Pre-operative localisation of axillary lymph nodes using radiofrequency identification (RFID) tags: a feasibility assessment in 75 cases.

AIM: To evaluate the safety and feasibility of using radiofrequency identification (RFID) tags for the localisation of axillary nodes prior to targeted excision in a National Health Service (NHS) breast unit. MATERIALS AND METHODS: Retrospective data collection was carried out to analyse the first 75 cases of RFID-targeted axillary nodes inserted between 12 June 2019 and 27 October 2022, during which an overall total of 1,296 breast and axillary tags were deployed in 1,120 patients. RESULTS: Of the 75 axillary tags, 70 (93%) had a primary breast cancer and five (7%) had no known breast cancer but had an abnormal node targeted for diagnostic excision. Of the 70 with breast cancer, 20 (29%) underwent neoadjuvant chemotherapy (NAC) including one neoadjuvant endocrine therapy. Localisations were performed an average of 11 days before surgery (median 6, range 1-95; n=75). Patients undergoing NAC had their tags inserted after completing treatment due to the artefact caused by the tags on magnetic resonance imaging (MRI). Tag deployment had a 100% success rate, with 62 tags (83%) lying within the node and 13 tags (17%) lying directly adjacent to the node, either in direct contact (nine of 13), or a maximum of 8 mm from the target (four of 13). All tags and their respective nodes were excised successfully at surgery with no significant complications. There were four cases of tag dislodgement during excision, but overall, this did not compromise retrieval of the tag or the node. CONCLUSIONS: The use of RFID tags for the preoperative localisation of axillary nodes is safe and feasible.

Exhaled Pneumocystis jirovecii output and detection of asymptomatic exhalation by facemask sampling in HIV-uninfected, immunocompromised patients.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) transmission is poorly defined. Previous studies have sampled air of rooms occupied by HIV-infected patients with PJP, while natural and direct exhalations of HIV-uninfected subjects remain under-investigated. Here, clinical facemasks were used to examine and quantify potential P. jirovecii exhalations from HIV-uninfected patients with suspected PJP and to determine whether pathogen exhalation was definable clinically or radiologically. METHODS: Forty-five patients in Leicester (England), highly suspected of having PJP based on European Conference on Infections in Leukaemia (ECIL-5) guidelines, each wore one facemask carrying a gelatine/PVA sampling matrix for 1 h while respiring normally. Mask contamination with P. jirovecii was assessed using a modified quantitative polymerase chain reaction targeting mitochondrial large subunit (MtLSU). Radiological findings on chest X-ray (CXR) and computed tomography (CT) were graded and analysed for correlation with P. jirovecii signals alongside relevant clinical and laboratory findings. RESULTS: P. jirovecii was detected in seven of 20 patients diagnosed with PJP and three of 19 patients with suspected but undiagnosed PJP. The median captured signal was 8.59 × 104 MtLSU copies/mask (interquartile range (IQR) = 3.01 × 105-1.81 × 104). Blood ß-D-glucan test results correlated with the mask detection data (r = 0.65; P<0.0001) but other clinical indices and radiological features did not. Five of the 10 P. jirovecii-exhalers exhibited normal CXR with a median exhalation burden 1.28 × 105 copies/mask (IQR = 1.51 × 105-2.27 × 104). Two P. jirovecii-exhalers (7.64 × 104 copies/mask) were asymptomatic. CONCLUSION: P. jirovecii was exhaled sufficiently during normal respiration to be detectable in facemasks worn by HIV-uninfected patients. Neither clinical nor radiological features correlated with P. jirovecii exhalation.

Selective use of Peptide Receptor Radionuclide Therapy following comparative imaging of Ga-68 DOTATATE PET/CT against I-131 MIBG scintigraphy in a small Asian cohort of Adult Neuroblastoma.

Adult neuroblastoma (AN) is rare with an extremely poor prognosis. No standard therapy exists for this entity and treatment options are limited in recurrent or refractory disease. 131I-MIBG has been used in combination with myeloablative therapy before autologous bone marrow transplantation or in a salvage therapy setting. However, myelotoxicity is a dose-limiting factor in heavily pre-treated patients and response is not always sustained. Somatostatin receptor scintigraphy and theranostics with radiolabelled somatostatin receptor analogues are becoming more commonplace with the recognition of these receptors in over 90% of neuroblastoma cells. We describe three AN patients assessed for somatostatin receptor status and the novel use of 177Lu-based peptide recep-tor radionuclide therapy (PRRT) in two of them and a literature review.

COVID-19: Initial experience of an international group of hand surgeons.

The emergence of the COVID-19 pandemic has severely affected medical treatment protocols throughout the world. While the pandemic does not affect hand surgeons at first glance, they have a role to play. The purpose of this study was to describe the different measures that have been put in place in response to the COVID-19 pandemic by hand surgeons throughout the world. The survey comprised 47 surgeons working in 34 countries who responded to an online questionnaire. We found that the protocols varied in terms of visitors, health professionals in the operating room, patient waiting areas, wards and emergency rooms. Based on these preliminary findings, an international consensus on hand surgery practices for the current viral pandemic, and future ones, needs to be built rapidly.

Results from the Survey of Antibiotic Resistance (SOAR) 2016-18 in Vietnam, Cambodia, Singapore and the Philippines: data based on CLSI, EUCAST (dose-specific) and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints.

OBJECTIVES: To determine antibiotic susceptibility of Streptococcus pneumoniae and Haemophilus influenzae isolates collected from community-acquired respiratory tract infections (CA-RTIs) in 2016-18 in four Asian countries. METHODS: MICs were determined by CLSI broth microdilution and susceptibility was assessed using CLSI, EUCAST (dose-specific) and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints. RESULTS: In total, 260 S. pneumoniae and 258 H. influenzae isolates were tested. Pneumococci from Vietnam (n = 161) were the least susceptible, with rates of susceptibility >90% for fluoroquinolones by CLSI breakpoints, ∼60% for amoxicillin, amoxicillin/clavulanic acid and ceftriaxone but <14% for most other agents. Pneumococcal isolates from Cambodia (n = 48) and Singapore (n = 34) showed susceptibilities ranging from ∼30% for trimethoprim/sulfamethoxazole and oral penicillin to 100% for fluoroquinolones. Among isolates of H. influenzae from Cambodia (n = 30), the Philippines (n = 59) and Singapore (n = 80), rates of susceptibility using CLSI breakpoints were >90% for amoxicillin/clavulanic acid, cephalosporins [except cefaclor in Singapore (77.5%)], macrolides and fluoroquinolones; for isolates from Vietnam (n = 89) the rates of susceptibility were >85% only for amoxicillin/clavulanic acid (95.5%), ceftriaxone (100%) and macrolides (87.6%-89.9%). Susceptibility to other antibiotics ranged from 7.9% (trimethoprim/sulfamethoxazole) to 57.3%-59.6% (fluoroquinolones) and 70.8% (cefixime). The application of different EUCAST breakpoints for low and higher doses for some of the antibiotics (amoxicillin, amoxicillin/clavulanic acid, ampicillin, penicillin, ceftriaxone, clarithromycin, erythromycin, levofloxacin and trimethoprim/sulfamethoxazole) allowed, for the first time in a SOAR study, the effect of raising the dosage on susceptibility to be quantified. A limitation of the study was the small sample sizes and only one or two sites participating per country; however, since susceptibility data are scarce in some of the participating countries any information concerning antibiotic susceptibility is of value. CONCLUSIONS: Antibiotic susceptibility varied across countries and species, with isolates from Vietnam demonstrating the lowest susceptibility. Knowledge of resistance patterns can be helpful for clinicians when choosing empirical therapy options for CA-RTIs.

Relative movement on the articular surfaces of the tibiotalar and subtalar joints during walking.

OBJECTIVES: The objective of this study was to quantify the relative movement between the articular surfaces in the tibiotalar and subtalar joints during normal walking in asymptomatic individuals. METHODS: 3D movement data of the ankle joint complex were acquired from 18 subjects using a biplanar fluoroscopic system and 3D-to-2D registration of bone models obtained from CT images. Surface relative velocity vectors (SRVVs) of the articular surfaces of the tibiotalar and subtalar joints were calculated. The relative movement of the articulating surfaces was quantified as the mean relative speed (RS) and synchronization index (SIENT) of the SRVVs. RESULTS: SIENT and mean RS data showed that the tibiotalar joint exhibited translational movement throughout the stance, with a mean SIENT of 0.54 (sd 0.21). The mean RS of the tibiotalar joint during the 0% to 20% post heel-strike phase was 36.0 mm/s (sd 14.2), which was higher than for the rest of the stance period. The subtalar joint had a mean SIENT value of 0.43 (sd 0.21) during the stance phase and exhibited a greater degree of rotational movement than the tibiotalar joint. The mean relative speeds of the subtalar joint in early (0% to 10%) and late (80% to 90%) stance were 23.9 mm/s (sd 11.3) and 25.1 mm/s (sd 9.5), respectively, which were significantly higher than the mean RS during mid-stance (10% to 80%). CONCLUSION: The tibiotalar and subtalar joints exhibited significant translational and rotational movement in the initial stance, whereas only the subtalar joint exhibited significant rotational movement during the late stance. The relative movement on the articular surfaces provided deeper insight into the interactions between articular surfaces, which are unobtainable using the joint coordinate system.Cite this article: C-B. Phan, D-P. Nguyen, K. M. Lee, S. Koo. Relative movement on the articular surfaces of the tibiotalar and subtalar joints during walking. Bone Joint Res 2018;7:501-507. DOI: 10.1302/2046-3758.78.BJR-2018-0014.R1.

Incidence of cephalosporin-induced anaphylaxis and clinical efficacy of screening intradermal tests with cephalosporins: A large multicenter retrospective cohort study.

BACKGROUND: Few studies have investigated the incidence of anaphylaxis induced by individual or structurally similar cephalosporins. The aims of the study were to assess the incidence of cephalosporin-induced anaphylaxis and evaluate the clinical efficacy of screening skin tests. METHODS: In this retrospective cohort study, we obtained information on total cephalosporin use and cephalosporin-induced anaphylaxis in intravenous cephalosporin recipients in 12 general hospitals between 2013 and 2015. Cephalosporins were divided into 4 groups according to similar side-chain structures. The incidence of cephalosporin-induced anaphylaxis was assessed for each cephalosporin, cephalosporin generation, and side-chain group. To verify the efficacy of screening intradermal tests (IDT) with cephalosporin, the 12 hospitals were assigned to the intervention or control group depending on whether they performed screening IDT before the administration of cephalosporins. RESULTS: We identified 76 cases of cephalosporin-induced anaphylaxis with 1 123 345 exposures to intravenous cephalosporins (6.8 per 100 000 exposures), and the incidence of fatal anaphylaxis by cephalosporin was 0.1 cases per 100 000 exposures. The highest incidences of anaphylaxis occurred in the ceftizoxime (13.0 cases per 100 000 exposures) and side-chain group 1 (cefepime, cefotaxime, ceftizoxime, ceftriaxone, and cefuroxime; 9.3 per 100 000). There was no case of anaphylaxis induced by cefoxitin, cefmetazole, cefminox, and cefotiam. The clinical effectiveness of routine screening IDT was not significant (P = .06). CONCLUSIONS: The incidence of cephalosporin-induced anaphylaxis differed according to individual drugs and side-chain structure. Screening IDT showed no clinical efficacy at a population level.

Complex chromosomal rearrangements by single catastrophic pathogenesis in NUT midline carcinoma.

Background: Nuclear protein in testis (NUT) midline carcinoma (NMC) is a rare aggressive malignancy often occurring in the tissues of midline anatomical structures. Except for the pathognomonic BRD3/4-NUT rearrangement, the comprehensive landscape of genomic alterations in NMCs has been unexplored. Patients and methods: We investigated three NMC cases, including two newly diagnosed NMC patients in Seoul National University Hospital, and a previously reported cell line (Ty-82). Whole-genome and transcriptome sequencing were carried out for these cases, and findings were validated by multiplex fluorescence in situ hybridization and using individual fluorescence probes. Results: Here, we present the first integrative analysis of whole-genome sequencing, transcriptome sequencing and cytogenetic characterization of NUT midline carcinomas. By whole-genome sequencing, we identified a remarkably similar pattern of highly complex genomic rearrangements (previously denominated as chromoplexy) involving the BRD3/4-NUT oncogenic rearrangements in two newly diagnosed NMC cases. Transcriptome sequencing revealed that these complex rearrangements were transcribed as very simple BRD3/4-NUT fusion transcripts. In Ty-82 cells, we also identified a complex genomic rearrangement involving the BRD4-NUT rearrangement underlying the simple t(15;19) karyotype. Careful inspections of rearrangement breakpoints indicated that these rearrangements were likely attributable to single catastrophic events. Although the NMC genomes had >3000 somatic point mutations, canonical oncogenes or tumor suppressor genes were rarely affected, indicating that they were largely passenger events. Mutational signature analysis showed predominant molecular clock-like signatures in all three cases (accounting for 54%-75% of all base substitutions), suggesting that NMCs may arise from actively proliferating normal cells. Conclusion: Taken together, our findings suggest that a single catastrophic event in proliferating normal cells could be sufficient for neoplastic transformation into NMCs.

Differential inflammasome activation signatures following intracellular infection of human macrophages with Mycobacterium bovis BCG or Trypanosoma cruzi.

Pathogens frequently exploit or evade inflammasome activation in order to survive and proliferate. Alternatively, inadequate inflammasome activation by attenuated microorganisms or adjuvanted subunit vaccines may contribute to poor longevity of protection. To further understand these pathways, we determined the differential inflammasome transcriptome of human THP monocyte-derived macrophages in response to Mycobacterium bovis BCG, as compared to LPS or Trypanosoma cruzi. The results identify the highly specific innate recognition programs associated with inflammasome activation by human macrophages exposed to these microbial stimuli. BCG, T. cruzi, and LPS strongly induced expression of both unique and overlapping genes downstream of TLR signaling pathways including cytokines and chemokines that mediate inflammation and regulate cell death pathways. Compared to LPS, BCG failed to directly activate anti-apoptotic molecules and multiple NLR and inflammasome complex components including caspase-1, and actively repressed important signaling intermediates in AP-1 and NFκB transcription factor pathways. Both BCG and T. cruzi repressed expression of TXNIP, an anti-oxidant inhibitor that recruits caspase-1 to the NLRP3 inflammasome, while T. cruzi infection uniquely failed to activate TNF-α. These results identify unique pathogen specific strategies to activate inflammation and modulate cell death that may drive inflammatory outcomes and suggest avenues of investigation to optimize host immunity.

Is there a Relationship between Bone Morphology and Injured Ligament on Imaging Studies and Laxity on Ankle Stress Radiographs?

This study aimed to investigate the relationship between bone morphology and injured ligaments on imaging studies and laxity on ankle stress radiographs in patients with lateral ankle instability. In total, 115 patients who had undergone ankle MRI, ankle radiography, and stress radiography were included. Distal tibial articular surface angle, bimalleolar tilt, medial and lateral malleolar relative length, medial malleolar slip angle, anterior inclination of the tibia, and fibular position were measured on ankle radiographs. Tibiotalar tilt angle and anterior translation of the talus were measured on ankle stress radiographs. Degree of ligament injury was evaluated on ankle MRIs. Multiple regression analysis was performed using the following independent variables: age, sex, and factors significantly associated with ankle stress view on univariate linear regression analysis. Age (p=0.041), sex (p=0.014), degree of anterior talofibular ligament injury (p<0.001), and bimalleolar tilt (p=0.016) were correlated with tibiotalar tilt angle. Fibular position and degree of posterior talofibular ligament injury were factors significantly related to anterior translation of the talus. Differences in patient characteristics might predispose ankle stress radiograph results. Comparison of both ankles on stress radiographs is superior to applying fixed numerical values to the injured side in order to reduce the influence of patient factors.

Complete transposition of the great arteries with double outlet right ventricle in a dog.

A 2-year old intact male Collie dog presented to the cardiology service at Oregon State University for evaluation of cyanosis and suspected congenital cardiac disease. Echocardiography revealed a constellation of cardiac abnormalities including a single large vessel exiting the right ventricle with a diminutive left ventricular outflow tract, a ventricular septal defect, and marked concentric right ventricular hypertrophy with moderate right atrial dilation. Cardiac-gated computed tomography confirmed the previous anomalies in addition to supporting a diagnosis of complete transposition of the great arteries, double outlet right ventricle, and pulmonic hypoplasia with a single coronary ostium. Prominent bronchoesophageal collateral vessels were concurrently identified. Clinically, the dog was stable despite mild cyanosis that worsened with exercise; no intervention was elected at the time. This case report describes a rare combination of congenital cardiac defects and the usefulness of cardiac-gated cross-sectional imaging in the anatomic diagnosis.

Application of whole-exome sequencing for detecting copy number variants in CMT1A/HNPP.

Large insertions and deletions (indels), including copy number variations (CNVs), are commonly seen in many diseases. Standard approaches for indel detection rely on well-established methods such as qPCR or short tandem repeat (STR) markers. Recently, a number of tools for CNV detection based on next-generation sequencing (NGS) data have also been developed; however, use of these methods is limited. Here, we used whole-exome sequencing (WES) in patients previously diagnosed with CMT1A or HNPP using STR markers to evaluate the ability of WES to improve the clinical diagnosis. Patients were evaluated utilizing three CNV detection tools including CONIFER, ExomeCNV and CEQer, and array comparative genomic hybridization (aCGH). We identified a breakpoint region at 17p11.2-p12 in patients with CMT1A and HNPP. CNV detection levels were similar in both 6 Gb (mean read depth = 80×) and 17 Gb (mean read depth = 190×) data. Taken together, these data suggest that 6 Gb WES data are sufficient to reveal the genetic causes of various diseases and can be used to estimate single mutations, indels, and CNVs simultaneously. Furthermore, our data strongly indicate that CNV detection by NGS is a rapid and cost-effective method for clinical diagnosis of genetically heterogeneous disorders such as CMT neuropathy.

Phylogenetic group distributions, virulence factors and antimicrobial resistance properties of uropathogenic Escherichia coli strains isolated from patients with urinary tract infections in South Korea.

UNLABELLED: Urinary tract infections (UTIs) are one of the most common diseases by which humans seek medical help and are caused mainly by uropathogenic Escherichia coli (UPEC). Studying the virulence and antibiotic resistance of UPEC with respect to various phylogenetic groups is of utmost importance in developing new therapeutic agents. Thus, in this study, we analysed the virulence factors, antibiotic resistance and phylogenetic groups among various UPEC isolates from children with UTIs. The phylogenetic analysis revealed that majority of the strains responsible for UTIs belonged to the phylogenetic groups B2 and D. Of the 58 E. coli isolates, 79·31% belonged to group B2, 15·51% to group D, 3·44% to group A and 1·72% to B1. Simultaneously, the number of virulence factors and antibiotic resistance exhibited were also significantly high in groups B2 and D compared to other groups. Among the isolates, 44·8% were multidrug resistant and of that 73% belonged to the phylogenetic group B2, indicating the compatibility of antibiotic resistance and certain strains carrying virulence factor genes. The antibiotic resistance profiling of UPEC strains elucidates that the antimicrobial agents such as chloramphenicol, cefoxitin, cefepime, ceftazidime might still be used in the therapy for treating UTIs. SIGNIFICANCE AND IMPACT OF THE STUDY: As the antibiotic resistance pattern of uropathogenic Escherichia coli varies depending on different geographical regions, the antibiotic resistance pattern from this study will help the physicians to effectively administer antibiotic therapy for urinary tract infections. In addition, the frequency of virulence factors and antibiotic resistance genes among various phylogenic groups could be effectively used to draw new targets for uropathogenic Escherichia coli antibiotic-independent therapies. The study emphasizes need of public awareness on multidrug resistance and for more prudent use of antimicrobials.

A scoring model for predicting survival following primary tumour resection in stage IV colorectal cancer patients with unresectable metastasis.

BACKGROUND: Stage IV colorectal cancer patients with unresectable metastasis who undergo elective primary tumour resection experience heterogeneous post-operative survival. We aimed to develop a scoring model for predicting post-operative survival using pre-operative variables to identify patients who are least likely to experience extended survival following the procedure. METHODS: Survival data were collected from stage IV colorectal cancer patients who had undergone elective primary tumour resection between January 1999 and December 2007. Coefficients of significant covariates from the multivariate Cox regression model were used to compute individual survival scores to classify patients into three prognostic groups. A survival function was derived for each group via Kaplan-Meier estimation. Internal validation was performed. RESULTS: Advanced age (hazard ratio, HR 1.43 (1.16-1.78)); poorly differentiated tumour (HR 2.72 (1.49-5.04)); metastasis to liver (HR 1.76 (1.33-2.33)), lung (HR 1.37 (1.10-1.71)) and bone (HR 2.08 ((1.16-3.71)); carcinomatosis (HR 1.68 (1.30-2.16)); hypoalbuminaemia (HR 1.30 (1.04-1.61) and elevated carcinoembryonic antigen levels (HR 1.89 (1.49-2.39)) significantly shorten post-operative survival. The scoring model separated patients into three prognostic groups with distinct median survival lengths of 4.8, 12.4 and 18.6 months (p < 0.0001). Internal validation revealed a concordance probability estimate of 0.65 and a time-dependent area under receiver operating curve of 0.75 at 6 months. Temporal split-sample validation implied good local generalizability to future patient populations (p < 0.0001). CONCLUSION: Predicting survival following elective primary tumour resection using pre-operative variables has been demonstrated with the scoring model developed. Model-based survival prognostication can support clinical decisions on elective primary tumour resection eligibility.

Quantitative accuracy of the simplified strong ion equation to predict serum pH in dogs.

BACKGROUND: Electrochemical approach to the assessment of acid-base states should provide a better mechanistic explanation of the metabolic component than methods that consider only pH and carbon dioxide. HYPOTHESIS/OBJECTIVES: Simplified strong ion equation (SSIE), using published dog-specific values, would predict the measured serum pH of diseased dogs. ANIMALS: Ten dogs, hospitalized for various reasons. METHODS: Prospective study of a convenience sample of a consecutive series of dogs admitted to the Massey University Veterinary Teaching Hospital (MUVTH), from which serum biochemistry and blood gas analyses were performed at the same time. Serum pH was calculated (Hcal+) using the SSIE, and published values for the concentration and dissociation constant for the nonvolatile weak acids (Atot and Ka ), and subsequently Hcal+ was compared with the dog's actual pH (Hmeasured+). To determine the source of discordance between Hcal+ and Hmeasured+, the calculations were repeated using a series of substituted values for Atot and Ka . RESULTS: The Hcal+ did not approximate the Hmeasured+ for any dog (P = 0.499, r(2) = 0.068), and was consistently more basic. Substituted values Atot and Ka did not significantly improve the accuracy (r(2) = 0.169 to <0.001). Substituting the effective SID (Atot-[HCO3-]) produced a strong association between Hcal+ and Hmeasured+ (r(2) = 0.977). CONCLUSIONS AND CLINICAL IMPORTANCE: Using the simplified strong ion equation and the published values for Atot and Ka does not appear to provide a quantitative explanation for the acid-base status of dogs. Efficacy of substituting the effective SID in the simplified strong ion equation suggests the error lies in calculating the SID.

Fibroblast growth factor 21 analogue LY2405319 lowers blood glucose in streptozotocin-induced insulin-deficient diabetic mice by restoring brown adipose tissue function.

AIM: To investigate the effects of LY2405319, an analogue of fibroblast growth factor 21 (FGF21), on glucose homeostasis in streptozotocin (STZ)-induced insulin-deficient mice (STZ mice). METHODS: Nine-week-old male C57BL/6J mice were administered a single intraperitoneal injection of STZ (150 mg/kg). One week later, after confirmation of hyperglycaemia, saline or LY2405319 (5 mg/kg) was injected subcutaneously daily for 4 weeks. Changes in glucose homeostasis, energy metabolism and brown adipose tissue (BAT) function were assessed. RESULTS: The STZ mice had elevated blood glucose and reduced plasma FGF21 levels, impaired glucose uptake in the BAT, and BAT mitochondria with absent or swollen cristae and fewer lipid vacuoles. LY2405319 significantly reduced blood glucose levels and this was associated with increased BAT glucose uptake and changes in gene expression and morphology, indicating improved mitochondrial lipid metabolism in the BAT. Importantly, the ability of LY2405319 to lower blood glucose in STZ mice was compromised after removing interscapular BAT. CONCLUSIONS: Our results show that LY2405319 reduces blood glucose levels in insulin-deficient diabetes by improving BAT metabolism. Additional studies investigating the therapeutic potential of FGF21 for the treatment of type 1 diabetes are warranted.

Pharmacogenomic diversity in Singaporean populations and Europeans.

Differences in the frequency of pharmacogenomic variants may influence inter-population variability in drug efficacy and risk of adverse drug reactions (ADRs). We investigated the diversity of ∼ 4500 genetic variants in key drug-biotransformation and -response genes among three South East Asian populations compared with individuals of European ancestry. We compared rates of reported ADRs in these Asian populations to determine if the allelic differentiation corresponded to an excess of the associated ADR. We identified an excess of ADRs related to clopidogrel in Singaporean Chinese, consistent with a higher frequency of a known risk variant in CYP2C19 in that population. We also observed an excess of ADRs related to platinum compounds in Singaporean CHS, despite a very low frequency of known ADR risk variants, suggesting the presence of additional genetic and non-genetic risk factors. Our results point to substantial diversity at specific pharmacogenomic loci that may contribute to inter-population variability in drug response phenotypes.

Incidence and risk factors for herpes zoster following heart transplantation.

BACKGROUND: Data on the incidence, timing, and risk factors for herpes zoster (HZ) in heart transplant (HT) recipients are limited. METHODS: We determined HZ incidence rates and actuarial estimates of time to first HZ episode in 314 HT recipients at our institution from 1995 to 2010. We developed Cox models to assess potential risk factors for HZ in HT. RESULTS: Median age at HT was 54 (range, 17-71) years; 237 (76%) were male. There were 60 episodes of HZ in 51 patients, with an overall incidence rate of 31.6 cases (95% confidence interval [CI], 23.5-41.6)/1000 person-years. Although most cases occurred during the first post-HT year, cumulative HZ incidence was 0.078 at 1, 0.15 at 5, and 0.20 at 10 years. Many patients had substantial HZ morbidity, including 14% with HZ ophthalmicus and 45% with post-herpetic neuralgia. Adjusting for age, gender, and acute cellular rejection episodes, exposure to mycophenolate mofetil (MMF) was an independent risk factor for HZ (adjusted hazard ratio [HR] 2.18; 95% CI, 1.20-3.96; P = 0.01), while ganciclovir-based cytomegalovirus prophylaxis reduced HZ risk (adjusted HR 0.09; 95% CI, 0.01-0.71; P = 0.02). Although age and female gender increased HZ risk, the magnitude of their effect was not statistically significant in Cox models. CONCLUSIONS: HZ is common and morbid after HT, particularly with MMF exposure. Ganciclovir prophylaxis is effective in reducing the short-term risk of HZ, but the steady incidence of cases for years post HT makes long-term HZ prevention challenging. Augmenting varicella zoster virus immunity post HT with vaccines warrants further exploration.