19 vaccine clinic.

Anaphylaxis is a rare side-effect of COVID-19 vaccines. To (a) provide direct advice and reassurance to certain persons with a history of anaphylaxis/complex allergy, in addition to that available in national guidelines, and (b) to provide a medically supervised vaccination, a specialist regional vaccine allergy clinic was established. The main objective was to determine if risk stratification through history can lead to safe COVID-19 vaccination for maximum population coverage. A focused history was taken to establish contraindications to giving COVID-19 vaccines. People who reported a high-risk allergy history were given a vaccine not containing the excipient thought to have directly caused previous anaphylaxis. All vaccines were monitored for 30 min after administration. A total of 206 people were vaccinated between 6 July 2021 and 31 August 2021; Comirnaty (Pfizer-BioNTech) (n = 34), and Janssen (n = 172). In total, 78% were women. Ninety-two people (45%) reported a high-risk allergy history. There were no cases of anaphylaxis. Three people developed urticaria and one of these also developed transient tachycardia. One vaccinee developed a pseudoseizure. Two of 208 people (<1%) referred during this time declined vaccination based on personal preference, despite the assessment of low clinical risk. In our experience, all vaccines with high-risk allergy histories were administered Pfizer BioNTech or Janssen Covid-19 vaccines uneventfully following screening based on allergy-focussed history. Our data support that drug allergy is not associated with a higher risk of vaccine-related anaphylaxis but may act to guide the administration of alternate vaccines to people with polyethylene glycol/polysorbate 80/trometamol allergies or anaphylaxis after the first dose.

The Study to Investigate COVID-19 Infection in People Living in Ireland (SCOPI): A seroprevalence study, June to July 2020.

BackgroundRobust data on SARS-CoV-2 population seroprevalence supplement surveillance data in providing evidence for public health action.AimTo conduct a SARS-CoV-2 population-based seroprevalence survey in Ireland.MethodsUsing a cross-sectional study design, we selected population samples from individuals aged 12-69 years in counties Dublin and Sligo using the Health Service Executive Primary Care Reimbursement Service database as a sampling frame. Samples were selected with probability proportional to the general population age-sex distribution, and by simple random sampling within age-sex strata. Antibodies to SARS-CoV-2 were detected using the Abbott Architect SARS-CoV-2 IgG Assay and confirmed using the Wantai Assay. We estimated the population SARS-CoV-2 seroprevalence weighted for age, sex and geographic area.ResultsParticipation rates were 30% (913/3,043) and 44% (820/1,863) in Dublin and Sligo. Thirty-three specimens had detectable SARS-CoV-2 antibodies (1.9%). We estimated weighted seroprevalences of 3.12% (95% confidence interval (CI): 2.05-4.53) and 0.58% (95% CI: 0.18-1.38) for Dublin and Sligo, and 1.69% (95% CI: 1.13-2.41) nationally. This equates to an estimated 59,482 (95% CI: 39,772-85,176) people aged 12-69 years nationally having had infection with SARS-CoV-2, 3.0 (95% CI: 2.0-4.3) times higher than confirmed notifications. Ten participants reported a previous laboratory-confirmed SARS-CoV-2 -infection; eight of these were antibody-positive. Twenty-five antibody-positive participants had not reported previous laboratory-confirmed infection.ConclusionThe majority of people in Ireland are unlikely to have been infected with SARS-CoV-2 by June-July 2020. Non-pharmaceutical public health measures remained key pending widespread availability of vaccination, and effective treatments.

Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study.

Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.

The Irish living kidney donor program - why potential donors do not proceed to live kidney donation?

BACKGROUND: Living donation is not only a method to increase access to kidney transplantation but can also offer superior outcomes. We report the experience of the living donor (LD) program in the Republic of Ireland and explore reasons why potential donors do not proceed to live donation. METHODS: Retrospective cohort study of all potential donors from January 2000 to March 2014 who presented wishing to undergo donor work-up and their subsequent outcomes. RESULTS: A total of 956 donors for 496 recipients contacted the live kidney donation program of which 883 potential donors proceeded to the initial stage of assessment. The donor dropout rate at this stage was 64.2% (614/956 potential donors did not proceed to further evaluation). Thereafter, 269 (28.1%) donors underwent further assessment by the multidisciplinary team. In total, 93 (9.7%) donors were declined following this assessment with 176 (18.4%) donors ultimately proceeding to live kidney donation. The major reason for declining a donor was a medical contraindication (n = 63, 67.7%). In term of recipients, 54.2% (n = 269/496) had a potential donor proceed for further assessment of which 65.4% (n = 176/269) ultimately proceeding to live donation. CONCLUSION: Further evaluation of the declined donor group is warranted to allow for expansion of the LD program.

Whole Body MRI in the Staging of Esophageal Cancer--A Prospective Comparison with Whole Body 18F-FDG PET-CT.

BACKGROUND: Positron emission tomography and computed tomography (PET-CT) is established in the staging of esophageal cancer. In this study, an MRI protocol was designed to emulate the anatomical (T1-weighed (T1W) and T2W imaging) and functional information (diffusion-weighted imaging) provided by PET-CT. METHODS: In all, 49 patients with carcinoma of the esophagus underwent PET-CT and whole-body MRI (WBMRI). WBMRI was carried out using dedicated sequences tailored to detect metastatic disease at each area corresponding to the anatomical coverage of PET-CT. Nodal status was determined from histopathology and endoscopic ultrasound biopsy (EUS). RESULTS: PET-CT and WBMRI identified the primary tumor in 46/49 (94%) and 48/49 (98%) patients, respectively. Nodal analysis in patients undergoing surgery (n = 18) yielded sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of 27, 100, 100, 47 and 56% for PET-CT, compared with 30, 100, 100, 53 and 61% for WBMRI. When nodal analysis included both surgical specimens and EUS criteria (n = 39), sensitivity, specificity, PPV, NPV and accuracy were 46, 91, 93, 40 and 59% for PET-CT compared with 59, 92, 94, 50 and 67% for WBMRI. Both imaging modalities identified distant metastases in 2 patients. CONCLUSION: WBMRI has similar accuracy to PET-CT in detecting the primary tumor, nodal deposits and for exclusion of systemic metastatic disease.

18F-FDG-PET/CT is of limited value in primary staging of early stage cervical cancer.

PURPOSE: To assess the clinical benefit of 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG-PET/CT) in evaluating pelvic lymph nodes in patients with early stage cervical cancer (FIGO stage 1a­1b1), who have magnetic resonance imaging (MRI)-defined lymph node negative disease, with histopathologic results as the reference standard. MATERIALS AND METHODS: We assessed one hundred and seventy nine sequential 18F-FDG-PET/CT scans in women with newly diagnosed cervical carcinoma between January 2009 and September 2011. 47 of these patients had early stage disease (FIGO stage 1a­1b1) with no suspicious lymph nodes on MRI. 18F-FDG-PET/CT images were analyzed and histopathological findings (pelvic lymph node resection) served as the reference standard. RESULTS: The median age of patients was 48 (range 22­86) years. 66 % had squamous histotype. Median number of nodes dissected per patient was 21 (range 8­47), 2 of 47 patients had nodal metastases (4.25 %). All patients in this group had no suspicious lymph nodes on 18F-FDG-PET/CT. Overall patient based sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 18F-FDG-PET/CT for detection of nodal disease were 0 %, 100 %, 0 %, 96 %, and 96 % respectively. CONCLUSION: Pathologic validation of 18F-FDG-PET/CT imaging demonstrates little value for 18F-FDG-PET/CT in patients with early stage (FIGO stage 1a­1b1) MRI-defined lymph node negative cervical carcinoma. Since the likelihood of metastatic nodal disease is very low in women with stage 1a­1b1 cervical cancer, we believe that 18F-FDG-PET/CT should not have a role in the routine pre-treatment evaluation of these women.

A genome-wide association study of recipient genotype and medium-term kidney allograft function.

BACKGROUND: We examined, through genome-wide association studies (GWAS), the correlation between recipient genetic variation and renal function at five yr. METHODS: Our cohort contained 326 Irish, first time, kidney-only, deceased donor, transplant recipients on calcineurin inhibitors (263 had a functioning graft at five yr) between 1993 and 2002. Outcomes were creatinine at five yr and long-term graft function. RESULTS: Two variants were identified showing borderline genome-wide significance - one on chromosome 18 (p = 4.048e-08, rs6565887) and another on chromosome 14 (p = 7.631e-08, rs3811321). Individually, the two SNPs explained up to 8.8% and 11.29% of five-yr creatinine variance, respectively, while together they explained up to 17.4% of trait variance. Both variants were predictors of long-term allograft function (p = 0.004, 70% vs 30% survival at 10 yr). The chromosome 14 variant is located in the intergenic region of the T-Cell Receptor Alpha locus. CONCLUSIONS: Using a genome-wide approach, we have identified two associations with five-yr creatinine levels in renal transplant recipients treated with calcineurin inhibitors. Independent replication is now warranted to clarify the clinical significance of these results.

Core curriculum in pathology for future Irish medical students.

Pathology is important in training to become a medical doctor but as curricula become more integrated, there is a risk that key aspects of pathology may be excluded. Following a survey of the current delivery of teaching in Ireland under the auspices of the Faculty of Pathology at the Royal College of Physicians of Ireland, suggested components of a core curriculum in pathology have been developed to be delivered at some stage during the medical course. These have been based on key principles and themes required by the Medical Council in Ireland. Professionalism is one of the core principles emphasised by the Medical Council. It includes the role of the pathologist in patient care and other professional values such as patient-centred care, clinical competencies and skills, e.g. explaining results, and knowledge under the various sub-disciplines, i.e. histopathology (including neuropathology), clinical microbiology, haematology, chemical pathology and immunology. In each of these, we suggest key aspects and activities that the medical graduate should be comfortable in carrying out. The methods of delivery of teaching and assessment across pathology disciplines have evolved and adapted to recent circumstances. Lessons have been learned and insights gained during the COVID-19 pandemic as educators have risen to the challenge of continuing to educate medical students. Integrated and multi-disciplinary teaching is recommended to reflect best the professional environment of the medical graduate who works as an integral part of a multi-disciplinary team, with the minimum dependence on the traditional lecture, where at all possible. Finally, options on assessment are discussed, e.g. multiple-choice questions, including their respective advantages and disadvantages.

Anti-NMDA receptor encephalitis: an important differential diagnosis in psychosis.

We present four cases of confirmed anti-NMDA receptor encephalitis; three presented initially with serious psychiatric symptoms and the other developed significant psychiatric symptoms during the initial phase of illness. Brain biopsy findings of one patient are also described. Psychiatrists should consider anti-NMDA receptor encephalitis in patients presenting with psychosis and additional features of dyskinesias, seizures and catatonia, particularly where there is no previous history of psychiatric disorder.

Braak's Unfinished Hypothesis: A Clinicopathological Case Report of α-Synuclein Peripheral Neuropathy Preceding Parkinsonism by 20 Years.

BACKGROUND: α-synuclein aggregates in the form of Lewy bodies and Lewy neurites are the pathological hallmark of Parkinson disease (PD) and dementia with Lewy bodies (DLB). Autopsy studies suggest that α-synuclein aggregates appear in localized areas of the central nervous system before spreading in a sequential pattern from the brainstem to the cerebral cortex, known as the Braak hypothesis. Increased prevalence of peripheral neuropathy in PD is recognized, with multiple hypothesized mechanisms including α-synuclein deposition. METHOD: We describe a patient who developed a peripheral sensory neuropathy at age 60, which progressed insidiously over the following decade. RESULTS: During the patient's eighth decade, the patient developed a fluctuant cognitive disturbance with hallucinations before becoming overtly parkinsonian at age 78 years leading to a diagnosis of DLB. At this point, histology slides from a sural nerve biopsy taken at age 72 were re-evaluated and immunohistochemistry demonstrated α-synuclein deposition. CONCLUSION: This case provides important in vivo clinical correlation for the Braak hypothesis, extending its scope beyond idiopathic PD. A growing body of evidence supports the α-synuclein spreading hypothesis that posits the pathologic process begins in the peripheral nerves and spreads trans-synaptically to the CNS in an ascending pattern.

Magnetic resonance imaging for the evaluation of acute abdominal pain in pregnancy.

The investigation of acute abdominal pain in pregnancy is challenging. The use of ultrasound may be limited due to the patient's change in body habitus and computed tomography is not desirable due to fetal irradiation. Magnetic resonance imaging (MRI) has thus become increasingly popular in the evaluation of such patients, due to its lack of ionizing radiation, multiplanar capability and high contrast resolution. This review will detail the MRI technique required to image the pregnant abdomen and describe the MRI features of common causes of acute abdominal pain in pregnancy.

Constitutional trisomy 8 and Behçet syndrome.

The characteristic clinical features of constitutional trisomy 8 include varying degrees of developmental delay, joint contractures and deep palmar and plantar creases. There is an established literature, which describes features of Behçet syndrome occurring in phenotypically normal individuals with myelodysplastic syndromes and trisomy 8 in their bone marrow. In this article, we describe four patients with constitutional trisomy 8, all with varying clinical phenotypes, who developed features of Behçet, in particular but not exclusively mucocutaneous ulceration. In addition, we examined gene copy numbers of the variable-number neutrophil defensin genes DEFA1A3 in one of the cases (case 1) and her parents, together with 14 cases of Behçet syndrome in comparison with 121 normal controls. The gene copy number was highest in case 1 (copy number 14) and was also increased in her parents (both copy number 9). However the mean copy number for DEFA1A3 among the 14 Behçet syndrome patients was actually lower (5.1) than among the controls (mean of 6.8 copies). Thus, we conclude that patients with constitutional trisomy 8 and those with trisomy 8 confined to the bone marrow are both at increased risk of developing features of Behçet syndrome. The mechanism may relate to increased chromosome 8 gene dosage with further analysis of candidate genes on chromosome 8 required.

The relationship of clinical and inflammatory markers to outcome in stable patients with cystic fibrosis.

Decreased survival in patients with cystic fibrosis has been related to FEV1, BMI, and infection with Burkholderia cepacia complex (BCC). We have assessed the relationship of blood, sputum, and urine inflammatory markers to lung function, BMI, colonization with B cenocepacia (Bc), and patient survival. Thirty-nine stable cystic fibrosis (CF) patients (10 with Bc) were enrolled in a study to determine the effect of alpha-1-antitrypsin on airways inflammation. Pre-treatment measurements were used in this study. Demographics, sputum microbiology, heart rate, oxygen saturation, lung function were recorded. Blood samples were obtained for white blood count (WBC), C-Reactive Protein (CRP), and plasma neutrophil elastase/AAT complexes (pNEC). Neutrophil elastase (NE), neutrophil elastase/AAT complexes (sNEC), interleukin-8 (IL-8), TNF-receptor 1 (sTNFr), and myeloperoxidase (MPO) were measured in sputum and urinary desmosine concentration determined. Patients with Bc had significantly higher levels of pNEC, 332 +/- 91.4 ng/ml (mean +/- SEM) versus 106 +/- 18.2 ng/ml (P = 0.0005) and sNEC, 369 +/- 76.6 ng/ml versus 197 +/- 36.0 ng/ml compared to those who were not. Five deaths were reported at the end of 1 year, (four with Bc) (P = 0.011). Patients who subsequently died had significantly lower lung function FEV1, 1.2 +/- 0.2 L versus 2.0 +/- 0.1 L (P = 0.03) and FVC, 2 +/- 0.3 L versus 3.1 +/- 0.2 L (P = 0.01), compared to those that survived. There was significantly higher NE activity, 3.6 +/- 1.6 U/ml versus 1.5 +/- 0.6 U/ml (P = 0.03), pNEC, 274 +/- 99 ng/ml versus 142 +/- 30 ng/ml (P = 0.05), MPO, 163 +/- 62 mcg/ml versus 54 +/- 6.9 mcg/ml (P = 0.03), and urinary desmosines 108 +/- 19.9 pM/mg creatinine versus 51.1 +/- 3.3 pM/mg creatinine (P = 0.001), in those patients who subsequently died compared to those that survived. These data suggest there is increased neutrophil degranulation in patients infected with Bc and these patients have a poor outcome.

Safety and efficacy of recombinant alpha(1)-antitrypsin therapy in cystic fibrosis.

Neutrophil elastase (NE) is thought to be the most important protease which damages the cystic fibrosis (CF) lung. Attempts have been made to suppress this activity using the plasma-derived inhibitor, alpha(1)-antitrypsin (AAT). In this pilot study, the safety and efficacy of inhaled recombinant human AAT (rAAT) as a treatment for CF were investigated. Thirty-nine patients participated in a prospective, double-blinded, randomized, placebo-controlled phase II trial to examine the effect of rAAT (500, 250, and 125 mg) on sputum NE activity. Sputum myeloperoxidase (MPO), interleukin-8, tumor necrosis factor receptors, sputum and plasma NE/AAT complexes, and safety parameters were also measured. Subjects were randomized to receive nebulized treatment once a day for 4 weeks, followed by 2-4 weeks with no study treatment, and then a 2-week rechallenge phase. Trends toward a reduction in NE activity were observed in patients treated with 500 mg and 250 mg of rAAT compared to placebo. Sputum NE/AAT complex and MPO levels were lower on rAAT compared to placebo. No major adverse events and, in particular, no allergic reactions to rAAT were observed. Although significant differences between rAAT and placebo for sputum NE activity were not observed, some improvements were found for secondary efficacy variables. This study demonstrated that nebulized rAAT is safe and well-tolerated, but has a limited effect on NE activity and other markers of inflammation.

Cytomegalovirus Infection in Ireland: Seroprevalence, HLA Class I Alleles, and Implications.

Cytomegalovirus (CMV) infections occur worldwide and primary infection usually occurs in early childhood and is often asymptomatic whereas primary infection in adults may result in symptomatic illness. CMV establishes a chronic latent infection with intermittent periods of reactivation. Primary infection or reactivation associate with increased mortality and morbidity in those who are immunocompromised. Transplacental transmission may result in significant birth defects or long-term sensorineural hearing loss.We performed a study to determine the CMV seroprevalence and the association between HLA Class I alleles and frequency of CMV infection in Ireland. The presence of CMV IgG, a marker of previous CMV infection, was determined for a cohort of 1849 HLA typed solid organ transplant donors between 1990 and 2013. The presence of CMV IgG was correlated with HLA type.The CMV seroprevalence in solid organ transplant donors was 33.4% (range 22-48% per annum) over the time period 1990 to 2013. Multivariate logistic regression analysis showed that both age and HLA alleles were associated with CMV seropositivity. A significant and positive relationship between age and CMV seropositivity was observed (OR = 1.013, P < 0.001, CI [1.007, 1.019]). Chi-square analysis revealed that the female gender was independently associated with CMV seropositivity (P < 0.01). Seroprevalence in women of reproductive age (20-39 years) was significantly higher than men of the same age (37% vs 26%, P < 0.01). The frequencies of HLA-A1, HLA-A2, and HLA-A3 in our cohort were 40.8%, 48.8%, and 25.9%, respectively. Logistic regression analysis showed that the presence of HLA-A1 but not HLA-A2 or HLA-A3 was independently associated with CMV seronegativity (P < 0.01). Interestingly, individuals who co-expressed HLA-A2 and HLA-A3 alleles were significantly more likely to be CMV seropositive (P < 0.02). The frequencies of HLA-B5, HLA-B7, and HLA-B8 in our cohort were 6.1%, 31.2%, and 30.8%, respectively. The presence of the most common inherited haplotype in the Irish population, HLA-A1, B8 was significantly associated with CMV seronegativity (OR = 1.278, P < 0.001, CI [1.049, 1.556]).CMV seroprevalence is lower in Ireland compared with other countries. The high frequency of HLA-A1 in the Irish population may, in part, have a role in the reduced susceptibility to CMV infection.

Spatial and Temporal Clustering of Anti-Glomerular Basement Membrane Disease.

BACKGROUND AND OBJECTIVES: An environmental trigger has been proposed as an inciting factor in the development of anti-GBM disease. This multicenter, observational study sought to define the national incidence of anti-GBM disease during an 11-year period (2003-2014) in Ireland, investigate clustering of cases in time and space, and assess the effect of spatial variability in incidence on outcome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We ascertained cases by screening immunology laboratories for instances of positivity for anti-GBM antibody and the national renal histopathology registry for biopsy-proven cases. The population at risk was defined from national census data. We used a variable-window scan statistic to detect temporal clustering. A Bayesian spatial model was used to calculate standardized incidence ratios (SIRs) for each of the 26 counties. RESULTS: Seventy-nine cases were included. National incidence was 1.64 (95% confidence interval [95% CI], 0.82 to 3.35) per million population per year. A temporal cluster (n=10) was identified during a 3-month period; six cases were resident in four rural counties in the southeast. Spatial analysis revealed wide regional variation in SIRs and a cluster (n=7) in the northwest (SIR, 1.71; 95% CI, 1.02 to 3.06). There were 29 deaths and 57 cases of ESRD during a mean follow-up of 2.9 years. Greater distance from diagnosis site to treating center, stratified by median distance traveled, did not significantly affect patient (hazard ratio, 1.80; 95% CI, 0.87 to 3.77) or renal (hazard ratio, 0.76; 95% CI, 0.40 to 1.13) survival. CONCLUSIONS: To our knowledge, this is the first study to report national incidence rates of anti-GBM disease and formally investigate patterns of incidence. Clustering of cases in time and space supports the hypothesis of an environmental trigger for disease onset. The substantial variability in regional incidence highlights the need for comprehensive country-wide studies to improve our understanding of the etiology of anti-GBM disease.