Association of COVID-19 with skin diseases and relevant biologics: a cross-sectional study using nationwide claim data in South Korea.

BACKGROUND: As the coronavirus disease 2019 (COVID-19) pandemic has spread, information about COVID-19 and skin disease or related biologics is still lacking. OBJECTIVES: To identify the association between COVID-19 and skin diseases or biologics. METHODS: A nationwide claim dataset relevant to COVID-19 in South Korea was analysed. This dataset included insurance claim data before and during COVID-19 treatment and clinical outcomes. Claim data related to skin diseases and relevant biologics were analysed to determine the association of COVID-19 with skin diseases and relevant biologics. RESULTS: The dataset contained a total of 234 427 individuals (111 947 male and 122 480 female) who underwent COVID-19 testing. Of them, 7590 (3·2%) were confirmed as having COVID-19, and 227 (3·0%) confirmed patients died. Among various skin diseases and biologics, no significant increase in the presence of specific skin diseases or exposure to biologics was observed in the COVID-19-positive group, even after adjusting for or matching covariates. The presence of skin diseases and exposure to biologics also did not seem to affect clinical outcomes including mortality. CONCLUSIONS: Underlying skin diseases did not appear to increase susceptibility to COVID-19 or mortality from COVID-19. Considering the risks and benefits, biologics for dermatological conditions might be continuously used during the COVID-19 pandemic.

Lymph node size is not a reliable criterion for predicting nodal metastasis in rectal neuroendocrine tumours.

AIM: The study was designed to assess the correlation between lymph node (LN) size and LN metastasis in patients with rectal neuroendocrine tumours (NETs). METHOD: Forty patients who underwent curative resection with lymphadenectomy for a rectal NET between January 2007 and December 2012 were included. The short and long diameters of entire nodes were microscopically measured using a slide gauge. RESULTS: In all, 1052 LNs were collected from the 40 patients, with 49 (4.7%) showing evidence of metastasis. Metastasis-positive LNs had significantly greater long and short diameters (P < 0.001) than metastasis-negative LNs. Of the 49 metastatic LNs, 29 (59.2%) were ≤ 5 mm in largest diameter. In five patients, the largest metastatic LN was only 2-3 mm in diameter. In clinically node-negative (cN0) patients, 18 (51.4%) patients had metastatic LNs (pN1). CONCLUSION: The size of LNs containing metastasis varied widely, with some being very small. LN size alone is therefore not a sufficient predictor of tumour metastasis in rectal NETs. Radical surgery with lymphadenectomy should be considered for patients with rectal NETs with high risk factors for LN metastasis, even those without LN enlargement.

Comparative analysis of bacterial diversity and communities inhabiting the fairy ring of Tricholoma matsutake by barcoded pyrosequencing.

AIMS: Comparative analysis of the soil bacterial communities inhabiting the fairy ring of Tricholoma matsutake. METHODS AND RESULTS: The bacterial communities in soil samples collected from inside, beneath and outside the T. matsutake fairy ring were investigated using barcoded pyrosequencing. A total of 15 129 reads were obtained, and 500-536 operational taxonomic units were observed at a 97% similarity level. Taxonomic analysis showed similar taxa distribution patterns inside and beneath the fairy ring. Three bacterial phyla, Proteobacteria, Acidobacteria and Actinobacteria, were dominant in all sampling sites. A heat-map analysis of the bacterial genera showed that the uncultured bacterium EU445199 was remarkably abundant outside the fairy ring, and the uncultured bacteria GU727715 and DQ451510 were more and less abundant, respectively, beneath the fairy ring than inside and outside the fairy ring. CONCLUSIONS: The results indicated that there was no significant difference in bacterial diversity inside, beneath and outside the fairy ring even though T. matsutake is predominant beneath the fairy ring. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first report on the numerous culturable, unculturable and unclassified bacteria in the fairy ring of T. matsutake using the pyrosequencing method.

Optimizing EEMCO guidance for the assessment of dry skin (xerosis) for pharmacies.

PURPOSE: People with dry skin (xerosis) are common in community pharmacies, but there is no consistent guidance for community pharmacists to evaluate and alleviate dry skin. Through evaluating any difference of the clinical scoring systems of EEMCO guidance between a dermatologist and pharmacists and the efficacy of moisturizers for the treatment of dry skin recommended by community pharmacists, we aim to validate a dry skin guidance through the help of community pharmacists. These results provide insight into how community pharmacists can help patients with dry skin. METHODS: The clinical scoring systems of EEMCO guidance used in this study comprised analog scales, the overall dry skin score (ODS), and the specific symptom sum score (SRRC) system. All pictures of the dry skin scored by pharmacists were visually evaluated by a dermatologist. The efficacy of the moisturizers was determined by the difference of the scales on day 0 and on day 28. RESULTS: In this study, 387 patients with dry skin from 157 community pharmacies were evaluated by pharmacists. Visual scale with divisions, ODS and SRRC that were evaluated by pharmacists on day 0 and day 28 were moderately reliable by a dermatologist. All parameters of dry skin were significantly improved by the moisturizers which were recommended by community pharmacists on day 28. CONCLUSION: Visual scale, ODS and SRRC can be generally measured to evaluate dry skin in community pharmacies with moderate degree of reliability. This finding has possible applications for investigating the assessment of the community pharmacists on clinical scoring system of dry skin and moisturizers.

Pantothenate kinase-associated neurodegeneration in Korea: recurrent R440P mutation in PANK2 and outcome of deep brain stimulation.

BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the mutation status of PANK2 among Korean patients with pantothenate kinase-associated neurodegeneration (PKAN) and to document the outcome of pallidal deep brain stimulation (DBS). METHODS: Direct sequencing and deletion/duplication analysis of PANK2 were conducted in 12 patients (11 unrelated) with PKAN, diagnosed on the basis of extrapyramidal dysfunction and the 'eye-of-the-tiger sign' on brain magnetic resonance imaging (MRI). Pallidal DBS was conducted in four patients, and the outcomes were measured using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). RESULTS: A PANK2 mutation was identified in both alleles in all patients. The most prevalent mutation was c.1319G>C (p.R440P) in 8/22 mutated alleles (36%). An intragenic deletion ranging from exons 2 to 4 was found in one allele (1/22, 4.5%) using deletion/duplication analysis. The outcome of pallidal DBS was favorable in two patients with atypical PKAN and moderate severity of dystonia. However, two patients with typical PKAN and relatively severe symptoms showed variable responses. CONCLUSIONS: The c.1319G>C (p.R440P) mutation appears to be a founder genotype among Korean patients with PKAN. Furthermore, this study provides additional data for the recent international effort to evaluate the efficacy of pallidal DBS in the treatment of patients with PKAN.

Metabolic parameters and nonalcoholic fatty liver disease in hypopituitary men.

Patients with hypopituitarism have the feature of metabolic syndrome, including central obesity, insulin resistance, and dyslipidemia. Because metabolic syndrome, including insulin resistance, is the main pathogenesis of the development of nonalcoholic fatty liver disease (NAFLD), we considered that patients diagnosed with hypopituitarism have an increased risk of developing NAFLD. We compared control subjects and hypopituitary men in metabolic parameters and the frequency of fatty liver on abdominal ultrasonography, and analyzed associating factors with the severity of the fatty liver in patients with hypopituitarism. 34 male patients with hypopituitarism and 40 age and sex-matched control subjects were included. The frequency of fatty liver on abdominal ultrasonography was significantly higher in hypopituitary men compared to control subjects (32.5% vs. 70.6%, p=0.001). Ln CRP and free fatty acids were significantly elevated in hypopituitary patients with fatty liver compared to patients without fatty liver. Ln GH was significantly lower in hypopituitary patients with fatty liver. The severity of fatty liver on abdominal ultrasonography correlated with negatively Ln GH, after adjusting for the BMI effect (p=0.020). There is a difference only between the severe fatty liver group and normal liver group in the analysis of the mean Ln GH level between 4 groups according to the severity of fatty liver (p=0.036). In conclusion, NAFLD is more common in hypopituitary patients than control subject. Severe growth hormone deficiency in hypopituitarism was associated with the severe degree of hepatic steatosis in NAFLD.

High intra- and inter-individual variability of plasma vitamin K concentrations in patients with atrial fibrillation under warfarin therapy.

BACKGROUND/OBJECTIVES: Vitamin K intake is considered as a controllable contributor to warfarin sensitivity. It is restricted in warfarin-treated patients. However, little study has assessed the vitamin K status in warfarin-treated patients. We directly measured plasma vitamin K in warfarin-treated patients and evaluated its effect on anticoagulation. SUBJECTS/METHODS: A total of 302 plasma vitamin K concentrations were assessed using high-performance liquid chromatography for 203 outpatients with atrial fibrillation under warfarin treatment. Clinical and laboratory information including warfarin dosage, plasma warfarin concentrations, prothrombin time international normalized ratio (PT INR) and CYP2C9/VKORC1 genotypes was reviewed retrospectively. The anticoagulation stability (intra-individual variability, frequency of PT INR tests and complications) was investigated in 163 patients with long-term warfarin therapy. Plasma vitamin K was measured in 40 healthy subjects and in 40 patients before and after initial warfarin treatment. RESULTS: Vitamin K concentrations were significantly decreased after the initiation of warfarin treatment (before treatment: 1.72 ng/ml; after treatment: 0.59 ng/ml, P<0.05). There was a large inter-individual variability in vitamin K levels (0.2-4.2 ng/ml) in warfarin-treated patients. PT INR was more frequently checked in patients with low plasma vitamin K levels than in those with high vitamin K levels (9.5 times/year vs 7.5 times/year, P=0.029). Two patients with gross hematuria showed very low vitamin K levels (<0.4 ng/ml). CONCLUSIONS: We found high inter- and intra-individual variability in vitamin K concentration in warfarin-treated patients. Low vitamin K concentration in warfarin-treated patients suggested excessive dietary restriction. Plasma vitamin K measurement would be helpful for dietary control and anticoagulation stability.

The geography of survival after surgery for colo-rectal cancer in southern England.

This study investigates variations in survival following surgery for colo-rectal cancer in the Wessex region (part of southern England), using 5147 cases diagnosed between 1 September 1991 and 31 August 1995. Survival curve estimation by life tables and Cox's proportional hazards model were used to examine geographical variation in cancer survival, with a specific focus on distance between place of residence and treatment centre, and district of treatment. We also consider whether area deprivation has an impact on survival. In seeking to answer these questions we control for possible confounders, including: age, gender, site of tumour, stage of disease at operation, hospital size and surgery type (whether elective or non-elective). District of treatment, distance and deprivation all show a relationship to outcome using survival curves, but when adjusting for other covariates using the Cox model, and considering deaths from all causes, only district of treatment was a very significant covariate (p < 0.0001). Distance, deprivation, and gender were only weakly significant (p < 0.10). Considering only deaths related to operation (within 30 days) district of treatment remained significant, but while distance had some effect on outcome, deprivation and gender ceased to be significant covariates. There is some evidence that those who live furthest from centres of treatment have the worst outcomes but the 'geography of survival' manifests itself more through where patients are treated than through area (deprivation) effects or relative location. The results have important policy implications, as they show variations among treatment centres having controlled for potentially confounding factors.

An analytical investigation of the mechanics of spinal instrumentation.

Three-dimensional nonlinear finite element models of the intact L4-5 one motion segment/two-vertebrae and L3-5 two motion segments/three-vertebrae were developed using computed tomography (CT) films. The finite element mesh of the L4-5 motion segment model was modified to simulate bilateral decompression surgery. The mesh was further altered to achieve stabilization, using an interbody bone graft and a set of Steffee plates and screws. The model behavior of the intact specimen in all loading modes and of the stabilized model in compression, flexion, and extension modes were studied. The stresses in the cancellous bone region were found to decrease. The interbody bone graft, due to an overall decrease in stresses in the bone below the screw, transmits about 80% of the axial load as compared with 96% transmitted by an intact disc in an intact model. Thus, the use of a fixation device induces a stress shielding effect in the vertebral body. The results indicate that although the bone graft transmits lesser loads than the intact disc, it is active in transmitting loads. The presence of low stresses in the cancellous bone region and high localized stresses in the cortical pedicle region surrounding the screw, compared with the intact case, suggests that the screws are likely to become loose over time. The use of an interbody bone graft alone or in combination with any existing fixation device also induces higher stresses at the adjacent levels. This may be responsible for the adverse iatrogenic effects seen clinically.

Effect of disc degeneration at one level on the adjacent level in axial mode.

Nonlinear three-dimensional finite element models of a ligamentous two motion segments spine specimen (L3-L4-L5) were developed to investigate the effects of disc degeneration, simulated at the L4-L5 level, on the biomechanical behavior of the adjacent intact L3-L4 motion segment. The disc degeneration was simulated by removing the hydrostatic capabilities of the nucleus and making the L4-L5 disc stiffer than a normal disc. The results of the degenerated model were compared with the predictions for a model in which the L4-L5 disc was left intact. The loads on the facets decreased, and intradiscal pressure in the intact L3-L4 disc increased as a result of disc degeneration compared with the intact model. The predicted increase in the intradiscal pressure and the associated increase in the disc bulge in the posterior region over time may trigger the degenerative process at the L3-L4 motion segment. This is in accordance with the Wolff's law; living tissue responds to chronic changes in stresses and strains. The limitations of the present two motion segments model and the potentials of multisegmental models are discussed.

Impact response of the intervertebral disc in a finite-element model.

STUDY DESIGN: A three-dimensional nonlinear poroelastic finite-element model of a vertebra disc was used to analyze the biomechanical effects of impact loading on the spinal segment. OBJECTIVES: To predict changes in biomechanical parameters such as intradiscal pressure, dynamic stiffness, stresses in the endplate region, and the shock-absorbing mechanism of the spine under different impact duration/loading rates, and to investigate the relation between the rate of loading and the fracture potential of the vertebral body. SUMMARY OF BACKGROUND DATA: It is not practical to discern the role of impact duration using experimental protocols. Analytical studies are better suited to this purpose. However, previous poroelastic finite-element models of the motion segments have dealt mostly with creep phenomena. METHODS: A three-dimensional, L3-L4 motion-segment, finite-element model was modified to incorporate the poroelastic properties of the disc, endplate, and cancellous core, and thus simulate the shock-absorbing phenomena. The results were analyzed under variable impact durations for a constant maximum compressive impact load of 3 kN. RESULTS: For a shorter impact duration and a given F(max), relatively high cancellous core pressure was generated as compared with a case of long impact duration, although the amount of impulse was increased. In contrast, relatively constant pore pressures were generated in the nucleus regardless of the impact duration. The changes in spinal segment stiffness as a function of impact duration indicated that for a shorter duration of impact, high dynamic stiffness increases the stability of the spinal segment against the impact load. However, the corresponding increase in stresses within the vertebral body and endplate may produce fractures. CONCLUSIONS: The finite-element technique was used to address the role of impact duration in producing trauma to the spinal motion segment. Within the limitations of the model, the results suggest that fractures are likely to occur under shorter impact duration conditions. Depending on the strength of the region, a fracture may be initiated in the endplate region or the posterior wall of the cortical shell. The nucleus pressure is independent of the impact duration and depends only on the magnitude of the impact force.

Effects of injury on the spinal motion segment mechanics in the axial compression mode.

The changes in the biomechanical characteristics of a ligamentous motion segment as a result of two clinically relevant injuries are investigated using the finite element technique. A three-dimensional, finite element model of a one-half intact motion segment was developed from 1 mm thick transverse CT cross-sections of a lumbar spine specimen. A total denucleation with other structures left intact, and bilateral total discectomy injuries induced in the intact model, led to an approximately two-fold decrease in the disc height and a similar increase in flexion-rotation, in comparison to the intact model. The total removal of the nucleus simulated in both of the injury models increased the force per unit area of contact across the facets. The stresses in the region adjacent to the facets also increased as a consequence of this. Due to the presence of facets and an increase in load transmitted across them, the change in stresses in the vertebral body for the two injury models in comparison to the intact model was not severe. The disc bulge in the posterior region decreased following the two injuries.

Effect of FK506 ointment (Protopic) on rat skin allograft model.

OBJECTIVE: FK-506 (tacrolimus) is a well known immunosuppressive agent used to prevent allograft rejection. The need for chronic allograft immunosuppression and the consequent harmful systemic effects preclude the use of tissue allograft as a routine surgical reconstructive option. This study assessed the effects of FK-506 ointment (Protopic) therapy versus subcutaneous injection of FK-506 (Prograf) on rat skin graft model. METHODS: Donor Wistar rat dorsal skin was grafted to recipient Sprague-Dawley rats. Animals groups were divided into 2 groups: Group I was treated with intravenous injection of FK-506, and group II was treated with FK-506 ointment for 2 weeks after surgery. Graft appearance challenges were assessed. RESULTS: FK506 ointment could prolong the median allograft survival time (16.7 days) compared with group I (15.8). Hematoxylin-eosin staining performed on the allo-skin biopsy samples obtained from both group I and II animals at 2 weeks after graft revealed moderate degree of skin rejection accompanied by mixed lymphocyte infiltration. Tacrolimus mean blood levels were much lower in group II (<0.2 ng/mL) than in group I (0.45 ng/mL) CONCLUSIONS: Immunosuppressive FK506 ointment therapy has similar effect to intravenous injection and it could be a useful therapy in the prevention of skin allograft rejection.

Critical role of presenilin-dependent γ-secretase activity in DNA damage-induced promyelocytic leukemia protein expression and apoptosis.

Promyelocytic leukemia (PML) is a major component of macromolecular multiprotein complexes called PML nuclear-bodies (PML-NBs). These PML-NBs recruit numerous proteins including CBP, p53 and HIPK2 in response to DNA damage, senescence and apoptosis. In this study, we investigated the effect of presenilin (PS), the main component of the γ-secretase complex, in PML/p53 expression and downstream consequences during DNA damage-induced cell death using camptothecin (CPT). We found that the loss of PS in PS knockout (KO) MEFs (mouse embryonic fibroblasts) results in severely blunted PML expression and attenuated cell death upon CPT exposure, a phenotype that is fully reversed by re-expression of PS1 in PS KO cells and recapitulated by γ-secretase inhibitors in hPS1 MEFs. Interestingly, the γ-secretase cleavage product, APP intracellular domain (AICD), together with Fe65-induced PML expression at the protein and transcriptional levels in PS KO cells. PML and p53 reciprocally positively regulated each other during CPT-induced DNA damage, both of which were dependent on PS. Finally, elevated levels of PML-NB, PML protein and PML mRNA were detected in the brain tissues from Alzheimer's disease (AD) patients, where γ-secretase activity is essential for pathogenesis. Our data provide for the first time, a critical role of the PS/AICD-PML/p53 pathway in DNA damage-induced apoptosis, and implicate this pathway in AD pathogenesis.

Antiviral prophylaxis versus preemptive therapy to prevent cytomegalovirus infection and related death in liver transplantation: a retrospective study with propensity score matching.

BACKGROUND: Cytomegalovirus (CMV), the most significant viral infection in liver transplant recipients, is addressed by 2 methods: Preemptive therapy (PT) or universal prophylaxis (UP). METHODS: We analyzed medical records including at least 1 year follow-up of patients who underwent liver transplantation from 2006 to 2009 in 3 tertiary hospitals. PT was used in 2 hospitals (PT group), whereas UP with valganciclovir for 3 months was adopted in the other hospital (UP group). The 2 groups were matched using propensity scoring by perioperative variables. We performed a 1:1 comparison of the efficacy of UP and PT. RESULTS: We analyzed 634 liver transplant patients, including 562 matched subjects. Baseline characteristics and underlying liver status were comparable. CMV immunoglobulin G of recipients was positive in 98.9% of the PT group and 99.3% of the UP group. CMV viremia episodes that required administration of an antiviral agent occurred in 26 (9.3%) PT and 37 (13.2%) UP subjects (P = .18). CMV-related mortalities were similar (0.7% vs 1.8%; P = .45), but all-cause mortality was higher in the PT group (18.5% vs 13.2%; P = .08). CONCLUSION: The efficacy of PT was similar to UP to prevent CMV disease and related mortality among a group at moderate risk for CMV infection.

Possible role of stresses in inducing spinal stenosis--a long term complication following disk excision.

A three-dimensional finite element model of an intact ligamentous lumbar motion segment (L3-4) was used to predict stresses in the pars interarticularis regions of the modeled vertebral bodies. The changes in stresses following disk excision, as compared to the intact model, also were computed. The predicted results show an increase in stresses in the posterior bony elements following disk excision. In some patients over a long period of time this increase in stresses, in association with other clinical factors, may lead to bony hypertrophy of the structures that surround the nerve roots. Ultimately, over a long period of time the increase in pressure on the entrapped nerve root may induce recurrent pain and other complications reported in the literature.

Load sharing among spinal elements of a motion segment in extension and lateral bending.

A linear optimization model was formulated using a semi-experimental protocol to estimate the forces in the spinal elements of a lumbar motion segment subjected to an extension or lateral bending moment with and without a 120 N compressive preload. A morphometer was used to acquire the three-dimensional locations of the disk center, facet centers and ligament origin and insertion sites with the specimen in a "neutral" position. The relative motion of the superior vertebra, under the loading conditions tested, was monitored using a Selspot II system. These data allowed the formulation of the static equilibrium equations for the superior vertebra at each of the loading conditions mentioned above. A linear optimization technique was used, along with a suitable cost function, to find an optimum solution for the set of equations and imposed constraints. Results showed that for 6.9 Nm of extension moment, each facet carried a load of 52 N, with the disk carrying an axial tensile load of 104 N. At the 6.9 Nm extension moment coupled with 120 N preload, each facet carried a load of 77.2 N and the disk an axial tensile load of 37 N. In right lateral bending, with and without preload, the load was distributed among the right facet, the disk, the left ligamentum flavum and the left capsular ligament. At the 6.9 Nm load step without preload the right facet carried an axial load of 127.01 N with the disk carrying an axial compressive load of 7.8 N. Ligament forces for this step for the left ligamentum flavum and capsular ligament, respectively, were 61.03 N and 65.14 N. The addition of 120 N of preload reduced the load on the right facet to 83.5 N. The compressive load in the disk increased to 107.5 N. The corresponding ligament forces were 43.2 N (left ligamentum flavum) and 50.7 N (left capsular ligament).

Comparison of transplacental and neonatal initiation of mouse lung and liver tumors by N-nitrosodimethylamine (NDMA) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and promotability by a polychlorinated biphenyls mixture (Aroclor 1254).

We have previously shown a positive tumor-promoting effect of a single dose of Aroclor 1254 on lung and liver tumors initiated neonatally in the mouse by N-nitrosodimethylamine (NDMA). In this study, we have confirmed and extended this observation with NDMA and the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) given either transplacentally or postnatally, followed by a single dose of Aroclor 1254 on day 56. This polychlorinated biphenyl (PCB) mixture was an effective promoter of both lung and liver tumors; however, there were specific initiator and sex-related differences in this response. Aroclor administration significantly increased the incidence of lung tumors initiated transplacentally by NDMA or NNK in male mice. Neither nitrosamine initiated tumors transplacentally in females, but lung tumors initiated with NNK and liver tumors caused by NDMA in neonatal females were promoted by PCBs. Both liver and lung tumors initiated neonatally by NDMA in male animals, but not NNK-initiated tumors, were promoted by PCBs. These data confirm that PCBs are able to promote both NDMA- and NNK-initiated tumors, but with chemical-, sex- and age-dependent difference; this suggests influences of both quantitative and qualitative factors in susceptibility to tumor promotion.