Significance CRYPTOCHROMES (CRYs) are blue light photoreceptors that mediate phototransduction in brain arousal neurons, as well as circadian light entrainment in Drosophila fruit flies. We describe ...how light-activated Drosophila CRY couples to membrane depolarization and increased action potential firing rate in large ventral lateral arousal neurons. Pharmacological treatments that specifically disrupt the CRY redox-sensitive flavin chromophore or block voltage-gated K ⁺ channels abolish the light response. Correspondingly, we find that the Kvβ channel subunit Hyperkinetic with a well conserved redox sensor domain links light-evoked redox changes in CRY to rapid changes in membrane electrical potential.
Blue light activation of the photoreceptor CRYPTOCHROME (CRY) evokes rapid depolarization and increased action potential firing in a subset of circadian and arousal neurons in Drosophila melanogaster . Here we show that acute arousal behavioral responses to blue light significantly differ in mutants lacking CRY, as well as mutants with disrupted opsin-based phototransduction. Light-activated CRY couples to membrane depolarization via a well conserved redox sensor of the voltage-gated potassium (K ⁺) channel β-subunit (Kvβ) Hyperkinetic (Hk). The neuronal light response is almost completely absent in hk ⁻/⁻ mutants, but is functionally rescued by genetically targeted neuronal expression of WT Hk, but not by Hk point mutations that disable Hk redox sensor function. Multiple K ⁺ channel α-subunits that coassemble with Hk, including Shaker, Ether-a-go-go, and Ether-a-go-go–related gene, are ion conducting channels for CRY/Hk-coupled light response. Light activation of CRY is transduced to membrane depolarization, increased firing rate, and acute behavioral responses by the Kvβ subunit redox sensor.
Light-responsive neural activity in central brain neurons is generally conveyed through opsin-based signaling from external photoreceptors. Large lateral ventral arousal neurons (lLNvs) in Drosophila ...melanogaster increase action potential firing within seconds in response to light in the absence of all opsin-based photoreceptors. Light-evoked changes in membrane resting potential occur in about 100 milliseconds. The light response is selective for blue wavelengths corresponding to the spectral sensitivity of CRYPTOCHROME (CRY). cry-null lines are light-unresponsive, but restored CRY expression in the lLNv rescues responsiveness. Furthermore, expression of CRY in neurons that are normally unresponsive to light confers responsiveness. The CRY-mediated light response requires a flavin redox-based mechanism and depends on potassium channel conductance, but is independent of the classical circadian CRY-TIMELESS interaction.
Blue light activation of the photoreceptor CRYPTOCHROME (CRY) evokes rapid depolarization and increased action potential firing in a subset of circadian and arousal neurons in Drosophila ...melanogaster. Here we show that acute arousal behavioral responses to blue light significantly differ in mutants lacking CRY, as well as mutants with disrupted opsin-based phototransduction. Light-activated CRY couples to membrane depolarization via a well conserved redox sensor of the voltage-gated potassium (K+) channel β-subunit (Kvβ) Hyperkinetic (Hk). The neuronal light response is almost completely absent in ... mutants, but is functionally rescued by genetically targeted neuronal expression of WT Hk, but not by Hk point mutations that disable Hk redox sensor function. Multiple K+ channel a-subunits that coassemble with Hk, including Shaker, Ether-a-go-go, and Ether-a-go-go-related gene, are ion conducting channels for CRY/Hk-coupled light response. Light activation of CRY is transduced to membrane depolarization, increased firing rate, and acute behavioral responses by the Kvβ subunit redox sensor. (ProQuest: ... denotes formulae/symbols omitted.)
Clear communication of systematic review findings will help readers and decision makers. We built on previous work to develop an approach that improves the clarity of statements to convey findings ...and that draws on Grading of Recommendations Assessment, Development and Evaluation (GRADE).
We conducted workshops including 80 attendants and a survey of 110 producers and users of systematic reviews. We calculated acceptability of statements and revised the wording of those that were unacceptable to ≥40% of participants.
Most participants agreed statements should be based on size of effect and certainty of evidence. Statements for low, moderate and high certainty evidence were acceptable to >60%. Key guidance, for example, includes statements for high, moderate and low certainty for a large effect on intervention x as: x results in a large reduction…; x likely results in a large reduction…; x may result in a large reduction…, respectively.
Producers and users of systematic reviews found statements to communicate findings combining size and certainty of an effect acceptable. This article provides GRADE guidance and a wording template to formulate statements in systematic reviews and other decision tools.
Context
Prostate‐specific antigen (PSA) testing increases prostate cancer diagnoses and reduces long‐term disease‐specific mortality, but also results in overdiagnoses and treatment‐related harms.
...Objective
To systematically assess the benefits and harms of population‐based PSA screening and the potential net benefit to inform health policy decision‐makers in Germany.
Evidence Acquisition
We performed a protocol‐guided comprehensive literature search according to the Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) statement. All steps were performed by one or two investigators; any discrepancies were resolved by consensus. To allow subgroup analyses for identifying the optimal screening parameters, the eight national trials conducted under the umbrella of the European Randomised study of Screening for Prostate Cancer (ERSPC) were included as individual trials.
Evidence Synthesis
We included a total 11 randomised controlled trials (RCTs) with a total of 416 000 study participants. For all‐cause mortality, we found neither benefit nor harm. PSA screening was associated with a reduced risk of both prostate cancer mortality and the development of metastases. For the outcomes of health‐related quality of life, adverse effects and the consequences of false‐negative screening results there was no difference; however, this was due to the lack of eligible RCT data. Finally, PSA screening was associated with large numbers of overdiagnoses with adverse downstream consequences of unnecessary treatment (e.g. incontinence, erectile dysfunction) and large numbers of false‐positive PSA tests leading to biopsies associated with a small but not negligible risk of complications. Limitations of this assessment include the clinical heterogeneity and methodological limitations of the underlying studies.
Conclusions
The benefits of PSA‐based prostate cancer screening do not outweigh its harms. We failed to identify eligible screening studies of newer biomarkers, PSA derivatives or modern imaging modalities, which may alter the balance of benefit to harm.
Patient Summary
In the present study, we reviewed the evidence on the PSA blood test to screen men without symptoms for prostate cancer. We found that the small benefits experienced by some men do not outweigh the harms to many more men.
•Attention-Deficit Hyperactivity Disorder is comorbid with speech disorders.•ADHD-related symptoms are correlated with differences in speech production.•Speech scientists may want to screen for ADHD ...when collecting normative data samples.
Attention-Deficit Hyperactivity Disorder (ADHD) is a predominant neurobehavioral disorder of childhood with motor and sensory symptoms often persisting into adulthood. Motor control theories highlight the importance of the bidirectional relationship between sensation and movement for maintaining skilled behaviors like speech. The impact of ADHD on speech in adults has not been well established. The purpose of this study is to assess group differences in quantitative speech and oral somatosensory measures in adults with and without ADHD and to describe the relationship between ADHD symptomology and speech production. A total of 50 adults (18–26 years) were recruited and divided in two groups based on diagnosis: those with (n = 28) and those without (n = 22) ADHD. All participants provided a speech sample to measure articulatory accuracy and speech rate and completed quantitative point-pressure testing using tactile detection and discrimination on bilateral sites on the lower lip and lateral edge of the tongue tip. Independent t-tests corrected for multiple comparisons identified significant group differences using FDR corrected q values in speech production for correct syllables per second and overall speech rate (q<.05). Additionally, there were significant group differences (q<.05) for detection and discrimination threshold estimates at one testing location. Bivariate correlations identified a relationship between several speech measures and self-reported ADHD symptoms such that as symptom severity increased, speech accuracy for correct syllables per second decreased. Young adults with ADHD have subtle differences in speech production compared to non-ADHD control participants. Speech scientists might consider screening for ADHD when collecting normative data samples.
New approaches to evidence synthesis, which use human effort and machine automation in mutually reinforcing ways, can enhance the feasibility and sustainability of living systematic reviews. Human ...effort is a scarce and valuable resource, required when automation is impossible or undesirable, and includes contributions from online communities (“crowds”) as well as more conventional contributions from review authors and information specialists. Automation can assist with some systematic review tasks, including searching, eligibility assessment, identification and retrieval of full-text reports, extraction of data, and risk of bias assessment. Workflows can be developed in which human effort and machine automation can each enable the other to operate in more effective and efficient ways, offering substantial enhancement to the productivity of systematic reviews. This paper describes and discusses the potential—and limitations—of new ways of undertaking specific tasks in living systematic reviews, identifying areas where these human/machine “technologies” are already in use, and where further research and development is needed. While the context is living systematic reviews, many of these enabling technologies apply equally to standard approaches to systematic reviewing.
The cellular response to DNA double-strand breaks (DSBs) is mobilized by the protein kinase ATM, which phosphorylates key players in the DNA damage response (DDR) network. A major question is how ATM ...controls DSB repair. Optimal repair requires chromatin relaxation at damaged sites. Chromatin reorganization is coupled to dynamic alterations in histone posttranslational modifications. Here, we show that in human cells, DSBs induce monoubiquitylation of histone H2B, a modification that is associated in undamaged cells with transcription elongation. We find that this process relies on recruitment to DSB sites and ATM-dependent phosphorylation of the responsible E3 ubiquitin ligase: the RNF20-RNF40 heterodimer. H2B monoubiquitylation is required for timely recruitment of players in the two major DSB repair pathways—nonhomologous end-joining and homologous recombination repair—and optimal repair via both pathways. Our data and previous data suggest a two-stage model for chromatin decondensation that facilitates DSB repair.
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► The ATM protein kinase facilitates double-strand break repair ► ATM signals monoubiquitylation of histone H2B at double-strand break sites ► The responsible ubiquitin ligase, the RNF20-RNF40 heterodimer, is an ATM target ► This pathway facilitates the recruitment of repair proteins and timely DSB repair
ObjectiveTo compare cancer-related systematic reviews (SRs) published in the Cochrane Database of SRs (CDSR) and high-impact journals, with respect to type, content, quality and citation ...rates.DesignMethodological SR with assessment and comparison of SRs and meta-analyses. Two authors independently assessed methodological quality using an Assessment of Multiple Systematic Reviews (AMSTAR)-based extraction form. Both authors independently screened search results, extracted content-relevant characteristics and retrieved citation numbers of the included reviews using the Clarivate Analytics Web of Science database.Data sourcesCancer-related SRs were retrieved from the CDSR, as well as from the 10 journals which publish oncological SRs and had the highest impact factors, using a comprehensive search in both the CDSR and MEDLINE.Eligibility criteria for selecting studiesWe included all cancer-related SRs and meta-analyses published from January 2011 to May 2016. Methodological SRs were excluded.ResultsWe included 346 applicable Cochrane reviews and 215 SRs from high-impact journals. Cochrane reviews consistently met more individual AMSTAR criteria, notably with regard to an a priori design (risk ratio (RR) 3.89; 95% CI 3.10 to 4.88), inclusion of the grey literature and trial registries (RR 3.52; 95% CI 2.84 to 4.37) in their searches, and the reporting of excluded studies (RR 8.80; 95% CI 6.06 to 12.78). Cochrane reviews were less likely to address questions of prognosis (RR 0.04; 95% CI 0.02 to 0.09), use individual patient data (RR 0.03; 95% CI 0.01 to 0.09) or be based on non-randomised controlled trials (RR 0.04; 95% CI 0.02 to 0.09). Citation rates of Cochrane reviews were notably lower than those for high-impact journals (Cochrane reviews: mean number of citations 6.52 (range 0–143); high-impact journal SRs: 74.45 (0–652)).ConclusionsWhen comparing cancer-related SRs published in the CDSR versus those published in high-impact medical journals, Cochrane reviews were consistently of higher methodological quality, but cited less frequently.
Background
Since the approval of tyrosine kinase inhibitors, angiogenesis inhibitors and immune checkpoint inhibitors, the treatment landscape for advanced renal cell carcinoma (RCC) has changed ...fundamentally. Today, combined therapies from different drug categories have a firm place in a complex first‐line therapy. Due to the large number of drugs available, it is necessary to identify the most effective therapies, whilst considering their side effects and impact on quality of life (QoL).
Objectives
To evaluate and compare the benefits and harms of first‐line therapies for adults with advanced RCC, and to produce a clinically relevant ranking of therapies. Secondary objectives were to maintain the currency of the evidence by conducting continuous update searches, using a living systematic review approach, and to incorporate data from clinical study reports (CSRs).
Search methods
We searched CENTRAL, MEDLINE, Embase, conference proceedings and relevant trial registries up until 9 February 2022. We searched several data platforms to identify CSRs.
Selection criteria
We included randomised controlled trials (RCTs) evaluating at least one targeted therapy or immunotherapy for first‐line treatment of adults with advanced RCC. We excluded trials evaluating only interleukin‐2 versus interferon‐alpha as well as trials with an adjuvant treatment setting. We also excluded trials with adults who received prior systemic anticancer therapy if more than 10% of participants were previously treated, or if data for untreated participants were not separately extractable.
Data collection and analysis
All necessary review steps (i.e. screening and study selection, data extraction, risk of bias and certainty assessments) were conducted independently by at least two review authors. Our outcomes were overall survival (OS), QoL, serious adverse events (SAEs), progression‐free survival (PFS), adverse events (AEs), the number of participants who discontinued study treatment due to an AE, and the time to initiation of first subsequent therapy. Where possible, analyses were conducted for the different risk groups (favourable, intermediate, poor) according to the International Metastatic Renal‐Cell Carcinoma Database Consortium Score (IMDC) or the Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Our main comparator was sunitinib (SUN). A hazard ratio (HR) or risk ratio (RR) lower than 1.0 is in favour of the experimental arm.
Main results
We included 36 RCTs and 15,177 participants (11,061 males and 4116 females). Risk of bias was predominantly judged as being 'high' or 'some concerns' across most trials and outcomes. This was mainly due to a lack of information about the randomisation process, the blinding of outcome assessors, and methods for outcome measurements and analyses. Additionally, study protocols and statistical analysis plans were rarely available.
Here we present the results for our primary outcomes OS, QoL, and SAEs, and for all risk groups combined for contemporary treatments: pembrolizumab + axitinib (PEM+AXI), avelumab + axitinib (AVE+AXI), nivolumab + cabozantinib (NIV+CAB), lenvatinib + pembrolizumab (LEN+PEM), nivolumab + ipilimumab (NIV+IPI), CAB, and pazopanib (PAZ). Results per risk group and results for our secondary outcomes are reported in the summary of findings tables and in the full text of this review. The evidence on other treatments and comparisons can also be found in the full text.
Overall survival (OS)
Across risk groups, PEM+AXI (HR 0.73, 95% confidence interval (CI) 0.50 to 1.07, moderate certainty) and NIV+IPI (HR 0.69, 95% CI 0.69 to 1.00, moderate certainty) probably improve OS, compared to SUN, respectively. LEN+PEM may improve OS (HR 0.66, 95% CI 0.42 to 1.03, low certainty), compared to SUN. There is probably little or no difference in OS between PAZ and SUN (HR 0.91, 95% CI 0.64 to 1.32, moderate certainty), and we are uncertain whether CAB improves OS when compared to SUN (HR 0.84, 95% CI 0.43 to 1.64, very low certainty). The median survival is 28 months when treated with SUN. Survival may improve to 43 months with LEN+PEM, and probably improves to: 41 months with NIV+IPI, 39 months with PEM+AXI, and 31 months with PAZ. We are uncertain whether survival improves to 34 months with CAB. Comparison data were not available for AVE+AXI and NIV+CAB.
Quality of life (QoL)
One RCT measured QoL using FACIT‐F (score range 0 to 52; higher scores mean better QoL) and reported that the mean post‐score was 9.00 points higher (9.86 lower to 27.86 higher, very low certainty) with PAZ than with SUN. Comparison data were not available for PEM+AXI, AVE+AXI, NIV+CAB, LEN+PEM, NIV+IPI, and CAB.
Serious adverse events (SAEs)
Across risk groups, PEM+AXI probably increases slightly the risk for SAEs (RR 1.29, 95% CI 0.90 to 1.85, moderate certainty) compared to SUN. LEN+PEM (RR 1.52, 95% CI 1.06 to 2.19, moderate certainty) and NIV+IPI (RR 1.40, 95% CI 1.00 to 1.97, moderate certainty) probably increase the risk for SAEs, compared to SUN, respectively. There is probably little or no difference in the risk for SAEs between PAZ and SUN (RR 0.99, 95% CI 0.75 to 1.31, moderate certainty). We are uncertain whether CAB reduces or increases the risk for SAEs (RR 0.92, 95% CI 0.60 to 1.43, very low certainty) when compared to SUN. People have a mean risk of 40% for experiencing SAEs when treated with SUN. The risk increases probably to: 61% with LEN+PEM, 57% with NIV+IPI, and 52% with PEM+AXI. It probably remains at 40% with PAZ. We are uncertain whether the risk reduces to 37% with CAB. Comparison data were not available for AVE+AXI and NIV+CAB.
Authors' conclusions
Findings concerning the main treatments of interest comes from direct evidence of one trial only, thus results should be interpreted with caution. More trials are needed where these interventions and combinations are compared head‐to‐head, rather than just to SUN. Moreover, assessing the effect of immunotherapies and targeted therapies on different subgroups is essential and studies should focus on assessing and reporting relevant subgroup data. The evidence in this review mostly applies to advanced clear cell RCC.
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