Survey of Laboratory Medicine's national response to the HSE cyberattack in the Republic of Ireland.

BACKGROUND: On Friday 14 May 2021, the Health Service Executive (HSE) was subjected to a serious cyberattack on their information technology (IT) infrastructure. Healthcare workers lost access to HSE-provided clinical and non-clinical IT systems, including laboratory systems. AIM: The aim of this national survey was to capture Laboratory Medicine's response across the Republic of Ireland during the HSE cyberattack. METHOD: An electronic survey developed using Microsoft Forms® was emailed on 24 September 2021 to 58 local representatives of the PeriAnalytic and Laboratory Medicine Society (PALMSoc). RESULTS: The survey was sent to 43 clinical laboratories across the Republic of Ireland. A total of 41 responses from 43 laboratories across all laboratory disciplines were received (95% response rate). From these, 55% did not have access to a functioning LIS, with 56% of these not having access to a LIS for greater than 2 weeks. A decrease in specimen requests received during this period was reported by 74% of laboratories, with 32% experiencing a reduction that lasted in excess of one month. Over half of the laboratories (55%) experienced a reduction of > 30% in requests, indicating that clinicians stopped investigating patients (87% reduction in primary care), further escalating the disruption to healthcare. CONCLUSION: The cyberattack burdened the HSE and laboratories at a time when healthcare staffs were coming to terms with the impact of the COVID-19 pandemic. Despite this, the survey confirms the agility of laboratory staff in meeting the demands placed on it during this time.

Multi-institutional retrospective study of canine foot pad malignant melanomas: 20 cases.

Melanomas arising from the foot pad are a rare clinical entity in dogs. The biologic behaviour of foot pad malignant melanoma is not well understood, and these tumours are infrequently described. The objective of this study was to evaluate the clinical characteristics of primary canine foot pad melanoma in a larger cohort of patients. Eligible cases were solicited from the American College of Veterinary Internal Medicine (ACVIM) Oncology listserv for retrospective review. Included dogs had a cytologic and/or histologic diagnosis of foot pad melanoma evaluated by a board-certified clinical or anatomic pathologist. Dogs with cutaneous, oral, digital, subungual or interdigital melanomas were excluded. A total of 20 cases were included. Eleven dogs received various adjuvant therapies including chemotherapy, radiation therapy, and/or the ONCEPT canine melanoma vaccine following surgery. At diagnosis, regional lymph node metastasis was observed in four dogs (20%). Seven dogs developed subsequent regional and/or distant metastasis for an overall metastatic rate of 55%. The progression-free interval (PFI) was 101 days (range, 20-960 days). The median survival time (MST) was 240 days (range, 25-479 days). For dogs receiving adjuvant therapy, the MST was 159 days (range, 25-387 days). Canine foot pad melanoma is a rare neoplasm that can exhibit an aggressive behaviour.

Previous SARS-CoV-2 Infection, Age, and Frailty Are Associated With 6-Month Vaccine-Induced Anti-Spike Antibody Titer in Nursing Home Residents.

OBJECTIVES: Older nursing home residents make up the population at greatest risk of morbidity and mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. No studies have examined the determinants of long-term antibody responses post vaccination in this group. DESIGN: Longitudinal cohort study. SETTING AND PARTICIPANTS: Residents from 5 nursing homes assessed before vaccination, and 5 weeks and 6 months post vaccination, with the BNT162b2 messenger RNA SARS-CoV-2 vaccine. METHODS: Comprehensive clinical assessment was performed, including assessment for comorbidity, frailty, and SARS-CoV-2 infection history. Serum nucleocapsid and anti-spike receptor binding domain (RBD) antibodies were analyzed at all timepoints. An in vitro angiotensin-converting enzyme (ACE2) receptor-spike RBD neutralization assay assessed serum neutralization capacity. RESULTS: Of 86 participants (81.1 ± 10.8 years; 65% female), just under half (45.4%; 39 of 86) had evidence of previous SARS-CoV-2 infection. All participants demonstrated a significant antibody response to vaccination at 5 weeks and a significant decline in this response by 6 months. SARS-CoV-2 infection history was the strongest predictor of antibody titer (log-transformed) at both 5 weeks [ß: 3.00; 95% confidence interval (CI): 2.32-3.70; P < .001] and 6 months (ß: 3.59; 95% CI: 2.89-4.28; P < .001). Independent of SARS-CoV-2 infection history, both age in years (ß: -0.05; 95% CI: -0.08 to -0.02; P < .001) and frailty (ß: -0.22; 95% CI: -0.33 to -0.11; P < .001) were associated with a significantly lower antibody titer at 6 months. Anti-spike antibody titers at both 5 weeks and 6 months significantly correlated with in vitro neutralization capacity. CONCLUSIONS AND IMPLICATIONS: In older nursing home residents, SARS-CoV-2 infection history was the strongest predictor of anti-spike antibody titers at 6 months, whereas age and frailty were independently associated with lower titers at 6 months. Antibody titers significantly correlated with in vitro neutralization capacity. Although older SARS-CoV-2 naïve nursing home residents may be particularly vulnerable to breakthrough SARS-CoV-2 infection, the relationship between antibody titers, SARS-CoV-2 infection, and clinical outcomes remains to be fully elucidated in this vulnerable population.

Sweat testing in the modern era: A national survey of sweat testing practice in the Republic of Ireland.

BACKGROUND: The sweat test has been the "gold standard" diagnostic test for cystic fibrosis for more than 40 years. We hypothesized that there would be a change in the pattern of sweat testing in Ireland since the introduction of cystic fibrosis newborn screening in 2011, when practices were last reviewed. This is a follow up survey looking at sweat testing numbers and practices. METHODS: A national survey compiled data on sweat collection, conductivity and sweat chloride testing in all hospitals previously identified as performing sweat tests. RESULTS: All 13 centres in Ireland performing sweat testing in 2018 responded to the survey (100% return rate). Our results indicate that 1007 sweat tests were performed in 2018 compared to 2555 in 2011, equating to a 61% reduction. Seven out of 13 centres are performing less than 50 sweat tests per year. Nine out of 13 centres (69%) had a sweat test failure rate greater than the recommended allowable rate of ≤ 10%. We detected a trend of sweat testing in patients with an existing diagnosis of CF who had commenced cystic fibrosis transmembrane conductance regulator (CFTR) modulators. CONCLUSIONS: There has been a significant reduction in the number of sweat tests performed in Ireland since the introduction of newborn screening for CF. There remains a lack of standardisation in many aspects of the service ranging from sample collection to reporting of results. We have identified a new trend of sweat testing in the cystic fibrosis transmembrane conductance regulator modulator era.

High anti-SARS-CoV-2 antibody seroprevalence in healthcare workers in an Irish university teaching hospital.

INTRODUCTION: Healthcare workers are at very high risk for SARS-CoV-2 exposure and infection. This study evaluated anti-SARS-CoV-2 seroprevalence in healthcare workers in a tertiary care hospital and then correlated seroprevalence with confirmed or suspected SARS-CoV-2 infection in this population since the onset of the COVID-19 pandemic. METHOD: The study was approved by our institution's Joint Research Ethics Committee in June 2020. All volunteers were provided with a consent form, an information leaflet and a questionnaire on the day before phlebotomy. Serum samples were collected from 1176 participants over a 3-month period and analysed using the Elecsys Anti-SARS-CoV-2 assay (Roche Diagnostics GmbH, Mannheim, Germany) which detects total antibodies against the nucleocapsid protein of SARs-COV-2. RESULTS: Overall anti-SARS-CoV-2 seroprevalence among participating healthcare workers was 17.9%. The rate of confirmed infection by real-time polymerase chain reaction molecular testing prior to participation was 12.2%. Of 211 participants who had a reactive antibody test result, 37% did not have COVID-19 infection confirmed at any point prior to participation in this study, either having had a swab which did not detect SARS-CoV-2 RNA or having never been tested. Seropositivity was the highest (30%) in the youngest quintile of age (20-29 years old). Staff with more patient contact had a higher seroprevalence of 19.5% compared to 13.4% in staff with less patient contact. CONCLUSION: This study demonstrates that a substantial proportion of SARS-CoV-2 infections in healthcare workers may be asymptomatic or subclinical and thus potentially represent a significant transmission risk to colleagues and patients.

Outcome in dogs with curative-intent treatment of localized primary pulmonary histiocytic sarcoma.

Primary pulmonary histiocytic sarcoma (PHS) is a rare form of dendritic cell or macrophage neoplasia originating within the pulmonary parenchyma. There is limited literature describing prognosis in dogs with PHS receiving curative-intent treatment consisting of surgical excision and adjuvant chemotherapy. The primary objective of this study was to report outcomes in dogs with localized PHS treated with standardized local and systemic therapy. A secondary objective was to identify prognostic factors in this population. A multi-institutional retrospective study was performed and medical records including all surgical and histopathologic reports were retrospectively reviewed. For inclusion, dogs were required to have confirmed localized PHS and they must have undergone curative-intent surgery with resection of all gross primary tumour and enlarged tracheobronchial lymph nodes; additionally, they must have received curative-intent treatment with adjuvant single-agent CCNU chemotherapy. Twenty-seven dogs from six veterinary teaching hospitals and five private practices treated from 2008-2019 were included. The overall median survival time was 432 days. Higher CCNU dose was demonstrated to have a negative impact on survival on univariate, but not multivariable, analysis. Factors that were not found to be associated with survival on univariate analysis included body weight, breed, clinical signs at the time of diagnosis, hypoalbuminaemia, tumour size, lung lobe affected, lymph node metastasis, surgical margins and CCNU dose reductions. This study supports a favourable prognosis for dogs diagnosed with localized PHS treated with curative-intent surgery in addition to adjuvant CCNU chemotherapy and suggests that multimodal treatment may be advisable to attempt to prolong survival.

Mesoderm-specific Stat3 deletion affects expression of Sox9 yielding Sox9-dependent phenotypes.

To date, mutations within the coding region and translocations around the SOX9 gene both constitute the majority of genetic lesions underpinning human campomelic dysplasia (CD). While pathological coding-region mutations typically result in a non-functional SOX9 protein, little is known about what mechanism(s) controls normal SOX9 expression, and subsequently, which signaling pathways may be interrupted by alterations occurring around the SOX9 gene. Here, we report the identification of Stat3 as a key modulator of Sox9 expression in nascent cartilage and developing chondrocytes. Stat3 expression is predominant in tissues of mesodermal origin, and its conditional ablation using mesoderm-specific TCre, in vivo, causes dwarfism and skeletal defects characteristic of CD. Specifically, Stat3 loss results in the expansion of growth plate hypertrophic chondrocytes and deregulation of normal endochondral ossification in all bones examined. Conditional deletion of Stat3 with a Sox9Cre driver produces palate and tracheal irregularities similar to those described in Sox9+/- mice. Furthermore, mesodermal deletion of Stat3 causes global embryonic down regulation of Sox9 expression and function in vivo. Mechanistic experiments ex vivo suggest Stat3 can directly activate the expression of Sox9 by binding to its proximal promoter following activation. These findings illuminate a novel role for Stat3 in chondrocytes during skeletal development through modulation of a critical factor, Sox9. Importantly, they further provide the first evidence for the modulation of a gene product other than Sox9 itself which is capable of modeling pathological aspects of CD and underscore a potentially valuable therapeutic target for patients with the disorder.

IMpact of pocKet rEvision on the rate of InfecTion and other CompLications in patients rEquiring pocket mAnipulation for generator replacement and/or lead replacement or revisioN (MAKE IT CLEAN): A prospective randomized study.

BACKGROUND: The fibrous capsule around cardiac implantable device generators is known to promote bacterial colonization and latent infection. Removal of the capsule during device replacement procedures may reduce infection rates but may increase hemorrhagic complications. OBJECTIVE: The purpose of this study was to evaluate the effect of pocket capsule decortication procedure on infection and bleeding rates in patients undergoing device replacement procedures. METHODS: In a prospective randomized single-blind control study, patients undergoing device replacement, upgrade, or lead extraction were randomized to Group A "with pocket revision" (n = 131) and group B "without pocket revision" (n = 127). Deep and superficial infection rates, bleeding, and prolonged serous drainage were assessed during 12 months of follow-up. Data were analyzed according to intention-to-treat principle. RESULTS: A total of 258 patients were enrolled in the study. Rates of generator change, upgrade, and lead extraction/replacement were similar between both groups. There was no incidence of deep infection in either group at 12-month follow-up. There was no significant difference in the incidence of superficial infection between groups (1.5% vs 4.7%, P = .13) during 12-month follow-up. There was a significant increase in acute hematoma formation in group A compared to group B (6.1% vs 0.8%, P = .03). Two patients in group A had to undergo hematoma evacuation. CONCLUSION: There was increased incidence of hematoma formation in group A with no effect on infection rates. Our study suggests that there is no benefit to performing empiric pocket revision.

Substituent effects on spin state in a series of mononuclear manganese(III) complexes with hexadentate Schiff-Base ligands.

Eleven new mononuclear manganese(III) complexes prepared from two hexadentate ligands, L1 and L2, with different degrees of steric bulk in the substituents are reported. L1 and L2 are Schiff bases resulting from condensation of N,N'-bis(3-aminopropyl)ethylenediamine with 3-methoxy-2-hydroxybenzaldehyde and 3-ethoxy-2-hydroxybenzaldehyde respectively, and are members of a ligand series we have abbreviated as R-Sal2323 to indicate the 323 alkyl connectivity in the starting tetraamine and the substitution (R) on the phenolate ring. L1 hosts a methoxy substituent on both phenolate rings, while L2 bears a larger ethoxy group in the same position. Structural and magnetic properties are reported in comparison with those of a previously reported analogue with L1, namely, [MnL1]NO3, (1e). The BPh4(-) and PF6(-) complexes [MnL1]BPh4, (1a), [MnL2]BPh4, (2a), [MnL1]PF6, (1b'), and [MnL2]PF6, (2b), with both ligands L1 and L2, remain high-spin (HS) over the measured temperature range. However, the monohydrate of (1b') [MnL1]PF6·H2O, (1b), shows gradual spin-crossover (SCO), as do the ClO4(-), BF4(-), and NO3(-) complexes [MnL1]ClO4·H2O, (1c), [MnL2]ClO4, (2c), [MnL1]BF4·H2O, (1d), [MnL2]BF4·0.4H2O, (2d), [MnL1]NO3, (1e), and [MnL2]NO3·EtOH, (2e). The three complexes formed with ethoxy-substituted ligand L2 all show a higher T1/2 than the analogous complexes with methoxy-substituted ligand L1. Analysis of distortion parameters shows that complexes formed with the bulkier ligand L2 exhibit more deformation from perfect octahedral geometry, leading to a higher T1/2 in the SCO examples, where T1/2 is the temperature where the spin state is 50% high spin and 50% low spin. Spin state assignment in the solid state is shown to be solvate-dependent for complexes (1b) and (2e), and room temperature UV-visible and NMR spectra indicate a solution-state spin assignment intermediate between fully HS and fully low spin in 10 complexes, (1a)-(1e) and (2a)-(2e).

Elevated brain natriuretic peptide level in patients undergoing atrial fibrillation ablation: is it a predictor of failed ablation or a mere function of atrial rhythm and rate at a point in time?

BACKGROUND: Pre- and postablation atrial fibrillation (AF) brain natriuretic peptide (BNP) levels were shown to predict increased recurrence of AF following ablation. OBJECTIVE: Our objective was to assess whether elevated BNP levels merely represent the presence of AF at the time of measurement or indeed the true recurrence of AF. METHODS AND RESULTS: In a prospective study of 88 patients undergoing AF ablation, BNP levels were measured immediately before, after, 24 h, and 4-6 months postablation. BNP levels were stratified by presenting rhythm and ventricular rate at the time of measurement. Median BNP level preablation was higher in patients presenting in AF compared to sinus rhythm (SR) (54(44-79) pg/ml vs. 30(18-47) pg/ml, p < 0.001). Postablation restoration of SR in patients presenting in AF reduced median BNP levels from 54(44-79) pg/ml to 40(37-51) pg/ml, (p < 0.001). However, no change was noted in patients who presented in and maintained SR throughout the procedure (30(18-47) pg/ml to 27(16-40) pg/ml, p = 0.270). At 4-6 months, BNP measured in patients in SR was not significantly different from postablation BNP (35(22-53) pg/ml vs. 38(20-52) pg/ml, p = 0.656), although 35% of them had AF recurrence in 1-year follow-up. Median BNP level measured in five patients while in atrial arrhythmia was elevated compared to postablation BNP (464(421-464) pg/ml to 37(36-37) pg/ml, p = 0.043). BNP levels and ventricular rates are positively correlated at all times pre- and postablation. CONCLUSIONS: BNP level rises acutely during AF and with rapid ventricular rates. BNP level seems to be a function of atrial rhythm and ventricular rate rather than short- or long-term predictor of AF ablation success.

The importance of a full clinical examination: assessment of index lesions referred to a skin cancer clinic without a total body skin examination would miss one in three melanomas.

Traditional clinical teaching emphasises the importance of a full clinical examination. In the clinical assessment of lesions that may be skin cancer, full examination allows detection of incidental lesions, as well as helping in the characterisation of the index lesion. Despite this, a total body skin examination is not always performed. Based on two prospective studies of over 1,800 sequential patients in two UK centres we show that over one third of melanomas detected in secondary care are found as incidental lesions, in patients referred for assessment of other potential skin cancers. The majority of these melanomas occurred in patients whose index lesion turned out to be benign. Alternative models of care--for instance some models of teledermatology in which a total body skin examination is not performed by a competent practitioner--cannot be considered equivalent to a traditional consultation and, if adopted uncritically, without system change, will likely lead to melanomas being missed.

Co-crystallisation of competing structural modes in geometrically constrained Jahn-Teller manganese(III) complexes.

The combination of Jahn-Teller distortion and chelating ligands produces a fine balance between competing coordination modes in manganese(III) resulting in well-ordered co-crystallization of two distinct assemblies from one set of components under a single set of conditions.

Lattice effects on the spin-crossover profile of a mononuclear manganese(III) cation.

Six solvated salts of a mononuclear manganese(III) complex with a chelating hexadentate Schiff base ligand are reported. One member of the series, [MnL]PF(6)⋅0.5 CH(3)OH (1), shows a rare low-spin (LS) electronic configuration between 10-300 K. The remaining five salts, [MnL]NO(3)⋅C(2)H(5)OH(2), [MnL]BF(4)⋅C(2)H(5)OH(3), [MnL]CF(3)SO(3)⋅C(2)H(5)OH (4), [MnL]ClO(4)⋅C(2)H(5)OH (5) and [MnL]ClO(4)⋅0.5 CH(3)CN (6), all show gradual incomplete spin-crossover (SCO) behaviour. The structures of all were determined at 100 K, and also at 293 K in the case of 3-6. The LS salt [MnL]PF(6)⋅0.5 CH(3)OH is the only member of the series that does not exhibit strong hydrogen bonding. At 100 K two of the four SCO complexes (2 and 4) assemble into 1D hydrogen-bonded chains, which weaken or rupture on warming. The remaining SCO complexes 3, 5 and 6 do not form 1D hydrogen-bonded chains, but instead exhibit discrete hydrogen bonding between cation/counterion, cation/solvent or counterion/solvent and show no significant change on warming.

Radiofrequency ablation of atrial fibrillation in patients with mitral or aortic mechanical prosthetic valves: a feasibility, safety, and efficacy study.

BACKGROUND: Patients with prosthetic valves have a high prevalence of atrial fibrillation (AF). We report a multicenter experience of performing pulmonary vein antral isolation (PVAI) in this challenging, high-risk cohort of patients. OBJECTIVE: The purpose of this study was to assess the feasibility, safety, and efficacy of radiofrequency (RF) ablation for sinus rhythm restoration in AF patients with mitral or aortic mechanical prosthetic valves. METHODS: A total of 50 patients with prosthetic valves (group I) who underwent RF ablation for AF between January 1, 2007, and April 30, 2009, were identified prospectively at four tertiary care centers. A matched group of 50 patients (group II) acted as controls. RESULTS: Total procedural time (199.4 ± 49 minutes vs 166.6 ± 27.5 minutes, P <.001) and fluoroscopy time (60 ± 17 minutes vs 53.8 ± 6.8 minutes, P <.01) were prolonged, with a higher incidence of atrial flutter at 3 months in group I (18% vs 6%, P = .1) compared to group II. At 12 months, 80% of patients in the valve group were in sinus rhythm after an average of 1.3 procedures, and 82% of controls were in sinus rhythm after an average 1.2 procedures (P = .9). There was a trend toward a higher nonfatal complication rate in the valve group than in the control group (8% vs 4%, P = .1). CONCLUSION: In patients with prosthetic valves, RF ablation for AF is feasible, safe, and efficacious, with a trend toward a higher nonfatal complication rate and an increased rate of postablation atrial flutter.

The 12q14 microdeletion syndrome: six new cases confirming the role of HMGA2 in growth.

We report six patients with array deletions encompassing 12q14. Out of a total of 2538 array investigations carried out on children with developmental delay and dysmorphism in three diagnostic testing centres, six positive cases yielded a frequency of 1 in 423 for this deletion syndrome. The deleted region in each of the six cases overlaps significantly with previously reported cases with microdeletions of this region. The chromosomal range of the deletions extends from 12q13.3q15. In the current study, we report overlapping deletions of variable extent and size but primarily comprising chromosomal bands 12q13.3q14.1. Four of the six deletions were confirmed as de novo events. Two cases had deletions that included HMGA2, and both children had significant short stature. Neither case had osteopoikilosis despite both being deleted for LEMD3. Four cases had deletions that ended proximal to HMGA2 and all of these had much better growth. Five cases had congenital heart defects, including two with atrial septal defects, one each with pulmonary stenosis, sub-aortic stenosis and a patent ductus. Four cases had moderate delay, two had severe developmental delay and a further two had a diagnosis of autism. All six cases had significant speech delay with subtle facial dysmorphism.

Are subjective accounts of itch to be relied on? The lack of relation between visual analogue itch scores and actigraphic measures of scratch.

There is a widespread belief that subjective accounts of disease are key components of measures of disease severity and quality of life. In the present study we have set out to test this hypothesis using visual analogue scales (VAS) for itch, as a subjective measure, and actigraphy as an objective measure. One-hundred and seventeen itchy children and adults (and 25 controls) were studied for clusters of nights (total number 1,654) and actigraphy scores and VAS itch taken daily. Fifty-six percent of the night-to-night variation in actigraphy scores occurred between different individuals, while 44% was intra-subject. Neither age nor sex (children's or adults') predicted actigraphy scores, and the only significant predictor of actigraphy score was disease type (p = 0.001, r² = 0.51). In a multivariate model VAS itch score was not a significant determinant of actigraphy scores for either children or adults (p = 0.26). In order to see if there was a relation between VAS itch and actigraphy within the same patients (rather than between patients), 20 eczema patients wore the actigraph and scored VAS itch nightly for 42 nights. Little relationship was found between the actigraphy score and the VAS itch. Empirical autocorrelation analysis of VAS itch and actigraphy score reveal a clear autocorrelation for subjective VAS scores that was not found for the objective actigraphy score. Our data suggest a dissociation between scratch and perceived or recalled itch. One explanation is that VAS itch scores suffer from considerable anchoring, and context bias, and that their use in measures of disease severity is problematic.

How robust are the Dermatology Life Quality Index and other self-reported subjective symptom scores when exposed to a range of experimental biases?

Subjective-symptom tools used in dermatology have rarely been experimentally tested for cognitive "focus" and "framing" biases. We investigated the effects of affective biases on the Dermatology Life Quality Index (DLQI), the Global Health Question and visual analogue scores. Two experiments tested the response to affect-eliciting words and film. We demonstrated no significant difference in median DLQI scores for subjects exposed to negative vs. neutral words (medians 8.5 and 9.5, respectively), or negative vs. positive words (medians 6.0 and 9.0, respectively, overall p = 0.41.) Median DLQI scores were similar for groups who had (8.0), or had not (9.0), seen a video clip about a severe skin condition (p = 0.34). Finally, we compared an Amended DLQI (ADLQI), the DLQI re-worded into neutral "frames", with the standard DLQI. ADLQI median scores were higher (ADLQI 8.25, DLQI 6.75), but not significantly so (p = 0.47). We have been unable to demonstrate any effects of the biases studied, but the statistical power of our study is modest.