Outcomes of pregnancy in adolescents with severe asthma

Asthma in adolescent pregnancies is not rare and may make patient management difficult, especially since mortality from asthma is of particular concern in the adolescent age group. We present a series of 21 pregnant adolescents with severe asthma. During 28 pregnancies, there were 56 exacerbations of asthma, including 22 hospitalizations and 20 emergency room visits. For 18 (64%) of the 28 pregnancies, outpatient systemic corticosteroids were administered, and inhaled corticosteroids were prescribed for 8 (29%). Factors associated with exacerbations included respiratory tract infections (59%) and noncompliance with medical regimens (27%). There were no maternal or fetal deaths or evidence for intrauterine growth retardation. Two infants were premature, with one experiencing acute respiratory distress syndrome. Aggressive treatment of asthma and associated respiratory tract infections, as well as careful ambulatory care, to encourage patient compliance are advisable to achieve a favorable maternal-fetal outcome.     

Late Pleistocene age and archaeological context for the hominin calvaria from GvJm-22 (Lukenya Hill,Kenya)

Kenya National Museums Lukenya Hill Hominid 1 (KNM-LH 1) is a Homo sapiens partial calvaria from site GvJm-22 at Lukenya Hill, Kenya, associated with Later Stone Age (LSA) archaeological deposits. KNM-LH 1 is securely dated to the Late Pleistocene, and samples a time and region important for understanding the origins of modern human diversity. A revised chronology based on 26 accelerator mass spectrometry radiocarbon dates on ostrich eggshells indicates an age range of 23,576–22,887 y B.P. for KNM-LH 1, confirming prior attribution to the Last Glacial Maximum. Additional dates extend the maximum age for archaeological deposits at GvJm-22 to >46,000 y B.P. (>46 kya). These dates are consistent with new analyses identifying both Middle Stone Age and LSA lithic technologies at the site, making GvJm-22 a rare eastern African record of major human behavioral shifts during the Late Pleistocene. Comparative morphometric analyses of the KNM-LH 1 cranium document the temporal and spatial complexity of early modern human morphological variability. Features of cranial shape distinguish KNM-LH 1 and other Middle and Late Pleistocene African fossils from crania of recent Africans and samples from Holocene LSA and European Upper Paleolithic sites.For Late Pleistocene African populations of modern humans, the constellation of behavioral changes encapsulated in the transition from the Middle Stone Age (MSA) to the Later Stone Age (LSA) ∼70–20 kya represents a series of some of the most pronounced changes in the archaeological record before the adoption of domesticated animals and plants and the use of ceramics for cooking and storage. It is among LSA sites that the strongest parallels with ethnographic and historic foragers are observed. Typical archaeological signatures include lithic technologies focused on the production of microliths (small flakes, blades, and bladelets with one edge blunted or “backed”) from bipolar, single-, and opposed-platform cores; an increased use of ground-stone tools; and implements made of wood and bone. These new technologies occur with the appearance of material correlates of social identity and networks of long-distance exchange, including ostrich eggshell (OES) beads, ochre, and nonlocal stone raw material, as well as increased dietary breadth, all consistent with larger, more dense, or more interconnected populations (1–9).This same interval of ∼70–20 kya witnessed a number of human dispersals across Africa, with eastern Africa host to one or more candidate populations for the expansion of Homo sapiens out of Africa (10–15). However, the eastern African hominin fossil record for this interval is extremely sparse and poorly dated, and it consists largely of isolated teeth or highly fragmentary crania and postcrania (16–18). Here, we reassess the age and context of the Kenya National Museums Lukenya Hill Hominid 1 (KNM-LH 1) partial calvaria from site GvJm-22 at Lukenya Hill, Kenya, the only eastern African fossil hominin from a Last Glacial Maximum [LGM; 19–26.4 kya (19)] LSA archaeological context. We construct a revised accelerator mass spectrometry (AMS) radiocarbon chronology built on 26 new dates on OES fragments. The revised chronology confirms the LGM age of KNM-LH 1 and expands the maximum age of the site to beyond the limits of the radiocarbon method. Increased radiometric age is consistent with new technological analyses that demonstrate previously unrecognized MSA elements that indicate assemblages spanning the MSA/LSA transition from deposits underlying KNM-LH 1. Morphometric analyses using a robust comparative dataset demonstrate the variability among African Late Pleistocene hominins, including candidate populations for out-of-Africa dispersals. They indicate that KNM-LH 1 is distinct from (i) modern Africans, (ii) H. sapiens from Holocene LSA sites, and (iii) European Upper Paleolithic modern humans, suggesting that it may sample a now extinct lineage.     

Determining research priorities for adolescent and young adult cancer in Australia

The Australian Youth Cancer Service (YCS) is part of a growing international movement to provide advocacy and better targeted health‐care services for adolescents and young adults (AYAs) with cancer. One of the key initiatives of the YCS is to determine and implement priorities within Australian AYA cancer research. The YCS used the value‐weighting online survey technique of allocating 100 hypothetical units of funding across pre‐determined topics of research in order to determine Australian consumers' and health professionals' AYA cancer research priorities. A total of 101 participants (26 consumers and 75 health professionals) took part in the online survey. Biomedical and Clinical Medicine Research was allocated the greatest proportion of available funding. A number of priority populations were also identified, although these were distributed across pre‐treatment and post‐treatment stages. The preferences of consumers and health professionals to invest available AYA cancer research funds in Biomedical and Clinical Medicine Research will be an important consideration in guiding the Australian YCS decision‐making process in the immediate future. ‘Prevention, screening and early detection’ was also an important research funding target, along with survivorship populations.     

A Review of Unmet Needs in Obesity Management

The prevalence of obesity continues to escalate in the USA; however, there is no consensus regarding the optimal therapy for obesity. For the vast majority of severely obese patients, conventional medical therapies (i.e., diet, exercise, behavioral counseling) often fail over the long term. Existing pharmacotherapy adjunctive to behavioral therapy has limited effectiveness and an imperfect safety record. In contrast, bariatric surgery has a high degree of weight loss efficacy, yet only a small fraction of the qualifying obese population undergoes these procedures because of the associated perioperative risks and potential late complications. In addition, the role of bariatric surgery is unclear in certain patient populations, such as patients with lower body mass index (BMI, 30-35 kg/m(2)), the high-risk super-super obese patients (BMI > 60), the morbidly obese adolescent, and obese patients requiring weight reduction in preparation for other procedures, such as orthopedic, transplant, or vascular surgeries. In these circumstances, there is a need for an effective but less invasive treatment to bridge the gap between medical and surgical therapy. This review examines current treatment outcomes, identifies prominent areas of unmet clinical needs, and provides an overview of two minimally invasive "temporary procedures for weight loss" that may eventually address some of the unmet needs in obesity management.     

Donor ABCB1 Variant Associates with Increased Risk for Kidney Allograft Failure

The impact of variation within genes responsible for the disposition and metabolism of calcineurin inhibitors (CNIs) on clinical outcomes in kidney transplantation is not well understood. Furthermore, the potential influence of donor, rather than recipient, genotypes on clinical endpoints is unknown. Here, we investigated the associations between donor and recipient gene variants with outcome among 4471 white, CNI-treated kidney transplant recipients. We tested for 52 single-nucleotide polymorphisms (SNPs) across five genes: CYP3A4, CYP3A5, ABCB1 (MDR1; encoding P-glycoprotein), NR1I2 (encoding the pregnane X receptor), and PPIA (encoding cyclophilin). In a discovery cohort of 811 patients from Birmingham, United Kingdom, kidney donor CC genotype at C3435T (rs1045642) within ABCB1, a variant known to alter protein expression, was associated with an increased risk for long-term graft failure compared with non-CC genotype (hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.20–2.40; P=0.003). No other donor or recipient SNPs were associated with graft survival or mortality. We validated this association in 675 donors from Belfast, United Kingdom (HR, 1.68; 95% CI, 1.21–2.32; P=0.002), and in 2985 donors from the Collaborative Transplant Study (HR, 1.84; 95% CI, 1.08–3.13; P=0.006). In conclusion, these data suggest that an ABCB1 variant known to alter protein expression represents an attractive candidate for future study and risk stratification in kidney transplantation.Calcineurin inhibitors (CNIs) remain principal components of most immunosuppression regimens in kidney transplantation. CNI dose adjustments based on CNI blood levels is the traditional approach to drug administration; however, this is an imperfect approach because CNIs have a narrow therapeutic index and high pharmacokinetic variability.¹ The unpredictable response to CNI drug dosing has been attributed to interindividual differences in expression of drug-metabolizing enzymes and transporters. Important components of this CNI disposition “axis” are the nuclear pregnane X receptor (PXR, encoded by the nuclear receptor subfamily 1, group I, member 2 [NR1I2] gene), which is proposed to be a “master regulator” of hepatic drug handling; cytochrome P450 (CYP) enzymes 3A4 and 3A5; the drug transporter P-glycoprotein (P-gp, encoded by the ATP-binding cassette, sub-family B, member 1 [ABCB1] gene, also known as the multidrug resistance 1 [MDR-1] gene); and cyclophilin A (Cyp, encoded by the peptidylprolyl isomerase A [PPIA] gene), the target of cyclosporine.^2–6Although data are inconsistent, there is evidence that single-nucleotide polymorphisms (SNPs) within these genes are associated with variation in cyclosporine and tacrolimus pharmacokinetics.^7–9 Preliminary and unreplicated reports also suggest that recipient genotype for ABCB1 is associated with delayed graft function¹⁰ and acute rejection,^11,12 and recipient CYP3A5 genotype is associated with mortality.¹³ However, with the exception of this report by Kreutz and colleagues,¹³ no studies have addressed the relationship between recipient genotype and the important “hard” clinical endpoints of renal transplantation (i.e., allograft failure or mortality), with limitations stemming from small sample sizes and short follow-up.¹⁴In contrast to studies of recipient genotype, far less information is available on the relationship between SNPs within genes of the kidney transplant donor and subsequent outcome. Although reduced expression of CYP3A5 and P-gp within the transplanted kidney have been associated with CNI toxicity,^15,16 only two small published studies to date have addressed the relationship between donor SNPs and clinical outcomes in cyclosporine-treated patients. These provide some evidence for an association between genetic variation in donor ABCB1 and acute cyclosporine nephrotoxicity¹⁷ and allograft failure.¹⁸ Both studies focused on the C3435T polymorphism within the ABCB1 gene, an exonic SNP whereby the TT genotype is associated with reduced P-gp expression.¹⁹The purpose of this study was to assess the relationship of both donor and recipient genotype with kidney allograft survival and recipient mortality. The study was not restricted to the limited number of SNPs previously studied but rather involved a comprehensive survey of common sequence variation in the target genes involved in CNI disposition. This was accomplished by interrogating the International HapMap resource²⁰ and selecting 52 tagging SNPs to capture the majority of common variation within five candidate genes. Preliminary positive findings from an initial discovery cohort were examined in two further independent populations, incorporating a total of 4471 renal transplant recipients followed for up to 20 years.     

Antibodies to K‐α 1 Tubulin and Collagen V Are Associated With Chronic Rejection After Lung Transplantation

Bronchiolitis obliterans syndrome (BOS), the clinical correlate of chronic rejection after lung transplantation, is the leading obstacle to better long‐term outcomes. We previously instituted a clinical protocol to screen for donor‐specific human leukocyte antigen (HLA) antibodies (DSA) and a preemptive antibody‐directed therapy protocol consisting of rituximab and/or intravenous immune globulin. In this study, we retrospectively analyzed serum samples from lung transplant recipients (n = 108) for antibodies to self‐antigens (K‐α 1 tubulin and collagen V) before and after antibody‐directed therapy and correlated the results with the subsequent development of BOS. Seventy‐two of the 108 recipients developed antibodies to self‐antigens. There was a correlation between the development of antibodies to self‐antigens and DSA. Sixteen of the 54 patients who had antibodies to self‐antigens and were treated with antibody‐directed therapy cleared the antibodies, and they were significantly less likely to develop BOS than those who had persistent antibodies. Furthermore, those who cleared DSA after treatment but had persistent antibodies to self‐antigens were significantly more likely to develop BOS than those who cleared these antibodies. We conclude that antibodies to self‐antigens are an important risk factor for the development of BOS.     

Comparison of rates and risk factors for development of anaemia and erythropoiesis-stimulating agent utilization after radical or partial nephrectomy

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? The consequences and significance of iatrogenically‐induced CKD are poorly understood. Most data regarding risk of CKD and its complications are inferred from the medical literature. This is the first study to examine impact of surgical management of renal masses on development of anaemia. Patients who underwent radical nephrectomy had a significantly higher incidence of anaemia and ESA utilization than a contemporary well‐matched cohort that underwent partial nephrectomy. The results obtained add to the growing body of data supporting the use of partial nephrectomy in the management of clinically appropriate renal masses.

OBJECTIVE

• ? To examine the incidence of and risk factors for the development of anaemia and erythropoiesis‐stimulation agent (ESA) treatment in patients undergoing radical nephrectomy (RN) and partial nephrectomy (PN) because anaemia is a significant cause of morbidity in chronic kidney disease.

PATIENTS AND METHODS

• ? The study comprised a retrospective review of 905 patients (610 RN/295 PN; mean age, 57.5 years; mean follow‐up, 6.4 years) who underwent surgery for renal tumours at two institutions from July 1987 to June 2007.
• ? Demographics, disease characteristics and pre‐ and postoperative (i.e. renal function, metabolic parameters, anaemia and ESA treatment) were recorded.
• ? Data were analyzed within subgroups based on treatment (RN vs PN).
• ? Multivariate analysis was conducted to determine the risk factors for developing anaemia after surgery.

RESULTS

• ? Tumour size (cm) was significantly larger for RN (RN 7.0 vs PN 3.7; P < 0.001). No significant differences were noted with respect to demographics and preoperative anaemia (RN 16.4% vs PN 18.6%; P= 0.454) and ESA‐treatment (RN 0.7% vs PN 1.4%; P= 0.499).
• ? After surgery, significantly less de novo anaemia (PN 4.1% vs RN 17.5%; P < 0.001) and ESA utilization (PN 2.7% vs RN 13.4%; P < 0.001) occurred in the PN cohort.
• ? Multivariate analysis showed that age ≥60 years (odds ratio, OR, 1.62; P= 0.008), African American ethnicity (OR, 2.30; P < 0.001), smoking (OR, 1.60; P= 0.013), glomerular filtration rate (GFR) <60 mL/min/1.73 m² (OR, 4.09; P < 0.001), ≥1+ proteinuria (OR, 2.19; P < 0.03), metabolic acidosis (OR, 4.08; P= 0.007) and RN (OR, 2.58; P < 0.001) were significantly associated with de novo anaemia.

CONCLUSIONS

• ? Patients who underwent RN had a significantly higher prevalence of anaemia and ESA‐treatment compared to a well‐matched cohort that underwent PN.
• ? In addition to RN, age ≥60 years, African American ethnicity, history of smoking, GFR < 60 mL/min/1.73 m², proteinuria and metabolic acidosis were associated with developing anaemia.

     

South Australian Scleroderma Register: autoantibodies as predictive biomarkers of phenotype and outcome

Aim: To investigate the relationship between scleroderma‐specific autoantibodies and clinical phenotype and survival in South Australian patients with scleroderma. Method: Two cohorts of patients were studied from the South Australian Scleroderma Register (SASR). In the first, the sera of 129 consecutive patients were analyzed for anticentromere (ACA), anti‐Scl70, anti‐RNA polymerase III, anti‐U1RNP, anti‐Th/To, anti‐Pm/Scl, anti‐Ku and anti‐fibrillarin antibodies using the Euroline immunoblot assay. Statistical analysis was performed to look for a significant association between specific antibodies and various clinical features. In the second cohort survival from first symptom onset was analyzed in 285 patients in whom the autoantibody profile was available, including ACA, Anti‐Scl70, anti‐U1RNP and anti‐RNA polymerase III measured using multiple methods. Survival analysis compared mortality between different groups of patients with specific antibodies. Results: ACA, Th/To and Ku antibodies were associated with limited scleroderma, Scl70 and RNA Pol III antibodies were associated with diffuse scleroderma and antibodies to U1RNP were associated with overlap syndrome. Significant associations between Scl70 and interstitial lung disease (P = 0.004), RNA Pol III and renal crisis (P = 0.002), U1RNP and pulmonary hypertension (P = 0.006) and Th/To and pulmonary hypertension (P = 0.034) were seen. Trends were observed with an increased frequency of lung disease with Pm/Scl and Th/To and an increased frequency of myositis with Ku. The presence of Scl70, RNA Pol III and U1RNP was associated with significantly reduced survival as compared with patients with ACA. Conclusions: Scleroderma‐specific autoantibodies are associated with clinical phenotype and survival.