Prognostic benefits of His-Purkinje capture in physiological pacemakers for bradycardia.

INTRODUCTION: Clinical outcomes of long-term ventricular septal pacing (VSP) without His-Purkinje capture remain unknown. This study evaluated the differences in clinical outcomes between conduction system pacing (CSP), VSP, and right ventricular pacing (RVP). METHODS: Consecutive patients with bradycardia indicated for pacing from 2016 to 2022 were prospectively followed for the clinical endpoints of heart failure (HF)-hospitalizations and all-cause mortality at 2 years. VSP was defined as septal pacing due to unsuccessful CSP implant or successful CSP followed by loss of His-Purkinje capture within 90 days. RESULTS: Among 1016 patients (age 73.9 ± 11.2 years, 47% female, 48% atrioventricular block), 612 received RVP, 335 received CSP and 69 received VSP. Paced QRS duration was similar between VSP and RVP, but both significantly longer than CSP (p < .05). HF-hospitalizations occurred in 130 (13%) patients (CSP 7% vs. RVP 16% vs. VSP 13%, p = .001), and all-cause mortality in 143 (14%) patients (CSP 7% vs. RVP 19% vs. VSP 9%, p < .001). The association of pacing modality with clinical events was limited to those with ventricular pacing (Vp) > 20% (pinteraction < .05). Adjusting for clinical risk factors among patients with Vp > 20%, VSP (adjusted hazard ratio [AHR]: 4.74, 95% confidence interval [CI]: 1.57-14.36) and RVP (AHR: 3.08, 95% CI: 1.44-6.60) were associated with increased hazard of HF-hospitalizations, and RVP (2.52, 95% CI: 1.19-5.35) with increased mortality, compared to CSP. Clinical endpoints did not differ between VSP and RVP with Vp > 20%, or amongst groups with Vp < 20%. CONCLUSION: Conduction system capture is associated with improved clinical outcomes. CSP should be preferred over VSP or RVP during pacing for bradycardia.

Efficacy and safety of narrowband ultraviolet B versus combined ultraviolet A/narrowband ultraviolet B phototherapy in the treatment of chronic atopic dermatitis: A randomised double-blind study.

Phototherapy is a useful treatment modality for atopic dermatitis (AD). This is a prospective randomised double-blind study comparing the clinical efficacy of combined ultraviolet-A (UVA)/narrowband ultraviolet-B (NBUVB) versus NBUVB phototherapy in the treatment of chronic AD. Patients with moderate-to-severe AD were randomised to receive either UVA/NBUVB or NBUVB phototherapy twice weekly over 12 weeks. At baseline, weeks 6 and 12, Eczema Area And Severity Index (EASI), itch score and adverse effects were assessed. At baseline and week 12, disease-related quality of life was evaluated using the Dermatology Life Quality Index (DLQI). Nine patients were randomised to receive UVA/NBUVB and 10 received NBUVB. At week 12, both groups showed significant improvement in EASI and itch scores (p < 0.05). Significant improvement in DLQI was seen in the UVA/NBUVB arm (p = 0.009) with a trend towards improvement in the NBUVB arm (p = 0.11). The efficacy of both modalities were comparable, as were reported adverse effects aside from skin dryness which was higher in the NBUVB arm (40% vs. 0%, p = 0.033). Combined UVA/NBUVB and NBUVB phototherapy have comparable clinical efficacy and safety in the treatment of chronic AD. NBUVB may induce greater skin dryness.

Exploring the Association Between Isotretinoin and Sexual Dysfunction: A Comprehensive Scoping Review.

BACKGROUND: The potential link between isotretinoin and sexual dysfunction has been reported in various studies. However, such an association has not been explored within the context of a literature review until now. OBJECTIVES: To evaluate the methodology and quality of studies investigating this association, and to examine the definitions of sexual dysfunction used. METHODS: A scoping review approach was used to identify peer-reviewed research articles. The search terms used were: "isotretinoin", "sexual dysfunction", "erectile dysfunction", "ejaculatory disorders" "decreased libido", "female sexual interest", "female arousal disorder", "libido", "pelvic pain", "dyspareunia", "orgasmic disorder", "impotence", "ovaries", "fertility" and "menstrual irregularity". RESULTS: 54 peer-reviewed manuscripts consisting of 8 animal studies and 46 human studies consisting of 2,420 patients were included. Of the studies in humans, there were 18 case reports/case series, 2 case-controls, 4 cross-sectional studies, 6 longitudinal studies, 3 pharmacovigilance reports and 13 cohort studies. The most frequently observed dose range of isotretinoin was 0.5-1.0mg/kg/day usually for a duration of 1-6 months. More than half of the studies (54%, n=25) reported a beneficial or neutral effect of isotretinoin on sexual function. The majority of studies (89%, n = 41) were categorized as Oxford evidenced-based-medicine level 4. CONCLUSIONS: This scoping review revealed very weak evidence supporting a link between isotretinoin and sexual dysfunction. Notably, the diverse definitions of sexual dysfunction pose a significant challenge for comparative analysis. The authors advocate for a standardized definition of sexual dysfunction and a framework for determining causality in order to contribute to a more comprehensive understanding of the relationship between isotretinoin and sexual dysfunction.

Sustainable dermatology-A practical guide for the Australian dermatologist.

Globally, healthcare systems can account for up to 10% of national CO2 emissions. There is increasing awareness of the need to act to reduce the impact on our planet by living sustainably in our personal and professional lives. Literature on sustainability can be complex, and with so many demands on our attention and time, it is challenging for the practising dermatologist to grasp where to begin. This manuscript provides a practical guide with quantifiable impacts for each action. With mindful use of resources, both profitability and the well-being of patients and doctors can align with environmental protection.

Conduction system versus biventricular pacing in heart failure with non-left bundle branch block.

INTRODUCTION: The benefits of cardiac resynchronization therapy (CRT) with biventricular pacing (BiV) is significantly lower when applied to heart failure (HF) patients with non-left bundle branch block (LBBB) conduction delay. We investigated clinical outcomes of conduction system pacing (CSP) for CRT in non-LBBB HF. METHODS: Consecutive HF patients with non-LBBB conduction delay undergoing CSP were propensity matched for age, sex, HF-etiology, and atrial fibrillation (AF) in a 1:1 ratio to BiV from a prospective registry of CRT recipients. Echocardiographic response was defined as an increase in left ventricular ejection fraction (LVEF) by ≥10%. The primary outcome was the composite of HF-hospitalizations or all-cause mortality. RESULTS: A total of 96 patients were recruited (mean age 70 ± 11years, 22% female, 68% ischemic HF and 49% AF). Significant reductions in QRS duration and LV dimensions were seen only after CSP, while LVEF improved significantly in both groups (p < 0.05). Echocardiographic response occurred more frequently in CSP than BiV (51% vs. 21%, p < 0.01), with CSP independently associated with four-fold increased odds (adjusted odds ratio 4.08, 95% confidence interval [CI] 1.34-12.41). The primary outcome occurred more frequently in BiV than CSP (69% vs. 27%, p < 0.001), with CSP independently associated with 58% risk reduction (adjusted hazard ratio [AHR] 0.42, 95% CI 0.21-0.84, p = 0.01), driven by reduced all-cause mortality (AHR 0.22, 95% CI 0.07-0.68, p < 0.01), and a trend toward reduced HF-hospitalization (AHR 0.51, 95% CI 0.21-1.21, p = 0.12). CONCLUSIONS: CSP provided greater electrical synchrony, reverse remodeling, improved cardiac function and survival compared to BiV in non-LBBB, and may be the preferred CRT strategy for non-LBBB HF.

Clinical and patient-reported outcomes from the first 4 years of a Psoriasis Biologics Registry in Singapore.

Interim analysis of the National Skin Centre Singapore Psoriasis Biologics Registry (SINGPSOR) from August 2017 to May 2021, in which 58 patients were analysed, showing that those receiving biologic treatment had significantly more severe psoriasis based on PASI (Psoriasis Area and Severity Index), BSA (body surface area) and PGA (Physician Global Assessment) measures at baseline, demonstrated a statistically non-significant trend towards greater improvement with treatment, and had a lower percentage of adverse events compared to those receiving conventional systemic therapy. Future analyses of SINGPSOR, with larger sample size and longer follow-up, will be invaluable to further characterize these patients and their treatment outcomes.

Photopatch testing in Singapore: A 10-year retrospective study.

BACKGROUND: Photopatch testing represents the gold standard for the diagnosis of photoallergic contact dermatitis (PACD). We aimed to identify common photoallergens in our tertiary dermatological referral centre from 2012 to 2021, to compare this to the preceding period studied, and data from other communities. METHODS: We conducted a retrospective review of all 90 patients who underwent photopatch testing at the National Skin Centre, Singapore, between 2012 and 2021. RESULTS: Of 90 patients, 19 (21.1%) were male, and the mean age was 41.6 years. Eighty-four (93.3%) underwent testing to our standard sunscreen series, 10 (11.1%) to our extended series, and 73 (81.1%) to their own items. Seventeen (18.9%) were diagnosed with PACD (i.e., photocontact allergy with present or past relevance), 12 (13.3%) with ACD, and 4 (4.4%) with photoaugmented ACD. Relevant reactions were commonest to oxybenzone (8, 9.5%) and mexenone (3, 3.6%). Eleven (15.1%) had PACD to their own items, with 3 of 4 (75%) tested to ketoprofen diagnosed with PACD and the remaining 1 (25%) with photoaugmented ACD. Age, race, sex, atopy, and site of involvement were not associated with photocontact allergy. Compared to the preceding time period, the overall frequency of photocontact allergy and PACD decreased, but rates of photoallergic reactions to individual photoallergens were not significantly different. CONCLUSION: Organic ultraviolet absorbers such as oxybenzone and mexenone remained the most relevant photoallergens. Personal item testing was valuable, and testing to ketoprofen should be considered.

Selecting embedding delays: An overview of embedding techniques and a new method using persistent homology.

Delay embedding methods are a staple tool in the field of time series analysis and prediction. However, the selection of embedding parameters can have a big impact on the resulting analysis. This has led to the creation of a large number of methods to optimize the selection of parameters such as embedding lag. This paper aims to provide a comprehensive overview of the fundamentals of embedding theory for readers who are new to the subject. We outline a collection of existing methods for selecting embedding lag in both uniform and non-uniform delay embedding cases. Highlighting the poor dynamical explainability of existing methods of selecting non-uniform lags, we provide an alternative method of selecting embedding lags that includes a mixture of both dynamical and topological arguments. The proposed method, Significant Times on Persistent Strands (SToPS), uses persistent homology to construct a characteristic time spectrum that quantifies the relative dynamical significance of each time lag. We test our method on periodic, chaotic, and fast-slow time series and find that our method performs similar to existing automated non-uniform embedding methods. Additionally, n-step predictors trained on embeddings constructed with SToPS were found to outperform other embedding methods when predicting fast-slow time series.

Stroke Recurrence in Embolic Stroke of Undetermined Source Without Atrial Fibrillation on Invasive Cardiac Monitoring.

BACKGROUND: More than half of patients with embolic stroke of undetermined source (ESUS) suffer from recurrent ischaemic stroke, despite the absence of atrial fibrillation (AF) on invasive cardiac monitoring (ICM). This study investigated the predictors and prognosis of recurrent stroke in ESUS without AF on ICM. METHOD: This prospective study included patients with ESUS at two tertiary hospitals from 2015 to 2021 who underwent comprehensive neurological imaging, transthoracic echocardiography, and inpatient continuous electrographic monitoring for ≥48 hours prior to ICM for definitive exclusion of AF. Recurrent ischaemic stroke, all-cause mortality, and functional outcome by the modified Rankin scale (mRS) at 3 months were evaluated in patients without AF. RESULTS: Of 185 consecutive patients with ESUS, AF was not detected in 163 (88%) patients (age 62±12 years, 76% men, 25% prior stroke, median time to ICM insertion 26 [7, 123] days), and stroke recurred in 24 (15%) patients. Stroke recurrences were predominantly ESUS (88%), within the first 2 years (75%), and involved a different vascular territory from qualifying ESUS (58%). Pre-existing cancer was the only independent predictor of recurrent stroke (adjusted hazard ratio [AHR] 5.43, 95% CI 1.43-20.64), recurrent ESUS (AHR 5.67, 95% CI 1.15-21.21), and higher mRS score at 3 months (ß 1.27, 95% CI 0.23-2.42). All-cause mortality occurred in 17 (10%) patients. Adjusting for age, cancer, and mRS category (≥3 vs <3), recurrent ESUS was independently associated with more than four times greater hazard of death (AHR 4.66, 95% CI 1.76-12.34). CONCLUSIONS: Patients with recurrent ESUS are a high-risk subgroup. Studies elucidating optimal diagnostic and treatment strategies in non-AF-related ESUS are urgently required.

Dearomatization of (Hetero)arenes through Photodriven Interplay between Polysulfide Anions and Formate.

The facile construction of C(sp3 )-rich carbo- and heterocyclic compounds is a pivotal synthetic strategy to foster contemporary drug discovery programs. The downstream dearomatization of readily accessible two-dimensional (2D) planar arenes represents a direct pathway towards accessing three-dimensional (3D) aliphatic scaffolds. Here, we demonstrate that polysulfide anions are capable of catalyzing a dearomatization process of substituted naphthalenes, indoles, and other related heteroaromatic compounds in the presence of potassium formate and methanol under visible light irradiation. The developed protocol exhibits broad functional group tolerance, operational simplicity, scalability, and cost-effectiveness, representing a practical and sustainable synthetic tool for the arene dearomatization.

Late pacemaker implantation after atrioventricular nodal reentrant tachycardia ablation: A systematic review and meta-analysis.

INTRODUCTION: Catheter ablation (CA) of atrioventricular nodal reentrant tachycardia (AVNRT) is associated with late pacemakers for AV block (AVB). We performed a systematic review and meta-analysis of the pooled incidence of late pacemakers for AVB after CA of AVNRT. METHODS AND RESULTS: Relevant studies were identified from four electronic databases (PubMed, EMBASE, Scopus, and Cochrane Trial Register) from inception to 2022. A random effects model was used to calculate the odds of late pacemakers in CA of AVNRT compared to atrioventricular reentrant tachycardia (AVRT). Of 533 articles screened, 13 were included in systematic review. CA for AVNRT was performed in 16 471 patients (mean age 54 ± 17 years, 63% females), of which 68 (0.4%) underwent pacemaker implantation for late AVB. Meta-analysis was performed in 5 of the 13 studies (mean follow-up duration 7 ± 4 years). Patients who underwent CA of AVNRT were older (58 ± 17 vs. 52 ± 20 years, p < .001), and more likely female (60% vs. 41%, p < .001) than AVRT. Pooled estimates of late pacemakers for AVB were higher in CA of AVNRT than AVRT (0.5% vs. 0.2%, p = .006), with CA in AVNRT associated with almost twofold increased odds of late pacemakers indicated for AVB (odds ratio: 1.94, 95% confidence interval: 1.08-3.47, p = .027) compared to AVRT. CONCLUSION: AVNRT ablation is safe but associated with a low but definitely increased risk of requiring pacing in the later years due to AVB. This association is confirmed by pooling over 16 000 AVNRT patients receiving clinically indicated ablation and is helpful in providing informed consent for prospective patients undergoing ablation for AVNRT.

Use of extendable helix leads for conduction system pacing: Differences in lead handling and performance lead design impacts conduction system pacing.

INTRODUCTION: Pacing leads with extendable-retractable helix (EHL) are alternatives to fixed-helix leads (FHL) for conduction system pacing (CSP), but data on handling characteristics are limited. This study evaluated a dual-center experience of lead handling and performance during CSP. METHODS AND RESULTS: Consecutive patients with His-bundle pacing (HBP) or left bundle branch pacing (LBBP) were evaluated for the primary outcome of lead failure, defined as structural damage to the lead necessitating lead replacement. Differences in pacing characteristics were compared. Among 280 patients (mean age 74 ± 11 years, 44% male, 50% LBBP), 246 (88%) received FHL and 34 (12%) received EHL. Of 299 leads used, lead failure occurred more frequently among patients with EHL than FHL (29% vs. 2%, p < .001), regardless of CSP modality. Majority of damaged leads (89%) in the form of helix deformation were successfully removed, with failure occurring in only two patients, both EHL, leading to helix fracture and retention within the septal myocardium. EHL, compared to FHL, was associated with 25-fold increased odds of lead failure (odds ratio: 25.21, 95% confidence interval: 7.35-86.51), and persisted after adjustment in turn for age, pacing modality and indication. CSP implant success rates did not differ by lead design (FHL 80% vs. EHL 71%, p = .18), with similar pacing thresholds at implant and follow-up. CONCLUSION: Helix deformation and fracture were more frequent with EHL in CSP despite similar implant success. These findings have significant implications for lead selection during CSP and raises concerns about the long-term extractability of EHL in CSP.

Adopting permanent His bundle pacing: learning curves and medium-term outcomes.

AIMS: This study aims to determine procedural characteristics, acute success rates, and medium-term outcomes of consecutive patients undergoing His bundle pacing (HBP); and learning curves of experienced electrophysiologists adopting HBP. METHODS AND RESULTS: Consecutive HBP patients at three hospitals were recruited. Clinical characteristics, acute procedural details, and medium-term outcomes were extracted from electronic medical records. Two hundred and thirty-three patients [mean age 74.6 ± 10.1 years, 48% female, 68% narrow QRS, 71% normal left ventricular ejection fraction (LVEF), 55.8% atrioventricular block] underwent HBP. Acute procedural success was 81.1% (mean procedural and fluoroscopic times of 105.5 ± 36.5 and 13.8 ± 9.3 min). Broad QRS was associated with lower HBP success (odds ratio 0.39, P = 0.02). Fluoroscopic and procedural times decreased and plateaued after 30-40 cases per operator. Implant HBP threshold was 1.3 ± 0.7 V at 1.0 ± 0.2 ms and R wave was 5.0 ± 3.9 mV. During follow-up, loss of HBP occurred in a further 12.4% and 11.3% of patients experienced a ≥1 V increase in HBP threshold. Five (2.6%) patients required HBP revision for pacing difficulties. About 8.6% of patients had a >50% decrease in R wave but lead revision for sensing issues was not necessary. On an intention to treat basis, 56.7% of patients in whom HBP was attempted had persisting HBP capture and thresholds of <2 V. CONCLUSION: Physicians adopting HBP should be cognizant of the learning curve and preferentially select non-dependent patients with normal QRS and LVEF, to minimize risk of lead revision. Further rises in HBP threshold may increase battery drain and need for reoperations, important considerations when choosing HBP for cardiac resynchronization therapy.

Acute suppression of epicardial left ventricular summit premature ventricular ectopy by occlusive venogram.

We describe the unique phenomenon of occlusive venogram-induced suppression of premature ventricular complexes (PVC) arising from the epicardial left ventricular summit (LVS). Prior to ablation through the coronary sinus, routine occlusive venogram performed at the focus of PVC origin led to localized myocardial staining and simultaneous, sustained PVC suppression. Pace-mapping adjacent to the area of myocardial staining revealed near-identical PVC morphology match (98%). Routine occlusive venogram prior to ablation within the coronary venous system is safe and contributed to localization of the PVC focus.

Outcomes of supraventricular tachycardia ablation: Results from the Singapore ablation and cardiac devices registry.

BACKGROUND: The Singapore Cardiac Databank was designed to monitor the performance and outcomes of catheter ablation. We investigated the outcomes of paroxysmal supraventricular tachycardia (PSVT)-ablation in a prospective, nationwide, cohort study. METHODS: Atrioventricular nodal re-entrant tachycardia (AVNRT), atrioventricular re-entry tachycardia (AVRT), or atrial tachycardia (AT)-ablations in Singapore from 2010 to 2018 were studied. Outcomes include acute success, periprocedural-complications, postoperative pacing requirement, arrhythmic recurrence and 1-year all-cause mortality. RESULTS: Among 2260 patients (mean age 45 ± 18 years, 50% female, 57% AVNRT, 37% AVRT, 6% AT), overall acute success rates of PSVT-ablation was 98.4% and increased in order of AT, AVRT, and AVNRT (p < .001). Periprocedural cardiac tamponade occurred in two AVRT patients. A total of 15 pacemakers (6 within first 30-days, 9 after 30-days) were implanted (seven AV block, eight sinus node dysfunction [SND]), with the highest incidence of pacemaker implantation after AT-ablation (5% vs. 0.6% AVNRT vs. 0.1% AVRT, p < .001). Repeat ablations (0.9% AVNRT, 7% AVRT, 4% AT, p < .001) were performed in 78 (3.5%) patients and 13 (0.6%) patients died within a year of ablation. Among outcomes considered adjusting for age, sex, PSVT-type and procedure-time, AT was independently associated with 6-fold increased odds of total (adjusted odds ratio [AOR] 6.32, 95% confidence interval [CI] 1.95-20.53) and late (AOR 6.38, 95% CI 1.39-29.29) pacemaker implantation, while AVRT was associated with higher arrhythmic recurrence with repeat ablations (AOR 4.72, 95% CI 2.36-9.44) compared to AVNRT. CONCLUSIONS: Contemporary PSVT ablation is safe with high acute success rates. Long-term outcomes differed by nature of the PSVT.

Atrial Fibrillation and the Prognostic Performance of Biomarkers in Heart Failure.

BACKGROUND: Consideration of circulating biomarkers for risk stratification in heart failure (HF) is recommended, but the influence of atrial fibrillation (AF) on prognostic performance of many markers is unclear. We investigated the influence of AF on the prognostic performance of circulating biomarkers in HF. METHODS: N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional-pro-atrial natriuretic peptide, C-type natriuretic peptide (CNP), NT-proCNP, high-sensitivity troponin-T, high-sensitivity troponin-I, mid-regional-propeptide adrenomedullin, co-peptin, growth differentiation factor-15, soluble Suppressor of Tumorigenicitiy (sST2), galectin-3, and procalcitonin plasma concentrations were measured in a prospective, multicenter study of adults with HF. AF was defined as a previous history of AF, and/or presence of AF/flutter on baseline 12-lead electrocardiogram. The primary outcome was the composite of HF-hospitalization or all-cause mortality at 2 years. RESULTS: Among 1099 patients (age 62 ± 12years, 28% female), 261(24%) patients had AF. Above-median concentrations of all biomarkers were independently associated with increased risk of the primary outcome. Significant interactions with AF were detected for galectin-3 and sST2. In considering NT-proBNP for additive risk stratification, sST2 (adjusted hazard ratio [AHR]1.85, 95%confidence interval [C.I.] 1.17-2.91) and galectin-3 (AHR1.85, 95%C.I. 1.09-2.45) were independently associated with increased primary outcome only in the presence of AF. The prognostic performance of sST2 was also stronger in AF for all-cause mortality (AF: AHR2.82, 95%C.I. 1.26-6.21; non-AF: AHR1.78, 95% C.I. 1.14-2.76 without AF), while galectin-3 predicted HF-hospitalization only in AF (AHR1.64, 95%C.I. 1.03-2.62). CONCLUSIONS: AF modified the prognostic utility of selected guideline-endorsed HF-biomarkers. Application of markers for prognostic purposes in HF requires consideration of the presence or absence of AF. CLINICAL TRIAL REGISTRATION: ACTRN12610000374066.

Carbon footprint of dermatologic surgery.

Healthcare is a potent emitter of greenhouse gases amounting up to 7% of total estimated greenhouse gas emissions (CO2 e) for Australia. Australia has one of the highest incidences of skin cancer in the world but there is a paucity of data on the ecological impact of skin cancer excision/dermatologic surgery. The authors reviewed the various impact inventories in order to perform a life cycle assessment of skin cancer excision. A total of 8641 tonnes of estimated CO2 e are produced from dermatologic surgery annually in Australia (6751 tonnes from private clinical rooms and 1890 tonnes from hospitals) and the waste generated contributes significantly to terrestrial ecotoxicity and acidification of land and water. Various means can be carried out to reduce this impact, ranging from simple behavioural changes to larger, policy changes.

Grading your models: Assessing dynamics learning of models using persistent homology.

Assessing model accuracy for complex and chaotic systems is a non-trivial task that often relies on the calculation of dynamical invariants, such as Lyapunov exponents and correlation dimensions. Well-performing models are able to replicate the long-term dynamics and ergodic properties of the desired system. We term this phenomenon "dynamics learning." However, existing estimates based on dynamical invariants, such as Lyapunov exponents and correlation dimensions, are not unique to each system, not necessarily robust to noise, and struggle with detecting pathological errors, such as errors in the manifold density distribution. This can make meaningful and accurate model assessment difficult. We explore the use of a topological data analysis technique, persistent homology, applied to uniformly sampled trajectories from constructed reservoir models of the Lorenz system to assess the learning quality of a model. A proposed persistent homology point summary, conformance, was able to identify models with successful dynamics learning and detect discrepancies in the manifold density distribution.

Clinical and genetic differences between pustular psoriasis subtypes.

BACKGROUND: The term pustular psoriasis indicates a group of severe skin disorders characterized by eruptions of neutrophil-filled pustules. The disease, which often manifests with concurrent psoriasis vulgaris, can have an acute systemic (generalized pustular psoriasis [GPP]) or chronic localized (palmoplantar pustulosis [PPP] and acrodermatitis continua of Hallopeau [ACH]) presentation. Although mutations have been uncovered in IL36RN and AP1S3, the rarity of the disease has hindered the study of genotype-phenotype correlations. OBJECTIVE: We sought to characterize the clinical and genetic features of pustular psoriasis through the analysis of an extended patient cohort. METHODS: We ascertained a data set of unprecedented size, including 863 unrelated patients (251 with GPP, 560 with PPP, 28 with ACH, and 24 with multiple diagnoses). We undertook mutation screening in 473 cases. RESULTS: Psoriasis vulgaris concurrence was lowest in PPP (15.8% vs 54.4% in GPP and 46.2% in ACH, P < .0005 for both), whereas the mean age of onset was earliest in GPP (31.0 vs 43.7 years in PPP and 51.8 years in ACH, P < .0001 for both). The percentage of female patients was greater in PPP (77.0%) than in GPP (62.5%; P = 5.8 × 10-5). The same applied to the prevalence of smokers (79.8% vs 28.3%, P < 10-15). Although AP1S3 alleles had similar frequency (0.03-0.05) across disease subtypes, IL36RN mutations were less common in patients with PPP (0.03) than in those with GPP (0.19) and ACH (0.16; P = 1.9 × 10-14 and .002, respectively). Importantly, IL36RN disease alleles had a dose-dependent effect on age of onset in all forms of pustular psoriasis (P = .003). CONCLUSIONS: The analysis of an unparalleled resource revealed key clinical and genetic differences between patients with PPP and those with GPP.