Diabetes mellitus, hemoglobin A1C, and the incidence of total joint arthroplasty infection

Patients with diabetes have a higher incidence of infection after total joint arthroplasty (TJA) than patients without diabetes. Hemoglobin A1c (HbA1c) levels are a marker for blood glucose control in diabetic patients. A total of 3468 patients underwent 4241 primary or revision total hip arthroplasty or total knee arthroplasty at one institution. Hemoglobin A1c levels were examined to evaluate if there was a correlation between the control of HbA1c and infection after TJA. There were a total of 46 infections (28 deep and 18 superficial [9 cellulitis and 9 operative abscesses]). Twelve (3.43%) occurred in diabetic patients (n = 350; 8.3%) and 34 (0.87%) in nondiabetic patients (n = 3891; 91.7%) (P < .001). There were 9 deep (2.6%) infections in diabetic patients and 19 (0.49%) in nondiabetic patients. In noninfected, diabetic patients, HbA1c level ranged from 4.7% to 15.1% (mean, 6.92%). In infected diabetic patients, HbA1c level ranged from 5.1% to 11.7% (mean, 7.2%) (P < .445). The average HbA1c level in patients with diabetes was 6.93%. Diabetic patients have a significantly higher risk for infection after TJA. Hemoglobin A1c levels are not reliable for predicting the risk of infection after TJA.     

Ethnoveterinary Application of Morinda Citrifolia Fruit Puree on a Commercial Heifer Rearing Facility with Endemic Salmonellosis

We have previously reported that Morinda citrifolia (noni) puree modulates neonatal calves developmental maturation of the innate and adaptive immune system. In this study, the effect of noni puree on respiratory and gastrointestinal (GI), health in preweaned dairy calves on a farm with endemic salmonellosis was examined. Two clinical trials were conducted whereby each trial evaluated one processing technique of noni puree. Trials 1 and 2 tested noni versions A and B, respectively. Puree analysis and trial methods were identical to each other, with the calf as the experimental unit. Calves were designated to 1 of 3 treatment groups in each trial and received either: 0, 15 or 30 mL every 12 hr of noni supplement for the first 3 weeks of life. Health scores, weaning age, weight gain from admission to weaning, and weaned by 6 weeks, were used as clinical endpoints for statistical analysis. In trial 1, calves supplemented with 15 mL noni puree of version A every 12 hr had a higher probability of being weaned by 6 weeks of age than control calves (P = 0.04). In trial 2, calves receiving 30 mL of version B every 12 hr had a 54.5% reduction in total medical treatments by 42 days of age when compared to controls (P = 0.02). There was a trend in reduced respiratory (61%), and GI (52%) medical treatments per calf when compared to controls (P = 0.06 and 0.08, respectively). There were no differences in weight gain or mortality for any treatment group in either trial.     

Rare allelic forms of PRDM9 associated with childhood leukemogenesis

One of the most rapidly evolving genes in humans, PRDM9, is a key determinant of the distribution of meiotic recombination events. Mutations in this meiotic-specific gene have previously been associated with male infertility in humans and recent studies suggest that PRDM9 may be involved in pathological genomic rearrangements. In studying genomes from families with children affected by B-cell precursor acute lymphoblastic leukemia (B-ALL), we characterized meiotic recombination patterns within a family with two siblings having hyperdiploid childhood B-ALL and observed unusual localization of maternal recombination events. The mother of the family carries a rare PRDM9 allele, potentially explaining the unusual patterns found. From exomes sequenced in 44 additional parents of children affected with B-ALL, we discovered a substantial and significant excess of rare allelic forms of PRDM9. The rare PRDM9 alleles are transmitted to the affected children in half the cases; nonetheless there remains a significant excess of rare alleles among patients relative to controls. We successfully replicated this latter observation in an independent cohort of 50 children with B-ALL, where we found an excess of rare PRDM9 alleles in aneuploid and infant B-ALL patients. PRDM9 variability in humans is thought to influence genomic instability, and these data support a potential role for PRDM9 variation in risk of acquiring aneuploidies or genomic rearrangements associated with childhood leukemogenesis.Most of the effort in cancer genomics has focused on capturing somatic mutations from the screening of tumor and normal somatic tissue genomes, to identify factors mutated somatically during tumor progression. Genetic approaches aim to find genomic regions predisposing individuals to cancer, to capture inherited predisposing mutations segregating in the population by using genetic linkage or association studies. For late-onset cancers, such as breast and colorectal cancers (Turnbull et al. 2010; Peters et al. 2012), many predisposing allelic variants have been described, supporting a polygenic model of susceptibility (Easton and Eeles 2008), but only a few genetic risk factors for pediatric cancer have been established (Healy et al. 2007; Sherborne et al. 2010). Dominant mutations causing cancer early in life are likely to be rapidly eliminated from the population, and as a result, it is unlikely that affected children will share inherited mutations. Parental germline events may play a role in pediatric cancer development with early evidence for epigenetically marking of imprinted genes during meiosis (Joyce and Schofield 1998), which may be involved directly in tumorigenesis for cancers of embryonal origin, such as Wilms'' tumors, rhabdomyosarcoma, adrenocortical carcinoma, and hepatoblastoma. Besides this, little is known about the contribution of meiotic events to the genetic instability driving the early onset of childhood cancer. In particular, novel genomic changes that occur during meiosis will not be detectable using standard genetic mapping approaches. However, interrogating normal and tumor genomes from families of patients provides an ideal framework to study de novo genomic events potentially linked to childhood malignancies.Recent genomic studies using family data have shown that many early onset diseases arise from defects caused by de novo genetic aberrations, be they point mutations (Awadalla et al. 2010), copy number variants (Greenway et al. 2009), structural rearrangements (Kloosterman et al. 2011), or aneuploidies (Hassold et al. 2007). Recombination rates in children correlate negatively with maternal age at birth (Hussin et al. 2011), which may have implications for understanding aneuploid conceptions. Intriguingly, children born with constitutional aneuploidies and rearrangements are at an increased risk for various malignancies (Ganmore et al. 2009). For example, children with Down syndrome have nearly a 20-fold increased risk for acute leukemia (Ross et al. 2005), suggesting that carcinogenesis and congenital anomalies may have a common basis for some pediatric cancers (Bjorge et al. 2008). Known recombination associated factors, such as DNA repair and histone modifications, are associated with genomic instabilities and cancers (Fernandez-Capetillo et al. 2004; Helleday 2010), and congenital genomic rearrangements and aneuploidies have been associated with errors in meiotic recombination (Hassold and Hunt 2001; Sasaki et al. 2010). Such gross genomic events are frequent in pediatric cancers.Cancer is the leading cause of death by disease among children in western countries, and the overall incidence rate continues to rise steadily. The most common pediatric cancer, acute lymphoblastic leukemia (ALL), is a hematological malignancy resulting from chromosomal alterations and mutations affecting molecular pathways that disrupt lymphoid progenitor cell differentiation (Greaves 1999). Childhood ALL is likely explained by a combination of genetic predisposition and environmental exposure during early development, in fetal life and in infancy. However, genetic association studies for childhood ALL have been hampered by insufficient sample sizes. Furthermore, ALL is a heterogenous disease presenting many molecular subtypes, with different populations having different incidence rates, such that the power of stratified analyses will be limited due to a small number of cases in each subgroup. Finally, there is well-established evidence for prenatal initiation of the leukemogenesis process in children (Wiemels et al. 1999; Greaves 2006), and focusing exclusively on child genetic material in ALL association studies may be insufficient for understanding disease etiology.To characterize the importance of parental germline events in susceptibility to childhood ALL, we first set out to determine whether meiotic recombination patterns can lead to factors associated with the development of childhood ALL. From exome sequencing and genotyping data, we characterized meiotic recombination patterns in a unique family (referred herein as the ALL quartet) with two siblings having hyperdiploid B-cell precursor ALL (B-ALL). We observed unusual localization of maternal meiotic recombination events, with a small number of crossovers taking place in previously well-characterized population recombination hotspots. Such hotspots are short segments (1–2 kb) identified to be highly recombinogenic in the human genome (Myers et al. 2005). The mother of the family carries a rare PRDM9 allele, potentially explaining the unusual placement of recombination events observed (Berg et al. 2011). PRDM9 is a meiosis-specific histone H3 methyltransferase that controls the activation of recombination hotspots via its zinc finger (ZnF) DNA binding domain recognizing a short sequence motif, which then triggers hotspot activity through modification of the chromatin state (Grey et al. 2011). Analyses of next-generation sequencing and Sanger re-sequencing read data from a cohort of parents with B-ALL affected children of French-Canadian descent revealed a substantial excess of rare allelic forms of PRDM9. This association was successfully replicated in an independent cohort of children with B-ALL diagnosed in Tennessee, USA, where the effect was found particularly in aneuploid and infant B-ALL patients. Not only has PRDM9 variability been associated with hotspot activation, but in humans it has been suggested to influence genomic instability (Berg et al. 2010; McVean and Myers 2010). The results presented here point to rare PRDM9 allelic forms of involvement in the development of preleukemic clones in B-ALL patients and we propose that PRDM9 histone H3K4 methyltransferase activity in the parental germline could lead to the genomic instability associated with childhood ALL, a plausible mechanism consistent with the current understanding of molecular pathways of leukemogenesis and the disease.     

A Method to Determine Significant Levels of Immunoglobulin G to Aspergillus Fumigatus Antigens in an Elisa System and a Comparison with Counterimmunoelectrophoresis and Double Diffusion Techniques

A method is described which assesses results obtained from in ELISA system for the determination of human serum levels of IgG class antibodies to Aspergillus fumigatus. The method is used to discriminate positive from negative samples, and significant antibody activity may be reported to the clinician, relative to a reference positive control serum monitored simultaneously under the same test conditions. Antibody content is expressed as the absorbance of a certain dilution of serum. Duplicate samples were analysed at a single serum dilution and their absorbtion values obtained from a semi-automated ELISA microplate reader. These were entered into a computer programmed to convert the data into units on a logarithmic scale.

In parallel experiments, ELISA results were compared with those obtained by the techniques of counterimmunoelectrophoresis and double diffusion which measure precipitating antibody of all classes. A relatively good degree of correlation between tests was found only among sera with a high level of antibody.     

Comparison of the quick mild cognitive impairment (Qmci) screen and the SMMSE in screening for mild cognitive impairment

Introduction: differentiating mild cognitive impairment (MCI) from normal cognition (NC) is difficult. The AB Cognitive Screen (ABCS) 135, sensitive in differentiating MCI from dementia, was modified to improve sensitivity and specificity, producing the quick mild cognitive impairment (Qmci) screen. Objective: this study compared the sensitivity and specificity of the Qmci with the Standardised MMSE and ABCS 135, to differentiate NC, MCI and dementia. Methods: weightings and subtests of the ABCS 135 were changed and a new section 'logical memory' added, creating the Qmci. From four memory clinics in Ontario, Canada, 335 subjects (154 with MCI, 181 with dementia) were recruited and underwent comprehensive assessment. Caregivers, attending with the subjects, without cognitive symptoms, were recruited as controls (n?=?630). Results: the Qmci was more sensitive than the SMMSE and ABCS 135, in differentiating MCI from NC, with an area under the curve (AUC) of 0.86 compared with 0.67 and 0.83, respectively, and in differentiating MCI from mild dementia, AUC of 0.92 versus 0.91 and 0.91. The ability of the Qmci to identify MCI was better for those over 75 years. Conclusion: the Qmci is more sensitive than the SMMSE in differentiating MCI and NC, making it a useful test, for MCI in clinical practice, especially for older adults.     

Epidemiological evidence in forensic pharmacovigilance

Until recently epidemiological evidence was not regarded as helpful in determining cause and effect. It generated associations that then had to be explained in terms of bio-mechanisms and applied to individual patients. A series of legal cases surrounding possible birth defects triggered by doxylamine (Bendectin) and connective tissue disorders linked to breast implants made it clear that in some instances epidemiological evidence might have a more important role, but the pendulum swung too far so that epidemiological evidence has in recent decades been given an unwarranted primacy, partly perhaps because it suits the interests of certain stakeholders. Older and more recent epidemiological studies on doxylamine and other antihistamines are reviewed to bring out the ambiguities and pitfalls of an undue reliance on epidemiological studies.     

Neonatal screening programme for CF: Results from the Irish Comparative Outcomes Study (ICOS)

The introduction of NBS in Ireland in July 2011, provided a unique opportunity to investigate clinical outcomes using a comparative historical cohort study. Clinical cohort: children clinically diagnosed with CF born 1 July 2008 to 30 June 2011, and NBS cohort: children diagnosed with CF through NBS born 1 July 2011 to 30 June 2016. Clinical data were collected from the CF Registry of Ireland, medical charts, and data on weight/height before diagnosis from public health nurses and family doctors. SPSS was used for analysis. A total of 232 patients were recruited (response 93%) (93 clinically diagnosed, 139 NBS‐detected). Following exclusions of meconium ileus (MI) (40), diagnosis outside Ireland (4), and being designated as CFSPID (2), a total of 77 clinically diagnosed patients and 109 NBS detected children were included in analysis. Over half were homozygous for F508del mutation. Being clinically diagnosed was independently associated with hospitalization for infective exacerbation of CF < 36 months (OR, 2.80; 95%CI 1.24‐6.29). Diagnosis to first acquisition of Pseudomonas aeruginosa was significantly longer in NBS than clinically detected; from birth there was no significant difference. Weight and length/height were significantly greater in NBS cohort at 6 and 12 months. We provide evidence of improved growth, reduced hospitalization for acute exacerbations, and delayed P. aeruginosa acquisition (from diagnosis) to age 3 for the NBS cohort. Screening practices likely account for the non‐significant difference in P. aeruginosa acquisition from birth.     

Sedentary Behavior and Diabetes Risk Among Women Over the Age of 65 Years: The OPACH Study

OBJECTIVETo evaluate whether sedentary time (ST) and/or sedentary behavior patterns are related to incident diabetes in the U.S.’s oldest age-groups.RESEARCH DESIGN AND METHODSWomen without physician-diagnosed diabetes (n = 4,839, mean ± SD age = 79 ± 7 years) wore accelerometers for ≥4 days and were followed up to 6 years for self-reported newly diagnosed diabetes requiring treatment with medications. Hazard ratios (HRs) for incident diabetes were estimated across quartiles of accelerometer-measured ST and mean bout duration with use of Cox proportional hazards models. We conducted isotemporal substitution analyses using Cox regression and tested associations with risk for diabetes after statistically replacing ST with light physical activity (PA) or moderate-to-vigorous PA (MVPA) and after replacing light PA with MVPA.RESULTSDuring 20,949 person-years, 342 diabetes cases were identified. Women in ST quartile (Q)2, Q3, and Q4 (vs. Q1) had incident diabetes HR 1.20 (95% CI 0.87–1.65), 1.33 (0.97–1.82), and 1.21 (0.86–1.70); P_trend = 0.04. Respective HRs following additional adjustment for BMI and MVPA were 1.04 (95% CI 0.74–1.47), 1.04 (0.72–1.50), and 0.85 (0.56–1.29); P_trend = 0.90. Fully adjusted isotemporal substitution results indicated that each 30 min of ST replaced with MVPA (but not light PA) was associated with 15% lower risk for diabetes (HR 0.85 [95% CI 0.75–0.96]; P = 0.01); the HR for replacing 30 min of light PA with MVPA was 0.85 (95% CI 0.73–0.98); P = 0.03. Mean bout duration was not associated with incident diabetes.CONCLUSIONSStatistically replacing ST or light PA with MVPA was associated with lower diabetes risk in older women. While reducing ST is important for several health outcomes, results indicate that to reduce diabetes risk among older adults, the primary public health focus should be on increasing MVPA.