Oncology clinical trial disruption during the COVID-19 pandemic: a COVID-19 and cancer outcomes study.

BACKGROUND: COVID-19 disproportionately impacted patients with cancer as a result of direct infection, and delays in diagnosis and therapy. Oncological clinical trials are resource-intensive endeavors that could be particularly susceptible to disruption by the pandemic, but few studies have evaluated the impact of the pandemic on clinical trial conduct. PATIENTS AND METHODS: This prospective, multicenter study assesses the impact of the pandemic on therapeutic clinical trials at two large academic centers in the Northeastern United States between December 2019 and June 2021. The primary objective was to assess the enrollment on, accrual to, and activation of oncology therapeutic clinical trials during the pandemic using an institution-wide cohort of (i) new patient accruals to oncological trials, (ii) a manually curated cohort of patients with cancer, and (ii) a dataset of new trial activations. RESULTS: The institution-wide cohort included 4756 new patients enrolled to clinical trials from December 2019 to June 2021. A major decrease in the numbers of new patient accruals (-46%) was seen early in the pandemic, followed by a progressive recovery and return to higher-than-normal levels (+2.6%). A similar pattern (from -23.6% to +30.4%) was observed among 467 newly activated trials from June 2019 to June 2021. A more pronounced decline in new accruals was seen among academically sponsored trials (versus industry sponsored trials) (P < 0.05). In the manually curated cohort, which included 2361 patients with cancer, non-white patients tended to be more likely taken off trial in the early pandemic period (adjusted odds ratio: 2.60; 95% confidence interval 1.00-6.63), and substantial pandemic-related deviations were recorded. CONCLUSIONS: Substantial disruptions in clinical trial activities were observed early during the pandemic, with a gradual recovery during ensuing time periods, both from an enrollment and an activation standpoint. The observed decline was more prominent among academically sponsored trials, and racial disparities were seen among people taken off trial.

Day 5 vitrified blastocyst transfer versus day 6 vitrified blastocyst transfer in oocyte donation program.

The superiority of day 5 blastocysts compared to day 6 blastocysts in fresh cycle transfers was previously demonstrated and attributed mainly to endometrial asynchrony. Data from frozen blastocysts transfers showed conflicting results, possibly due to heterogeneous patient population and embryo quality. The aim of this study was to compare clinical pregnancy rate (CPR) and live birth rate (LBR) between transfers of vitrified day 5 blastocysts and day 6 blastocysts in oocyte donation, blastocyst-only cycles. In a retrospective, multi-center study, with a single oocyte donation program, a total of 1840 frozen embryo transfers (FET's) were analyzed, including 1180 day 5 blastocysts and 660 day 6 blastocysts transfers. Day 5 blastocyst transfers had better embryonic development and significantly higher CPRs (34.24% vs. 20.15%, P < 0.0001), higher LBRs (26.89% vs. 14.77%, P < 0.0001), less cycles to LBR (1.83 ± 0.08 vs. 2.39 ± 0.18, P = 0.003) and shorter time to LBRs (76.32 ± 8.7 vs. 123.24 ± 19.1 days, P = 0.01), compared to day 6 transfers, respectively. A multivariate stepwise logistic regression indicated, that day 5 transfer was an independent factor for CPRs (OR 1.91; 95% CI 1.43-2.54, P < 0.001) and LBRs (OR 2.26; 95% CI 1.19-4.28, P = 0.01), regardless of embryo quality, compared to day 6. In conclusion, day 5 blastocysts in oocyte donation program have significantly higher CPRs and LBRs, and present shorter time to delivery, compared to day 6 blastocysts, regardless of embryo quality.

Elective egg freezing and its underlying socio-demography: a binational analysis with global implications.

BACKGROUND: What are the underlying socio-demographic factors that lead healthy women to preserve their fertility through elective egg freezing (EEF)? Many recent reviews suggest that women are intentionally postponing fertility through EEF to pursue careers and achieve reproductive autonomy. However, emerging empirical evidence suggests that women may be resorting to EEF for other reasons, primarily the lack of a partner with whom to pursue childbearing. The aim of this study is thus to understand what socio-demographic factors may underlie women's use of EEF. METHODS: A binational qualitative study was conducted from June 2014 to August 2016 to assess the socio-demographic characteristics and life circumstances of 150 healthy women who had undertaken at least one cycle of elective egg freezing (EEF) in the United States and Israel, two countries where EEF has been offered in IVF clinics over the past 7-8 years. One hundred fourteen American women who completed EEF were recruited from 4 IVF clinics in the US (2 academic, 2 private) and 36 women from 3 IVF clinics in Israel (1 academic, 2 private). In-depth, audio-recorded interviews lasting from 0.5 to 2 h were undertaken and later transcribed verbatim for qualitative data analysis. RESULTS: Women in both countries were educated professionals (100%), and 85% undertook EEF because they lacked a partner. This "lack of a partner" problem was reflected in women's own assessments of why they were single in their late 30s, despite their desires for marriage and childbearing. Women themselves assessed partnership problems from four perspectives: 1) women's higher expectations; 2) men's lower commitments; 3) skewed gender demography; and 4) self-blame. DISCUSSION: The "lack of a partner" problem reflects growing, but little discussed international socio-demographic disparities in educational achievement. University-educated women now significantly outnumber university-educated men in the US, Israel, and nearly 75 other societies around the globe, according to World Bank data. Thus, educated women increasingly face a deficit of educated men with whom to pursue childbearing. CONCLUSION: Among healthy women, EEF is a technological concession to gender-based socio-demographic disparities, which leave many highly educated women without partners during their prime childbearing years. This information is important for reproductive specialists who counsel single EEF patients, and for future research on EEF in diverse national settings.

How Artificial Intelligence Can Improve Our Understanding of the Genes Associated with Endometriosis: Natural Language Processing of the PubMed Database.

Endometriosis is a disease characterized by the development of endometrial tissue outside the uterus, but its cause remains largely unknown. Numerous genes have been studied and proposed to help explain its pathogenesis. However, the large number of these candidate genes has made functional validation through experimental methodologies nearly impossible. Computational methods could provide a useful alternative for prioritizing those most likely to be susceptibility genes. Using artificial intelligence applied to text mining, this study analyzed the genes involved in the pathogenesis, development, and progression of endometriosis. The data extraction by text mining of the endometriosis-related genes in the PubMed database was based on natural language processing, and the data were filtered to remove false positives. Using data from the text mining and gene network information as input for the web-based tool, 15,207 endometriosis-related genes were ranked according to their score in the database. Characterization of the filtered gene set through gene ontology, pathway, and network analysis provided information about the numerous mechanisms hypothesized to be responsible for the establishment of ectopic endometrial tissue, as well as the migration, implantation, survival, and proliferation of ectopic endometrial cells. Finally, the human genome was scanned through various databases using filtered genes as a seed to determine novel genes that might also be involved in the pathogenesis of endometriosis but which have not yet been characterized. These genes could be promising candidates to serve as useful diagnostic biomarkers and therapeutic targets in the management of endometriosis.

Icosahedra clustering and short range order in Ni-Nb-Zr amorphous membranes.

Crystalline Pd/Pd-Ag membranes are widely used for hydrogen separation from CO2 and other gases in power generation applications. To substitute these high cost noble metal alloy membranes, the Ni-Nb-Zr amorphous alloys are being developed that exhibit relatively high permeability of hydrogen between 200-400 °C. Atom probe tomography (APT) experiments performed on these ribbons revealed nm-scale Nb-rich and Zr-rich regions (clusters) embedded in a ternary matrix, indicating phase separation within the Ni-Nb-Zr amorphous alloy. Density functional theory (DFT) simulations have predicted that these clusters are composed of icosahedral coordination polyhedra. The interatomic distances and correlation lengths of the short range order of these alloys were determined by neutron total scattering which match well with our DFT based molecular dynamics (DFT-MD) simulations.

Effects of depot-medroxyprogesterone acetate on the immune microenvironment of the human cervix and endometrium: implications for HIV susceptibility.

Depot-medroxyprogesterone acetate is a commonly used injectable contraceptive that has been associated with an increased risk of HIV acquisition. This study compares effects of depot-medroxyprogesterone acetate on immune parameters from several upper reproductive tract compartments relevant to HIV-1 susceptibility in repetitive samples from 15 depot-medroxyprogesterone acetate users and 27 women not on hormonal contraceptives. Compared with samples from unexposed women in the mid-luteal phase, depot-medroxyprogesterone acetate use was associated with: increased endocervical concentrations of MCP1 and IFNalpha2; decreased endocervical concentrations of IL1beta and IL6; increased proportions of endometrial CD4+ and CD8+ cells expressing the activation marker HLADR; increased density of endometrial macrophages; and decreased density of endometrial regulatory T cells. Unlike previous reports with samples from the vagina, we did not observe increased expression of the HIV co-receptor CCR5 on CD4+ T cells in the endocervix or endometrium. Our results indicate important differences in anatomic compartments regarding mechanisms by which depot-medroxyprogesterone acetate could be associated with increased risk of HIV acquisition, including increased recruitment of macrophages to the endometrium, decreased levels of pro-inflammatory cytokines in the endocervix possibly leading to enhanced susceptibility to viral infection, and activation of endometrial T cells.

Temporal bone fracture: Evaluation in the era of modern computed tomography.

BACKGROUND: Temporal bone fractures (TBFs) are harbingers of high energy head trauma that can result in a variety of significant complications of the auditory, vestibular, nervous, and vascular systems. Multiple cohort studies have identified the incidence and proper evaluation of these fractures. We hypothesize that these have changed with the advent of modern high resolution computer tomography (CT) imaging. METHODS: We performed a retrospective review of all TBFs admitted to an urban level one trauma center between June 1, 2011 and May 31, 2015. A database was compiled including demographics, physical exam findings, imaging performed and results, morphology and directionality of fracture as well as outcomes and follow-up. RESULTS: One hundred thirteen patients were identified, representing 4.7% of skull fractures and 35.9% of skull base fractures. Most were subsequent to falls (41.6%) followed by pedestrian vehicular trauma (19.5%). The majority of TBF patients (67.3%) had additional fractures of the skull and 77.9% of TBF patients also had some kind of intracranial hemorrhage. The morphology of TBF and the overall mortality (7.9%) was consistent with previous reports. The incidence of facial nerve paralysis (1.6%), CSF leak (1.7%), and hearing loss (18.6%) were all lower than previously reported. Trauma imaging was able to identify 98.6% of TBF, calling the utility of routine temporal bone CT imaging into question. CONCLUSION: TBFs are less common than they once were and though they still carry a mortality rate similar to previously reported cohorts, the incidence of complications among survivors has dramatically improved. Additionally, modern CT imaging is very capable of identifying these injuries and dedicated temporal bone CT may only be of utility in cases where facial nerve injury or vascular injury is suspected. LEVEL OF EVIDENCE: Epidemiologic study, Level III.

The role of fertility preservation in patients with endometriosis.

Patients affected with severe endometriosis are at significant risk for ovarian tissue damage, which may lead to infertility, reduced response to ovarian stimulation, and occasionally, premature ovarian failure. The risk for a compromised ovarian reserve in young patients is especially high following repeated surgical intervention and in the presence of bilateral endometriomas. In many cases, enhanced loss of ovarian reserve may also result from the damaging effect of the pathologic process on follicle reservoir even without surgical interventions. Women diagnosed with severe endometriosis and those designated for extensive ovarian surgical intervention are frequently not planning to conceive. In light of recent advances in fertility preservation techniques (FPT), such as oocytes and ovarian tissue freezing, as well as their increasing success rates, we critically evaluate the options for FPT in patients suffering from endometriosis. Personalized counseling should be offered to all patients with endometriosis taking into account age, extent of ovarian involvement, current ovarian reserve, previous and impending surgeries for endometriosis, along with current success rates and possible risks associated with FPT.

Phonon Engineering in Isotopically Disordered Silicon Nanowires.

The introduction of stable isotopes in the fabrication of semiconductor nanowires provides an additional degree of freedom to manipulate their basic properties, design an entirely new class of devices, and highlight subtle but important nanoscale and quantum phenomena. With this perspective, we report on phonon engineering in metal-catalyzed silicon nanowires with tailor-made isotopic compositions grown using isotopically enriched silane precursors (28)SiH4, (29)SiH4, and (30)SiH4 with purity better than 99.9%. More specifically, isotopically mixed nanowires (28)Si(x)(30)Si(1-x) with a composition close to the highest mass disorder (x ∼ 0.5) were investigated. The effect of mass disorder on the phonon behavior was elucidated and compared to that in isotopically pure (29)Si nanowires having a similar reduced mass. We found that the disorder-induced enhancement in phonon scattering in isotopically mixed nanowires is unexpectedly much more significant than in bulk crystals of close isotopic compositions. This effect is explained by a nonuniform distribution of (28)Si and (30)Si isotopes in the grown isotopically mixed nanowires with local compositions ranging from x = ∼0.25 to 0.70. Moreover, we also observed that upon heating, phonons in (28)Si(x)(30)Si(1-x) nanowires behave remarkably differently from those in (29)Si nanowires suggesting a reduced thermal conductivity induced by mass disorder. Using Raman nanothermometry, we found that the thermal conductivity of isotopically mixed (28)Si(x)(30)Si(1-x) nanowires is ∼30% lower than that of isotopically pure (29)Si nanowires in agreement with theoretical predictions.

Preparation of nanowire specimens for laser-assisted atom probe tomography.

The availability of reliable and well-engineered commercial instruments and data analysis software has led to development in recent years of robust and ergonomic atom-probe tomographs. Indeed, atom-probe tomography (APT) is now being applied to a broader range of materials classes that involve highly important scientific and technological problems in materials science and engineering. Dual-beam focused-ion beam microscopy and its application to the fabrication of APT microtip specimens have dramatically improved the ability to probe a variety of systems. However, the sample preparation is still challenging especially for emerging nanomaterials such as epitaxial nanowires which typically grow vertically on a substrate through metal-catalyzed vapor phase epitaxy. The size, morphology, density, and sensitivity to radiation damage are the most influential parameters in the preparation of nanowire specimens for APT. In this paper, we describe a step-by-step process methodology to allow a precisely controlled, damage-free transfer of individual, short silicon nanowires onto atom probe microposts. Starting with a dense array of tiny nanowires and using focused ion beam, we employed a sequence of protective layers and markers to identify the nanowire to be transferred and probed while protecting it against Ga ions during lift-off processing and tip sharpening. Based on this approach, high-quality three-dimensional atom-by-atom maps of single aluminum-catalyzed silicon nanowires are obtained using a highly focused ultraviolet laser-assisted local electrode atom probe tomograph.

Morphology control of nanostructures: Na-doped PbTe-PbS system.

The morphology of crystalline precipitates in a solid-state matrix is governed by complex but tractable energetic considerations driven largely by volume strain energy minimization and anisotropy of interfacial energies. Spherical precipitate morphologies are favored by isotropic systems, while anisotropic interfacial energies give energetic preference to certain crystallographically oriented interfaces, resulting in a faceted precipitate morphology. In conventional solid-solution precipitation, a precipitate's morphological evolution is mediated by surface anchoring of capping molecules, which dramatically alter the surface energy in an anisotropic manner, thereby providing exquisite morphology control during crystal growth. Herein, we present experimental evidence and theoretical validation for the role of a ternary element (Na) in controlling the morphology of nanoscale PbS crystals nucleating in a PbTe matrix, an important bulk thermoelectric system. The PbS nanostructures formed by phase separation from a PbI(2)-doped or undoped PbTe matrix have irregular morphologies. However, replacing the iodine dopant with Na (1-2 mol %) alters dramatically the morphology of the PbS precipitates. Segregation of Na at PbTe/PbS interfaces result in cuboidal and truncated cuboidal morphologies for PbS. Using analytical scanning/transmission electron microscopy and atom-probe tomography, we demonstrate unambiguously that Na partitions to the precipitates and segregates at the matrix/precipitate interfaces, inducing morphological anisotropy of PbS precipitates. First-principles and semiclassical calculations reveal that Na as a solute in PbTe has a higher energy than in PbS and that Na segregation at a (100) PbTe/PbS interface decreases the total energy of matrix/precipitate system, resulting in faceting of PbS precipitates. These results provide an impetus for a new strategy for controlling morphological evolution in matrix/precipitate systems, mediated by solute partitioning of ternary additions.

Recurrence of empty follicle syndrome with stimulated IVF cycles.

AIM: To determine the incidence of recurrent empty follicle syndrome (EFS) and to analyse the factors associated with this phenomenon. METHODS: Retrospective analysis comparing all EFS cycles with cycles in which oocytes were retrieved in our in vitro fertilization (IVF) unit between 1998 and 2006. RESULTS: Of 8292 IVF cycles, 163 (2.0%) resulted in empty follicles. Risk factors for EFS included advanced age (37.7 ± 6.0 years vs. 34.2 ± 6.0 years, p < 0.001), longer infertility (8.8 ± 10.6 years vs. 6.3 ± 8.4 years, p < 0.05), higher baseline follicle-stimulating hormone levels (8.7 ± 4.7 IU/L vs. 6.7 ± 2.9 IU/L, p < 0.001) and lower E2 levels before the human chorionic gonadotropin injection (499.9 ± 480.9 pg/mL vs. 1516.3 ± 887.5 pg/mL, p < 0.001) compared with cases in which ova were retrieved. Among patients with EFS, recurrent EFSs occurred in 15.8% of subsequent cycles. CONCLUSION: The EFS is a sporadic event in the majority of patients. However, in about 16% of the patients, EFS may recur. These cases may be a variant form of poor response and patients with repetitive EFS syndrome should be counseled concerning their chances to conceive.

Severe intraabdominal bleeding caused by endometriotic lesions during the third trimester of pregnancy.

OBJECTIVE: Endometriosis is known to be associated with an increased risk for early pregnancy complications, including ectopic pregnancy and miscarriage. However, little has so far been reported on complications linked to severe endometriosis occurring during the third trimester of pregnancy. STUDY DESIGN: A retrospective review of 800 women attending the endometriosis clinic of the Sheba Medical Center during the years 2002-2006 was performed. Cases with severe endometriosis and associated complications during late pregnancy were identified. RESULTS: Three women were found who experienced significant intraabdominal bleeding in the third trimester of pregnancy attributed to a lesion resulting from severe endometriosis. The intraabdominal bleeding occurred between 26-29 weeks of gestation. In all cases the major presenting prenatal symptom was severe lower abdominal pain. The pain was not relieved by the administration of tocolytics or mild analgesics. Explorative laparotomy, performed in all 3 cases, revealed the presence of significant intraabdominal bleeding requiring immediate transfusion of blood products stemming from endometriotic lesions. Fetal complications occurred in all 3 cases. CONCLUSION: The symptoms of endometriosis are often relieved during pregnancy. Yet lesions caused by severe endometriosis can lead to significant intraabdominal bleeding during the third trimester of the pregnancy. Physicians must be aware that close antenatal follow-up and prompt intervention may be required in such cases.

Effects of 10 MeV electron irradiation at high temperature of a Ni-Mo-based Hastelloy.

A Hastelloy alloy was irradiated with 10 MeV electrons at 650 degrees C for 700 h to a total dose of 2 x 10(-3) displacements per atom (dpa). The microstructure of irradiated and non-irradiated specimens of this alloy were investigated by transmission electron microscopy (TEM). The non-irradiated specimens were analyzed by 3-D atom probe tomography (APT) in a local-electrode atom-probe (LEAP). TEM analysis before the irradiation detects small precipitates with a mean diameter of 22 nm, which are coherent with the FCC matrix. The number density of these precipitates is approximately 7 x 10(18) m(-3). Electron diffraction patterns from these precipitates exhibit superlattice reflections corresponding to the L1(2) ordered structure. The chemical composition of the precipitates, as measured by APT, is around 75 at% Ni with additions of Al, Ti and Mo. After electron irradiation, small precipitates with an irregular morphology are observed. The number density of these new precipitates about 10(20) m(-3) is greater than that of the L1(2) ordered precipitates before irradiation. The L1(2) superlattice reflections disappear completely, instead diffuse diffraction spots are observed at 1(1/2)0(FCC), which is attributed to compositional short-range order (SRO). The results are discussed with respect to the influence of the electron irradiation on the morphology and structure of the ordered precipitates.

Elevated day 3 FSH/LH ratio due to low LH concentrations predicts reduced ovarian response.

Adequate ovarian response, essential for successful IVF, cannot be accurately predicted. This study retrospectively reviewed all patients undergoing IVF from 1998 to 2001. Inclusion criteria were age <41 years at treatment onset and a basal day 3 serum FSH concentration <12 IU/l. Women with FSH or=3 in group 1 and <3 in group 2 (controls). Age at treatment initiation, basal serum day 3 FSH and LH concentrations, peak serum oestradiol concentration, number of retrieved and fertilized oocytes and pregnancy rate were analysed. Groups 1 (n = 41, 111 IVF treatment cycles) and 2 (n = 596, 1,434 IVF treatment cycles) were similar in term of woman's mean age. Group 1 had significantly higher mean basal day 3 FSH concentration (P < 0.01) and significantly lower oestradiol concentrations at oocyte retrieval (P < 0.01), mean number of oocytes retrieved and fertilized (P < 0.01) and pregnancy rate (P = 0.016). The same trend persisted after excluding 98 patients with basal FSH concentrations >8 IU/l. In conclusion, elevated day 3 FSH/LH ratio is associated with an inferior outcome in IVF treatment cycles and may be used as an additional predictor for decreased ovarian response.

[Aromatase inhibitors--new applications in gynecology].

P-450 aromatase inhibitors, designed for suppressing estradiol production, were first approved for the treatment of advanced breast cancer. Recent studies have provided evidence that aromatase inhibitors may be effective in the short term for induction of ovulation and in the long-term for treatment of endometriosis. Based on current data, the role of aromatase inhibitors in the management of various gynecological conditions may soon be widely determined.

[Perinatal group B streptococcal disease: a review and revised guidelines for prevention].

Group B Streptococcus (GBS) is a common inhabitant of the maternal genital and gastrointestinal tracts, and colonizes approximately 20% of pregnant women. About 50% of infants born to colonized women will become colonized at birth. Early onset GBS disease affects 5/1000 newborns, and is related to a 5-16% mortality rate and severe morbidity. Selective intra-partum chemoprophylaxis can prevent most cases of GBS early-onset disease. In 1996, the federal Centers for Disease Control and Prevention (CDC), the American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics (AAP) recommended either a culture-based or risk-based approach for prevention of early onset GBS disease. Understanding the epidemiology of the disease and comparing efficacy of the two prevention strategies may elucidate the dispute surrounding this issue. Accordingly, new recommendations from the CDC and the ACOG were published, and their implementation in Israel should now be considered.

[Medical termination of pregnancy with mifepristone--initial experience at the Sheba Medical Center].

OBJECTIVE: To assess the early implementation of medical termination of pregnancy as an alternative treatment option for women in early pregnancy who wish to avoid a surgical procedure. METHODS: The use of mifepristone (RU-486) for medical termination was recently approved in Israel. We performed a prospective follow-up study of the 189 women who underwent medical termination of pregnancy with mifepristone and misoprostol in our center between January 2000 and April 2001. RESULTS: Complete outcome data was obtained for 176 women. Within this group 152 women (86.4%) did not need any surgical procedure to complete the abortion. Uterine curettage was performed in 17 (9.6%) and operative hysteroscopy in 7 (4.0%) of the women because of incomplete abortion or suspected residua of pregnancy. CONCLUSION: Medical abortion offers an efficient and safe treatment option to women who wish to avoid surgical evacuation.

Mg segregation at Al/Al3Sc heterophase interfaces on an atomic scale: experiments and computations.

Microscopic factors governing solute partitioning in ternary two-phase Al-Sc-Mg alloys are investigated combining three-dimensional-atom-probe (3DAP) microscopy measurements with first-principles computations. 3DAP is employed to measure composition profiles with subnanometer-scale resolution, leading to the identification of a large enhancement of Mg solute at the coherent alpha-Al/Al(3)Sc (fcc/L1(2)) heterophase interface. First-principles calculations establish an equilibrium driving force for this interfacial segregation reflecting the nature of the interatomic interactions.