Background A variety of estimates of the benefits and harms of mammographic screening for breast cancer have been published and national policies vary. This is an update of a review previously updated 2013 and originally published 2001. Objectives To assess the effect of screening for breast cancer with mammography on mortality and morbidity. Search methods For this 2023 update, we searched PubMed, CENTRAL, the Cochrane Breast Cancer Group Specialised Register, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov up to 28 February 2023. Selection criteria Randomised clinical trials (RCTs) comparing mammographic screening with no mammographic screening. Data collection and analysis Two authors independently extracted data. Study authors were contacted for additional information. Our main outcomes of interest were deaths due to breast cancer, any cancer, and due to any cause, and harms measured as overdiagnosis, number of mastectomies, lumpectomies, use of radiotherapy and of chemotherapy. Certainty of evidence was assessed with GRADE. Main results Eight eligible trials from Europe and North America that compared women offered screening mammography with women not offered screening were included. We excluded a trial because the randomisation failed to produce comparable groups. The eligible trials included 600,000 women in the age range 39 to 74 years. The trials with adequate randomisation did not show a benefit in terms of a reduction in breast cancer mortality at 13 years (risk ratio (RR) 0.90, 95% confidence interval (CI) 0.79 to 1.02; 33 vs 30 deaths from breast cancer per 10,000 women; 3 RCTs; 292,153 participants). The findings at 24 years were similar to those at 13 years. Our certainty in both estimates was downgraded 1 level to 'low' due to changes in technology and treatment (indirectness) and due to imprecision. The trials with suboptimal randomisation showed a reduction in breast cancer mortality at 13 years with an RR of 0.75 (95% CI 0.67 to 0.83; 4 RCTs; 306,937 participants; very low certainty evidence). In women below age 50 years, the results from adequately randomised trials did not show a reduction in breast cancer mortality at 13 years of follow-up (RR 0.87, CI 0.73 to 1.03; 28 vs 24 deaths from breast cancer per 10,000 women; 3 RCTs; 218,697 participants, low certainty evidence), nor for women at least 50 years (RR 0.94, CI 0.77 to 1.15; 53 vs 50 deaths from breast cancer per 10,000 women; 2 RCTs; 74,261 participants, low certainty evidence). Only one trial included women aged 70 years and above and could not provide a reliable effect estimate.We found that breast cancer mortality was an unreliable outcome that was biased in favour of screening, mainly because of the risk of differential misclassification of cause of death. The trials with adequate randomisation did not find an effect of screening on total cancer mortality, including breast cancer, (RR 1.00, 95% CI 0.96 to 1.04; 288 vs 288 cancer deaths per 10,000 women; 3 RCTs; 292,954 participants; moderate certainty evidence; the follow-up was 10.5 years for Canada, 9 years for Malmo and 23 years for the UK age trial). All-cause mortality was not reduced (RR 0.98, 95% CI 0.94 to 1.03 after 7 years; RR 0.99, 95% CI 0.95 to 1.03 after 13 years; 324 vs 328 deaths per 10,000 women; and RR 1.01, 95% CI 0.99 to 1.04 after 24 years; 773 vs 765 deaths per 10,000 women; 2 RCTs; 250,671 participants; moderate certainty evidence) in the adequately randomised trials. There were more lumpectomies and mastectomies combined in the screened groups, likely reflecting overtreatment (RR 1.31, 95% CI 1.22 to 1.42; 164 vs 214 operations per 10,000 women; 2 RCTs; 132,321 participants; moderate certainty evidence), as were the number of mastectomies alone (RR 1.20, 95% CI 1.08 to 1.32; 122 vs 102 per 10,000 women; 2 RCTs; 132,321; moderate certainty evidence). The use of radiotherapy was similarly increased whereas there was no difference in the use of chemotherapy (data for each outcome available from only one adequately randomised trial; low certainty evidence). Breast screening increased the number of breast cancer diagnoses (overdiagnosis)(RR 1.25, CI 1.18 to 1.34, 142 vs 113 diagnoses at 7 to 9 years of follow-up; 3 RCTs, 292,979 participants; moderate certainty evidence) in trials that did not screen the control group after the intervention phase. Authors' conclusions Because of substantial changes in screening technology, treatment, and breast cancer awareness since the trials were done, the estimates from the trials are uncertain in today's setting. As breast cancer mortality is an unreliable outcome that is biased in favour of screening, it is noteworthy that screening did not reduce total cancer mortality or total mortality. Breast screening does not meet the criteria that population screening should be based on rigorously performed randomised trials that show that the benefits outweigh the harms. No studies have been completed in low income countries and one small study from Colombia has yet to provide data on long term outcomes. Women, clinicians and policy makers should consider the trade-offs and the uncertainties carefully when they decide whether or not to attend or support breast screening programmes.

BACKGROUND: Depression drugs can be difficult to come off due to withdrawal symptoms. Gradual tapering with tapering support is needed to help patients withdraw safely. OBJECTIVE: To review the withdrawal success rates, using any intervention, and the effects on relapse/recurrence rates, symptom severity, quality of life, and withdrawal symptoms. METHODS: Systematic review based on PubMed and Embase searches (last search 4 October 2022) of randomised trials with one or more treatment arms aimed at helping patients withdraw from a depression drug, regardless of indication for treatment. We calculated the mean and median success rates and the risk difference of depressive relapse when discontinuing or continuing depression drugs. RESULTS: We included 13 studies (2085 participants). Three compared two withdrawal interventions and ten compared drug discontinuation vs. continuation. The success rates varied hugely between the trials (9% to 80%), with a weighted mean of 47% (95% confidence interval 38% to 57%) and a median of 50% (interquartile range 29% to 65%). A meta-regression showed that the length of taper was highly predictive for the risk of relapse (P = 0.00001). All the studies we reviewed confounded withdrawal symptoms with relapse; did not use hyperbolic tapering; withdrew the depression drug too fast; and stopped it entirely when receptor occupancy was still high. CONCLUSION: The true proportion of patients on depression drugs who can stop safely without relapse is likely considerably higher than the 50% we found.

Abstract Aims We have previously described the European Medicines Agency’s (EMA) and the US Food and Drug Administration’s guidelines, each for a specific psychiatric indication, on how to design pivotal drug trials used in new drug applications. Here, we report on our efforts over 3 years to retrieve conflicts of interest declarations from EMA. We wanted to assess potential internal industry influence judged as the proportion of guideline committee members with industry conflicts of interest. Methods We submitted Freedom of Information requests in February 2020 to access EMA’s lists of committee members (and their declared conflicts of interest) involved in drafting the 13 ‘Clinical efficacy and safety’ guidelines available on EMA’s website pertaining to psychiatric indications. In our request, we did not specify the exact EMA committees. Here, we describe the received documents and report the proportion of members with industry interests (i.e. defined as any financial industry relationship). It is a follow-up paper to our first report (http://doi.org/10.1017/S2045796021000147). Results After 2 years and 9 months (November 2022), the EMA sent us member lists and corresponding conflicts of interest declarations from the Committee for Medicinal Products for Human use (CHMP) from 2012, 2013 and 2017. These member lists pertained to 3 of the 13 requested guidelines (schizophrenia, depression and autism spectrum disorder). The 10 remaining guidelines were published before 2011 and EMA stated that they needed to require permission from their expert members (with unknown retrieval rate) and foresaw excessive workload and long wait. Therefore, we withdrew our request. The CHMPs from 2012, 2013 and 2017 had from 34 to 36 members; 39%–44% declared any interests and we judged 14%–18% as having industry interests. For the schizophrenia guideline, we identified two members with industry interests to companies who submitted feedback on the guideline. We did not receive declarations from the Central Nervous System (CNS) Working Party, the CHMP appointed expert group responsible for drafting and incorporating feedback into the guidelines. Conclusions After almost 3 years, we received information, which only partly addressed our request. We recommend EMA to improve transparency by publishing the author names and their corresponding conflicts of interest declarations directly in the ‘Clinical efficacy and safety’ guidelines and to not remove conflicts of interest declarations after 1 year from their website to reduce the risk of stealth corporate influence during the development of these influential guidelines.

의학 연구의 대부분은 관찰 연구이다. 관찰 연구의 보고는 종종 불충분한 품질을 보이기도 한다. 부실한 보고는 연구의 강점과 약점을 평가하고 연구 결과의 일반화 가능성을 평가하는 데 방해가 된다. 방법론 전문가, 연구자, 편집자 그룹은 경험적 근거와 이론적 고려 사항을 고려하여 관찰 연구 보고의 질을 개선하기 위한 역학 STROBE 권고안을 개발했다. STROBE statement은 논문의 제목, 초록, 서론, 방법, 결과 및 토론 부분에 대한 22개 항목의 체크리스트로 구성되어 있다. 18개 항목은 코호트연구, 환자 대조군 연구, 단면연구에 공통으로 적용되며, 4개 항목은 세 가지 연구설계 각각에 따라 다르다. STROBE statement는 저자에게 관찰 연구에 대한 보고를 개선하는 방법에 대한 지침을 제공하고 심사자, 편집자 및 독자가 연구를 비판적으로 평가하고 해석하는 데 도움이 된다. 이 설명 문서는 STROBE statement의 사용, 이해 및 보급을 향상 시키는 것이 목적이다. 각 체크리스트 항목의 의미와 근거가 제시되어 있다. 각 항목에 대해 하나 또는 여러 개의 출판된 예시 논문과 가능한 경우 관련 경험적 연구 및 방법론 문헌에 대한 내용이 참고사항으로 제공된다. 유용한 흐름도의 예도 포함되어 있다. 본 문서 및 관련 웹사이트(http://www.strobe-statement.org/)는 관찰 연구 보고를 개선하는 데 유용한 자료가 될 것이다.

의학 연구의 대부분은 관찰 연구이다. 관찰 연구의 보고는 종종 불충분한 품질을 보이기도 한다. 부실한 보고는 연구의 강점과 약점을 평가하고 연구 결과의 일반화 가능성을 평가하는 데 방해가 된다. 방법론 전문가, 연구자, 편집자 그룹은 경험적 근거와 이론적 고려 사항을 고려하여 관찰 연구 보고의 질을 개선하기 위한 역학 STROBE 권고안을 개발했다. STROBE statement은 논문의 제목, 초록, 서론, 방법, 결과 및 토론 부분에 대한 22개 항목의 체크리스트로 구성되어 있다. 18개 항목은 코호트연구, 환자 대조군 연구, 단면연구에 공통으로 적용되며, 4개 항목은 세 가지 연구설계 각각에 따라 다르다. STROBE statement는 저자에게 관찰 연구에 대한 보고를 개선하는 방법에 대한 지침을 제공하고 심사자, 편집자 및 독자가 연구를 비판적으로 평가하고 해석하는 데 도움이 된다. 이 설명 문서는 STROBE statement의 사용, 이해 및 보급을 향상 시키는 것이 목적이다. 각 체크리스트 항목의 의미와 근거가 제시되어 있다. 각 항목에 대해 하나 또는 여러 개의 출판된 예시 논문과 가능한 경우 관련 경험적 연구 및 방법론 문헌에 대한 내용이 참고사항으로 제공된다. 유용한 흐름도의 예도 포함되어 있다. 본 문서 및 관련 웹사이트(http://www.strobe-statement.org/)는 관찰 연구 보고를 개선하는 데 유용한 자료가 될 것이다.

An open letter by healthcare professionals calls for specialist NHS services to support patients harmed by taking prescription medications

Background Psychiatric patients' human rights are often violated when forced treatment orders are issued.Methods We assessed the records for 30 consecutive petitions for mental health commitment in which an involuntary medication order was requested, from Anchorage, Alaska.Results In 29 cases, the commitment petition was granted. The forced medication order was granted in 27 of the 30 cases. In 26 cases, in violation of previous Supreme Court rulings, the patients' desires, fears, wishes and experiences were ignored even when the patients were afraid that the neuroleptics might kill them or when they had experienced serious harms such as tardive dyskinesia. The ethical and legal imperative of offering a less intrusive treatment was also ignored. Benzodiazepines were not offered. Psychotherapy was not offered or mentioned in 15 cases. The providers claimed, contrary to the evidence, that psychotherapy does not work.Dicussion The legal procedures can best be characterized as a sham, in which the patients are defenseless. The power imbalance and abuse were extreme, and several of the psychiatrists who argued for forced treatment obtained court orders for administering drugs and dosages that were dangerous. We suggest forced medication be abandoned.

and safety" and "benefits and risks" of drugs are misleading terms, argues Peter C. Gøtzsche

Randomized controlled trials remain the reference standard for healthcare research on effects of interventions, and the need to report both benefits and harms is essential. The Consolidated Standards of Reporting Trials (the main CONSORT) statement includes one item on reporting harms (i.e., all important harms or unintended effects in each group). In 2004, the CONSORT group developed the CONSORT Harms extension; however, it has not been consistently applied and needs to be updated. Here, we describe CONSORT Harms 2022, which replaces the CONSORT Harms 2004 checklist, and shows how CONSORT Harms 2022 items could be incorporated into the main CONSORT checklist. Thirteen items from the main CONSORT were modified to improve harms reporting. Three new items were added. In this article, we describe CONSORT Harms 2022 and how it was integrated into the main CONSORT checklist and elaborate on each item relevant to complete reporting of harms in randomized controlled trials. Until future work from the CONSORT group produces an updated checklist, authors, journal reviewers, and editors of randomized controlled trials should use the integrated checklist presented in this paper.

Anonymous sources are used by journalists when it is important to protect whistleblowers from repercussions. Healthcare is heavily influenced by vested interests which are often financial, but academic prestige and protection of guild interests also play a major role. If anonymous authorship is not allowed, many potential whistleblowers would prefer to keep quiet, even though their stepping forward would serve the public interest and might save many lives, particularly by reducing prescription drug deaths. This is especially important since drugs are the third leading cause of death in the Western world.

BACKGROUND: Fluoxetine was approved for depression in children and adolescents based on two placebo-controlled trials, X065 and HCJE, with 96 and 219 participants, respectively. OBJECTIVE: To review these trials, which appear to have been misreported. METHODS: Systematic review of the clinical study reports and publications. The primary outcomes were the efficacy variables in the trial protocols, suicidal events, and precursors to suicidality or violence. RESULTS: Essential information was missing and there were unexplained numerical inconsistencies. (1) The efficacy outcomes were biased in favour of fluoxetine by differential dropouts and missing data. The efficacy on the Children's Depression Rating Scale-Revised was 4% of the baseline score, which is not clinically relevant. Patient ratings did not find fluoxetine effective. (2) Suicidal events were missing in the publications and the study reports. Precursors to suicidality or violence occurred more often on fluoxetine than on placebo. For trial HCJE, the number needed to harm was 6 for nervous system events, 7 for moderate or severe harm, and 10 for severe harm. Fluoxetine reduced height and weight over 19 weeks by 1.0 cm and 1.1 kg, respectively, and prolonged the QT interval. CONCLUSIONS: Our reanalysis of the two pivotal trials showed that fluoxetine is unsafe and ineffective.

Introduction: Serious harms of the COVID-19 vaccines have been underreported in published trial reports. Methods: Systematic review of papers with data on serious adverse events (SAEs) associated with a COVID-19 vaccine. Results: We included 18 systematic reviews, 14 randomised trials, and 34 other studies with a control group. Most studies were of poor quality. The most reliable one was a systematic review of regulatory data on the two pivotal randomised trials of the mRNA vaccines. It found significantly more SAEs of special interest with the vaccines than with placebo, and the excess risk was considerably larger than the benefit, measured as the risk of hospitalisation. The adenovirus vector vaccines increased the risk of venous thrombosis and thrombocytopenia, and the mRNA-based vaccines increased the risk of myocarditis, with a mortality of about 1-2 per 200 cases. We also found evidence of serious neurological harms, including Bel's palsy, Guillain-Barre syndrome, myasthenic disorder and stroke, which are likely due to an autoimmune reaction, as has been suggested also for the HPV vaccines. Severe harms, i.e. those that prevent daily activities, were hugely underreported in the randomised trials. These harms were very common in studies of booster doses after a full vaccination and in a study of vaccination of previously infected people. Discussion: Serious and severe harms of the COVID-19 vaccines have been ignored or downplayed, and sometimes been deliberately excluded by the study sponsors in high impact medical journals. This area needs further study. Authorities have recommended virtually everyone get vaccinated and receive booster doses. They fail to consider that the balance between benefits and harms becomes negative in low-risk groups such as children and people who have already acquired natural immunity.

Citation bias occurs when authors preferentially cite research that supports their own findings or claims, or research that showed what they had hoped to find but didn’t find in their research. In research articles, citation bias may occur in the Introduction section, where the researchers argue why their own research is important, and in the Discussion section, where they put their findings into context and perspective. The first use of the term ‘citation bias’, of which I am aware, was not in biomedicine. In 1985, researchers in physics referred to ‘a citation bias against Eastern-bloc [particle] accelerators’.

BACKGROUND Attention deficit hyperactivity disorder (ADHD) is a psychiatric diagnosis increasingly used in adults. The recommended first-line pharmacological treatment is central nervous system (CNS) stimulants, such as methylphenidate, but uncertainty remains about its benefits and harms. OBJECTIVES To assess the beneficial and harmful effects of extended-release formulations of methylphenidate in adults diagnosed with ADHD. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, nine other databases and four clinical trial registries up to February 2021. We searched 12 drug regulatory databases for clinical trial data up to 13 May 2020. In addition, we cross-referenced all available trial identifiers, handsearched reference lists, searched pharmaceutical company databases, and contacted trial authors. SELECTION CRITERIA Randomised, double-blind, parallel-group trials comparing extended-release methylphenidate formulations at any dose versus placebo and other ADHD medications in adults diagnosed with ADHD. DATA COLLECTION AND ANALYSIS Two review authors independently extracted data. We assessed dichotomous outcomes as risk ratios (RRs), and rating scales and continuous outcomes as mean differences (MDs) or standardised mean differences (SMDs). We used the Cochrane risk of bias tool to assess risks of bias, and GRADE to assess the certainty of the evidence. We meta-analysed the data using a random-effects model. We assessed three design characteristics that may impair the trial results' 'generalisability'; exclusion of participants with psychiatric comorbidity; responder selection based on previous experience with CNS stimulants; and risk of withdrawal effects. Our prespecified primary outcomes were functional outcomes, self-rated ADHD symptoms, and serious adverse events. Our secondary outcomes included quality of life, ADHD symptoms rated by investigators and by peers such as family members, cardiovascular variables, severe psychiatric adverse events, and other adverse events. MAIN RESULTS We included 24 trials (5066 participants), of which 21 reported outcome data for this review. We also identified one ongoing study. We included documents from six drug regulatory agencies covering eight trials. Twenty-one trials had an outpatient setting and three were conducted in prisons. They were primarily conducted in North America and Europe. The median participant age was 36 years. Twelve trials (76% of participants) were industry-sponsored, four (14% of participants) were publicly funded with industry involvement, seven (10% of participants) were publicly funded, and one had unclear funding. The median trial duration was eight weeks. One trial was rated at overall unclear risk of bias and 20 trials were rated at overall high risk of bias, primarily due to unclear blinding of participants and investigators, attrition bias, and selective outcome reporting. All trials were impaired in at least one of the three design characteristics related to 'generalisability'; for example, they excluded participants with psychiatric comorbidity such as depression or anxiety, or included participants only with a previous positive response to methylphenidate, or similar drugs. This may limit the trials' usefulness for clinical practice, as they may overestimate the benefits and underestimate the harms. Extended-release methylphenidate versus placebo (up to 26 weeks) For the primary outcomes, we found very low-certainty evidence that methylphenidate had no effect on 'days missed at work' at 13-week follow-up (mean difference (MD) -0.15 days, 95% confidence interval (CI) -2.11 to 1.81; 1 trial, 409 participants) or serious adverse events (risk ratio (RR) 1.43, CI 95% CI 0.85 to 2.43; 14 trials, 4078 participants), whereas methylphenidate improved self-rated ADHD symptoms (small-to-moderate effect; SMD -0.37, 95% CI -0.43 to -0.30; 16 trials, 3799 participants). For secondary outcomes, we found very low-certainty evidence that methylphenidate improved self-rated quality of life (small effect; SMD -0.15, 95% CI -0.25 to -0.05; 6 trials, 1888 participants), investigator-rated ADHD symptoms (small-to-moderate effect; SMD -0.42, 95% CI -0.49 to -0.36; 18 trials, 4183 participants), ADHD symptoms rated by peers such as family members (small-to-moderate effect; SMD -0.31, 95% CI -0.48 to -0.14; 3 trials, 1005 participants), and increased the risk of experiencing any adverse event (RR 1.27, 95% CI 1.19 to 1.37; 14 trials, 4214 participants). We rated the certainty of the evidence as 'very low' for all outcomes, primarily due to high risk of bias and 'indirectness of the evidence'. One trial (419 participants) had follow-up at 52 weeks and two trials (314 participants) included active comparators, hence long-term and comparative evidence is limited. AUTHORS' CONCLUSIONS We found very low-certainty evidence that extended-release methylphenidate compared to placebo improved ADHD symptoms (small-to-moderate effects) measured on rating scales reported by participants, investigators, and peers such as family members. Methylphenidate had no effect on 'days missed at work' or serious adverse events, the effect on quality of life was small, and it increased the risk of several adverse effects. We rated the certainty of the evidence as 'very low' for all outcomes, due to high risk of bias, short trial durations, and limitations to the generalisability of the results. The benefits and harms of extended-release methylphenidate therefore remain uncertain.