Atmospheric Carbon and Transport - America (ACT-America) Data Sets: Description, Management, and Delivery.

The ACT-America project is a NASA Earth Venture Suborbital-2 mission designed to study the transport and fluxes of greenhouse gases. The open and freely available ACT-America data sets provide airborne in situ measurements of atmospheric carbon dioxide, methane, trace gases, aerosols, clouds, and meteorological properties, airborne remote sensing measurements of aerosol backscatter, atmospheric boundary layer height and columnar content of atmospheric carbon dioxide, tower-based measurements, and modeled atmospheric mole fractions and regional carbon fluxes of greenhouse gases over the Central and Eastern United States. We conducted 121 research flights during five campaigns in four seasons during 2016-2019 over three regions of the US (Mid-Atlantic, Midwest and South) using two NASA research aircraft (B-200 and C-130). We performed three flight patterns (fair weather, frontal crossings, and OCO-2 underflights) and collected more than 1,140 h of airborne measurements via level-leg flights in the atmospheric boundary layer, lower, and upper free troposphere and vertical profiles spanning these altitudes. We also merged various airborne in situ measurements onto a common standard sampling interval, which brings coherence to the data, creates geolocated data products, and makes it much easier for the users to perform holistic analysis of the ACT-America data products. Here, we report on detailed information of data sets collected, the workflow for data sets including storage and processing of the quality controlled and quality assured harmonized observations, and their archival and formatting for users. Finally, we provide some important information on the dissemination of data products including metadata and highlights of applications of ACT-America data sets.

Protocol of a two arm randomised, multi-centre, 12-month controlled trial: evaluating the impact of a Cognitive Behavioural Therapy (CBT)-based intervention Supporting UPtake and Adherence to antiretrovirals (SUPA) in adults with HIV.

BACKGROUND: Delay to start antiretroviral therapy (ART) and nonadherence compromise the health and wellbeing of people living with HIV (PLWH), raise the cost of care and increase risk of transmission to sexual partners. To date, interventions to improve adherence to ART have had limited success, perhaps because they have failed to systematically elicit and address both perceptual and practical barriers to adherence. The primary aim of this study is to determine the efficacy of the Supporting UPtake and Adherence (SUPA) intervention. METHODS: This study comprises 2 phases. Phase 1 is an observational cohort study, in which PLWH who are ART naïve and recommended to take ART by their clinician complete a questionnaire assessing their beliefs about ART over 12 months. Phase 2 is a randomised controlled trial (RCT) nested within the observational cohort study to investigate the effectiveness of the SUPA intervention on adherence to ART. PLWH at risk of nonadherence (based on their beliefs about ART) will be recruited and randomised 1:1 to the intervention (SUPA intervention + usual care) and control (usual care) arms. The SUPA intervention involves 4 tailored treatment support sessions delivered by a Research Nurse utilising a collaborative Cognitive Behavioural Therapy (CBT) and Motivational Interviewing (MI) approach. Sessions are tailored to individual needs and preferences based on the individual patient's perceptions and practical barriers to ART. An animation series and intervention manual have been developed to communicate a rationale for the personal necessity for ART and illustrate concerns and potential solutions. The primary outcome is adherence to ART measured using Medication Event Monitoring System (MEMS). Three hundred seventy-two patients will be sufficient to detect a 15% difference in adherence with 80% power and an alpha of 0.05. Costs will be compared between intervention and control groups. Costs will be combined with the primary outcome in cost-effectiveness analyses. Quality adjusted life-years (QALYs) will also be estimated over the follow-up period and used in the analyses. DISCUSSION: The findings will enable patients, healthcare providers and policy makers to make informed decisions about the value of the SUPA intervention. TRIAL REGISTRATION: The trial was retrospectively registered 21/02/2014, ISRCTN35514212 .

"Reversible" myelodysplastic syndrome or ineffectual clonal haematopoiesis? - add(6p) myeloid neoplasm with a spontaneous cytogenetic remission.

Cytotoxic chemotherapy has inherent mutagenic potential and alters the bone marrow microenvironment after therapy. In some cases, this potentiates expansion of an aberrant clone and may lead to a therapy-related myeloid neoplasm if the clone overcomes selective pressure. We present the case of a 43-year-old woman diagnosed with an indolent, therapy-related myeloid neoplasm with an isolated chromosome 6p abnormality following treatment for de novo Acute Myeloid Leukaemia (AML), who manifest a sustained spontaneous cytogenetic remission two years later, possibly due to an ineffectual or non-dominant founding clone. This case reminds us to be mindful of the possibility that clonal haematopoiesis may not always equate to clinically relevant disease, even in the setting of an abnormal clonal karyotype.

An ecological role for assortative mating under infection?

Wildlife diseases are emerging at a higher rate than ever before meaning that understanding their potential impacts is essential, especially for those species and populations that may already be of conservation concern. The link between population genetic structure and the resistance of populations to disease is well understood: high genetic diversity allows populations to better cope with environmental changes, including the outbreak of novel diseases. Perhaps following this common wisdom, numerous empirical and theoretical studies have investigated the link between disease and disassortative mating patterns, which can increase genetic diversity. Few however have looked at the possible link between disease and the establishment of assortative mating patterns. Given that assortative mating can reduce genetic variation within a population thus reducing the adaptive potential and long-term viability of populations, we suggest that this link deserves greater attention, particularly in those species already threatened by a lack of genetic diversity. Here, we summarise the potential broad scale genetic implications of assortative mating patterns and outline how infection by pathogens or parasites might bring them about. We include a review of the empirical literature pertaining to disease-induced assortative mating. We also suggest future directions and methodological improvements that could advance our understanding of how the link between disease and mating patterns influences genetic variation and long-term population viability.

Endolymphatic hydrops is prevalent in the first weeks following cochlear implantation.

AIM: To explore morphological or electrophysiological evidence for the presence of endolymphatic hydrops (EH) in guinea pig cochleae in the first 3 months after cochlear implantation. METHODS: Dummy silastic electrodes were implanted atraumatically into the basal turn of scala tympani via a cochleostomy. Round window electrocochleography (ECochG) was undertaken prior to and after implantation. Animals survived for 1, 7, 28 or 72 days prior to a terminal experiment, when ECochG was repeated. The cochleae were imaged using micro-CT after post-fixing with osmium tetroxide to reveal the inner ear soft tissue structure. EH was assessed by visual inspection at a series of frequency specific places along the length of the cochlea, and the extent to which Reissner's membrane departed from its neutral position was quantified. Tissue response volumes were calculated. Using ECochG, the ratio of the summating potential to the action potential (SP/AP ratio) was calculated in response to frequencies between 2 and 32 kHz. RESULTS: There was minimal evidence of electrode trauma from cochlear implantation on micro-CT imaging. Tissue response volumes did not change over time. EH was most prevalent 7 days after surgery in implanted ears, as determined by visual inspection. Scala media areas were increased, as expected in cases of EH, over the first month after cochlear implantation. SP/AP ratios decreased immediately after surgery, but were elevated 1 and 7 days after implantation. CONCLUSIONS: EH is prevalent in the first weeks after implant surgery, even in the absence of significant electrode insertion trauma.

Spectrum of chronic kidney disease in HIV-infected patients.

OBJECTIVES: The aim of the study was to investigate the prevalence and aetiology of chronic kidney disease (CKD) and trends in estimated glomerular filtration rate (eGFR) in HIV-infected patients. METHODS: Ascertainment and review of CKD cases among patients attending King's College and Brighton Hospitals, UK were carried out. CKD was defined as eGFR <60 mL/min for > or =3 months. Longitudinal eGFR slopes were produced to examine trends in renal function before, during and after exposure to indinavir (IDV) or tenofovir (TFV). RESULTS: CKD prevalence was 2.4%. While HIV-associated nephropathy accounted for 62% of CKD in black patients, 95% of CKD in white/other patients was associated with diabetes mellitus, hypertension, atherosclerosis and/or drug toxicity. Exposure to IDV or TFV was associated with an accelerated decline in renal function (4.6-fold and 3.7-fold, respectively) in patients with CKD. In patients initiating IDV, age > or =50 years increased the odds of CKD [odds ratio (OR) 4.9], while in patients initiating TFV, age > or =50 years (OR 5.4) and eGFR 60-75 mL/min (OR 17.2) were associated with developing CKD. CONCLUSION: This study highlights the importance of metabolic and vascular disease to the burden of CKD in an ageing HIV-infected cohort. In patients who developed CKD, treatment with IDV or TFV was associated with an accelerated decline in renal function.

Wound epidermis formation and function in urodele amphibian limb regeneration.

Upon amputation of the urodele limb, the epidermal cells surrounding the amputation plane migrate to heal the wound. The resulting wound epidermis (WE) induces the regeneration process, resulting in blastema formation, cell division, and ultimately repatterning into a new limb. Despite its central role in the initiation of limb regeneration, little is known about how the WE forms. Here we discuss various models of WE formation and the experimental data in support of each.

Dicentric chromosomes and 20q11.2 amplification in MDS/AML with apparent monosomy 20.

FISH analysis of 41 previously karyotyped cases of MDS and AML with apparent monosomy of chromosome 20 revealed a variety of dicentric abnormalities involving chromosome 20. These usually, but not always, involved a breakpoint in the long arm of chromosome 20 and loss of the common deleted region at 20q12. Not one case of true monosomy 20 was confirmed. We found evidence for dicentric chromosome formation in 21 of 24 unbalanced translocations containing chromosome 20 and that were studied in more detail. Subsequent loss of one of the centromeres had occurred in eight of these 24 cases, and was more frequent than centromere inactivation as a means of resolving the inherent instability of a dicentric chromosome. In the three cases with dicentric chromosomes from which proximal 20q had been excised along with the 20 centromere, the excised segment was retained, and in two of these it was amplified. Proximal 20q was clearly retained in all but three cases, and present in three or more copies in 17 of 41 cases. The retention and amplification of proximal 20q provides support for the hypothesis that there is an oncogene located in this region of 20q that is activated in cases of MDS/AML with del(20q). Apparent monosomy 20 in MDS/AML should be treated as evidence of unidentified chromosome 20 abnormalities, and familiarity with the typical G-banded morphology of these derivatives can help with their identification. The reported incidence of dicentric chromosomes is clearly an under-estimate but is increasing in myeloid disorders as more cases are studied with methods allowing their detection.

hTERT, the catalytic component of telomerase, is downregulated in the haematopoietic stem cells of patients with chronic myeloid leukaemia.

Telomere shortening is associated with disease progression in chronic myeloid leukaemia (CML). To investigate the biology and regulation of telomerase in CML, we evaluated expression of the telomerase components, its regulators and several telomeric-associated proteins. Quantitative real-time-polymerase chain reaction (PCR) was used to compare gene expression in the CD34+/leukaemic blast cells of 22 CML patient samples to the CD34+ cell population of healthy individuals. hTERT, the catalytic component of telomerase, was downregulated in eight of 12 chronic phase (CP) patients (P = 0.0387). Furthermore, hTERT was significantly downregulated in two of three patients in accelerated phase (AP) and seven of seven patients in blast crisis (BC), P = 0.0017. Expression of hTR and telomeric-associated proteins TEP1, TRF1, TRF2, tankyrase and PinX1 was high in the majority of CP and AP patients. With the exceptions of TEP1 and hTR, expression of these factors was highest in CP and decreased during disease progression. Expression of c-Myc, a positive regulator of hTERT transcription, correlated with hTERT expression and decreased with disease progression, falling below control levels in BC. hTERT levels were increased in CP patients following successful treatment with imatinib, relative to untreated CP patients. We suggest that reduced hTERT expression directly causes the shortened telomeres observed in CML.

The development and evaluation of a three-dimensional ultrasound-guided breast biopsy apparatus.

We have designed a prototype three-dimensional ultrasound guidance (3D USB) apparatus to improve the breast biopsy procedure. Features from stereotactic mammography and free-hand US-guided biopsy have been combined with 3D US imaging. This breast biopsy apparatus accurately guides a needle into position for the sampling of target tissue. We have evaluated this apparatus in three stages. First, by testing the placement accuracy of a needle in a tissue mimicking phantom. Second, with tissue mimicking phantoms that had embedded lesions for biopsy. Finally, by comparison to free-hand US-guided biopsy, using chicken breast phantoms. The first two stages of evaluation quantified the mechanical biases in the 3D USB apparatus. Compensating for these, a 96% success rate in targeting 3.2 mm "lesions" in chicken breast phantoms was achieved when using the 3D USB apparatus. The expert radiologists performing biopsies with free-hand US guidance achieved a 94.5% success rate. This has proven an equivalence between our apparatus, operated by non-experts, and free-hand biopsy performed by expert radiologists, for 3.2 mm lesions in vitro, with a 95% confidence.

Sequential transformation of t(8;13)-related disease: a case report.

We report a case of an atypical myeloproliferative disorder with t(8;13) that presented as B-lineage acute lymphoblastic leukaemia (B-ALL). Following induction chemotherapy, the disease manifested as chronic myeloproliferative state, which responded to hydroxyurea. Terminally, the disease transformed into acute myeloid leukaemia (AML) with additional chromosomal abnormalities including monosomy 7. To our knowledge, this is the first case of this rare atypical myeloproliferative disorder with t(8;13) that presented as B-ALL and terminally transformed to AML with additional chromosomal abnormalities.

Deletions of the derivative chromosome 9 occur at the time of the Philadelphia translocation and provide a powerful and independent prognostic indicator in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is characterized by formation of the BCR-ABL fusion gene, usually as a consequence of the Philadelphia (Ph) translocation between chromosomes 9 and 22. Large deletions on the derivative chromosome 9 have recently been reported, but it was unclear whether deletions arose during disease progression or at the time of the Ph translocation. Fluorescence in situ hybridization (FISH) analysis was used to assess the deletion status of 253 patients with CML. The strength of deletion status as a prognostic indicator was then compared to the Sokal and Hasford scoring systems. The frequency of deletions was similar at diagnosis and after disease progression but was significantly increased in patients with variant Ph translocations. In patients with a deletion, all Ph(+) metaphases carried the deletion. The median survival of patients with and without deletions was 38 months and 88 months, respectively (P =.0001). By contrast the survival difference between Sokal or Hasford high-risk and non-high-risk patients was of only borderline significance (P =.057 and P =.034). The results indicate that deletions occur at the time of the Ph translocation. An apparently simple reciprocal translocation may therefore result in considerable genetic heterogeneity ab initio, a concept that is likely to apply to other malignancies associated with translocations. Deletion status is also a powerful and independent prognostic factor for patients with CML. The prognostic significance of deletion status should now be studied prospectively and, if confirmed, should be incorporated into management decisions and the analysis of clinical trials.

Chromosome 20 deletions in myeloid malignancies: reduction of the common deleted region, generation of a PAC/BAC contig and identification of candidate genes. UK Cancer Cytogenetics Group (UKCCG).

Deletion of the long arm of chromosome 20 represents the most common chromosomal abnormality associated with the myeloproliferative disorders (MPDs) and is also found in other myeloid malignancies including myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). Previous studies have identified a common deleted region (CDR) spanning approximately 8 Mb. We have now used G-banding, FISH or microsatellite PCR to analyse 113 patients with a 20q deletion associated with a myeloid malignancy. Our results define a new MPD CDR of 2.7 Mb, an MDS/AML CDR of 2.6 Mb and a combined 'myeloid' CDR of 1.7 Mb. We have also constructed the most detailed physical map of this region to date--a bacterial clone map spanning 5 Mb of the chromosome which contains 456 bacterial clones and 202 DNA markers. Fifty-one expressed sequences were localized within this contig of which 37 lie within the MPD CDR and 20 within the MDS/AML CDR. Of the 16 expressed sequences (six genes and 10 unique ESTs) within the 'myeloid' CDR, five were expressed in both normal bone marrow and purified CD34 positive cells. These data identify a set of genes which are both positional and expression candidates for the target gene(s) on 20q.

Secondary acute myeloid leukemia with inv(16): report of two cases following paclitaxel-containing chemotherapy and review of the role of intensified ara-C therapy.

Acute myeloid leukemia developing secondary to prior cytotoxic chemotherapy (s-AML) encompasses a range of distinct entities. We report two cases of s-AML with inv(16)(p13q22) who had prior exposure to paclitaxel. Additionally, two previously reported cases of s-AML with inv(16) had prior paclitaxel exposure raising the possibility that the taxanes may predispose to this specific syndrome of s-AML. One of our patients received escalated-dose ara-C chemotherapy, achieving a complete remission (12+ months). We therefore examined the prognosis of previously reported cases of s-AML with inv(16) and analyzed the influence of escalated-dose ara-C (>/=400 mg/m2/day). A total of 25 evaluable cases were identified, with 96% attaining CR independent of ara-C dose. The estimated median remission duration was 40 months and the median survival has not been reached (actuarial 5-year survival 52 +/- 18%). Although not achieving statistical significance, patients treated with escalated dose ara-C (n = 15) had longer remission duration and overall survival than those treated with standard dose ara-C (n = 10) (P = 0.063 and 0.20, respectively). In univariate analysis, younger age, male gender, and the presence of additional cytogenetic abnormalities were associated with a tendency towards adverse outcomes (P< 0.1). Age and gender were equally distributed between ara-C dose cohorts, but more patients treated with standard-dose ara-C had additional cytogenetic abnormalities (P = 0.048). Within the limitations of this retrospective study, this analysis suggests that, similar to de novo AML with inv(16), secondary cases may also potentially benefit from treatment with escalated-dose ara-C. This is consistent with the premise that the underlying molecular defect, rather than the presence of prior cytotoxic drug exposure, may be the most important determinant of disease behavior and chemotherapy responsiveness in AML.

MYC amplification in two further cases of acute myeloid leukemia with trisomy 4 and double minute chromosomes.

We report two cases of trisomy 4 with double minute chromosomes (dmin): one in a woman with acute myeloid leukemia (AML), French-American-British subtype M2, the other in a man with chronic myelomonocytic leukemia. In the former case, many cells without trisomy 4 but with dmin were present, a finding not observed in previously reported cases. In both cases, fluorescence in situ hybridization studies demonstrated the double minutes to be MYC amplicons. Ten cases of AML with trisomy 4 and dmin have now been described; in the five cases investigated, the dmin have been shown to be amplified MYC gene sequences.

Correlation of cytogenetics, BCR-ABL PCR studies and fluorescence in situ hybridisation (FISH) in adult acute lymphoblastic leukaemia.

BACKGROUND: Philadelphia positive (Ph+) acute lymphoblastic leukaemia (ALL) accounts for 11-29% of adult ALL. Reverse transcriptase polymerase chain reaction (RT-PCR) for the BCR-ABL fusion mRNA has identified patients with the fusion mRNA without cytogenetic evidence of the 9;22 translocation. The reason for discrepancies between cytogenetic and molecular diagnoses is unclear. AIM: Our aim was to study cases of ALL with discordant cytogenetic and RT-PCR results and identify any reasons for such discrepancies. METHODS: Laboratory records were scanned for cases of ALL tested by both RT-PCR and cytogenetics and positive by either for the 9;22 translocation. Fluorescence in situ hybridisation (FISH) was used to study discordant results where a specimen was available. RESULTS: We identified 15 patients with ALL who had both cytogenetic and RT-PCR studies for BCR-ABL. Seven had discordant results; five patients had positive RT-PCR studies with normal (four/five) or abnormal but Ph negative cytogenetics (one/five), and two were Ph+ but RT-PCR negative. FISH, using Vysis LSI bcr/abl translocation probes, showed fused signals in 12% interphase cells but not in metaphase cells in one specimen with normal cytogenetics, and 6% interphase cells in the Ph negative patient with abnormal cytogenetics. This second patient subsequently relapsed with a minor Ph+ cell line derived from the Ph negative line. CONCLUSIONS: These results confirmed the need for both cytogenetics and RT-PCR to identify Ph+ ALL. FISH did not show sub-microscopic rearrangements of BCR-ABL in normal metaphases. Failure to identify the Philadelphia chromosome cytogenetically appeared due rather to Ph+ cells failing to divide.

Report and abstracts of the Sixth International Workshop on chromosome 9.

A meeting on chromosome 9 was held on Tuesday, 27 October 1998 in Denver, with 38 participants (see appendix). Since the last meeting several of the positional cloning efforts on chromosome 9q have come to fruition, and the most detailed discussion was on 9p. Dr Ian Dunham from the Sanger Centre explained the strategy to be used for sequencing chromosome 9, and encouraged collaboration in the preparatory mapping. He indicated that some priority could be given to those regions where people in the field had a strong interest and could identify relevant PAC clones. At this short meeting it was clearly not possible to construct a comprehensive map of chromosome 9, and it was decided that efforts should be made to maintain links to sources of information on the chromosome 9 web page (http:@www.gene.ucl.ac.uk/chr9/). The discussions at the meeting are summarized in four sections: 9p, 9cen-q31, 9q32-9q34 and comparative mapping. Many of the posters presented at the meeting were also presented at the ASHG meeting (28-31 October 1998). They are listed here and are published in The American Journal of Human Genetics, vol. 63 (supplement). Abstracts for posters presented only at this meeting are appended to this report.

Frequent loss of heterozygosity in early non-small cell lung cancers at chromosome 9p21 proximal to the CDKN2a gene.

Deletions involving the chromosome 9p21 region have been reported as frequent events in non-small cell lung cancer (NSCLC). To investigate potential tumor-suppressor gene (TSG) loci within the 9p21 region, which also harbors the candidate TSG locus CDKN2a, we studied 32 cases of primary NSCLC for loss of heterozygosity (LOH). Tumor and paired normal lung cells were microdissected from lung tissue imprints and all samples screened using PCR-LOH analysis with 15 9p markers. In addition, 3 NSCLC cell lines and their matched normal lung and tumor DNA were similarly analyzed. LOH at the marker D9S259, which is proximal to the CDKN2a locus, was found most frequently (52%), while LOH at D9S942, the marker closest (5 kb) to the CDKN2a gene, was seen in only 17%. Homozygous loss of markers close to CDKN2a was, however, detected in 2 of the 3 cell lines and one accompanying tumor sample. We propose that a TSG in the region of deletion proximal to the CDKN2a gene within 9p21 may play a significant role in the pathogenesis and progression of NSCLC.

Application of interphase cytogenetics to monitor bone marrow transplants.

Chromosomal in situ hybridization (ISH) has extended the scope of cytogenetic analysis to nondividing cells by the use of chromosome-specific probes detected by nonisotopic techniques. This provides a rapid and sensitive method for identifying chromosomes in interphase cells, and is useful in gauging engraftment following bone marrow transplantation, particularly when the number of cells obtained is minimal. We have performed ISH using a Y-heterochromatin-specific probe to monitor patients with malignant hematological disease who have received a sex-mismatched transplant. The results have been compared with those obtained from concurrently performed standard cytogenetic analysis. Host cells were detected by interphase cytogenetics in all patients posttransplant, at times varying from 28-1,825 days, whereas routine analysis detected host cells in only 4 patients, 3 of whom were found to be in relapse. The significance of the persistence of host cells is unknown, but it does not appear to indicate impending relapse.