Genotype-guided tacrolimus dosing in African-American kidney transplant recipients.

Tacrolimus is dependent on CYP3A5 enzyme for metabolism. Expression of the CYP3A5 enzyme is controlled by several alleles including CYP3A5*1, CYP3A5*3, CYP3A5*6 and CYP3A5*7. African Americans (AAs) have on average higher tacrolimus dose requirements than Caucasians; however, some have requirements similar to Caucasians. Studies in AAs have primarily evaluated the CYP3A5*3 variant; however, there are other common nonfunctional variants in AAs (CYP3A5*6 and CYP3A5*7) that do not occur in Caucasians. These variants are associated with lower dose requirements and may explain why some AAs are metabolically similar to Caucasians. We created a tacrolimus clearance model in 354 AAs using a development and validation cohort. Time after transplant, steroid and antiviral use, age and CYP3A5*1, *3, *6 and *7 alleles were significant toward clearance. This study is the first to develop an AA-specific genotype-guided tacrolimus dosing model to personalize therapy.

A genome-wide analysis of putative functional and exonic variation associated with extremely high intelligence.

Although individual differences in intelligence (general cognitive ability) are highly heritable, molecular genetic analyses to date have had limited success in identifying specific loci responsible for its heritability. This study is the first to investigate exome variation in individuals of extremely high intelligence. Under the quantitative genetic model, sampling from the high extreme of the distribution should provide increased power to detect associations. We therefore performed a case-control association analysis with 1409 individuals drawn from the top 0.0003 (IQ >170) of the population distribution of intelligence and 3253 unselected population-based controls. Our analysis focused on putative functional exonic variants assayed on the Illumina HumanExome BeadChip. We did not observe any individual protein-altering variants that are reproducibly associated with extremely high intelligence and within the entire distribution of intelligence. Moreover, no significant associations were found for multiple rare alleles within individual genes. However, analyses using genome-wide similarity between unrelated individuals (genome-wide complex trait analysis) indicate that the genotyped functional protein-altering variation yields a heritability estimate of 17.4% (s.e. 1.7%) based on a liability model. In addition, investigation of nominally significant associations revealed fewer rare alleles associated with extremely high intelligence than would be expected under the null hypothesis. This observation is consistent with the hypothesis that rare functional alleles are more frequently detrimental than beneficial to intelligence.

Genomewide Association Study of Tacrolimus Concentrations in African American Kidney Transplant Recipients Identifies Multiple CYP3A5 Alleles.

We previously reported that tacrolimus (TAC) trough blood concentrations for African American (AA) kidney allograft recipients were lower than those observed in white patients. Subtherapeutic TAC troughs may be associated with acute rejection (AR) and AR-associated allograft failure. This variation in TAC troughs is due, in part, to differences in the frequency of the cytochrome P450 CYP3A5*3 allele (rs776746, expresses nonfunctional enzyme) between white and AA recipients; however, even after accounting for this variant, variability in AA-associated troughs is significant. We conducted a genomewide association study of TAC troughs in AA kidney allograft recipients to search for additional genetic variation. We identified two additional CYP3A5 variants in AA recipients independently associated with TAC troughs: CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343). All three variants and clinical factors account for 53.9% of the observed variance in troughs, with 19.8% of the variance coming from demographic and clinical factors including recipient age, glomerular filtration rate, anticytomegalovirus drug use, simultaneous pancreas-kidney transplant and antibody induction. There was no evidence of common genetic variants in AA recipients significantly influencing TAC troughs aside from the CYP3A gene. These results reveal that additional and possibly rare functional variants exist that account for the additional variation.

Childhood intelligence is heritable, highly polygenic and associated with FNBP1L.

Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6-18 years) from 17,989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22-46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 × 10(-15), 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 × 10(-5)), 3.5% (P=10(-3)) and 0.5% (P=6 × 10(-5)) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance.

Adenovirus causing fever, upper respiratory infection, and allograft nephritis complicated by persistent asymptomatic viremia.

A 20-year-old woman, with renal transplant complicated by recurrence of focal segmental glomerulosclerosis and post-transplant lymphoproliferative disorder, presented nearly 2 years after transplantation with fever, conjunctivitis, and sinus congestion. She was found to have severe adenovirus (ADV)-induced granulomatous interstitial nephritis, confirmed by immunohistochemical staining for ADV in the renal biopsy, without urinary symptoms, hematuria, or laboratory evidence of a change in allograft function. Fever, upper respiratory tract symptoms, and evidence of adenoviral infection in the allograft resolved with decreased immunosuppression and treatment with cidofovir and intravenous immunoglobulin. Creatinine rose during treatment and remained elevated, possibly related to cidofovir nephrotoxicity. Despite therapy and continued reduction in immunosuppression, asymptomatic low-level viremia persisted for a year. In renal transplant patients with ADV infection, allograft involvement should be highly suspected even without overt urinary symptoms or laboratory evidence of allograft dysfunction. Demonstration of allograft involvement may prompt alternative management that could limit continued allograft infection. No clear recommendations exist for management of asymptomatic ADV viremia in solid organ transplant patients.

The clinical impact of maternal COVID-19 on mothers, their infants, and placentas with an analysis of vertical transfer of maternal SARS-CoV-2-specific IgG antibodies.

INTRODUCTION: The effect of SARS-CoV-2 severity or the trimester of infection in pregnant mothers, placentas, and infants is not fully understood. METHODS: A retrospective, observational cohort study in Chapel Hill, NC of 115 mothers with SARS-CoV-2 and singleton pregnancies from December 1, 2019 to May 31, 2021 via chart review to document the infants' weight, length, head circumference, survival, congenital abnormalities, hearing loss, maternal complications, and placental pathology classified by the Amsterdam criteria. RESULTS: Of the 115 mothers, 85.2% were asymptomatic (n = 37) or had mild (n = 61) symptoms, 13.0% had moderate (n = 9) or severe (n = 6) COVID-19, and 1.74% (n = 2) did not have symptoms recorded. Moderate and severe maternal infections were associated with increased C-section, premature delivery, infant NICU admission, and were more likely to occur in Type 1 (p = 0.0055) and Type 2 (p = 0.0285) diabetic mothers. Only one infant (0.870%) became infected with SARS-CoV-2, which was not via the placenta. Most placentas (n = 63, 54.8%) did not show specific histologic findings; however, a subset showed mild maternal vascular malperfusion (n = 26, 22.6%) and/or mild microscopic ascending intrauterine infection (n = 28, 24.3%). The infants had no identifiable congenital abnormalities, and all infants and mothers survived. DISCUSSION: Most mothers and their infants had a routine clinical course; however, moderate and severe COVID-19 maternal infections were associated with pregnancy complications and premature delivery. Mothers with pre-existing, non-gestational diabetes were at greatest risk of developing moderate or severe COVID-19. The placental injury patterns of maternal vascular malperfusion and/or microscopic ascending intrauterine infection were not associated with maternal COVID-19 severity.

Scaling non-point-source mercury emissions from two active industrial gold mines: influential variables and annual emission estimates.

Open-pit gold mines encompass thousands of hectares of disturbed materials that are often naturally enriched in mercury (Hg). The objective of this study was to estimate annual non-point-source Hg emissions from two active gold mines in Nevada. This was achieved by measuring diel and seasonally representative Hg fluxes from mesocosms of materials collected from each mine. These measurements provided a framework for scaling emissions over space and time at each mine by identifying the important variables correlated with Hg flux. The validity of these correlations was tested by comparisons with measurements conducted in situ at the mines. Of the average diel fluxes obtained in situ (92 daily flux measurements), 81% were within the 95% prediction limits of the regressions developed from the laboratory-derived data. Some surfaces at the mines could not be simulated in the laboratory setting (e.g., material actively leached by cyanide solution and tailings saturated with cyanide solution), and as such in situ data were applied for scaling. Based on the surface areas of the materials and environmental conditions at the mines during the year of study, non-point-source Hg releases were estimated to be 19 and 109 kg·year(-1). These account for 56% and 14%, respectively, of the overall emissions from each mine (point + nonpoint sources). Material being heap-leached and active tailings impoundments were the major contributors to the releases (>60% combined) suggesting that as mining operations cease, releases will decline.

Diagnostic accuracy of the Xpert® MTB/RIF cycle threshold level to predict smear positivity: a meta-analysis.

SETTING: Xpert® MTB/RIF is the most widely used molecular assay for rapid diagnosis of tuberculosis (TB). The number of polymerase chain reaction cycles after which detectable product is generated (cycle threshold value, CT) correlates with the bacillary burden.OBJECTIVE To investigate the association between Xpert CT values and smear status through a systematic review and individual-level data meta-analysis. DESIGN: Studies on the association between CT values and smear status were included in a descriptive systematic review. Authors of studies including smear, culture and Xpert results were asked for individual-level data, and receiver operating characteristic curves were calculated. RESULTS: Of 918 citations, 10 were included in the descriptive systematic review. Fifteen data sets from studies potentially relevant for individual-level data meta-analysis provided individual-level data (7511 samples from 4447 patients); 1212 patients had positive Xpert results for at least one respiratory sample (1859 samples overall). ROC analysis revealed an area under the curve (AUC) of 0.85 (95%CI 0.82-0.87). Cut-off CT values of 27.7 and 31.8 yielded sensitivities of 85% (95%CI 83-87) and 95% (95%CI 94-96) and specificities of 67% (95%CI 66-77) and 35% (95%CI 30-41) for smear-positive samples. CONCLUSION: Xpert CT values and smear status were strongly associated. However, diagnostic accuracy at set cut-off CT values of 27.7 or 31.8 would not replace smear microscopy. How CT values compare with smear microscopy in predicting infectiousness remains to be seen.

Occurrence of methicillin-resistant Staphylococcus aureus in surface waters near industrial hog operation spray fields.

Industrial hog operations (IHOs) have been identified as a source of antibiotic-resistant Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA). However, few studies have investigated the presence of antibiotic-resistant S. aureus in the environment near IHOs, specifically surface waters proximal to spray fields where IHO liquid lagoon waste is sprayed. Surface water samples (n=179) were collected over the course of approximately one year from nine locations in southeastern North Carolina and analyzed for the presence of presumptive MRSA using CHROMagar MRSA media. Culture-based, biochemical, and molecular tests, as well as matrix-assisted laser desorption/ionization-time of flight mass spectrometry were used to confirm that isolates that grew on CHROMagar MRSA media were S. aureus. Confirmed S. aureus isolates were then tested for susceptibility to 16 antibiotics and screened for molecular markers of MRSA (mecA, mecC) and livestock adaptation (absence of scn). A total of 12 confirmed MRSA were detected in 9 distinct water samples. Nine of 12 MRSA isolates were also multidrug-resistant (MDRSA [i.e., resistant to ≥3 antibiotic classes]). All MRSA were scn-positive and most (11/12) belonged to a staphylococcal protein A (spa) type t008, which is commonly associated with humans. Additionally, 12 confirmed S. aureus that were methicillin-susceptible (MSSA) were recovered, 7 of which belonged to spa type t021 and were scn-negative (a marker of livestock-adaptation). This study demonstrated the presence of MSSA, MRSA, and MDRSA in surface waters adjacent to IHO lagoon waste spray fields in southeastern North Carolina. To our knowledge, this is the first report of waterborne S. aureus from surface waters proximal to IHOs.

Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium.

Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40-48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13-20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 × 10(-8)) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.

The left hemisphere's role in hypothesis formation.

In a probability guessing experiment, subjects try to guess which of two events will occur next. Humans tend to match the frequency of previous occurrences in their guesses. Animals other than humans tend to maximize or always choose the option that has occurred the most frequently in the past. Investigators have argued that frequency matching results from the attempt of humans to find patterns in sequences of events even when told the sequences are random. There is independent evidence that the left hemisphere of humans houses a cognitive mechanism that tries to make sense of past occurrences. We performed a probability guessing experiment with two split-brain patients and found that they approximated frequency matching in their left hemispheres and approached maximizing in their right hemispheres. We obtained a conceptual replication of that finding on patients with unilateral damage to either the left or right hemisphere. We conclude that the neural processes responsible for searching for patterns in events are housed in the left hemisphere.

The complexities of Xpert® MTB/RIF interpretation.

The Xpert(®) MTB/RIF assay has demonstrated robust capability for diagnosing tuberculosis (TB) and rifampin (RMP) resistance. Optimal use of Xpert in diverse settings will require knowledge of challenges when interpreting the results. We present three selected cases from the United States, a low-burden TB setting, to highlight important clinical scenarios encountered with Xpert testing: rapid RMP resistance detection in a patient with pre-extensively drug-resistant TB who immigrated from the Philippines, false-positive RMP resistance detection, and Mycobacterium tuberculosis detection in a culture-negative patient. These cases demonstrate that a low pre-test probability of TB or drug-resistant TB can complicate the interpretation of the Xpert assay.

Maintaining a cautious state of mind during a recognition test: a large-scale fMRI study.

Decision criterion is an important factor in recognition memory, determining the amount of evidence required to judge an item as previously encountered. For a typical recognition memory test involving the prior study of a set of items, a conservative criterion establishes a higher standard of evidence for recognition and designates fewer items as previously studied. In contrast, a liberal criterion establishes a lower standard of evidence and designates more items as previously studied. Therefore, the hit rate and the correct rejection rate on a recognition memory test can be affected by both the memory strength of the studied items and the criterion used to make that judgment. Yet most neuroimaging studies of the successful retrieval effect (a contrast between hits and correct rejections) fail to measure or consider decision criterion. The goal of the current fMRI study with ninety-five participants was to directly manipulate decision criteria on two tests of recognition memory by varying the likelihood of an item's prior occurrence. Our results indicate that regions of the lateral prefrontal and parietal cortex associated with successful retrieval are significantly more active when using conservative criteria than liberal criteria. Furthermore, our results reveal that activity in these regions associated with successful retrieval can be accounted for by individual differences in the conservativeness of the decision criterion above and beyond any differences in memory strength. These results expound on the role of cognitive control in recognition memory and the neural mechanisms that mediate this processing.

Creating false memories for visual scenes.

Creating false memories has become an important tool to investigate the processes underlying true memories. In the course of investigating the constructive and/or reconstructive processes underlying the formation of false memories, it has become clear that paradigms are needed that can create false memories reliably in a variety of laboratory settings. In particular, neuroimaging techniques present certain constraints in terms of subject response and timing of stimuli that a false memory paradigm needs to comply with. We have developed a picture paradigm which results in the false recognition of items of a scene which did not occur almost as often as the true recognition of items that did occur. It uses a single presentation of pictures with thematic, stereotypical scenes (e.g. a beach scene). Some of the exemplars from the scene were removed (e.g. a beach ball) and used as lures during an auditory recognition test. Subjects' performance on this paradigm was compared with their performance on the word paradigm reintroduced by Roediger and McDermott. The word paradigm has been useful in creating false memories in several neuroimaging studies because of the high frequency of false recognition for critical lures (words not presented but closely associated with lists of words that were presented) and the strong subjective sense of remembering accompanying these false recognitions. However, it has several limitations including small numbers of lures and a particular source confusion. The picture paradigm avoids these limitations and produces identical effects on normal subjects.

Hyperthyroxinemia in patients with acute psychiatric disorders.

Thyroid function tests were measured in 645 patients admitted to an acute psychiatric disorders unit. Thirty-three percent had elevated serum thyroxine (T4), and 18 percent had an elevated free T4 index (FTI). Serum triiodothyronine (T3) was low, normal, or minimally elevated in 77 patients, with a high initial free T4 index. Twenty-two patients with an initial elevation of their free T4 index were serially followed (study group). Serum T4, free T4 index, and free T4 fell in every patient: serum T4 from 13.95 +/- 1.93 micrograms/dl (mean +/- standard deviation: SD) to 9.33 +/- 2.4 micrograms/dl (p less than 0.001); free T4 index, from 6.15 +/- 0.83 to 3.79 +/- 1.1 (p less than 0.001); free T4, from 2.43 +/- 0.65 mg/dl to 1.38 +/- 0.35 ng/dl (p less than 0.001). Serum T3 was initially normal or low, and then fell in 17 patients, and rose in five. Serial testing of thyrotropin-releasing hormone (TRH) demonstrated both flat and normal responses in patients with a variety of psychiatric diagnoses and at varying stages of thyroid disease activity.

Pool cue chalk: a source of environmental lead.

Lead compounds are used as coloring agents for numerous products. Two cases of children with elevated blood lead concentrations encountered by the authors suggested that pool cue chalk may serve as a source of environmental lead. The objective of this study was to determine lead content of various brands and colors of pool cue chalk. Atomic absorption analyses were conducted of 23 different types of pool cue chalk for lead content. Three of 23 types of pool cue chalk contained more than 7000 ppm (mg/kg) lead: one manufacturer's green and tangerine chalk and another manufacturer's green chalk. It was concluded that some brands of pool cue chalk contain relatively large amounts of lead and could contribute to childhood lead poisoning.

Ventilation-perfusion scan in the acutely ill patient with unilateral hyperlucent lung.

A patient with a unilateral hyperlucent lung with acute respiratory complaints is presented. A ventilation-perfusion scan was performed to rule out pulmonary embolism. The perfusion scan ( [99mTC]MAA) showed peripheral perfusion defects in the hyperlucent lung. The ventilation study (133Xe) demonstrated peripheral ventilatory defects on the single breath image in the hyperlucent lung, the filling in of these on the equilibrium view, and diffusely delayed washout in the affected lung. These findings were suggestive of the Swyer-James syndrome and critical in excluding the numerous other causes of unilateral hyperlucent lung, which are discussed. The importance of the ventilation-perfusion study (and particularly the ventilation scan) in the patient with unilateral hyperlucent lung and acute respiratory symptoms is stressed. In addition, a discussion of the Swyer-James syndrome is included.

Iatrogenic and nurisgenic effects of prolonged immobilization of the ill aged.

The kinesio, phychopathologic and psychosocial effects of prolonged immobilization of the ill aged are outlined. The iatrogenic (physician-induced) and nurisgenic (nurse-induced) factors related to such functional disabilities are described. Illustrative case histories are given. The syndrome is reversible. Thus physicians and nurses have a continued responsibility to support a sustained rehabilitation program for these patients. The biochemical effects of prolonged inactivity indicate that immobilization of the elderly patient results in adverse physical and psychologic phenomena.

Errors and omissions in diagnostic records on admission of patients to a nursing home.

The primary and secondary diagnoses for 100 geriatric patients consecutively admitted to a nursing home were reviewed for accuracy and omissions. Primary diagnoses were identified as the direct basis for nursing home admission. Other physical, biochemical or behavioral disorders requiring continued therapeutic care were identified as secondary diagnoses. A comparison was made of the diagnosis offered by the referring physician and the diagnosis as determined by the medical staff of the nursing home immediately after admission. In 64 percent, the secondary diagnoses were either lacking or inaccurate. The extraordinarily inadequate medical performance with respect to identifying the primary clinical and therapeutic problems of the chronically ill aged was remarkably consistent, regardless of the source of the patient's referral, whether from a general or psychiatric hospital, a private home, or another nursing home. The results of this study revealed a significant degree of unpreparedness and malaise in some members of the medical profession concerning the care of the chronically ill aged, particularly when such patients demonstrate behavioral disorders superimposed upon physical disease. Failure to identify the patient's needs through diagnosis must result in poor, inadequate or inappropriate treatment programs.