Highly dynamic gamma-ray emissions are common in tropical thunderclouds.

Thunderstorms emit fluxes of gamma rays known as gamma-ray glows1,2, sporadically observed by aircraft1,3-7, balloons8-11 and from the ground12-18. Observations report increased gamma-ray emissions by tens of percent up to two orders of magnitude above the background, sometimes abruptly terminated by lightning discharges1,3-5. Glows are produced by the acceleration of energetic electrons in high-electric-field regions within thunderclouds8 and contribute to charge dissipation3. Glows had been considered as quasi-stationary phenomena3,5,12, with durations up to a few tens of seconds and spatial scales up to 10-20 km. However, no measurements of the full extension in space and time of a gamma-ray-glow region and their occurring frequency have been reported so far. Here we show that tropical thunderclouds over ocean and coastal regions commonly emit gamma rays for hours over areas up to a few thousand square kilometres. Emission is associated with deep convective cores; it is not uniform and continuous but shows characteristic timescales of 1-10 s and even subsecond for individual glows. The dynamics of gamma-glowing thunderclouds strongly contradicts the quasi-stationary picture of glows and instead resembles that of a huge gamma-glowing 'boiling pot' in both pattern and behaviour.

Flickering gamma-ray flashes, the missing link between gamma glows and TGFs.

Two different hard-radiation phenomena are known to originate from thunderclouds: terrestrial gamma-ray flashes (TGFs)1 and gamma-ray glows2. Both involve an avalanche of electrons accelerated to relativistic energies but are otherwise different. Glows are known to last for one to hundreds of seconds, have moderate intensities and originate from quasi-stationary thundercloud fields2-5. TGFs exhibit high intensities and have characteristic durations of tens to hundreds of microseconds6-9. TGFs often show a close association with an emission of strong radio signals10-17 and optical pulses18-21, which indicates the involvement of lightning leaders in their generation. Here we report unique observations of a different phenomenon, which we call flickering gamma-ray flashes (FGFs). FGFs resemble the usual multi-pulse TGFs22-24 but have more pulses and each pulse has a longer duration than ordinary TGFs. FGF durations span from 20 to 250 ms, which reaches the lower boundary of the gamma-ray glow duration. FGFs are radio and optically silent, which makes them distinct from normal TGFs. An FGF starts as an ordinary gamma-ray glow, then suddenly increases exponentially in intensity and turns into an unstable, 'flickering' mode with a sequence of pulses. FGFs could be the missing link between the gamma-ray glows and conventional TGFs, whose absence has been puzzling the atmospheric electricity community for two decades.

Pharmacists improve diabetes outcomes: a randomized controlled trial.

BACKGROUND: There is a growing shortage of primary care physicians. Pharmacists can fill the gap, and interdisciplinary teams are being evaluated as part of health care reform. OBJECTIVE: This study aimed to determine whether adding a pharmacist to an interprofessional health team will improve diabetes outcomes. METHODS: In this 2-phase pilot study, Medicaid-eligible patients with diabetes were randomized to receive standard of care (control arm) or standard of care plus the care of a pharmacist (intervention arm) for 12 months (phase 1). The primary outcome was change in glycated hemoglobin (A1C) from baseline. Secondary outcomes included identifying and correcting medication therapy problems (MTPs) for comorbid conditions, adherence to preventive care visits, health care utilization, self-rated health, and satisfaction surveys. After phase 1, patients in the control arm who did not achieve an A1C of < 8% were eligible to enroll into phase 2 where they received treatment with a pharmacist for 6 months. RESULTS: Of the 239 patients enrolled, 122 completed phase 1. At 12 months, intervention patients' mean A1C was 1.85 percentage point (pp) below baseline versus 0.94 pp for control (between-group difference 0.91 pp; P = 0.0218). Most control patients (79%) who completed phase 1 and enrolled into phase 2 improved their A1C by more than 1 pp (P < 0.01). The pharmacists completed 806 patient visits and identified 2638 MTPs. Intervention patients were more adherent to preventive care visits with nutrition (P = 0.043), ophthalmology (P = 0.002), and dentistry (P = 0.007). For intervention patients, 78% rated their experience with the pharmacist as excellent whereas, for control patients, 37% rated their experience with their provider as excellent. CONCLUSION: Pharmacist comanagement of patients with diabetes can significantly improve glucose control and patient satisfaction. Creative payment models were used to include pharmacists in the interprofessional patient care team.

First identification and molecular characterization of a novel cherry robigovirus.

A large contig with sequence similarities to members of the genus Robigovirus was identified by high-throughput sequencing analysis from a symptomless cherry accession. The complete genome sequence of this new virus is 8,384 nucleotides in length, excluding the 3' poly(A) tail. Its genome organization is very similar to those of four known robigoviruses, encoding a putative replicase, three 'triple gene block' proteins, a coat protein, and an unknown protein, 2a. Unlike the four cherry robigoviruses, the new virus does not contain a putative ORF5a. The full-length genome of the virus, which is provisionally named "cherry robigovirus 5" (CRV-5), is 52-57% identical to genome sequences of other robigoviruses. Phylogenetic analysis showed that CRV-5 and other robigoviruses group in a cluster, supporting its assignment to a new species in the genus Robigovirus.

Molecular characterization of a novel luteovirus from peach identified by high-throughput sequencing.

Contigs with sequence homologies to cherry-associated luteovirus were identified by high-throughput sequencing analysis in two peach accessions. Complete genomic sequences of the two isolates of this virus were determined to be 5,819 and 5,814 nucleotides long, respectively. The genome of the new virus is typical of luteoviruses, containing eight open reading frames in a very similar arrangement. Its genomic sequence is 58-74% identical to those of other members of the genus Luteovirus. These sequences thus belong to a new virus, which we have named "peach-associated luteovirus".

Optimising physiotherapy for people with lateral elbow tendinopathy - Results of a mixed-methods pilot and feasibility randomised controlled trial (OPTimisE).

BACKGROUND: The OPTimisE intervention was developed to address uncertainty regarding the most effective physiotherapy treatment strategy for people with Lateral Elbow Tendinopathy (LET). OBJECTIVES: To assess the feasibility of conducting a fully-powered randomised controlled trial (RCT) evaluating whether the OPTimisE intervention is superior to usual physiotherapy treatment for adults with LET. DESIGN: A mixed-methods multi-centred, parallel pilot and feasibility RCT, conducted in three outpatient physiotherapy departments in the UK. METHOD: Patients were independently randomised 1:1 in mixed blocks, stratified by site, to the OPTimisE intervention or usual care. Outcomes were assessed using pre-defined feasibility progression criteria. RESULTS: 50 patients were randomised (22 Female, 28 Male), mean age 48 years (range 27-75). Consent rate was 71% (50/70), fidelity to intervention 89% (16/18), attendance rate in the OPTimisE group 82% (55/67) vs 85% (56/66) in usual care, outcome measure completion 81% (39/48) at six-month follow-up. There were no related adverse events. Patients and physiotherapists reported that the OPTimisE intervention was acceptable but suggested improvements to the trial design. 49 patients were recruited from physiotherapy referrals vs one from primary care records. Outcome measure return rates were higher when completed online (74%) compared to postal questionnaire (50%). Exploratory analysis showed improvements in both groups over time. CONCLUSIONS: It is methodologically feasible to conduct a fully powered RCT comparing the clinical and cost-effectiveness of the OPTimisE intervention versus usual physiotherapy treatment. Considering the similar improvements observed in both groups, careful consideration is needed regarding the priority research question to be addressed in future research.

Another family with a euchromatic duplication variant of 9q13-q21.1 derived from segmentally duplicated pericentromeric euchromatin.

Microscopically visible copy number variations within the proximal short arm heterochromatin and proximal long arm of chromosome 9 have been described as euchromatic variants (EVs) and are derived from extensive segmental duplications (SDs) that map to both the proximal short and long arms of chromosome 9. Recently, 3-4 additional copies of an SD cassette were found in 2 families with duplication EVs of 9q13-q21. Here, we report a third family with a duplication EV of 9q13-q21.1 that was ascertained at prenatal diagnosis for advanced maternal age and found in the fetus and her phenotypically normal mother. Dual-colour fluorescence in situ hybridization with bacterial artificial chromosomes RP11-246P17 and RP11-211E19 was consistent with the EV chromosome having 1-2 additional copies of a similar SD cassette, except that the SD-boundary clone RP11-88I18 was not apparently included. It is important to distinguish the 9q13-q21.1 EVs from possible pathogenic imbalances of chromosome 9, especially at prenatal diagnosis, as these EVs have no established phenotypic or reproductive consequences. The nature of the G-dark bands in 9q13-q21 EVs is briefly discussed.

A novel pseudo-dicentric variant of 16p11.2-q11.2 contains euchromatin from 16p11.2-p11.1 and resembles pathogenic duplications of proximal 16q.

An unusually large G-light band between 2 G-dark bands in the proximal long arm of chromosome 16 was found in a boy of 5 years of age ascertained with growth retardation, microcephaly, and dysmorphic features. Dual color bacterial artificial chromosome fluorescence in situ hybridization (BAC FISH) and oligonucleotide array comparative genomic hybridization (oaCGH) were used to show that these bands contained a euchromatic duplication of a minimum of 940 kb between base pairs 34,197,413-35,137,025 in 16p11.2-p11.1 as well as a duplication of the centromere and major 16qh/16p11.2 heterochromatic block, covering a minimum of 12.3 Mb. The same pseudo-dicentric chromosome was found in the father who has attention deficit hyperactivity disorder (ADHD). The euchromatic region is not known to be subject to imprinting and overlaps multiple large copy number variations (CNVs) in the Database of Genomic Variants as well as similar CNVs that are benign or of uncertain significance in the International Standards for Cytogenomic Arrays database. We conclude that this family has a novel pseudo-dicentric euchromatic variant of chromosome 16 that is unlikely to be the cause of the variable phenotype in father and son but needs to be distinguished from heterochromatic variants or pathogenic duplications of proximal 16q.

Pharmacist-led review of empagliflozin and ertugliflozin following formulary update.

OBJECTIVES: To evaluate the appropriateness of the medication management for anyone who might have been affected by the Horizon New Jersey Health Medicaid Health Maintenance Organization (HNJH Medicaid HMO) formulary update from empagliflozin to ertugliflozin and to then optimize drug selection and monitoring. STUDY DESIGN: This is a single-center, 2-phase, pilot project led by 2 pharmacy students and the lead clinical pharmacist at a federally qualified health center in Trenton, New Jersey. METHODS: The primary outcome of the study is the number and percentage of patients whose prescription was changed inappropriately from empagliflozin to ertugliflozin. Secondary outcomes include the number and percentage of patients whose prescription was changed inappropriately because of failure to consider cardiovascular history and/or missed renal function checks and whether pharmacists were able to optimize therapy. Data were generated from electronic health record reports and analyzed in Microsoft Excel. RESULTS: A total of 126 unique patients were identified as receiving empagliflozin and/or ertugliflozin and 16 patients were switched from empagliflozin to ertugliflozin, all of whom had HNJH Medicaid HMO. Thirteen of the 16 (81.3%) patients were managed inappropriately based on their history of cardiovascular disease or inappropriate renal monitoring. Pharmacists recommended 22 interventions for patients who received empagliflozin and/or ertugliflozin, and all recommendations were accepted by providers. CONCLUSIONS: Following the HNJH Medicaid HMO's coverage update from empagliflozin to ertugliflozin, some patients received inappropriate therapy and providers accepted clinical pharmacists' recommendations to optimize therapy.

Post hoc depression analysis from a pharmacist-led diabetes trial.

Introduction: Diabetes and depression may present concurrently, and clinical pharmacists are well equipped to manage these conditions. Clinical pharmacists were grant funded to implement a diabetes-focused randomized controlled trial in a Federally Qualified Health Center. The objective of this analysis is to evaluate if glycemic control and depressive symptoms improve for patients with diabetes and depression with additional management from clinical pharmacists compared with those receiving the standard of care. Methods: This is a post hoc subgroup analysis of a diabetes-focused randomized controlled trial. Pharmacists enrolled patients with type 2 diabetes mellitus (T2DM) and a glycated hemoglobin (A1C) greater than 8% and randomly assigned them to 1 of 2 cohorts, one managed by the primary care provider alone and one with additional care from the pharmacist. Pharmacists completed encounters with patients who have T2DM with or without depression to comprehensively optimize pharmacotherapy while tracking glycemic and depressive outcomes throughout the study. Results: A1C improved from baseline to 6 months in patients with depressive symptoms who received additional care from pharmacists by -2.4 percentage points (SD, 2.41) compared with a -0.1 percentage point (SD, 1.78) reduction in the control arm (P .0081), and there was no change in depressive symptoms. Discussion: Patients with T2DM and depressive symptoms experienced better diabetes outcomes with additional pharmacist management compared with a similar cohort of patients with depressive symptoms, managed independently by primary care providers. These patients with diabetes and comorbid depression received a higher level of engagement and care from the pharmacists, which led to more therapeutic interventions.

Comparing an optimised physiotherapy treatment package with usual physiotherapy care for people with tennis elbow - protocol for the OPTimisE pilot and feasibility randomised controlled trial.

BACKGROUND: Physiotherapy is recommended for people with tennis elbow, but whilst a wide array of treatments is available, the optimal approach remains uncertain. We have therefore recently developed an optimised physiotherapy treatment package for tennis elbow based on a synthesis of the evidence, patient input and clinical consensus. It consists of detailed advice and education, a structured progressive exercise programme and provision of a counter-force elbow brace. Here, we report the protocol for our multicentre pilot and feasibility randomised controlled trial (RCT) designed to (a) examine the feasibility of our optimised physiotherapy treatment package and (b) to pilot trial processes for a future fully powered RCT to test clinical and cost-effectiveness compared with usual physiotherapy treatment. METHODS: A multicentre pilot and feasibility RCT will be conducted across three sites in England, recruiting up to 50 patients (or for a maximum of 12 months). Participants with tennis elbow, identified from physiotherapy clinic waiting lists and general practice surgeries, will be randomly allocated to receive the optimised physiotherapy treatment package or usual physiotherapy care. Analysis will focus on feasibility measures including consent rate, intervention fidelity, follow-up rate and outcome completion rate. A nested qualitative study will explore the acceptability of the study processes and patient and physiotherapist experiences of the new optimised intervention. DISCUSSION: This study will determine the feasibility of a new optimised physiotherapy treatment package for people with tennis elbow and pilot the processes for a future fully powered RCT. In the longer term, this treatment package may provide superior clinical outcomes for patients, in terms of pain and quality of life, and be more cost-effective for the health service. TRIAL REGISTRATION: Registered with the ISRCTN database 19/7/2021, https://www.isrctn.com/ISRCTN64444585.

Linked pharmacist-provider new patient visits in primary care.

OBJECTIVES: To implement a project of linked pharmacist-provider new patient visits and then evaluate the impact on the productivity of the provider and pharmacist. STUDY DESIGN: A clinical pharmacist was integrated into the workflow at 2 sites (sites A and B) of Henry J. Austin Health Center, a federally qualified health center, so that new patients were scheduled to see the pharmacist in a 15-minute encounter immediately before a 15-minute encounter with the primary care provider. METHODS: Reports generated in the electronic health record were downloaded into Microsoft Excel for statistical analysis. Two-sample 2-tailed t tests assuming unequal variances were used to evaluate changes in the mean number of appointments checked in and canceled before and after the project's implementation to study provider productivity, the primary study outcome. Descriptive statistics were used to report the pharmacist's productivity. RESULTS: Statistically significant increases in the number of checked-in new patient visits and in all visits of any type were observed at site A; however, these changes were not observed at site B. CONCLUSIONS: The linked visits between the pharmacist and provider allowed for increased provider productivity at 1 of the sites. Based on these results and provider feedback from both sites, this project was viewed as a positive initiative. Scheduling challenges were a barrier to project success at site B.

Current physiotherapy practice in the management of tennis elbow: A service evaluation.

BACKGROUND: Tennis elbow is a common painful condition that may affect daily function and ability to work. Physiotherapy is the most commonly used primary intervention but there is a wide range of treatment options within the umbrella of physiotherapy. Our aim was to report on the treatments that are currently used by physiotherapists in a UK National Health Service (NHS) setting. METHODS: A retrospective service evaluation was conducted at two NHS hospital trusts by reviewing patient attendance records over a 1-year period. All patients with tennis elbow were included, except those referred for postoperative rehabilitation. Patient notes were analysed using a predefined assessment template. RESULTS: A total of 65 patient records were identified, with patients having a mean age 48 years and mean symptom duration of 5.4 months. The mean treatment duration was 64 days, over 3.7 sessions. The most commonly used treatments were education and exercise, although the type and dosing of exercise varied greatly. Passive modalities such as ice, taping, manual therapy, acupuncture and electrotherapy were still used. CONCLUSIONS: Wide variations in treatment approaches were identified. There was no consistency in the choice of modality used, the type of exercise or the dose of exercise prescribed. The use of passive modalities and corticosteroid injections was found to remain commonplace, despite a lack of supporting research evidence. There is a clear need for evidence-based guidance for physiotherapists treating patients with tennis elbow.

Five-year follow-up of participants diagnosed with chronic airflow obstruction in a South African Burden of Obstructive Lung Disease (BOLD) survey.

BACKGROUND: A community-based prevalence survey performed in two suburbs in Cape Town, South Africa (SA), in 2005, using the international Burden of Obstructive Lung Disease (BOLD) method, confirmed a prevalence of chronic airflow obstruction (CAO) in 23.1% of adults aged >40 years. OBJECTIVES: To study the clinical course and prognosis over 5 years of patients with CAO identified in the 2005 survey. METHODS: Patients with CAO in 2005 were invited to participate. Standard BOLD and modified questionnaires were completed. Spirometry was performed using spirometers of the same make as in 2005. RESULTS: Of 196 eligible participants from BOLD 2005, 45 (23.0%) had died, 8 from respiratory causes, 10 from cardiovascular causes and 6 from other known causes, while in 21 cases the cause of death was not known. On multivariate analysis, only age and Global initiative for Obstructive Lung Disease (GOLD) stage 4 disease at baseline were significantly associated with death. Of the 151 survivors, 11 (5.6% of the original cohort) were unavailable and 33 (16.8%) declined or had medical exclusions. One hundred and seven survivors were enrolled in the follow-up study (54.6%, median age 63.1 years, 45.8% males). Post-bronchodilator spirometry performed in 106 participants failed to confirm CAO, defined as a forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio of <0.7, in 16 participants (15.1%), but CAO was present in 90. The median decline in FEV1 was 28.9 mL/year (interquartile range -54.8 - 0.0) and was similar between GOLD stages. The median total decline in FVC was 75 mL, and was significantly greater in GOLD stage 1 (-350 mL) than in stages 2 or 3 (-80  mL and +140 mL, respectively; p<0.01). Fifty-eight participants with CAO in 2005 (64.4%) remained in the same GOLD stage, while 21 (23.3%) deteriorated and 11 (12.2%) improved by ≥1 stage. Only one-third were receiving any treatment for chronic obstructive pulmonary disease (COPD). CONCLUSIONS: The prevalence, morbidity and mortality of CAO and COPD in SA are high and the level of appropriate treatment is very low, pointing to underdiagnosis and inadequate provision of and access to effective treatments and preventive strategies for this priority chronic non-communicable disease.

Derivation of the human embryonic stem cell line RCe009-A (RC-5).

The human embryonic stem cell line RCe009-A (RC-5) was derived from a frozen and thawed Day 2 embryo voluntarily donated as unsuitable and surplus to requirement for fertility treatment following informed consent under licence from the UK Human Fertilisation and Embryology Authority. RCe009-A carries the common DF508 mutation on the cystic fibrosis trans-membrane regulator gene associated with the disease cystic fibrosis. The cell line shows normal pluripotency marker expression and differentiation to the three germ layers in vitro. It has a normal 46XX female karyotype and microsatellite PCR identity, HLA and blood group typing data are available.

Derivation of the human embryonic stem cell line RCe006-A (RC-2).

The human embryonic stem cell line RCe006-A (RC-2) was derived from a frozen and thawed blastocyst voluntarily donated as surplus to fertility requirements following ethics committee approved informed consent under licence from the UK Human Fertilisation and Embryology Authority. The cell line exhibits expression of expected pluripotency markers and in vitro differentiation potential to three germinal lineage representative cell populations. It has a male trisomy 12 karyotype (47XY, +12). Microsatellite DNA marker identity and HLA and blood group typing data are available.

Derivation of the human embryonic stem cell line RCe010-A (RC-6).

The human embryonic stem cell line RCe010-A (RC-6) was derived from a frozen and thawed blastocyst voluntarily donated as unsuitable and surplus to fertility requirements following ethics committee approved informed consent under licence from the UK Human Fertilisation and Embryology Authority. The cell line shows normal pluripotency marker expression and differentiation to the three germ layers in vitro. It has a normal 46XY male karyotype and microsatellite PCR identity, HLA and blood group typing data are available.

Derivation of the human embryonic stem cell line RCe011-A (RC-7).

The human embryonic stem cell line RCe011-A (RC-7) was derived from a failed to fertilise oocyte voluntarily donated as unsuitable and surplus to fertility requirements following ethics committee approved informed consent under licence from the UK Human Fertilisation and Embryology Authority. The cell line shows normal pluripotency marker expression and differentiation to the three germ layers in vitro. It has a normal 46XY male karyotype and microsatellite PCR identity, HLA and blood group typing data are available.

Derivation of the human embryonic stem cell line RCe012-A (RC-8).

The human embryonic stem cell line RCe012-A (RC-8) was derived from a frozen and thawed day 5 embryo cultivated to the blastocyst stage. The embryo was voluntarily donated as unsuitable and surplus to fertility requirements following ethics committee approved informed consent under licence from the UK Human Fertilisation and Embryology Authority. The cell line shows normal pluripotency marker expression and differentiation to the three germ layers in vitro. It has a normal 46XX female karyotype and microsatellite PCR identity, HLA and blood group typing data is available.

Derivation of the human embryonic stem cell line RCe014-A (RC-10).

The human embryonic stem cell line RCe014-A (RC-10) was derived from a fresh oocyte voluntarily donated as unsuitable and surplus to fertility requirements following ethics committee approved informed consent under licence from the UK Human Fertilisation and Embryology Authority. The cell line shows normal pluripotency marker expression and differentiation to the three germ layers in vitro. It has a mixed 46XY and 47XY +12 male karyotype and microsatellite PCR identity, HLA and blood group typing data is available.