Host Genetic Associations with Salivary Microbiome in Oral Cancer.

Despite the growing recognition of a host genetic effect on shaping gut microbiota composition, the genetic determinants of oral microbiota remain largely unexplored, especially in the context of oral diseases. Here, we performed a microbiome genome-wide association study in 2 independent cohorts of patients with oral squamous cell carcinoma (OSCC, n = 144 and 67) and an additional group of noncancer individuals (n = 104). Besides oral bacterial dysbiosis and signatures observed in OSCC, associations of 3 loci with the abundance of genus-level taxa and 4 loci with ß diversity measures were detected (q < 0.05) at the discovery stage. The most significant hit (rs10906082 with the genus Lachnoanaerobaculum, P = 3.55 × 10-9 at discovery stage) was replicated in a second OSCC cohort. Moreover, the other 2 taxonomical associations, rs10973953 with the genus Kingella (P = 1.38 × 10-9) and rs4721629 with the genus Parvimonas (P = 3.53 × 10-8), were suggestive in the meta-analysis combining 2 OSCC cohorts. Further pathway analysis revealed that these loci were enriched for genes in regulation of oncogenic and angiogenic responses, implicating a genetic anchor to the oral microbiome in estimation of casual relationships with OSCC. Our findings delineate the role of host genotypes in influencing the structure of oral microbial communities.

Pre-operative Halo-Pelvic Traction for Neurofibromatosis Patients with Severe Proximal Thoracic Spinal Deformity: Indications and Early Treatment Outcome.

INTRODUCTION: To report the indications and early treatment outcomes of pre-operative halo-pelvic traction in patients with neurofibromatosis associated with severe proximal thoracic (PT) spinal deformity. MATERIALS AND METHODS: We reviewed four patients with neurofibromatosis with severe PT spinal deformity. Case 1, a 16-year-old male presented with severe PT kyphoscoliosis (scoliosis: 89°, kyphosis: 124°) and thoracic myelopathy. Case 2 was a 14-year-old, skeletally immature male who presented with a PT lordoscoliosis (scoliosis: 85°). Case 3, a 13-year-old male, presented with severe PT kyphoscoliosis (scoliosis: 100°, kyphosis: 95°). Case 4, a 35-year-old gentleman, presented with severe PT kyphoscoliosis (scoliosis: 113°, kyphosis: 103°) and thoracic myelopathy. All patients underwent pre-operative halo-pelvic traction. After a period of traction, all patients underwent posterior spinal fusion (PSF) with autologous bone grafts (local and fibula bone grafts) and recombinant human bone morphogenetic protein-2 (rhBMP-2). RESULTS: Both patients with thoracic myelopathy regained near normal neurological status after halo-pelvic traction. Following traction, the scoliosis correction rate (CR) ranged from 18.0% to 38.9%, while the kyphosis CR ranged from 14.6% to 37.1%. Following PSF, the scoliosis CR ranged from 24.0% to 58.8%, while the kyphosis CR ranged from 29.1% to 47.4%. The total distraction ranged from 50-70mm. Duration of distraction ranged from 26-95 days. The most common complication encountered during halo-pelvic traction was pin-related e.g. pin tract infection, pin loosening and migration, osteomyelitis, and halo-pelvic strut breakage. No patients had cranial nerve palsies or neurological worsening. CONCLUSION: Pre-operative correction of severe PT spinal deformities could be performed safely and effectively with the halo-pelvic device prior to definitive surgery.

Supportive care in the acute phase of Stevens-Johnson syndrome and toxic epidermal necrolysis: an international, multidisciplinary Delphi-based consensus.

BACKGROUND: Supportive care is the cornerstone of management of adult and paediatric Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, consensus on the modalities of supportive care is lacking. OBJECTIVES: Our aim in this international multicentric Delphi exercise was to establish a multidisciplinary expert consensus to standardize recommendations regarding supportive care in the acute phase of SJS/TEN. METHODS: Participants were sent a survey via the online tool SurveyMonkey, consisting of 103 statements organized into 11 topics: multidisciplinary team composition, suspect drug management, infection prevention, fluid resuscitation and prevention of hypothermia, nutritional support, pain and psychological distress management, management of acute respiratory failure, local skincare, ophthalmological management, management of other mucosa, and additional measures. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). The results were analysed according to the RAND/UCLA Appropriateness Method. RESULTS: Forty-five participants from 13 countries (on three continents) participated. After the first round, a consensus was obtained for 82.5% of the 103 initially proposed statements. After the second round, a final consensus was obtained for 102 statements. CONCLUSIONS: We have reached an international Delphi-based consensus on best supportive care practice for SJS/TEN. Our expert consensus should help guide physicians in treating patients with SJS/TEN and thereby improve short-term prognosis and the risk of sequelae.

The risk of anti-osteoporotic agent-induced severe cutaneous adverse drug reactions and their association with HLA.

BACKGROUND: There is increasing use of anti-osteoporotic agents (AOA) worldwide for prevention or management of patients with osteoporosis. However, there have been reports of severe cutaneous adverse reactions (SCAR) induced by AOA. A recent study showed weak association between HLA and strontium ranelate (SR)-SCAR. OBJECTIVE: To characterize patients with AOA-SCAR and investigate the HLA association and utility of in vitro diagnostic methods. METHODS: We enrolled 16 cases with AOA-cutaneous adverse drug reactions (cADR), including SCAR (n = 10: 8 with Stevens-Johnson syndrome [SJS] and 2 with drug rash with eosinophilia and systemic symptoms [DRESS]) and maculopapular exanthema (MPE) (n = 6) from Taiwan and Hong Kong. We analysed the clinical characteristics, outcomes, HLA alleles and in vitro testing of AOA-SCAR, and tolerability to alternative drugs. We further performed literature review and meta-analysis on the HLA association of AOA-SCAR. RESULTS: Our data showed strontium ranelate is the most common causality of AOA-SCAR in Asian populations. There was no cross-hypersensitivity of SR-SCAR with other AOA. HLA genotyping showed that SR-SJS was most significantly associated with HLA-A*33:03 (Pc = 5.17 × 10-3 , OR: 25.97, 95% CI: 3.08-219.33). Meta-analysis showed that HLA-A*33:03 was associated with SR-SJS (P = 5.01 × 10-5 ; sensitivity: 85.7%) in Asians. The sensitivity of lymphocyte activation test (LAT) for identifying the culprit drug of SR-SJS was 83.3%. CONCLUSIONS: Strontium ranelate is identified as the most notorious AOA associated with SCAR. The HLA-A*33:03 genetic allele and LAT testing may add benefits to the diagnosis of SR-SCAR in patients whose reaction developed while taking multiple drugs.

Minimally Invasive versus Conventional Open Surgery for Fixation of Spinal Fracture in Ankylosed Spine.

INTRODUCTION: This was a retrospective study aimed to investigate the perioperative outcomes of long construct minimally invasive spinal stabilisation (MISt) using percutaneous pedicle screws (PPS) versus conventional open spinal surgery in the treatment of spinal fracture in ankylosing spondylitis (AS) and diffuse idiopathic skeletal hyperostosis (DISH). MATERIAL AND METHODS: Twenty-one patients with AS and DISH who were surgically treated between 2009 and 2017 were recruited. Outcomes of interest included operative time, intra-operative blood loss, complications, duration of hospital stay and fracture union rate. RESULTS: Mean age was 69.2 ± 9.9 years. Seven patients had AS and 14 patients had DISH. 17 patients sustained AO type B3 fracture and 4 patients had type B1 fracture. Spinal trauma among these patients mostly involved thoracic spine (61.9%), followed by lumbar (28.6%) and cervical spine (9.5%). MISt using PPS was performed in 14 patients (66.7%) whereas open surgery in 7 patients (33.3%). Mean number of instrumentation level was 7.9 ± 1.6. Mean operative time in MISt and open group was 179.3 ± 42.3 minutes and 253.6 ± 98.7 minutes, respectively (p=0.028). Mean intra-operative blood loss in MISt and open group was 185.7 ± 86.4ml and 885.7 ± 338.8ml, respectively (p<0.001). Complications and union rate were comparable between both groups. CONCLUSION: MISt using PPS lowers the operative time and reduces intra-operative blood loss in vertebral fractures in ankylosed disorders. However, it does not reduce the perioperative complication rate due to the premorbid status of the patients. There was no significant difference in the union rate between MISt and open surgery.

Delayed Post-operative Spinal Epidural Haematoma after Posterior Spinal Surgery: Report of Two Cases.

Delayed post-operative spinal epidural haematoma (DPSEH) is diagnosed when the onset of symptoms is more than three days from the index surgery. DPSEH is a rare but serious complication of spinal surgery. Missed diagnosis will result in irreversible neurological deficit which may lead to permanent disabilities. We report two cases of DPSEH who presented with worsening neurological deficit four days after the index surgery. Magnetic resonance imaging (MRI) showed the presence of an epidural haematoma compressing the spinal cord. Surgical evacuation of haematoma were performed for both patients. Both patients experienced neurological improvement. Surgeons should have high index of suspicion to identify delayed onset of spinal epidural haematoma (SEH) and timely intervention should be taken to avoid irreversible neurological damage.

Serum and blister-fluid elevation and decreased epidermal content of high-mobility group box 1 protein in drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis.

BACKGROUND: High-mobility group box 1 (HMGB1) is a damage-associated molecular-pattern protein. Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are serious, immune-mediated skin-blistering conditions. OBJECTIVES: To determine serum and/or blister-fluid total HMGB1 levels in SJS/TEN cohorts, and HMGB1 expression in formalin-fixed, paraffin-embedded (FFPE) SJS/TEN skin vs. healthy and maculopapular exanthema (MPE) skin. Methods Serum HMGB1 was quantified in Malawian nevirapine-induced hypersensitivity, Taiwanese SJS/TEN and Spanish SJS/TEN cohorts. FFPE skin (healthy skin, MPE, SJS/TEN) was stained and assessed for HMGB1 expression. RESULTS: Serum total HMGB1 was not significantly elevated in patients with nevirapine-induced SJS/TEN (3·98 ± 2·17 ng mL-1 ), MPE (3·92 ± 2·75 ng mL-1 ) or drug reaction with eosinophilia and systemic symptoms (4·73 ± 3·00 ng mL-1 ) vs. tolerant controls (2·97 ± 3·00 ng mL-1 ). HMGB1 was significantly elevated in Taiwanese patients with SJS/TEN, highest during the acute phase (32·6 ± 26·6 ng mL-1 ) vs. the maximal (19·7 ± 23·2 ng mL-1 ; P = 0·007) and recovery (24·6 ± 25·3 ng mL-1 ; P = 0·027) phases. In blister fluid from Spanish patients with SJS/TEN, HMGB1 (486·8 ± 687·9 ng mL-1 ) was significantly higher than in serum (8·8 ± 7·6 ng mL-1 ; P <0·001). Preblistered SJS/TEN skin showed decreased epidermal nuclear HMGB1 expression in upper epidermis vs. healthy or MPE skin but retained basal/suprabasal expression. CONCLUSIONS: Epidermal HMGB1 expression was decreased in SJS/TEN skin. Retained basal/suprabasal epidermal HMGB1 expression may exacerbate localized injury in SJS/TEN.

Periorbital erythema and swelling as a presenting sign of lupus erythematosus in tertiary referral centers and literature review.

Background Cutaneous lupus erythematosus (CLE) includes a broad range of dermatologic manifestations. Periorbital involvement, however, is a relatively rare clinical presentation of CLE. Objectives This clinical study aimed to investigate the characteristics of this unique presentation of CLE in tertiary medical centers. Methods We enrolled patients with periorbital erythema and swelling as the presenting sign of lupus erythematosus, from January 2003 to November 2017, using the data of 553 pathologically proven CLE cases from the registration database of the Chang Gung Memorial Hospitals in Taiwan. Results We enrolled a total of 25 patients. The mean age was 46.7 years and 68% of the patients were female. Most of the patients (84.0%) presented with unilateral involvement, with the left orbit involved in 15 patients (60%); the upper eyelid was the most frequently involved (72%). Mean duration between the onset of clinical manifestations and the diagnosis of CLE was approximately 59 weeks. Nineteen patients had been previously misdiagnosed. All patients had features compatible with CLE on histopathological examination. In contrast, laboratory analysis of the autoimmune profile often revealed negative results, including those for antinuclear antibodies (25%). Notably, anti-SSA/SSB (45.5%) showed the highest positive rate. During follow-up, six patients developed systemic lupus erythematosus (SLE) and two patients developed Sjögren syndrome. Conclusions The diagnosis of CLE presenting as periorbital erythema and swelling is often delayed because of clinical mimicry and the high proportion of negative results on autoantibody tests. Increased clinical suspicion and prompt histopathological examination are crucial for early diagnosis. Moreover, one-fourth of the patients ultimately developed SLE, which highlights the importance of clinical awareness.

Delayed-type hypersensitivity reactions induced by proton pump inhibitors: A clinical and in vitro T-cell reactivity study.

BACKGROUND: Proton pump inhibitors (PPIs) have been known to induce type I hypersensitivity reactions. However, severe delayed-type hypersensitivity reactions (DHR) induced by PPI, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS), are rarely reported. We conducted a study of a large series of PPI-related DHR, followed up their tolerability to alternative anti-ulcer agents, and investigated the T-cell reactivity to PPI in PPI-related DHR patients. METHODS: We retrospectively analyzed patients with PPI-related DHR from multiple medical centers in Taiwan during the study period January 2003 to April 2016. We analyzed the causative PPI, clinical manifestations, organ involvement, treatment, and complications. We also followed up the potential risk of cross-hypersensitivity or tolerability to other PPI after their hypersensitivity episodes. Drug lymphocyte activation test (LAT) was conducted by measuring granulysin and interferon-γ to confirm the causalities. RESULTS: There were 69 cases of PPI-related DHR, including SJS/TEN (n=27) and DRESS (n=10). The LAT by measuring granulysin showed a sensitivity of 59.3% and specificity of 96.4%. Esomeprazole was the most commonly involved in PPI-related DHR (51%). Thirteen patients allergic to one kind of PPI could tolerate other structurally different PPI without cross-hypersensitivity reactions, whereas three patients developed cross-hypersensitivity reactions to alternative structurally similar PPI. The cross-reactivity to structurally similar PPI was also observed in LAT assay. CONCLUSIONS: PPIs have the potential to induce life-threatening DHR. In patients when PPI is necessary for treatment, switching to structurally different alternatives should be considered.

[Diagnostic criteria for Menière's disease according to the Classification Committee of the Bárány Society]. / M. Menière: Diagnostische Kriterien des Internationalen Klassifikationskomitees der Bárány-Gesellschaft.

This paper presents diagnostic criteria for Menière's disease jointly formulated by the Classification Committee of the Bárány Society, The Japan Society for Equilibrium Research, the European Academy of Otology and Neurotology (EAONO), the Equilibrium Committee of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) and the Korean Balance Society. The classification includes two categories: definite Menière's disease and probable Menière's disease. The diagnosis of definite Menière's disease is based on clinical criteria and requires the observation of an episodic vertigo syndrome associated with low- to medium-frequency sensorineural hearing loss and fluctuating aural symptoms (hearing, tinnitus and/or fullness) in the affected ear. Duration of vertigo episodes is limited to a period between 20 min and 12 h. Probable Menière's disease is a broader concept defined by episodic vestibular symptoms (vertigo or dizziness) associated with fluctuating aural symptoms occurring in a period from 20 min to 24 h.

Complete genome sequence of the Bifidobacterium animalis subspecies lactis BL3, preventive probiotics for acute colitis and colon cancer.

We report the genome sequence of Bifidobacterium animalis subspecies lactis BL3, which has preventive properties on acute colitis and colon cancer. The genome of BL3, which was isolated from Korean faeces, consisted of a 1 944 323 bp size single chromosome, and its G+C content was 60.5%. Genome comparison against the closest Bifidobacterium animalis strain revealed that BL3 had particularly different regions of four areas encoding flavin-nucleotide-binding protein, transposase, multidrug ABC transporter and ATP binding protein.

Secular trends in caesarean section rates over 20 years in a regional obstetric unit in Hong Kong.

INTRODUCTION: Although caesarean section rates have been increasing over the years in both public and private sectors in Hong Kong, there has been a paucity of formal surveys on local trends in such rates. This study aimed to examine the trends in caesarean section rates over a 20-year period at a public regional obstetric unit in Hong Kong using the Robson's Ten-group Classification System. METHODS: All deliveries in a single obstetric unit during a 20-year period (1995-2014) were classified into 10 subgroups according to the Robson's classification. The annual caesarean section rate for each subgroup was calculated and then stratified into 5-year intervals to analyse any significant trends. RESULTS: The caesarean section rates in a total of 86 262 births with complete data were analysed. The overall caesarean section rate increased modestly from 15.4% to 24.6% during the study period. There was an obvious increasing trend for caesarean section in those with previous caesarean section (Robson's category 5), breech presentation at delivery (category 6 and 7), multiple pregnancy (category 8), and preterm labour (category 10). A gradual fall in caesarean section rate from 14.4% to 10.8% was seen in primiparous women with term spontaneous labour (category 1). Statistically significant differences (P<0.001) in these trends were confirmed when the data were stratified into 5-year intervals for comparison. CONCLUSION: The rising caesarean section rate may be associated with clinical management policies that allow women with relative risk factors (such as breech, previous caesarean section, or multiple pregnancy) to opt for caesarean section. This rise was counterbalanced by a decrease in primary caesarean section rate in primiparous women with spontaneous labour. The trend for caesarean section was more in line with patient expectations rather than evidence-based practice.

Pharmacogenomic Advances in the Prediction and Prevention of Cutaneous Idiosyncratic Drug Reactions.

Cutaneous idiosyncratic drug reactions (CIDRs) are usually unpredictable, ranging from mild maculopapular exanthema (MPE) to severe cutaneous adverse drug reactions (SCARs) such as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Increasing evidence suggests that HLA alleles are strongly associated with drug-induced-CIDRs. The pathomechanisms for CIDRs include genetic polymorphisms affecting complex immune-specific HLA/drug antigen/T-cell receptor interactions and drug metabolism. Pharmacogenomic tests to prevent CIDRs have been widely implemented in clinical practice in recent years.

Association of HLA-B*15:13 and HLA-B*15:02 with phenytoin-induced severe cutaneous adverse reactions in a Malay population.

Phenytoin (PHT) is a common cause of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Although HLA-B*15:02 is associated with PHT-induced SJS/TEN (PHT-SJS/TEN) in Han Chinese and Thais, the genetic basis for susceptibility to PHT-induced SCARs (PHT-SCAR) in other populations remains unclear. We performed a case-control association study by genotyping the human leukocyte antigen (HLA)-B alleles of 16 Malay PHT-SCAR patients (13 SJS/TEN and 3 DRESS), 32 PHT-tolerant controls and 300 healthy ethnicity-matched controls. A novel genetic biomarker, HLA-B*15:13, showed significant association with PHT-SJS/TEN (53.8%, 7/13 cases) (odds ratio (OR) 11.28, P=0.003) and PHT-DRESS (100%, 3/3 cases) (OR 59.00, P=0.003) when compared with PHT-tolerant controls (9.4%, 3/32 controls). We also confirmed HLA-B*15:02 association with PHT-SJS/TEN (61.5%, 8/13 cases vs 21.9%, 7/32 controls; OR 5.71, P=0.016) when compared with PHT-tolerant controls. These alleles may serve as markers to predict PHT-SCAR in Malays.

Identification of differentially expressed genes in longissimus muscle of pigs with high and low intramuscular fat content using RNA sequencing.

Intramuscular fat (IMF) content in pork is an important element of consumer preference and is positively correlated with meat quality, including tenderness and juiciness. With advances in RNA sequencing technologies, transcriptome-related differences can be associated with specific traits in animals. The objective of this study was to investigate differentially expressed genes (DEGs) closely related to IMF content in porcine longissimus muscle using RNA sequencing. A total of 107 Berkshire pigs were used for IMF content measurements, and significant differences between extremely high (H, n = 3) and low (L, n = 3) IMF content groups were found (P < 0.0001). From multi-dimensional scaling analyses, it was observed that the relationships between H and L groups were similar to each other. Here, we identified a total of 134 genes that were differentially expressed between the groups (false discovery rate <0.05; fold change ≥2). Functional analyses with DEGs revealed that lipid metabolism (SCD and FASN) was one of the significant biological processes related to IMF content determination. In addition, we found that DEGs related to muscle regeneration (MYOG and VEGFA) and extracellular matrix (COL1A1, COL1A2, COL5A1, COL14A1 and COL15A1) were changed among individuals with extreme IMF contents. These results will aid in understanding the regulation of IMF content in pigs.