Women's experiences of a telemedicine abortion service (up to 12 weeks) implemented during the coronavirus (COVID-19) pandemic: a qualitative evaluation.

OBJECTIVE: To explore the experiences of women in Scotland who accessed medical abortion at home up to 12 weeks' gestation, delivered via a telemedicine abortion service implemented in response to the coronavirus (COVID-19) pandemic, to identify areas for improvement and inform service provision. DESIGN: Qualitative interview study. SETTING: Abortion service in one National Health Service health board in Scotland. POPULATION OR SAMPLE: Twenty women who accessed telemedicine abortion services and self-administered mifepristone and misoprostol at home up to 12 weeks' gestation. METHODS: Thematic analysis of semi-structured qualitative interviews, informed by the Framework analytic approach. MAIN OUTCOME MEASURES: Women's experiences of accessing telemedicine for medical abortion at home, specifically: acceptability of the telephone consultation and remote support; views on no pre-abortion ultrasound scan; and self-administration of abortion medications at home. RESULTS: Novel study findings were three-fold: (1) participants valued the option of accessing abortion care via telemedicine and emphasised the benefits of providing a choice of telephone and in-person consultation to suit those with different life circumstances; (2) the quality of abortion care was enhanced by the telemedicine service in relation to access, comfort and flexibility, and ongoing telephone support; (3) participants described being comfortable with, and in some cases a preference for, not having an ultrasound scan. CONCLUSIONS: This research demonstrates support for the continuation of telemedicine abortion services beyond the temporary arrangements in place during COVID-19, and lends weight to the argument that offering the option of telemedicine abortion care can enable women to access this essential health service. TWEETABLE ABSTRACT: #Telemedicine provision of medical #abortion at home up to 12 weeks' gestation is acceptable and highly valued by #women #Research #SRHR @nbw80 @doctorjjrw @jeniharden @cameronsharon @mrc_crh @edinuniusher.

Phase I study of sorafenib and tipifarnib for recurrent glioblastoma: NABTC 05-02.

Recurrent glioblastoma (GBM) has a very low 6-month progression free survival (PFS) with currently available treatments. Combination chemotherapy to target multiple cell signaling pathways is currently being investigated in order to improve prognosis for recurrent disease. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) for the combination of tipifarnib and sorafenib for the treatment of recurrent GBM. Patients with pathologically proven WHO grade IV GBM and radiographically proven tumor recurrence were eligible for this study. Treatments included sorafenib at twice daily and escalating dosages of tipifarnib. Dose-limiting toxicity (DLT) was determined over the first 28-days of treatments, and the MTD was determined in a 3 + 3 study design. We enrolled 24 patients, and 21 patients completed the MTD period. The study was stopped early with no MTD determination for excessive toxicities. The last dose level reached was sorafenib at 200 mg twice a day and tipifarnib 100 mg twice a day on an alternating week schedule. The DLTs included diarrhea, lipase elevation, hypophosphatemia, and arthralgia. The combination of sorafenib and tipifarnib has excessive toxicities and full single agent dosages could not be achieved in combination.

A new diminutive genus and species of catfish from Lake Tanganyika (Siluriformes: Clariidae).

The examination of material representing one of Lake Tanganyika's six previously recognized endemic catfish lineages, has revealed the presence of an additional genus of clariid, described here as Pseudotanganikallabes new genus. This genus is represented by a single species, Pseudotanganikallabes prognatha sp. nov., which is distinguished from all other clariids by its lack of an infraorbital series, the presence of multiple osseous connections between the swim bladder capsules and elements of the neurocranium, the absence of an ethmoid notch, the presence of a very large, egg-shaped occipital fontanelle and the extension of the lower lip beyond the margin of the upper jaw. A combination of additional external and molecular characters serves to further distinguish this taxon from all currently recognized clariid species. Phylogenetic analysis of mitochondrial (cytb) and nuclear (18S-ITS1-5.8S-ITS2-28S) sequence data supports the creation of a new genus for this species, as it appears to represent an independent, monophyletic lineage within the family Clariidae.

1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanones as novel CCR1 antagonists.

A novel series of CCR1 antagonists based on the 1-(4-phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanone scaffold was identified by screening a compound library utilizing CCR1-expressing human THP-1 cells. SAR studies led to the discovery of the highly potent and selective CCR1 antagonist 14 (CCR1 binding IC(50)=4 nM using [(125)I]-CCL3 as the chemokine ligand). Compound 14 displayed promising pharmacokinetic and toxicological profiles in preclinical species.

A randomized phase II of gemcitabine and sorafenib versus sorafenib alone in patients with metastatic pancreatic cancer.

PURPOSE: Patients with metastatic pancreatic cancer have limited therapeutic options. The role of the Ras-Raf-MAPK pathway and of vascular endothelial growth factor in pancreatic carcinogenesis provided the rational to evaluate the efficacy of sorafenib with or without gemcitabine in a randomized phase II study. METHODS: Patients with metastatic pancreatic cancer were randomized to sorafenib alone (arm A) or sorafenib with gemcitabine (arm B). RESULTS: Arm A was closed to accrual at interim analysis due to the lack of objective response. Median PFS and OS were 2.3 and 4.3 months respectively. There was one partial response among the 37 patients in arm B. Median PFS and OS were 2.9 and 6.5 months respectively. There were more grade 3 and 4 toxicities in arm B with the most common being neutropenia (17%), thrombocytopenia (8%), alkaline phosphatase elevation (14%), venous thromboembolism (8%), diarrhea, hypokalemia and ALT elevation (5%) each. Several associations were noted between single nucleotide polymorphisms in ribonucleotide reductase, Cox-2, vascular endothelial growth factor and survival in patients treated with gemcitabine and sorafenib. CONCLUSIONS: Neither sorafenib alone or sorafenib in combination with gemcitabine manifested promising activity in metastatic pancreatic cancer.

Crizotinib in patients with tumors harboring ALK or ROS1 rearrangements in the NCI-MATCH trial.

The NCI-MATCH was designed to characterize the efficacy of targeted therapies in histology-agnostic driver mutation-positive malignancies. Sub-protocols F and G were developed to evaluate the role of crizotinib in rare tumors that harbored either ALK or ROS1 rearrangements. Patients with malignancies that progressed following at least one prior systemic therapy were accrued to the NCI-MATCH for molecular profiling, and those with actionable ALK or ROS1 rearrangements were offered participation in sub-protocols F or G, respectively. There were five patients who enrolled on Arm F (ALK) and four patients on Arm G (ROS1). Few grade 3 or 4 toxicities were noted, including liver test abnormalities, and acute kidney injury. For sub-protocol F (ALK), the response rate was 50% (90% CI 9.8-90.2%) with one complete response among the 4 eligible patients. The median PFS was 3.8 months, and median OS was 4.3 months. For sub-protocol G (ROS1) the response rate was 25% (90% CI 1.3-75.1%). The median PFS was 4.3 months, and median OS 6.2 months. Data from 3 commercial vendors showed that the prevalence of ALK and ROS1 rearrangements in histologies other than non-small cell lung cancer and lymphoma was rare (0.1% and 0.4% respectively). We observed responses to crizotinib which met the primary endpoint for ALK fusions, albeit in a small number of patients. Despite the limited accrual, some of the patients with these oncogenic fusions can respond to crizotinib which may have a therapeutic role in this setting.

Attractor dynamics and thermodynamic analogies in the cerebral cortex: synchronous oscillation, the background EEG, and the regulation of attention.

Ongoing changes in attention and cognition depend upon cortical/subcortical interactions, which select sequences of different spatial patterns of activation in the cortex. It is proposed that each pattern of cortical activation permits evolution of electrocortical wave activity toward statistically stationary states, analogous to thermodynamic equilibrium. In each steady-state, neurons fire with an intrinsic Poisson spike probability and also with a bursting pattern related to network oscillations. Excitatory cell dendrites act as a regenerative reservoir in which pulse generation is balanced against dissipations. Equilibria exhibit contrasting limits. One limit, at high cortical activation, generates widespread zero-lag synchrony among excitatory cells, with partial suppression of noise. Excitatory and inhibitory cells approach zero-lag local correlation, with 1/4 cycle lag-correlation at greater distances of separation. The high-activation limit defines a correlated system of attractor basins, capable of co-ordinating synaptic modifications and intracortical signal generation. Suppression of noise would enhance convergence about attractor basins in the manner of simulated annealing, while, conversely, the persistence of some noise prevents network paralysis by phase locking. At the opposite limit-that of low activation-spikes and waves have low cross- and auto-correlation, but have wide-spectrum sensitivity to inputs. It is hypothesised that cortical regions, transiently at equilibrium near these extremes, engage in interaction with each other and with subcortical systems, to generate ongoing sequences of attention and cognition. This account is compatible with classical and recently observed experimental phenomena. The principle features inferred from a simplified linear mathematical account are reproduced in a more physiologically realistic and non-linear numerical simulation.

The growth of cognition: Free energy minimization and the embryogenesis of cortical computation.

The assumption that during cortical embryogenesis neurons and synaptic connections are selected to form an ensemble maximising synchronous oscillation explains mesoscopic cortical development, and a mechanism for cortical information processing is implied by consistency with the Free Energy Principle and Dynamic Logic. A heteroclinic network emerges, with stable and unstable fixed points of oscillation corresponding to activity in symmetrically connected, versus asymmetrically connected, sets of neurons. Simulations of growth explain a wide range of anatomical observations for columnar and non-columnar cortex, superficial patch connections, and the organization and dynamic interactions of neurone response properties. An antenatal scaffold is created, upon which postnatal learning can establish continuously ordered neuronal representations, permitting matching of co-synchronous fields in multiple cortical areas to solve optimization problems as in Dynamic Logic. Fast synaptic competition partitions equilibria, minimizing "the curse of dimensionality", while perturbations between imperfectly partitioned synchronous fields, under internal reinforcement, enable the cortex to become adaptively self-directed. As learning progresses variational free energy is minimized and entropy bounded.

Characterization of CCX282-B, an orally bioavailable antagonist of the CCR9 chemokine receptor, for treatment of inflammatory bowel disease.

The chemokine system represents a diverse group of G protein-coupled receptors responsible for orchestrating cell recruitment under both homeostatic and inflammatory conditions. Chemokine receptor 9 (CCR9) is a chemokine receptor known to be central for migration of immune cells into the intestine. Its only ligand, CCL25, is expressed at the mucosal surface of the intestine and is known to be elevated in intestinal inflammation. To date, there are no reports of small-molecule antagonists targeting CCR9. We report, for the first time, the discovery of a small molecule, CCX282-B, which is an orally bioavailable, selective, and potent antagonist of human CCR9. CCX282-B inhibited CCR9-mediated Ca(2+) mobilization and chemotaxis on Molt-4 cells with IC(50) values of 5.4 and 3.4 nM, respectively. In the presence of 100% human serum, CCX282-B inhibited CCR9-mediated chemotaxis with an IC(50) of 33 nM, and the addition of α1-acid glycoprotein did not affect its potency. CCX282-B inhibited chemotaxis of primary CCR9-expressing cells to CCL25 with an IC(50) of 6.8 nM. CCX282-B was an equipotent inhibitor of CCL25-directed chemotaxis of both splice forms of CCR9 (CCR9A and CCR9B) with IC(50) values of 2.8 and 2.6 nM, respectively. CCX282-B also inhibited mouse and rat CCR9-mediated chemotaxis. Inhibition of CCR9 with CCX282-B results in normalization of Crohn's disease such as histopathology associated with the TNF(ΔARE) mice. Analysis of the plasma level of drug associated with this improvement provides an understanding of the pharmacokinetic/pharmacodynamic relationship for CCR9 antagonists in the treatment of intestinal inflammation.

Phase II trial of the farnesyltransferase inhibitor tipifarnib plus fulvestrant in hormone receptor-positive metastatic breast cancer: New York Cancer Consortium Trial P6205.

BACKGROUND: Fulvestrant produces a clinical benefit rate (CBR) of approximately 45% in tamoxifen-resistant, hormone receptor (HR)-positive metastatic breast cancer (MBC) and 32% in aromatase inhibitor (AI)-resistant disease. The farnesyltransferase inhibitor tipifarnib inhibits Ras signaling and has preclinical and clinical activity in endocrine therapy-resistant disease. The objective of this study was to determine the efficacy and safety of tipifarnib-fulvestrant combination in HR-positive MBC. PATIENTS AND METHODS: Postmenopausal women with no prior chemotherapy for metastatic disease received i.m. fulvestrant 250 mg on day 1 plus oral tipifarnib 300 mg twice daily on days 1-21 every 28 days. The primary end point was CBR. RESULTS: The CBR was 51.6% [95% confidence interval (CI) 34.0% to 69.2%] in 31 eligible patients and 47.6% (95% CI 26.3% to 69.0%) in 21 patients with AI-resistant disease. A futility analysis indicated that it was unlikely to achieve the prespecified 70% CBR. Tipifarnib dose modification was required in 8 of 33 treated patients (24%). CONCLUSIONS: The target CBR of 70% for the tipifarnib-fulvestrant combination in HR-positive MBC was set too high and was not achieved. The 48% CBR in AI-resistant disease compares favorably with the 32% CBR observed with fulvestrant alone in prior studies and merit further clinical and translational evaluation.

Expression of a zinc finger gene in HTLV-I- and HTLV-II-transformed cells.

Gene products encoded by the human T cell leukemia virus (HTLV) types I and II mediate transformation by the transactivation of cellular genes necessary for proliferation, probably including transcriptional regulatory factors. By searching for factors that may control proliferation, a zinc finger gene (225) was identified that was constitutively expressed in all HTLV-I- or HTLV-II-transformed cell lines examined, whereas in normal T cells it was only transiently expressed after mitogenic stimulation. The 225 gene was also constitutively expressed in two HTLV-I-transformed helper T cell clones, but not in the parental cell lines. Thus this putative cellular transcriptional factor, which was abnormally expressed in retrovirus-infected cells, may have a role in transformation.

Inhibitors of HIV-1 attachment. Part 3: A preliminary survey of the effect of structural variation of the benzamide moiety on antiviral activity.

1-(4-Benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1a) has been characterized as an inhibitor of HIV-1 attachment that interferes with the interaction of viral gp120 with the host cell receptor CD4. In previous studies, the effect of indole substitution pattern on antiviral activity was probed. In this Letter, the effect of structural variation of the benzamide moiety is described, a study that reveals the potential or the phenyl moiety to be replaced by five-membered heterocyclic rings and a restricted tolerance for the introduction of substituents to the phenyl ring.

Inhibitors of HIV-1 attachment. Part 2: An initial survey of indole substitution patterns.

The effects of introducing simple halogen, alkyl, and alkoxy substituents to the 4, 5, 6 and 7 positions of 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione, an inhibitor of the interaction between HIV gp120 and host cell CD4 receptors, on activity in an HIV entry assay was examined. Small substituents at C-4 generally resulted in increased potency whilst substitution at C-7 was readily tolerated and uniformly produced more potent HIV entry inhibitors. Substituents deployed at C-6 and, particularly, C-5 generally produced a modest to marked weakening of potency compared to the prototype. Small alkyl substituents at N-1 exerted minimal effect on activity whilst increasing the size of the alkyl moiety led to progressively reduced inhibitory properties. These studies establish a basic understanding of the indole element of the HIV attachment inhibitor pharmacophore.

T cell receptor alpha-, beta-, and gamma-genes in T cell and pre-B cell acute lymphoblastic leukemia.

We examined alpha-, beta-, and gamma-T cell receptor (TCR) gene activation within acute lymphoblastic leukemias (ALLs) that represent early stages of B and T cell development. We wished to determine if TCR rearrangement and expression was lineage restricted, showed any developmental hierarchy, or could identify new subsets of T cells. Rearrangement of gamma and beta TCR genes occurred early in development but in no set order, and most T-ALLs (22/26) were of sufficient maturity to have rearranged both genes. T-ALLs preferentially rearranged C gamma 2 versus the C gamma 1 complex; no preference within the beta locus was apparent. Once rearranged, the beta TCR continued to be expressed (11/13), whereas the gamma TCR was rarely expressed (3/14). The alpha TCR was expressed only in more mature T-ALLs (8/14) that usually displayed T3. The 3A-1 T cell associated antigen appeared earliest in development followed by T11 and T3. Within pre-B cell ALL a higher incidence of lineage spillover was noted for gamma TCR rearrangements (8/17) than for beta rearrangements (3/17). This also contrasts with the only occasional rearrangement of immunoglobulin (Ig) heavy chains (3/25) in T-ALL. However, in pre-B ALL the pattern of gamma TCR usage was distinct from that of T cells, with the C gamma 1 complex utilized more frequently. Almost all ALLs could be classified as pre-B or T cell in type by combining Ig and TCR genes with monoclonal antibodies recognizing surface antigens, although examples of lineage duality were noted. Unique subpopulations of cells were discovered including two genetically uncommitted ALLs that failed to rearrange either Ig or TCR loci. Moreover, two T lymphoblasts were identified that possessed the T3 molecule but failed to express alpha plus beta TCR genes. These T-ALLs may represent a fortuitous transformation of T cell subsets with alternative T3-Ti complexes.

Measurement of phase gradients in the EEG.

Previous research has shown that spatio-temporal waves in the EEG are generally of long spatial wavelength and form smooth patterns of phase gradients at particular time-samples. This paper describes a method to measure smooth phase gradients of long spatial wavelength in the EEG. The method depends on the global pattern of phase at a given frequency and time and is therefore robust to variations, over time, in phase-lag between particular sites. Phases were estimated in the EEG signal using wavelet or short time-series Fourier methods. During an auditory oddball task, phases across the scalp tend to fall within a limited circular range, a range that is not indicative of phase-synchrony nor waves with multiple periods. At times the phases tended to maintain a spatially and temporally ordered relationship. The relative phases were analysed using three phase gradient basis functions, providing a measure of the amount of variance explained, across the electrodes, by smooth changes in relative phase from a single minimum or single maximum. The data from 586 adult subjects were analysed and it was found that the probability of phase gradient events varies with time and frequency in the stimulus-locked average, and with task demands. The temporal extent of spatio-temporal waves was measured by detecting smoothly changing patterns of phase latencies across the scalp. The specific spatial pattern and timing of phase gradients correspond closely to the latency distributions of certain ERPs.

Contribution of lateral interactions in V1 to organization of response properties.

We propose a model of self-organization of synaptic connections in V1, emphasizing lateral interactions. Subject to Hebbian learning with decay, evolution of synaptic strengths proceeds to a stable state in which all synapses are either saturated, or have minimum pre/post-synaptic coincidence. The most stable configuration gives rise to anatomically realistic "local maps", each of macro-columnar size, and each organized as Mobius projections of retinotopic space. A tiling of V1, constructed of approximately mirror-image reflections of each local map by its neighbors is formed, accounting for orientation-preference singularities, linear zones, and saddle points-with each map linked by connections between sites of common orientation preference. Ocular dominance columns are partly explained as a special case of the same process. The occurrence of direction preference fractures always in odd numbers around singularities is a specific feature explained by the Mobius configuration of the local map. Effects of stimulus velocity, orientation relative to direction of motion, and extension, upon orientation preference, which are not accounted for by spatial filtering, are explained by interactions between the classic receptive field and global V1.

Clonal evolution of t(14;18) follicular lymphomas demonstrated by immunoglobulin genes and the 18q21 major breakpoint region.

A 2.8-kilobase major breakpoint region on chromosome segment 18q21 is the site of most t(14;18) translocations typical of human follicular lymphomas. Breaks are focused at the 5' end of joining (JH) regions of immunoglobulin (Ig) on chromosome 14, indicating that the translocation occurs at a pre-B-cell stage during attempted heavy (H) chain joining. A new gene from 18q21 (Bcl-2) is placed in the H chain locus creating a unique, translocation-specific JH;18q21 rearrangement that presumably represents a transformation event. In addition, normal Ig gene joining occurs in a H before light (L) chain and K before lambda cascade, creating ordered clonal markers. These serial markers were examined to determine if variations in Ig gene patterns during the natural history of lymphomas represent the emergence of truly separate neoplasms or heterogeneity of a single neoplasm. We examined 45 serial biopsies from 16 B follicular lymphoma patients; six cases showed variation in Ig gene patterns over time. Seven individuals had a detectable JH;18q21 rearrangement present, and it remained unchanged over 5-10 years. Further rearrangements of H chain genes occurred on the normal chromosome 14 within evolving subclones of the original tumor. Lambda L chains also underwent additional rearrangements in two instances, while K gene patterns remained unchanged. All variations in the normal H and L chain genes were 2 degrees rearrangements occurring at a mature B-cell stage following the initial successful rearrangement of a H and L chain. In contrast the t(14;18) breakpoint was conserved in each individual, indicating that evolving neoplastic subpopulations arose from a common clonal progenitor cell.

Gene rearrangements as markers of clonal variation and minimal residual disease in acute lymphoblastic leukemia.

Immunoglobulin (Ig) heavy (H) and light (L) chain gene rearrangements were used as molecular markers of clonal evolution and minimal residual disease in B cell precursor acute lymphoblastic leukemia (ALL). All leukemic episodes within individual patients shared at least one identical Ig rearrangement and thus arose from a common clonal progenitor cell. Nine of 11 patients displayed completely identical patterns between leukemic episodes, while two of 11 patients demonstrated genetic progression between diagnosis and relapse as evidenced by additional rearrangements. These genetic changes marked the emergence of leukemic subclones. Ig gene rearrangements were also used as sensitive markers to identify clonal cell populations in ALL patients following induction or reinduction therapy and to search for residual bone marrow disease in patients in clinical remission or with isolated extramedullary relapse. DNA rearrangements provide tumor-specific markers to follow the genetic variation of ALL and may facilitate the early detection of recurrent disease.

Molecular heterogeneity and function of EWS-WT1 fusion transcripts in desmoplastic small round cell tumors.

Desmoplastic small round cell tumor (DSRCT) is a primitive sarcoma with a consistent cytogenetic abnormality, t(11;22)(p13;q12). This chromosomal translocation generates a chimeric transcript that is formed by fusion of the 5' region of the Ewing's sarcoma gene, EWS, with the 3' DNA-binding segment of WT1, the Wilms' tumor suppressor gene. We collected 14 DSRCT tumor samples and examined the hybrid transcripts. We identified: (a) combinatorial heterogeneity of EWS exons fused to WT1 including use of EWS exons 7, 8, and 9; (b) subpopulations of variant transcripts in 6 of 14 tumors characterized by aberrant splicing resulting in loss of EWS exon 6 or WT1 exon 9; (c) multiple cDNA products with large internal deletions; and (d) insertion of small stretches of heterologous DNA at the fusion site or exon splice region in transcripts from two tumors. Most of the splice variants were in-frame, and in vitro translated fusion proteins with intact DNA-binding motifs formed complexes with a WT1 response element in gel mobility assays. Each of the chimeric proteins retains the ability to bind to the GC and TC elements of the early transcription factor EGR-1 as well as WT1 consensus sequences. We present evidence that various EWS-WT1 proteins up-regulated EGR-1 promoter activity and that this up-regulation is specifically dependent upon the absence of the exon 9 KTS domain of WT1. The molecular diversity and functionality exhibited by these fusion transcripts may have significant biological implications for their transactivating and tumorigenic potential.