A survey of the health interests of the people of Quincy, Massachusetts

Thesis (Ed. M.)--Boston University, 195

Primordial black holes as a tool for constraining non-Gaussianity

Primordial Black Holes (PBH's) can form in the early Universe from the collapse of large density fluctuations. Tight observational limits on their abundance constrain the amplitude of the primordial fluctuations on very small scales which can not otherwise be constrained, with PBH's only forming from the extremely rare large fluctuations. The number of PBH's formed is therefore sensitive to small changes in the shape of the tail of the fluctuation distribution, which itself depends on the amount of non-Gaussianity present. We study, for the first time, how quadratic and cubic local non-Gaussianity of arbitrary size (parameterised by f_nl and g_nl respectively) affects the PBH abundance and the resulting constraints on the amplitude of the fluctuations on very small scales. Intriguingly we find that even non-linearity parameters of order unity have a significant impact on the PBH abundance. The sign of the non-Gaussianity is particularly important, with the constraint on the allowed fluctuation amplitude tightening by an order of magnitude as f_nl changes from just -0.5 to 0.5. We find that if PBH's are observed in the future, then regardless of the amplitude of the fluctuations, non-negligible negative f_nl would be ruled out. Finally we show that g_nl can have an even larger effect on the number of PBH's formed than f_nl.Comment: 9 pages, 5 figures, v2: version to appear in Phys. Rev. D with minor changes, v3: typos corrected (including factor of 1/2 in erfc prefactor), no changes to result

Primordial black hole constraints in cosmologies with early matter domination

Moduli fields, a natural prediction of any supergravity and superstring-inspired supersymmetry theory, may lead to a prolonged period of matter domination in the early Universe. This can be observationally viable provided the moduli decay early enough to avoid harming nucleosynthesis. If primordial black holes form, they would be expected to do so before or during this matter dominated era. We examine the extent to which the standard primordial black hole constraints are weakened in such a cosmology. Permitted mass fractions of black holes at formation are of order $10^{-8}$, rather than the usual $10^{-20}$ or so. If the black holes form from density perturbations with a power-law spectrum, its spectral index is limited to $n \lesssim 1.3$, rather than the $n \lesssim 1.25$ obtained in the standard cosmology.Comment: 7 pages RevTeX file with four figures incorporated (uses RevTeX and epsf). Also available by e-mailing ARL, or by WWW at http://star-www.maps.susx.ac.uk/papers/infcos_papers.htm

Constraints on the density perturbation spectrum from primordial black holes

We re-examine the constraints on the density perturbation spectrum, including its spectral index $n$, from the production of primordial black holes. The standard cosmology, where the Universe is radiation dominated from the end of inflation up until the recent past, was studied by Carr, Gilbert and Lidsey; we correct two errors in their derivation and find a significantly stronger constraint than they did, $n \lesssim 1.25$ rather than their 1.5. We then consider an alternative cosmology in which a second period of inflation, known as thermal inflation and designed to solve additional relic over-density problems, occurs at a lower energy scale than the main inflationary period. In that case, the constraint weakens to $n \lesssim 1.3$, and thermal inflation also leads to a `missing mass' range, $10^{18} g \lesssim M \lesssim 10^{26} g$, in which primordial black holes cannot form. Finally, we discuss the effect of allowing for the expected non-gaussianity in the density perturbations predicted by Bullock and Primack, which can weaken the constraints further by up to 0.05.Comment: 10 pages RevTeX file with four figures incorporated (uses RevTeX and epsf). Also available by e-mailing ARL, or by WWW at http://star-www.maps.susx.ac.uk/papers/infcos_papers.htm

HIV-1 Epidemic in the Caribbean Is Dominated by Subtype B

The molecular epidemiology of HIV-1 in the Caribbean has been described using partial genome sequencing; subtype B is the most common subtype in multiple countries. To expand our knowledge of this, nearly full genome amplification, sequencing and analysis was conducted.Virion RNA from sera collected in Haiti, Dominican Republic, Jamaica and Trinidad and Tobago were reverse transcribed, PCR amplified, sequenced and phylogenetically analyzed. Nearly full genomes were completed for 15 strains; partial pol was done for 67 strains. All but one of the 67 strains analyzed in pol were subtype B; the exception was a unique recombinant of subtypes B and C collected in the Dominican Republic. Of the nearly full genomes of 14 strains that were subtype B in pol, all were subtype B from one end of the genome to the other and not inter-subtype recombinants. Surprisingly, the Caribbean subtype B strains clustered significantly with each other and separate from subtype B from other parts of the pandemic.The more complete analysis of HIV-1 from 4 Caribbean countries confirms previous research using partial genome analysis that the predominant subtype in circulation was subtype B. The Caribbean strains are phylogenetically distinct from other subtype B strains although the biological meaning of this finding is unclear

Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial.

PURPOSE: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER)-positive metastatic breast cancers include, among others, ER loss and acquired activating mutations in the ligand-binding domain of the ER gene (ESR1LBDm). ESR1 mutational mediated resistance may be overcome by selective ER degraders (SERD). During the first-in-human study of oral SERD AZD9496, early changes in circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) were explored as potential noninvasive tools, alongside paired tumor biopsies, to assess pharmacodynamics and early efficacy. EXPERIMENTAL DESIGN: CTC were enumerated/phenotyped for ER and Ki67 using CellSearch in serial blood draws. ctDNA was assessed for the most common ESR1LBDm by droplet digital PCR (BioRad). RESULTS: Before starting AZD9496, 11 of 43 (25%) patients had ≥5 CTC/7.5 mL whole blood (WB), none of whom underwent reduction to <5 CTC/7.5 mL WB on C1D15. Five of 11 patients had baseline CTC-ER+, two of whom had CTC-ER+ reduction. CTC-Ki67 status did not change appreciably. Patients with ≥5 CTC/7.5 mL WB before treatment had worse progression-free survival (PFS) than patients with <5 CTC (P = 0.0003). Fourteen of 45 (31%) patients had ESR1LBDm + ctDNA at baseline, five of whom had ≥2 unique mutations. Baseline ESR1LBDm status was not prognostic. Patients with persistently elevated CTC and/or ESR1LBDm + ctDNA at C1D15 had worse PFS than patients who did not (P = 0.0007). CONCLUSIONS: Elevated CTC at baseline was a strong prognostic factor in this cohort. Early on-treatment changes were observed in CTC-ER+ and ESR1LBDm + ctDNA, but not in overall CTC number. Integrating multiple biomarkers in prospective trials may improve outcome prediction and ET resistance mechanisms' identification over a single biomarker

The role of recombination in the emergence of a complex and dynamic HIV epidemic

<p>Abstract</p> <p>Background</p> <p>Inter-subtype recombinants dominate the HIV epidemics in three geographical regions. To better understand the role of HIV recombinants in shaping the current HIV epidemic, we here present the results of a large-scale subtyping analysis of 9435 HIV-1 sequences that involve subtypes A, B, C, G, F and the epidemiologically important recombinants derived from three continents.</p> <p>Results</p> <p>The circulating recombinant form CRF02_AG, common in West Central Africa, appears to result from recombination events that occurred early in the divergence between subtypes A and G, followed by additional recent recombination events that contribute to the breakpoint pattern defining the current recombinant lineage. This finding also corrects a recent claim that G is a recombinant and a descendant of CRF02, which was suggested to be a pure subtype. The BC and BF recombinants in China and South America, respectively, are derived from recent recombination between contemporary parental lineages. Shared breakpoints in South America BF recombinants indicate that the HIV-1 epidemics in Argentina and Brazil are not independent. Therefore, the contemporary HIV-1 epidemic has recombinant lineages of both ancient and more recent origins.</p> <p>Conclusions</p> <p>Taken together, we show that these recombinant lineages, which are highly prevalent in the current HIV epidemic, are a mixture of ancient and recent recombination. The HIV pandemic is moving towards having increasing complexity and higher prevalence of recombinant forms, sometimes existing as "families" of related forms. We find that the classification of some CRF designations need to be revised as a consequence of (1) an estimated > 5% error in the original subtype assignments deposited in the Los Alamos sequence database; (2) an increasing number of CRFs are defined while they do not readily fit into groupings for molecular epidemiology and vaccine design; and (3) a dynamic HIV epidemic context.</p

Protocol for Nearly Full-Length Sequencing of HIV-1 RNA from Plasma

Nearly full-length genome sequencing of HIV-1 using peripheral blood mononuclear cells (PBMC) DNA as a template for PCR is now a relatively routine laboratory procedure. However, this has not been the case when using virion RNA as the template and this has made full genome analysis of circulating viruses difficult. Therefore, a well-developed procedure for sequencing of full-length HIV-1 RNA directly from plasma was needed. Plasma from U.S. donors representing a range of viral loads (VL) was used to develop the assay. RNA was extracted from plasma and reverse-transcribed. Two or three overlapping regions were PCR amplified to cover the entire viral genome and sequenced for verification. The success of the procedure was sensitive to VL but was routinely successful for VL greater than 105 and the rate declined in proportion to the VL. While the two-amplicon strategy had an advantage of increasing the possibility of amplifying a single species of HIV-1, the three-amplicon strategy was more successful in amplifying samples with low viral loads. This protocol provides a useful tool for molecular analysis to understand the HIV epidemic and pathogenesis, as well as diagnosis, therapy and future vaccine strategies

Female Urethral Reconstruction

Female urethral strictures are rare; thus, the literature describing stricture management in women is sparse. Although urethral dilation continues to be performed at a high frequency in women despite lack of proven efficacy, this procedure is used for a variety of voiding complaints other than stricture. Hence, the long-term utility of dilation and urethrotomy for urethral stricture in women is unknown. This review describes the various urethroplasty techniques used in the management of female urethral stricture. Although grafts using a dorsal approach have been shown to be feasible in women, ventral flap techniques offer good long-term outcomes with minimal morbidity. Acute and delayed management of pelvic fracture–associated urethral distraction defects in women is also described. Unlike in men, immediate urethroplasty in women should be performed once the patient is hemodynamically stable

Serial monitoring of genomic alterations in circulating tumor cells of ER-positive/HER2-negative advanced breast cancer: feasibility of precision oncology biomarker detection.

Nearly all estrogen receptor (ER)-positive (POS) metastatic breast cancers become refractory to endocrine (ET) and other therapies, leading to lethal disease presumably due to evolving genomic alterations. Timely monitoring of the molecular events associated with response/progression by serial tissue biopsies is logistically difficult. Use of liquid biopsies, including circulating tumor cells (CTC) and circulating tumor DNA (ctDNA), might provide highly informative, yet easily obtainable, evidence for better precision oncology care. Although ctDNA profiling has been well investigated, the CTC precision oncology genomic landscape and the advantages it may offer over ctDNA in ER-POS breast cancer remain largely unexplored. Whole-blood (WB) specimens were collected at serial time points from patients with advanced ER-POS/HER2-negative (NEG) advanced breast cancer in a phase I trial of AZD9496, an oral selective ER degrader (SERD) ET. Individual CTC were isolated from WB using tandem CellSearch® /DEPArray™ technologies and genomically profiled by targeted single-cell DNA next-generation sequencing (scNGS). High-quality CTC (n = 123) from 12 patients profiled by scNGS showed 100% concordance with ctDNA detection of driver estrogen receptor α (ESR1) mutations. We developed a novel CTC-based framework for precision medicine actionability reporting (MI-CTCseq) that incorporates novel features, such as clonal predominance and zygosity of targetable alterations, both unambiguously identifiable in CTC compared to ctDNA. Thus, we nominated opportunities for targeted therapies in 73% of patients, directed at alterations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), fibroblast growth factor receptor 2 (FGFR2), and KIT proto-oncogene, receptor tyrosine kinase (KIT). Intrapatient, inter-CTC genomic heterogeneity was observed, at times between time points, in subclonal alterations. Our analysis suggests that serial monitoring of the CTC genome is feasible and should enable real-time tracking of tumor evolution during progression, permitting more combination precision medicine interventions