COVID-19 and cancer screening in Scotland: A national and coordinated approach to minimising harm.

Screening is an important component of cancer control internationally. In Scotland, the National Health Service Scotland provides screening programmes for cervical, bowel and breast cancers. The COVID-19 pandemic resulted in the suspension of these programmes in March 2020. We describe the integrated approach to managing the impact of the pandemic on cancer screening programmes in Scotland throughout 2020. We outline the policy context and decision-making process leading to suspension, and the criteria and framework informing the subsequent, staggered, restart in subsequent months. The decision to suspend screening services in order to protect screening invitees and staff, and manage NHS capacity, was made after review of numbers of screening participants likely to be affected, and the potential number of delayed cancer diagnoses. Restart principles and a detailed route map plan were developed for each programme, seeking to ensure broad consistency of approach across the programmes and nationally. Early data indicates bowel, breast and cervical screening participation has increased since restart. Primary care has had to adapt to new infection prevention control measures for delivery of cervical screening. Cancer charities provided cancer intelligence and policy briefs to national bodies and Scottish Government, as well as supporting the public, patients and screening invitees through information and awareness campaigns. Emerging from the pandemic, there is recognition of the need and the opportunity to transform and renew both cancer and screening services in Scotland, and in particular to address long-standing workforce capacity problems through innovation and investment, and to continue to prioritise addressing health inequalities.

Factors Associated with Participation in Elementary School-Based SARS-CoV-2 Testing - Salt Lake County, Utah, December 2020-January 2021.

During December 3, 2020-January 31, 2021, CDC, in collaboration with the University of Utah Health and Economic Recovery Outreach Project,* Utah Department of Health (UDOH), Salt Lake County Health Department, and one Salt Lake county school district, offered free, in-school, real-time reverse transcription-polymerase chain reaction (RT-PCR) saliva testing as part of a transmission investigation of SARS-CoV-2, the virus that causes COVID-19, in elementary school settings. School contacts† of persons with laboratory-confirmed SARS-CoV-2 infection, including close contacts, were eligible to participate (1). Investigators approached parents or guardians of student contacts by telephone, and during January, using school phone lines to offer in-school specimen collection; the testing procedures were explained in the preferred language of the parent or guardian. Consent for participants was obtained via an electronic form sent by e-mail. Analyses examined participation (i.e., completing in-school specimen collection for SARS-CoV-2 testing) in relation to factors§ that were programmatically important or could influence likelihood of SARS-CoV-2 testing, including race, ethnicity, and SARS-CoV-2 incidence in the community (2). Crude prevalence ratios (PRs) were calculated using univariate log-binomial regression.¶ This activity was reviewed by CDC and was conducted consistent with federal law and CDC policy.*.

Low SARS-CoV-2 Transmission in Elementary Schools - Salt Lake County, Utah, December 3, 2020-January 31, 2021.

School closures affected more than 55 million students across the United States when implemented as a strategy to prevent the transmission of SARS-CoV-2, the virus that causes COVID-19 (1). Reopening schools requires balancing the risks for SARS-CoV-2 infection to students and staff members against the benefits of in-person learning (2). During December 3, 2020-January 31, 2021, CDC investigated SARS-CoV-2 transmission in 20 elementary schools (kindergarten through grade 6) that had reopened in Salt Lake County, Utah. The 7-day cumulative number of new COVID-19 cases in Salt Lake County during this time ranged from 290 to 670 cases per 100,000 persons.† Susceptible§ school contacts¶ (students and staff members exposed to SARS-CoV-2 in school) of 51 index patients** (40 students and 11 staff members) were offered SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) testing. Among 1,041 susceptible school contacts, 735 (70.6%) were tested, and five of 12 cases identified were classified as school-associated; the secondary attack rate among tested susceptible school contacts was 0.7%. Mask use among students was high (86%), and the median distance between students' seats in classrooms was 3 ft. Despite high community incidence and an inability to maintain ≥6 ft of distance between students at all times, SARS-CoV-2 transmission was low in these elementary schools. The results from this investigation add to the increasing evidence that in-person learning can be achieved with minimal SARS-CoV-2 transmission risk when multiple measures to prevent transmission are implemented (3,4).

A spontaneous increase in intracellular Ca2+ in metaphase II human oocytes in vitro can be prevented by drugs targeting ATP-sensitive K+ channels.

STUDY QUESTION: Could drugs targeting ATP-sensitive K(+) (K(ATP)) channels prevent any spontaneous increase in intracellular Ca(2+) that may occur in human metaphase II (MII) oocytes under in vitro conditions? SUMMARY ANSWER: Pinacidil, a K(ATP) channel opener, and glibenclamide, a K(ATP) channel blocker, prevent a spontaneous increase in intracellular Ca(2+) in human MII oocytes. WHAT IS KNOWN ALREADY: The quality of the oocyte and maintenance of this quality during in vitro processing in the assisted reproductive technology (ART) laboratory is of critical importance to successful embryo development and a healthy live birth. Maintenance of Ca(2+) homeostasis is crucial for cell wellbeing and increased intracellular Ca(2+) levels is a well-established indicator of cell stress. STUDY DESIGN, SIZE, DURATION: Supernumerary human oocytes (n = 102) collected during IVF/ICSI treatment that failed to fertilize were used from October 2013 to July 2015. All experiments were performed on mature (MII) oocytes. Dynamics of intracellular Ca(2+) levels were monitored in oocytes in the following experimental groups: (i) Control, (ii) Dimethyl sulfoxide (DMSO; used to dissolve pinacidil, glibenclamide and 2,4-Dinitrophenol (DNP)), (iii) Pinacidil, (iv) Glibenclamide, (v) DNP: an inhibitor of oxidative phosphorylation, (vi) Pinacidil and DNP and (vii) Glibenclamide and DNP. PARTICIPANTS/MATERIALS/SETTINGS/METHODS: Oocytes were collected under sedation as part of routine treatment at an assisted conception unit from healthy women (mean ± SD) age 34.1 ± 0.6 years, n = 41. Those surplus to clinical use were donated for research. Oocytes were loaded with Fluo-3 Ca(2+)-sensitive dye, and monitored by laser confocal microscopy for 2 h at 10 min intervals. Time between oocyte collection and start of Ca(2+) monitoring was 80.4 ± 2.1 h. MAIN RESULTS AND THE ROLE OF CHANCE: Intracellular levels of Ca(2+) increased under in vitro conditions with no deliberate challenge, as shown by Fluo-3 fluorescence increasing from 61.0 ± 11.8 AU (AU = arbitrary units; n = 23) to 91.8 ± 14.0 AU (n = 19; P < 0.001) after 2 h of monitoring. Pinacidil (100 µM) inhibited this increase in Ca(2+) (85.3 ± 12.3 AU at the beginning of the experiment, 81.7 ± 11.0 AU at the end of the experiment; n = 13; P = 0.616). Glibenclamide (100 µM) also inhibited the increase in Ca(2+) (74.7 ± 10.6 AU at the beginning and 71.8 ± 10.9 AU at the end of the experiment; n = 13; P = 0.851. DNP (100 mM) induced an increase in intracellular Ca(2+) that was inhibited by glibenclamide (100 µM; n = 9) but not by pinacidil (100 µM; n = 5). LIMITATIONS, REASONS FOR CAUTION: Owing to clinical and ethical considerations, it was not possible to monitor Ca(2+) in MII oocytes immediately after retrieval. MII oocytes were available for our experimentation only after unsuccessful IVF or ICSI, which was, on average, 80.4 ± 2.1 h (n = 102 oocytes) after the moment of retrieval. As the MII oocytes used here were those that were not successfully fertilized, it is possible that they may have been abnormal with impaired Ca(2+) homeostasis and, furthermore, the altered Ca(2+) homeostasis might have been associated solely with the protracted incubation. WIDER IMPLICATIONS OF THE FINDINGS: These results show that maintenance of oocytes under in vitro conditions is associated with intracellular increase in Ca(2+), which can be counteracted by drugs targeting K(ATP) channels. As Ca(2+) homeostasis is crucial for contributing to a successful outcome of ART, these results suggest that K(ATP) channel openers and blockers should be tested as drugs for improving success rates of ART. STUDY FUNDING/COMPETING INTERESTS: University of Dundee, MRC (MR/K013343/1, MR/012492/1), NHS Tayside. Funding NHS fellowship (Dr Sarah Martins da Silva), NHS Scotland. The authors declare no conflicts of interest.

Neonatal development of hepatic UGT1A9: implications of pediatric pharmacokinetics.

This article reports on the development of UDP-glucuronosyltransferase 1A9 (UGT1A9) in neonatal and pediatric liver. The substrate 4-methylumbelliferone (4MU) with specific inhibition by niflumic acid was used to define specific UGT1A9 activity. Subsequently, in silico pharmacokinetic (PK) and physiology-based pharmacokinetic (PBPK) modeling was used to determine UGT1A9 maturation and hepatic clearance. Modeled maximal enzyme activity was 27.9 nmol · min(-1) · mg protein(-1) at 4 months of age, which had high concordance with the average V(max) in 45 individual adult (>20 years) livers of 29.0 nmol · min(-1) · mg protein(-1). The activity of UGT1A9 ranged 7.5-fold in the adult population (4.1-54.5 nmol · min(-1) · mg protein(-1)). Expression of UGT1A9 correlated with age only in children younger than 1 year (Spearman r = 0.70). Activity correlated with expression up to 18 years of age (Spearman r = 0.76). Furthermore, scaling intrinsic hepatic clearance of 4MU with an allometric PK model yielded a high clearance at birth and then fell to adult levels (1.3 l · h(-1) · kg(-1) at 18.1 years for well stirred or 1.4 l · h(-1) · kg(-1) at 18.7 years for parallel tube). The Simcyp PBPK models did not converge but showed an increase in clearance at under 1 year of age and then decreased to adult levels at approximately 20 years of age. Allometric scaling may be more accurate in cases of high-extraction drugs. Enzyme activities or hepatic clearances did not differ with gender or ethnicity. The UGT1A9 isoform has higher normalized clearance for 4MU at young ages, which may explain how other UGT1A9 substrates, such as propofol, have higher clearances in children than in adults.

Absolute immunoquantification of the expression of ABC transporters P-glycoprotein, breast cancer resistance protein and multidrug resistance-associated protein 2 in human liver and duodenum.

The ATP-binding cassette (ABC) transporters breast cancer resistance protein (BCRP), multidrug resistance-associated protein 2 (MRP2), and P-glycoprotein (Pgp) are important in the distribution and elimination of many drugs and endogenous metabolites. Due to their membrane location and hydrophobicity it is difficult to generate purified protein standards to quantify these transporters in human tissues. The present study generated transporter proteins fused with the S-peptide of ribonuclease for use as standards in immunoquantification in human liver and small intestine. Quantification of the S•tag™, a 15 amino acid peptide, is based on the formation of a functional ribonuclease activity upon its high affinity reconstitution with ribonuclease S-protein. S-tagged transporters were used as full-length protein standards in the immunoquantification of endogenous BCRP, MRP2, and Pgp levels in 14 duodenum and 13 liver human tissue samples. Expression levels in the duodenum were 305±248 (BCRP), 66±70 (MRP2), and 275±205 (Pgp) fmoles per cm(2). Hepatic levels were 2.6±0.9 (BCRP), 19.8±10.5 (MRP2), and 26.1±10.1 (total Pgp) pmoles per g of liver. The mean hepatic scaling factor was 35.8mg crude membrane per g of liver, and the mean duodenal scaling factor was 1.3mg crude membrane per cm(2) mucosal lining. Interindividual variability was greater in duodenal samples than liver samples. It is hoped that this innovative method of quantifying these transporters (and other membrane proteins) will improve in vivo-in vitro extrapolation and in silico prediction of drug absorption and elimination, thus supporting drug development.

A novel method for the immunoquantification of UDP-glucuronosyltransferases in human tissue.

Glucuronidation is a major pathway of drug and xenobiotic metabolism that is catalyzed by members of the UDP-glucuronosyltransferase (UGT) family. Predicting the contribution of individual UGTs to drug metabolism would be of considerable value in drug development and would be greatly aided by the availability of detailed absolute expression levels of these proteins; this is hampered by the lack of purified protein standards because of the hydrophobic membrane-associated nature of UGTs and the consequential difficulties in expression and purification. Here we describe a novel solution to this problem by expressing UGTs in Escherichia coli as fusion proteins with ribonuclease S-peptide, targeted to the periplasm with the pelB leader sequence. After addition of ribonuclease S-protein to membrane extracts, a functional ribonuclease is reconstituted that provides a direct and absolute quantification of the amount of UGT fusion protein; this is subsequently used to generate standard curves for immunoquantification by immunoblotting. To illustrate the value of the method, we have quantified the expression of UGT1A1 and UGT1A6 in human liver and kidney microsomes using new isoform-specific antibodies developed against peptides from these proteins. Expression levels of both proteins in liver were highly variable (28- and 20-fold, respectively) and correlated strongly with UGT enzyme activity toward the probe substrates bilirubin and 1-naphthol, respectively. The method is broadly applicable and provides a straightforward means of determining the absolute, as opposed to relative, quantities of UGT proteins present in human tissues.

Aortic valve replacement in a young patient with essential thrombocytosis.

Essential Thrombocythcythaemia (ET) is an uncommon type of myeloproliferative disorder, characterised by both thrombotic and haemorrhagic diathesis. No clear guidelines exist for the pre- and post-operative management of patients undergoing cardiac surgery in the haematological and surgical literature. This condition has profound implications in patients undergoing cardiac surgery with the use of cardiopulmonary bypass, where heparin is used for anti-coagulation. This dilemma is further compounded in the setting of a young patient undergoing aortic valve replacement (AVR), where insertion of a mechanical prosthesis would be the procedure of choice. This would require life-long anticoagulation with warfarin which can predispose these patients to catastrophic bleeding. Using a tissue valve will subject the patient to multiple redo operations in the patient's lifetime. We report a young patient with ET requiring AVR and discuss the dilemmas surrounding the choice of prosthesis in this patient.

Plasmacytoma relapses in the absence of systemic progression post-high-dose therapy for multiple myeloma.

Autologous (ASCT) and allogeneic stem cell transplantations (alloBMT) are well-established therapies for multiple myeloma. However, patients continue to relapse at a constant rate. We present here 15 out of 163 patients who underwent SCT and relapsed with plasmacytomas only without evidence of bone marrow disease progression (14/147 post-ASCT and 1/16 post-alloBMT). The median time from SCT to plasmacytoma relapse was 24 months. The sites of plasmacytoma included bone, skin, rectum, and testicles. Five patients were treated with local radiotherapy, while seven patients received a combination of radiotherapy and chemotherapy or thalidomide, and two patients received chemotherapy alone with or without thalidomide. The recipient of alloBMT was initially treated with VAD-chemotherapy and local radiotherapy followed by a mini-allograft from the original donor. Eleven patients died at a median of 10 months following diagnosis of the plasmacytoma. Four are still alive, 12-20 months post-plasmacytoma diagnosis. These cases of unconventional disease recurrence are likely to be seen due to sub-clinical seeding of tumour cells suggestive of the presence of an extramedullary (EM) clone of plasma cells with a high degree of chemoresistance. We also review all the available data in the literature for the optimal therapy for patients with isolated EM relapse.

Randomized comparison of low-dose versus high-dose interferon-alfa in chronic myeloid leukemia: prospective collaboration of 3 joint trials by the MRC and HOVON groups.

The optimal dose of interferon-alfa (IFN) for chronic myeloid leukemia (CML) is unknown. Retrospective analyses suggest that low doses are as effective as high doses, with less toxicity and fewer patients abandoning the drug. The Dutch Hemato-Oncology Association (HOVON) and British Medical Research Council (MRC) cooperative groups jointly performed randomized trials in newly diagnosed CML patients, comparing high-dose IFN (5 MIU/m(2) daily) with low-dose (3 MIU, 5 times a week). Both arms allowed additional hydroxyurea to keep the white blood cell count lower than 5 x 10(9)/L. Quality of life data were collected in a subset of patients. Between 1993 and 2001, 407 patients were randomized. At a median follow-up of 53 months, there were no significant differences in overall survival (odds ratio = 1.09, 95% confidence interval, 0.81-1.46), progression-free survival, and complete hematologic or major cytogenetic responses. Fewer patients in the low-dose group abandoned IFN for reasons other than transplant or progressive disease (P =.002, 58% vs 72% at 5 years). Quality of life data showed comparable results in both arms for most factors. There is no evidence of benefit for high-dose IFN compared with low-dose for the treatment of CML. Therefore, when IFN is combined with other drugs, low-dose IFN is advised, to minimize toxicity and costs.

Purification, cloning, and characterization of Nek8, a novel NIMA-related kinase, and its candidate substrate Bicd2.

We describe the isolation, cloning, and characterization of human Nek8, a new mammalian NIMA-related kinase, and its candidate substrate Bicd2. Nek8 was isolated as a beta-casein kinase activity in rabbit lung and has an N-terminal catalytic domain homologous to the Nek family of protein kinases. Nek8 also contains a central domain with homology to RCC1, a guanine nucleotide exchange factor for the GTPase Ran, and a C-terminal coiled-coil domain. Like Nek2, Nek8 prefers beta-casein over other exogenous substrates, has shared biochemical requirements for kinase activity, and is capable of autophosphorylation and oligomerization. Nek8 activity is not cell cycle regulated, but like Nek3, levels are consistently higher in G(0)-arrested cells. During the purification of Nek8 a second protein co-chromatographed with Nek8 activity. This protein, Bicd2, is a human homolog of the Drosophila protein Bicaudal D, a coiled-coil protein. Bicd2 is phosphorylated by Nek8 in vitro, and the endogenous proteins associate in vivo. Bicd2 localizes to cytoskeletal structures, and its subcellular localization is dependent on microtubule morphology. Treatment of cells with nocodazole leads to dramatic reorganization of Bicd2, and correlates with Nek8 phosphorylation. This may be indicative of a role for Nek8 and Bicd2 associated with cell cycle independent microtubule dynamics.