The p300/CBP-associated factor (PCAF) is a cofactor of ATF4 for amino acid-regulated transcription of CHOP

When an essential amino acid is limited, a signaling cascade is triggered that leads to increased translation of the ‘master regulator’, activating transcription factor 4 (ATF4), and resulting in the induction of specific target genes. Binding of ATF4 to the amino acid response element (AARE) is an essential step in the transcriptional activation of CHOP (a CCAAT/enhancer-binding protein-related gene) by amino acid deprivation. We set out to identify proteins that interact with ATF4 and that play a role in the transcriptional activation of CHOP. Using a tandem affinity purification (TAP) tag approach, we identified p300/CBP-associated factor (PCAF) as a novel interaction partner of ATF4 in leucine-starved cells. We show that the N-terminal region of ATF4 is required for a direct interaction with PCAF and demonstrate that PCAF is involved in the full transcriptional response of CHOP by amino acid starvation. Chromatin immunoprecipitation analysis revealed that PCAF is engaged on the CHOP AARE in response to amino acid starvation and that ATF4 is essential for its recruitment. We also show that PCAF stimulates ATF4-driven transcription via its histone acetyltransferase domain. Thus PCAF acts as a coactivator of ATF4 and is involved in the enhancement of CHOP transcription following amino acid starvation

Functional and Radiologic Outcomes of Degenerative Versus Traumatic Full-Thickness Rotator Cuff Tears Involving the Supraspinatus Tendon.

BACKGROUND Arthroscopic rotator cuff repair (ARCR) is among the most commonly performed orthopaedic procedures. Several factors-including age, sex, and tear severity-have been identified as predictors for outcome after repair. The influence of the tear etiology on functional and structural outcome remains controversial. PURPOSE To investigate the influence of tear etiology (degenerative vs traumatic) on functional and structural outcomes in patients with supraspinatus tendon tears. STUDY DESIGN Cohort study; Level of evidence, 2. METHODS Patients undergoing ARCR from 19 centers were prospectively enrolled between June 2020 and November 2021. Full-thickness, nonmassive tears involving the supraspinatus tendon were included. Tears were classified as degenerative (chronic shoulder pain, no history of trauma) or traumatic (acute, traumatic onset, no previous shoulder pain). Range of motion, strength, the Subjective Shoulder Value, the Oxford Shoulder Score (OSS), and the Constant-Murley Score (CMS) were assessed before (baseline) and 6 and 12 months after ARCR. The Subjective Shoulder Value and the OSS were also determined at the 24-month follow-up. Repair integrity after 12 months was documented, as well as additional surgeries up to the 24-month follow-up. Tear groups were compared using mixed models adjusted for potential confounding effects. RESULTS From a cohort of 973 consecutive patients, 421 patients (degenerative tear, n = 230; traumatic tear, n = 191) met the inclusion criteria. The traumatic tear group had lower mean baseline OSS and CMS scores but significantly greater score changes 12 months after ARCR (OSS, 18 [SD, 8]; CMS, 34 [SD,18] vs degenerative: OSS, 15 [SD, 8]; CMS, 22 [SD, 15]) (P < .001) and significantly higher 12-month overall scores (OSS, 44 [SD, 5]; CMS, 79 [SD, 9] vs degenerative: OSS, 42 [SD, 7]; CMS, 76 [SD, 12]) (P≤ .006). At the 24-month follow-up, neither the OSS (degenerative, 44 [SD, 6]; traumatic, 45 [SD, 6]; P = .346) nor the rates of repair failure (degenerative, 14 [6.1%]; traumatic 12 [6.3%]; P = .934) and additional surgeries (7 [3%]; 7 [3.7%]; P = .723) differed between groups. CONCLUSION Patients with degenerative and traumatic full-thickness supraspinatus tendon tears who had ARCR show satisfactory short-term functional results. Although patients with traumatic tears have lower baseline functional scores, they rehabilitate over time and show comparable clinical results 1 year after ARCR. Similarly, degenerative and traumatic rotator cuff tears show comparable structural outcomes, which suggests that degenerated tendons retain healing potential

“It doesn’t seem to make sense for a company that sells cigarettes to help smokers stop using them”: A case study of Philip Morris’s involvement in smoking cessation

In the late 1990s, American tobacco companies began offering limited cessation assistance to smokers by posting links on their company websites to government-sponsored smoking cessation resources. Philip Morris USA (PM) went further, funding youth cessation programs and creating its own online cessation program, QuitAssist. We explore why PM entered the cessation arena, and describe the variety of options considered and how PM-supported cessation programs were evaluated and promoted.We retrieved and analyzed archival PM documents from 1998-2005. We supplemented information from the documents with scholarly articles assessing QuitAssist and archived versions of the PM and QuitAssist websites.PM's Youth Smoking Prevention department began funding youth cessation projects and programs soon after its creation in 1998, motivated by the same issue that drove its interest in youth smoking prevention: regulatory threats posed by public and policymaker concern about youth smoking. The department took a similar approach to youth smoking cessation as it did with prevention, rejecting curricula with "anti-industry" themes. In 2002, a "cessation exploration team" examined a variety of rationales for and approaches to company support for adult smoking cessation. Ultimately, PM chose QuitAssist, a limited and less expensive option that nonetheless provided opportunities for engagement with a variety of public health and government officials. Independent research indicates that QuitAssist is not an effective cessation tool.While the transformation of ambitious plans into a mundane final product is a recurring theme with PM's corporate responsibility efforts, it would be inappropriate to dismiss PM's smoking cessation endeavors as half-hearted attempts to appear responsible. Such endeavors have the potential to inflict real harm by competing with more effective programs and by helping to maintain a tobacco-favorable policy environment. If PM truly wanted to support cessation, it could drop legal and other challenges to public policies that discourage smoking

Swiss-wide multicentre evaluation and prediction of core outcomes in arthroscopic rotator cuff repair: protocol for the ARCR_Pred cohort study

Introduction In the field of arthroscopic rotator cuff repair (ARCR), reporting standards of published studies differ dramatically, notably concerning adverse events (AEs). In addition, prognostic studies are overall methodologically poor, based on small data sets and explore only limited numbers of influencing factors. We aim to develop prognostic models for individual ARCR patients, primarily for the patient-reported assessment of shoulder function (Oxford Shoulder Score (OSS)) and the occurrence of shoulder stiffness 6 months after surgery. We also aim to evaluate the use of a consensus core event set (CES) for AEs and validate a severity classification for these events, considering the patient’s perspective.Methods and analysis A cohort of 970 primary ARCR patients will be prospectively documented from several Swiss and German orthopaedic clinics up to 24 months postoperatively. Patient clinical examinations at 6 and 12 months will include shoulder range of motion and strength (Constant Score). Tendon repair integrity status will be assessed by ultrasound at 12 months. Patient-reported questionnaires at 6, 12 and 24 months will determine functional scores (subjective shoulder value, OSS), anxiety and depression scores, working status, sports activities, and quality of life (European Quality of Life 5 Dimensions 5 Level questionnaire). AEs will be documented according to a CES. Prognostic models will be developed using an internationally supported regression methodology. Multiple prognostic factors, including patient baseline demographics, psychological, socioeconomic and clinical factors, rotator cuff integrity, concomitant local findings, and (post)operative management factors, will be investigated.Ethics and dissemination This project contributes to the development of personalised risk predictions for supporting the surgical decision process in ARCR. The consensus CES may become an international reference for the reporting of complications in clinical studies and registries. Ethical approval was obtained on 1 April 2020 from the lead ethics committee (EKNZ, Basel, Switzerland; ID: 2019-02076). All participants will provide informed written consent before enrolment in the study.Trial registration number NCT04321005.Protocol version Version 2 (13 December 2019)

Track Reconstruction with Cosmic Ray Data at the Tracker Integration Facility

The subsystems of the CMS silicon strip tracker were integrated and commissioned at the Tracker Integration Facility (TIF) in the period from November 2006 to July 2007. As part of the commissioning, large samples of cosmic ray data were recorded under various running conditions in the absence of a magnetic field. Cosmic rays detected by scintillation counters were used to trigger the readout of up to 15\,\% of the final silicon strip detector, and over 4.7~million events were recorded. This document describes the cosmic track reconstruction and presents results on the performance of track and hit reconstruction as from dedicated analyses