REGAL: galinpepimut-S vs. best available therapy as maintenance therapy for acute myeloid leukemia in second remission.

Jamy O ，Cicic D 《-》

Probiotics for maintenance of remission in ulcerative colitis.

Ulcerative colitis is an inflammatory condition affecting the colon, with an annual incidence of approximately 10 to 20 per 100,000 people. The majority of people with ulcerative colitis can be put into remission, leaving a group who do not respond to first- or second-line therapies. There is a significant proportion of people who experience adverse effects with current therapies. Consequently, new alternatives for the treatment of ulcerative colitis are constantly being sought. Probiotics are live microbial feed supplements that may beneficially affect the host by improving intestinal microbial balance, enhancing gut barrier function and improving local immune response. The primary objective was to determine the efficacy of probiotics compared to placebo, no treatment, or any other intervention for the maintenance of remission in people with ulcerative colitis. The secondary objective was to assess the occurrence of adverse events associated with the use of probiotics. We searched CENTRAL, MEDLINE, Embase, and two other databases on 31 October 2019. We contacted authors of relevant studies and manufacturers of probiotics regarding ongoing or unpublished trials that may be relevant to the review, and we searched ClinicalTrials.gov. We also searched references of trials for any additional trials. Randomised controlled trials (RCTs) that compared probiotics against placebo or any other intervention, in both adults and children, for the maintenance of remission in ulcerative colitis were eligible for inclusion. Maintenance therapy had to be for a minimum of three months when remission has been established by any clinical, endoscopic,histological or radiological relapse as defined by study authors. Two review authors independently conducted data extraction and 'Risk of bias' assessment of included studies. We analysed data using Review Manager 5. We expressed dichotomous and continuous outcomes as risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs). We assessed the certainty of the evidence using the GRADE methodology. In this review, we included 12 studies (1473 randomised participants) that met the inclusion criteria. Participants were mostly adults. The studies compared probiotics to placebo, probiotics to 5-aminosalicylic acid (5-ASA) and a combination of probiotics and 5-ASA to 5-ASA. The studies ranged in length from 12 to 52 weeks. The average age of participants was between 32 and 51, with a range between 18 and 88 years. Seven studies investigated a single bacterial strain, and five studies considered mixed preparations of multiple strains. The risk of bias was high in all except three studies due to selective reporting, incomplete outcome data and lack of blinding. This resulted in low- to very low-certainty of evidence. It is uncertain if there is any difference in occurrence of clinical relapse when probiotics are compared with placebo (RR 0.87, 95% CI 0.63 to 1.18; 4 studies, 361 participants; very low-certainty evidence (downgraded for risk of bias, imbalance in baseline characteristics and imprecision)). It is also uncertain whether probiotics lead to a difference in the number of people who maintain clinical remission compared with placebo (RR 1.16, 95% CI 0.98 to 1.37; 2 studies, 141 participants; very low-certainty evidence (downgraded for risk of bias, imbalance in baseline characteristics and imprecision)). When probiotics are compared with 5-ASA, there may be little or no difference in clinical relapse (RR 1.01, 95% CI 0.84 to 1.22; 2 studies, 452 participants; low-certainty evidence) and maintenance of clinical remission (RR 1.06, 95% CI 0.90 to 1.25; 1 study, 125 participants; low-certainty evidence). It is uncertain if there is any difference in clinical relapse when probiotics, combined with 5-ASA are compared with 5-ASA alone (RR 1.11, 95% CI 0.66 to 1.87; 2 studies, 242 participants; very low-certainty evidence (downgraded due to risk of bias and imprecision)). There may be little or no difference in maintenance of remission when probiotics, combined with 5-ASA, are compared with 5-ASA alone (RR 1.05, 95% CI 0.89 to 1.24; 1 study, 122 participants; low-certainty evidence). Where reported, most of the studies which compared probiotics with placebo recorded no serious adverse events or withdrawals due to adverse events. For the comparison of probiotics and 5-ASA, one trial reported 11/110 withdrawals due to adverse events with probiotics and 11/112 with 5-ASA (RR 1.02, 95% CI 0.46 to 2.25; 222 participants; very low-certainty evidence). Discontinuation of therapy was due to gastrointestinal symptoms. One study (24 participants) comparing probiotics combined with 5-ASA with 5-ASA alone, reported no withdrawals due to adverse events; and two studies reported two withdrawals in the probiotic arm, due to avascular necrosis of bilateral femoral head and pulmonary thromboembolism (RR 5.29, 95% CI 0.26 to 107.63; 127 participants; very low-certainty evidence). Health-related quality of life and need for additional therapy were reported infrequently. The effectiveness of probiotics for the maintenance of remission in ulcerative colitis remains unclear. This is due to low- to very low-certainty evidence from poorly conducted studies, which contribute limited amounts of data from a small number of participants. Future trials comparing probiotics with 5-ASA rather than placebo will better reflect conventional care given to people with ulcerative colitis. Appropriately powered studies with a minimum length of 12 months are needed.

Iheozor-Ejiofor Z ，Kaur L ，Gordon M ，Baines PA ，Sinopoulou V ，Akobeng AK ... -  《Cochrane Database of Systematic Reviews》

RETRACTED: Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial.

Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and reported to be efficient in Chinese COV-19 patients. We evaluate the effect of hydroxychloroquine on respiratory viral loads. French Confirmed COVID-19 patients were included in a single arm protocol from early March to March 16th, to receive 600mg of hydroxychloroquine daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clinical presentation, azithromycin was added to the treatment. Untreated patients from another center and cases refusing the protocol were included as negative controls. Presence and absence of virus at Day6-post inclusion was considered the end point. Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms. Twenty cases were treated in this study and showed a significant reduction of the viral carriage at D6-post inclusion compared to controls, and much lower average carrying duration than reported in the litterature for untreated patients. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination. Despite its small sample size, our survey shows that hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin. This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/locate/withdrawalpolicy). Concerns have been raised regarding this article, the substance of which relate to the articles' adherence to Elsevier's publishing ethics policies and the appropriate conduct of research involving human participants, as well as concerns raised by three of the authors themselves regarding the article's methodology and conclusions. Elsevier's Research Integrity and Publishing Ethics Team, in collaboration with the journal's co-owner, the International Society of Antimicrobial Chemotherapy (ISAC), and with guidance from an impartial field expert acting in the role of an independent Publishing Ethics Advisor, Dr. Jim Gray, Consultant Microbiologist at the Birmingham Children's and Women's Hospitals, U.K., conducted an investigation and determined that the below points constituted cause for retraction: • The journal has been unable to confirm whether any of the patients for this study were accrued before ethical approval had been obtained. The ethical approval dates for this article are stated as being 5th and 6th of March 2020 (ANSM and CPP respectively), while the article states that recruitment began in “early March”. The 17th author, Prof. Philippe Brouqui, has confirmed that the start date for patient accrual was 6th March 2020. The journal has not been able to establish whether all patients could have entered into the study in time for the data to have been analysed and included in the manuscript prior to its submission on the 20th March 2020, nor whether all patients were enrolled in the study upon admission as opposed to having been hospitalised for some time before starting the treatment described in the article. Additionally, the journal has not been able to establish whether there was equipoise between the study patients and the control patients. • The journal has not been able to establish whether the subjects in this study should have provided informed consent to receive azithromycin as part of the study. The journal has concluded that that there is reasonable cause to conclude that azithromycin was not considered standard care at the time of the study. The 17th author, Prof. Philippe Brouqui has attested that azithromycin treatment was not, at the time of the study, an experimental treatment but a possible treatment for, or preventative measure against, bacterial superinfections of viral pneumonia as described in section 2.4 of the article, and as such the treatment should be categorised as standard care that would not require informed consent. This does not fully address the journal's concerns around the use of azithromycin in the study. In section 3.1 of the article, it is stated that six patients received azithromycin to prevent (rather than treat) bacterial superinfection. All of these were amongst the patients who also received hydroxychloroquine (HCQ). None of the control patients are reported to have received azithromycin. This would indicate that only patients in the HCQ arm received azithromycin, all of whom were in one center. The recommendations for use of macrolides in France at the time the study was conducted indicate that azithromycin would not have been a logical agent to use as first-line prophylaxis against pneumonia due to the frequency of macrolide resistance amongst bacteria such as pneumococci. These two points suggest that azithromycin would not have been standard practice across southern France at the time the study was conducted and would have required informed consent. • Three of the authors of this article, Dr. Johan Courjon, Prof. Valérie Giordanengo, and Dr. Stéphane Honoré have contacted the journal to assert their opinion that they have concerns regarding the presentation and interpretation of results in this article and have stated they no longer wish to see their names associated with the article. • Author Prof. Valérie Giordanengo informed the journal that while the PCR tests administered in Nice were interpreted according to the recommendations of the national reference center, it is believed that those carried out in Marseille were not conducted using the same technique or not interpreted according to the same recommendations, which in her opinion would have resulted in a bias in the analysis of the data. This raises concerns as to whether the study was partially conducted counter to national guidelines at that time. The 17th author, Prof. Philippe Brouqui has attested that the PCR methodology was explained in reference 17 of the article. However, the article referred to by reference 17 describes several diagnostic approaches that were used (one PCR targeting the envelope protein only; another targeting the spike protein; and three commercially produced systems by QuantiNova, Biofire, and FTD). This reference does not clarify how the results were interpreted. It has also been noted during investigation of these concerns that only 76% (19/25) of patients were viral culture positive, resulting in uncertainty in the interpretation of PCR reports as has been raised by Prof. Giordanengo. As part of the investigation, the corresponding author was contacted and asked to provide an explanation for the above concerns. No response has been received within the deadline provided by the journal. Responses were received by the 3rd and 17th authors, Prof. Philippe Parola and Prof. Philippe Brouqui, respectively, and were reviewed as part of the investigation. These two authors, in addition to 1st author Dr. Philippe Gautret, 13th author Prof. Philippe Colson, and 15th author Prof. Bernard La Scola, disagreed with the retraction and dispute the grounds for it. Having followed due process and concluded the aforementioned investigation and based on the recommendation of Dr. Jim Gray acting in his capacity as independent Publishing Ethics Advisor, the co-owners of the journal (Elsevier and ISAC) have therefore taken the decision to retract the article.

Gautret P ，Lagier JC ，Parola P ，Hoang VT ，Meddeb L ，Mailhe M ，Doudier B ，Courjon J ，Giordanengo V ，Vieira VE ，Tissot Dupont H ，Honoré S ，Colson P ，Chabrière E ，La Scola B ，Rolain JM ，Brouqui P ，Raoult D ... -  《-》

Emulating an existing trial of treatments for prostate cancer using real-world data: challenges and lessons learned.

If randomized controlled trials can be successfully emulated using real-world data (RWD), confidence in the validity of RWD for estimating treatment effects for questions that have not been assessed in trials increases. We used routinely collected administrative and clinical national linked datasets from England to emulate the PR07 trial for high-risk prostate cancer patients, which compared the effects of radiotherapy added to hormone therapy (RT+HT) within 8 weeks of randomization (the "grace period") and hormone therapy (HT) only on all-cause mortality. We highlight methodological choices required and challenges encountered in emulating this trial. Patients diagnosed with prostate cancer from 2014 to 2020 were identified from the routine national linked datasets. Diagnosis was taken as the time zero. As few patients initiated radiotherapy within 8 weeks of diagnosis, we considered target trials with grace periods of 4-6 months. Estimands of interest were hazard ratios (HRs) and survival probabilities over 7 years. The cloning-censoring-and-weighting (CCW) approach was used to control for measured confounding and to allow for the grace period. We also used an extension (the "landmark-CCW" approach), in which we consider several time-origins post-diagnosis, enabling us to use a grace period of 8 weeks as in PR07. A total of 2,690 patients were eligible for inclusion in the emulated trial. The CCW analysis using a grace period of 6 months gave an estimated HR of 0.48 (95% confidence interval [CI]: 0.34-0.60) and 7-year survival estimates of 80.7% (95% CI: 74.3-87.0) for the RT+HT strategy and 65.6% (95% CI: 62.8-68.1) for HT only strategy, and corresponding risk difference of 15.1% (95% CI: 11.5-18.9). The corresponding HR from the landmark-CCW approach was 0.58 (95% CI: 0.51-0.65) and with survival estimates of 80.7% (95% CI: 77.7-83.8) for RT+HT strategy and 69.8% (95% CI: 68.2-71.4) for the HT only strategy, and a risk difference of 10.9% (95% CI: 6.3-15.9). Our findings from the emulated trial using RWD are broadly consistent with those from PR07, with RT+HT estimated to result in better survival compared to HT only. However, the findings were not replicated exactly, with PR07 reporting an HR of 0.77 (95% CI: 0.61-0.98) over 7 years of follow-up. Differences may be in part due to challenges in defining time zero and allowing for a treatment grace period of the same duration as in PR07. Our study considered ways in which these challenges can be addressed, and our findings affirm the utility of RWD for estimating treatment effects. Clinical trials are the best way to test whether treatments work, but they are expensive, take years to complete, and focus on narrow research questions. If we can use real-world data (RWD) such as patient health records to mimic these trials, we may be able to answer additional medical questions relevant to patients who are prescribed these medications. This study aimed to see if we could recreate the results of a past clinical trial (PR07) using national health data from England. The PR07 trial looked at two treatments for high-risk prostate cancer: hormone therapy (HT) alone and radiotherapy added to hormone therapy (RT+HT) within 8 weeks of starting the study. This trial was chosen for several reasons. It included high-risk patients who were studied for up to 7 years, meaning that there was enough information to study survival outcomes. Being a major UK-based trial, it was useful for comparing with the data recorded in UK national health data. The trial also allowed some flexibility in when treatment started, which was an interesting factor to examine. Its main goal was to see if adding radiotherapy to hormone therapy provided extra benefits to patients. We wanted to see whether the trial results were replicated using the UK health data. If results were replicated, it would provide confidence in further exploration of questions not covered by the trial. In a trial, randomization time is the point where doctors allocate patients to one of the treatments being assessed, usually 1 new treatment and 1 control treatment. Patients in the study are then followed up from that point. However, defining a starting point in a non-trial setting, using UK national health data, is not as straightforward. In the PR07 trial, patients started RT+HT within 8 weeks of randomization. In the UK datasets, we use diagnosis as a starting point, because it is available for both treatment groups. However, very few patients started RT+HT within 8 weeks of diagnosis. To address this, we allowed for longer periods of 4-6 months from diagnosis for RT+HT initiation. Recent developments provided statistical methods for estimating the cause-effect relationship between treatment received and survival patterns. In this study, we show how these approaches can be used to estimate survival patterns if all patients had RT+HT within 4-6 months from diagnosis compared with if no patients had any RT within 4-6 months. We account for the different treatment initiation times and the main differences between the RT+HT and HT only patients. Using these methods, we estimate that RT+HT has an 11%-15% higher survival rate at 7 years compared to HT only. We discuss similarities and differences between these findings and those in the original PR07 trial.

Chesang C ，Sharples LD ，Gray CM ，Nossiter J ，van der Meulen J ，Cowling TE ，Keogh RH ... -  《-》

Far Posterior Approach for Rib Fracture Fixation: Surgical Technique and Tips.

The present video article describes the far posterior or paraspinal approach to posterior rib fractures. This approach is utilized to optimize visualization intraoperatively in cases of far-posterior rib fractures. This technique is also muscle-sparing, and muscle-sparing posterolateral, axillary, and anterior approaches have been shown to return up to 95% of periscapular strength by 6 months postoperatively1. Like most fractures, the skin incision depends on the fracture position. The vertical incision is made either just medial to a line equidistant between the palpable spinous processes and medial scapular border or directly centered over the fracture line in this region. The incision and superficial dissection must be extended cranially and caudally, approximately 1 or 2 rib levels past the planned levels of instrumentation, in order to allow muscle elevation and soft-tissue retraction. Superficial dissection reveals the trapezius muscle, with its fibers coursing from inferomedial to superolateral caudal to the scapular spine, and generally coursing transversely above this level. The trapezius is split in line with its fibers (or elevated proximally at the caudal-most surface), and the underlying layer will depend on the location of the incision. The rhomboid minor muscle overlies ribs 1 and 2, the rhomboid major muscle overlies ribs 3 to 7, and the latissimus dorsi overlies the remaining rib levels. To avoid muscle transection, the underlying muscle is also split in line with its fibers. Next, the thoracolumbar fascia is encountered and sharply incised, revealing the erector spinae muscles, which comprise the spinalis thoracis, longissimus thoracis, and iliocostalis thoracis muscles. These muscles and their tendons must be sharply elevated from lateral to midline; electrocautery is useful for this because there is a robust blood supply in this region. Medially, while retracting the paraspinal musculature, visualization with this approach can extend to the head and neck of the rib, and even to the spine. Following deep dissection, the fractures are now visualized. During fracture reduction, it is critical to assess reduction of both the costovertebral joint and the costotransverse joint. With fractures closer to the spine, it is recommended to have at least 2 cm between the rib head and tubercle in order to allow 2 plate holes to be positioned on the neck of the rib; if comminution exists and plating onto the transverse process is needed, several screws are required here for stability as well. For appropriate stability if plating onto the spine is not required, a minimum of 3 locking screws on each side of the fracture are recommended. Contouring of the plates to match the curvature of the rib and to allow for proper apposition may be required with posterior rib fractures. Screws must be placed perpendicular to the rib surface. Following operative stabilization of the rib fractures, a layered closure is performed, and a soft dressing is applied. Nonoperative alternatives include non-opioid and opioid medications as well as corticosteroid injections for pain control. Supportive mechanical ventilation and physiotherapy breathing exercises can also be implemented as needed. Operative alternatives include open reduction and internal fixation utilizing conventional locking plates and screws. Rib fractures are often treated nonoperatively when nondisplaced because of the surrounding soft-tissue support2,3. According to Chest Wall Injury Society guidelines, contraindications to surgical fixation of rib fractures include patients requiring ongoing resuscitation; rib fractures involving ribs 1, 2, 11, or 12, which are relative contraindications; severe traumatic brain injury; and acute myocardial infarction. Patient age of <18 years is also a relative contraindication for the operative treatment of rib fractures. The current literature does not recommend surgical fixation in this age group because these fractures typically heal as the patient ages; however, fracture-dislocations may require the use of instrumentation to prevent displacement. Currently, the U.S. Food and Drug Administration does not approve most plating systems for patients <18 years old4. In certain cases, including those with substantial displacement, persistent respiratory distress, pain, or fracture nonunion, stabilization with open reduction and internal fixation may be appropriate5-7. In cases of flail chest injuries, surgery is often indicated6. Flail chest injuries have been noted in the literature to have an incidence of approximately 150 cases per 100,000 injuries and have been shown to carry a mortality rate of up to 33%8,9. Surgical treatment of rib fractures has been shown to be associated with a decreased hospital length of stay and mortality rate in patients with major trauma1. Expected outcomes of this procedure include low complication rates, decreased hospital and intensive care unit length of stay, and reduced mechanical ventilation time10,11. However, as with any procedure, there are also risks involved, including iatrogenic lung injury from long screws or an aortic or inferior vena cava injury with aggressive manipulation of displaced fractured fragments, especially on the left side of the body. During open reduction, there is also a risk of injuring the neurovascular bundle. Tanaka et al. demonstrated a significant reduction in the rate of postoperative pneumonia in their operative group (22%) compared with their nonoperative group (90%)12. Schuette et al. demonstrated a 23% rate of postoperative pneumonia, 0% mortality at 1 year, an average of 6.2 days in the intensive care unit, an average total hospital length of stay of 17.3 days, and an average total ventilator time of 4 days in the operative group10. Prins et al. reported a significantly lower incidence of pneumonia in operative (24%) versus nonoperative patients (47.3%; p = 0.033), as well as a significantly lower 30-day mortality rate (0% versus 17.7%; p = 0.018)3. This procedure utilizes a muscle-sparing technique, which has demonstrated successful results in the literature on the use of the posterolateral, axillary, and anterior approaches, returning up to 95% of periscapular strength, compared with the uninjured shoulder, by 6 months postoperatively1. The use of a muscle-sparing technique with the far-posterior approach represents a topic that requires further study in order to compare the results with the successful results previously shown with other approaches. The ipsilateral extremity can be prepared into the field to allow its intraoperative manipulation in order to achieve scapulothoracic motion and improved subscapular access.For costovertebral fracture-dislocations, the vertical incision line is made just medial to a line equidistant between the palpable spinous processes and medial scapular border.Lateral decubitus positioning can be utilized to allow for simultaneous access to fractures that extend more laterally and warrant a posterolateral approach; however, it is generally more difficult to access the fracture sites near the spine with this approach.This muscle-sparing technique is recommended to optimize postoperative periscapular strength, as previously demonstrated with other approaches.Incision and superficial dissection must be extended cranially and caudally approximately 1 or 2 rib levels past the planned levels of instrumentation in order to allow muscle elevation and soft-tissue retraction.To avoid muscle transection during surgical dissection, the underlying muscle is split in line with its fibers.During deep dissection, it can be difficult to delineate underlying muscles because these muscles have fibers that do not run in line with the trapezius, and some, like the rhomboid major, run nearly perpendicular to it.Electrocautery is useful while elevating the erector spinae muscles and tendons, as there is a robust blood supply in this region.The erector spinae muscle complex is relatively tight and adherent to the underlying ribs, which may make it difficult to achieve adequate visualization; therefore, at least 3 rib levels must be elevated to access a rib for reduction and instrumentation.Although internal rotation deformities are more common in this region, any external displacement of a fracture can lead to a muscle injury that can be utilized for access.During fracture reduction, it is critical to assess reduction of both the costovertebral joint and the costotransverse joint.Special attention must be given to contouring the implants because there are not any commercially available precontoured implants for this region at this time, and plating onto the spine remains an off-label use of any currently available implant.For the more challenging fracture patterns, the use of a right-angled power drill and screwdriver is recommended.Generally, the incision is utilized as previously described to provide access as far medial as the transverse process if needed. However, in cases in which this approach does not allow proper visualization with rib fracture-dislocations involving the posterior ribs or spine, a midline spinal incision can be utilized while working in combination with a spine surgeon.With fractures closer to the spine, it is recommended to have at least 2 cm between the rib head and tubercle in order to allow 2 plate holes to be positioned on the neck of the rib.If comminution exists and plating onto the transverse process is needed, several screws are required for stability.When measuring the length of screws to be placed in the transverse process, preoperative CT scans can be utilized. CT = computed tomographyCWIS = Chest Wall Injury SocietyIVC = inferior vena cava.

Manes TJ ，DeGenova DT ，Taylor BC ，Patel JN ... -  《-》