: Our goal was to identify the treatment, personal, interpersonal, and hormonal (testosterone) factors in breast cancer survivors (BCSs) that determine sexual dysfunction. The treatment variables ...studied were type of surgery, chemotherapy, radiation, and tamoxifen. The personal, interpersonal, and physiologic factors were depression, body image, age, relationship distress, and testosterone levels. A sample of 55 female breast cancer survivors seen for routine follow‐up appointments from July 2002 to September 2002 were recruited to complete the Female Sexual Functioning Index (FSFI), Hamilton Depression Inventory (HDI), Body Image Survey (BIS), Marital Satisfaction Inventory‐Revised (MSI‐R), a demographic questionnaire, and have a serum testosterone level drawn. The average time since diagnosis was 4.4 years (SD 3.4 years). No associations were found between the type of cancer treatment, hormonal levels, and sexual functioning. BCS sexual functioning was significantly poorer than published normal controls in all areas but desire. The BCSs’ level of relationship distress was the most significant variable affecting arousal, orgasm, lubrication, satisfaction, and sexual pain. Depression and having traditional role preferences were the most important determinants of lower sexual desire. BCSs on antidepressants had higher levels of arousal and orgasm dysfunction. Women who were older had significantly more concerns about vaginal lubrication and pain. Relationship concerns, depression, and age are important influences in the development of BCS sexual dysfunction. The relationship of testosterone and sexual dysfunction needs further study with larger samples and more accurate assay techniques.
Decades of under-investment into aging infrastructure have resulted in uncertain reliability and systemic under-performance. The infrastructure spending gap in the U.S has grown to $2.6 trillion, and ...estimates suggest half of that is necessary within the next five years to avoid major impact to GDP. Yet spending levels remain below needs and policymakers seek more efficient allocation models for public funds and alternative financing mechanisms to accelerate the pace of investment to meet society’s needs. There is substantial private capital ready to enter the infrastructure sector along with innovations in contractual public-private partnership models. Financing mechanisms, such as infrastructure banking, show promise in extending the value of federal spending. However, a gap exists in the modeling of revenue streams and risk exposures for private entities which are necessary for the integration of public and private capital. Big data analytics are applied in this research to reveal opportunity costs and risk exposures which we apply to model revenue streams and assess infrastructure funding decisions. This dissertation investigated the waterway infrastructure of the Great Lakes, which comprises a network of deep-draft ports and connecting channels that serve a prominent role for commerce and manufacturing in North America. The waterway system requires annual funding to maintain navigable depths and functional port and lock infrastructure. An obstacle to funding decisions is the uncertainty surrounding financial returns on investment from improved maritime efficiency, in part because transportation and logistics metrics or benchmarks are lacking. Iron ore, the primary commodity in the Great Lakes, serves as the use case in this work to assess performance metrics for the waterway infrastructure that enables efficient and sustainable transport from mines to steel mills. This dissertation integrates new data analytics across traditional disciplinary silos to gain new insight into the risks, performance, and funding mechanisms for harbor infrastructure. Corporate financial metrics are used to map and quantify interdependencies within the value chain from iron ore production to finished goods. These interdependencies are further applied to assess financial risk exposures to infrastructure disruption using analytic tools such as input-output modeling. We applied big data analytic tools to assess the performance of maritime shipping with highly granular spatial and temporal datasets, including vessel draft, transit time and cargo. Vessel position information from historic Automatic Identification System (AIS) was used to develop a novel Maritime Transportation Efficiency (MTE) metric, defined as mass per time and directly applicable to bulk carriers. Regression analysis of vessel performance to hydrologic conditions in the waterway provided a means to predict changes in logistics performance resulting from infrastructure investment. We use Monte Carlo simulation to calculate expected MTE for vessels in the waterway under varying conditions which are correlated to transportation costs. Analytics techniques, like those applied in this dissertation, are useful to model revenue streams and reveal potential for new funding mechanisms and market-driven financing models. We suggest a new funding model for harbor infrastructure based on user demand with a fee structure adaptive to actual vessel requirements, attainable through existing data sources and new analytical tools. Demand-driven funding decisions for harbor maintenance can maximize value returns for users. A fee structure, outside of the Congressional appropriations processes, is more responsive to user needs and provides a means to deploy alternative financing models such as infrastructure banking for waterway maintenance and port depth construction dredging.
Increasing numbers of people with autism and other developmental disabilities are being convicted of sex offences, resulting in draconian and public punishment. Yet even when evidence shows that ...people with these conditions often pose little threat to society, or lack a core understanding as to why their actions break the law, the "sex offender legal regime" doesn't allow any room to take the disability into account. This ground-breaking book offers a multi-disciplinary examination of how unjust sex offense laws trap vulnerable groups such as those with developmental disabilities. Drawing on research, empirical evidence and including case studies, experts from the fields of law, ethics, psychology and sociology explore what steps should be taken in order to ensure that laws are just and take into consideration factors such as the vulnerability of the perpetrators. Investigating the consequences caused by public hysteria over sex offenses, this book highlights the judicial failure to protect defendants with developmental disabilities in the context of the unjust and hyper- punishment of all those charged with sex offenses. Proposing a new way forward based on research and evidence-based sentencing for sex offenses, and elimination of the sex offender registry, this book offers an informed and compassionate view that is essential for all professionals working in this field.
Corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and a subset of frontotemporal dementia (FTD) are neurodegenerative disorders characterized by tau inclusions in neurons and glia ...(tauopathies). Although clinical, pathological and genetic evidence suggests overlapping pathobiology between CBD, PSP, and FTD, the relationship between these disorders is still not well understood. Using summary statistics (odds ratios and
p
values) from large genome-wide association studies (total
n
= 14,286 cases and controls) and recently established genetic methods, we investigated the genetic overlap between CBD and PSP and CBD and FTD. We found up to 800-fold enrichment of genetic risk in CBD across different levels of significance for PSP or FTD. In addition to NSF (tagging the
MAPT
H1 haplotype), we observed that SNPs in or near
MOBP
,
CXCR4
,
EGFR,
and
GLDC
showed significant genetic overlap between CBD and PSP, whereas only SNPs tagging the
MAPT
haplotype overlapped between CBD and FTD. The risk alleles of the shared SNPs were associated with expression changes in
cis
-genes. Evaluating transcriptome levels across adult human brains, we found a unique neuroanatomic gene expression signature for each of the five overlapping gene loci (omnibus ANOVA
p
< 2.0 × 10
−16
). Functionally, we found that these shared risk genes were associated with protein interaction and gene co-expression networks and showed enrichment for several neurodevelopmental pathways. Our findings suggest: (1) novel genetic overlap between CBD and PSP beyond the
MAPT
locus; (2) strong ties between CBD and FTD through the
MAPT
clade, and (3) unique combinations of overlapping genes that may, in part, influence selective regional or neuronal vulnerability observed in specific tauopathies.
Objectives/Hypothesis
To assess balloon dilation of the Eustachian tube with Eustachian tube balloon catheter in conjunction with medical management as treatment for Eustachian tube dilatory ...dysfunction.
Study Design
In this prospective, multicenter, randomized, controlled trial, we assigned, in a 2:1 ratio, patients age 22 years and older with Eustachian tube dilatory dysfunction refractory to medical therapy to undergo balloon dilation of the Eustachian tube with balloon catheter in conjunction with medical management or medical management alone.
Methods
The primary endpoint was normalization of tympanogram at 6 weeks. Additional endpoints were normalization of Eustachian Tube Dysfunction Questionaire‐7 symptom scores, positive Valsalva maneuver, mucosal inflammation, and safety.
Results
Primary efficacy results demonstrated superiority of balloon dilation of the Eustachian tube with balloon catheter + medical management compared to medical management alone. Tympanogram normalization at 6‐week follow‐up was observed in 51.8% (72/139) of investigational patients versus 13.9% (10/72) of controls (P < .0001). Tympanogram normalization in the treatment group was 62.2% after 24 weeks. Normalization of Eustachian Tube Dysfunction Questionaire‐7 Symptom scores at 6‐week follow‐up was observed in 56.2% (77/137) of investigational patients versus 8.5% (6/71) controls (P < .001). The investigational group also demonstrated substantial improvement in both mucosal inflammation and Valsalva maneuver at 6‐week follow‐up compared to controls. No device‐ or procedure‐related serious adverse events were reported for those who underwent balloon dilation of the Eustachian tube.
Conclusions
This study demonstrated superiority of balloon dilation of the Eustachian tube with balloon catheter + medical management compared to medical management alone to treat Eustachian tube dilatory dysfunction in adults.
Level of Evidence
1b. Laryngoscope, 128:1200–1206, 2018
Although the CCFSD attempts to clarify and modify the existing definitions of female sexual dysfunctions, the current authors (a sex therapist and a sex researcher) believe that the classification ...system has significant flaws that will prevent its widespread acceptance and application. The major concern is that the CCFSD is based on the triphasic model of sexual response. The triphasic model is based on male sexual response and does not take into account the documented variety of ways that women respond sexually. Instead, the parameters of male sexual response are extrapolated to women. The current authors suggest an alternative approach that considers a woman's subjective as well as physiological responses, and includes pleasure and satisfaction as characteristics of normal sexual function. A reconsideration of the CCFSD model is suggested and an alternative approach is offered.
Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated ...loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed.
Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders-namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)-and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD-immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal.
We show immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.
There are limited data on the effect of donor body mass index (BMI) on peripheral blood stem cell (PBSC) mobilization response to granulocyte colony-stimulating factor (G-CSF), especially in ...unrelated donors. Obesity has been associated with persistent leukocytosis, elevated circulating progenitor cells, and enhanced stem cell mobilization. Therefore, we hypothesized that adequate collection of CD34+ cells may be achieved with lower doses (per kilogram of body weight) of G-CSF in donors with higher BMI compared with donors with lower BMI. Using the Center for International Blood and Marrow Transplant Research database, we evaluated the impact of donor BMI on G-CSF–mobilized PBSC yield in healthy unrelated donors. We examined 20 884 PBSC donations collected at National Marrow Donor Program centers between 2006 and 2016. We found significantly higher collection yields in obese and severely obese donors compared with normal and overweight donors. An increase in average daily G-CSF dose was associated with an increase in stem cell yield in donors with normal or overweight BMI. In contrast, an increase in average daily G-CSF dose beyond 780 μg per day in obese and 900 μg per day in severely obese donors did not increase cell yield. Pain and toxicities were assessed at baseline, during G-CSF administration, and postcollection. Obesity was associated with higher levels of self-reported donation-related pain and toxicities in the pericollection and early postdonation recovery periods. This study suggests a maximum effective G-CSF dose for PBSC mobilization in obese and severely obese donors, beyond which higher doses of G-CSF add no increased yield.
•Higher donor BMI predicts better PBSC mobilization response to G-CSF.•There is a maximum effective G-CSF dose for PBSC mobilization in obese and severely obese donors, above which higher doses add no benefit.
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Background: The diagnosis of AML requires an integrated approach of clinical, morphologic, cytogenetic, and molecular assessments. The CONNECT MDS/AML Disease Registry (NCT01688011) is a prospective, ...longitudinal, multicenter, observational cohort study of patients (pts) in the United States with newly diagnosed AML, MDS, or idiopathic cytopenia of undetermined significance, designed to evaluate diagnostic and treatment (Tx) patterns, clinical and pt-reported outcomes, and correlative data, such as genetic mutations. This investigation was performed to assess how pts with AML are diagnosed at community and academic sites and compare how these diagnostic practices align with WHO 2008 recommendations for AML.
Methods: Pt enrollment began in December, 2013 and will continue until ~1500 pts from ~150 US sites are enrolled. Target enrollment for the AML cohort is 400 pts. To best capture the typical distribution of clinical practice settings in which AML pts are treated, ~80% of the sites will be community-based and ~20% will be academic institutions (ie, affiliated with a medical school). Pts aged ≥55 years (yrs) with newly diagnosed AML (excluding acute promyelocytic leukemia) are eligible. All decisions regarding pt care (Tx, testing) are determined by the study clinician, as the disease registry is non-interventional. AML diagnosis is confirmed by independent central review of all available diagnostic test reports, including bone marrow (BM) aspirates and biopsies, cytogenetics, molecular testing, and laboratory results. Diagnostic procedures are recorded in an electronic data capture system. Pt data will be entered quarterly for up to 8 years of follow-up.
Results: Between December 12, 2013 and May 19, 2016, 180 AML pts have enrolled in the registry from 73 sites; 125 pts (69%) enrolled at a community site (including 1 governmental site) and 55 pts (31%) enrolled at an academic center. Median age of all pts was 71 yrs (range 55-91), with 72% of pts aged ≥65 yrs (Table 1). Blast percentages were reported in 97% of cases, mainly in BM, although peripheral blood blasts were also assessed for 71% of pts (Table 2). Manual differential blast count was reported for 63% of pts, and flow cytometry and immunohistochemistry were used to determine blast counts for 10% of pts each. Immunophenotyping by flow cytometry was reported for 97% of pts. Erythroid, megakaryocytic, or neutrophilic dysplasia, and presence or absence of Auer rods, ring sideroblasts, or fibrosis were reported for <50% of all pts (Table 2). Conventional karyotyping was performed for 90% of pts and FISH testing was reported for 80% of pts (Table 3). Mutation testing was reported for 85 pts (47%).
Conclusions: The ongoing prospective CONNECT MDS/AML registry is uniquely positioned to assess current clinical practice patterns in AML. Flow cytometry and conventional karyotyping were done in most cases; however, manual blast count was missing for 37% of AML pt samples at diagnosis. Instead, ~10% of blasts counts were evaluated by flow cytometry or immunohistochemistry, and ~18% by 'other' means (ie, blast count estimations). Flow cytometry for blast enumeration is discouraged in WHO 2008 recommendations, as it may both under- and overestimate counts. Despite a 90% rate of conventional karyotyping, FISH testing was reported for 80% of pts, suggesting FISH may be used more than is necessary. Mutation testing was reported for approximately one-half of pts, which may reflect a lack of testing, a lag in mutational test reporting, or a combination of both. Diagnostic practices for AML pts enrolled thus far appear to be guided by WHO 2008 recommendations; awareness of updated recommendations may change diagnostic patterns as new AML pts enter the CONNECT MDS/AML registry.
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George:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Allakos: Research Funding; Allakos: Research Funding; Blueprint Medicines: Consultancy; Novartis: Consultancy; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy; GLG: Consultancy; Wiley Blackwell: Consultancy; American Registry of Pathology: Patents & Royalties; Wolters Kluwer: Patents & Royalties; UpToDate: Patents & Royalties. Erba:Sunesis: Consultancy; Novartis: Consultancy, Speakers Bureau; Celator: Research Funding; Ariad: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Agios: Research Funding; Pfizer: Consultancy; Gylcomimetics: Other: DSMB; Millennium Pharmaceuticals, Inc.: Research Funding; Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Steensma:Amgen: Consultancy; Ariad: Equity Ownership; Millenium/Takeda: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Genoptix: Consultancy. Pollyea:Alexion: Other: advisory board; Ariad: Other: advisory board; Celgene: Other: advisory board, Research Funding; Glycomimetics: Other: DSMB member; Pfizer: Other: advisory board, Research Funding. Abedi:Celgene: Consultancy. Bejar:Genoptix: Consultancy. Grinblatt:Celgene Corporation: Consultancy, Speakers Bureau. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Revicki:Celgene: Consultancy. Roboz:Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Savona:TG Therapeutics: Research Funding; Takeda: Research Funding; Amgen Inc.: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Incyte: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity’s Board of Directors or advisory committees; Sunesis: Research Funding; Ariad: Membership on an entity’s Board of Directors or advisory committees. Scott:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Sekeres:Millenium/Takeda: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees. Thompson:VIA Oncology: Membership on an entity’s Board of Directors or advisory committees; Takeda: Membership on an entity’s Board of Directors or advisory committees, Other: Multiple Myeloma International Registry; Celgene: Membership on an entity’s Board of Directors or advisory committees, Other: MDS/AML Registry; Doximity: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees; AIM Specialty Health: Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees. Fliss:Celgene Corporation: Employment, Equity Ownership. Swern:Celgene: Employment, Equity Ownership. Nifenecker:Celgene: Employment, Equity Ownership. Kiselev:Celgene: Employment, Equity Ownership. Sugrue:Celgene Corporation: Employment, Equity Ownership. Foucar:Celgene: Membership on an entity’s Board of Directors or advisory committees; ASCP press: Other: Book royalties; Elsevier: Other: Book royalties; Lippincott WW: Other: Book royalties.
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