Evaluating the efficacy and safety of pozelimab in patients with CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy disease: an open-label phase 2 and 3 study.

BACKGROUND: CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) is an ultra-rare genetic disorder characterised by intestinal lymphatic damage, lymphangiectasia, and protein-losing enteropathy caused by overactivation of the complement system. We assessed the efficacy and safety of pozelimab, an antibody blocking complement component 5. METHODS: This open-label, single-arm, historically controlled, multicentre phase 2 and 3 study evaluated ten patients with CHAPLE disease. This study was conducted at three hospitals in Thailand, Türkiye, and the USA. Patients aged 1 year or older with a clinical diagnosis of CHAPLE disease and a CD55 loss-of-function variant identified by genetic analysis and confirmed by flow cytometry or western blot of CD55 from peripheral blood cells were eligible for this study. Patients received a single intravenous loading dose of pozelimab 30 mg per kg of bodyweight, followed by a once-per-week subcutaneous dose over the treatment period based on bodyweight at a concentration of 200 mg/mL as either a single injection (<40 kg bodyweight) or two injections (≥40 kg bodyweight). The primary endpoint was proportion of patients with serum albumin normalisation with an improvement in active clinical outcomes and no worsening in inactive clinical outcomes (frequency of problematic abdominal pain, bowel movement frequency, facial oedema severity, and peripheral oedema severity) at week 24 compared with baseline, assessed in the full analysis set. This study is registered with ClinicalTrials.gov (NCT04209634) and is active but not recruiting. FINDINGS: 11 patients were recruited between Jan 27, 2020, and May 12, 2021, ten of which were enrolled in the study and included in the analysis populations. The efficacy data corresponded to all patients completing the week 48 assessment and having at least 52 weeks of treatment exposure, and the safety data included an additional 90 days of follow-up and corresponded to all patients having at least 72 weeks of treatment. Patients were predominantly paediatric (with a median age of 8·5 years), and originated from Türkiye, Syria, Thailand, and Bolivia. Patients had markedly low weight-for-age and stature-for-age at baseline, and mean albumin at baseline was 2·2 g/dL, which was considerably less than the local laboratory reference range. After pozelimab treatment, all ten patients had serum albumin normalisation and improvement with no worsening in clinical outcomes. There was a complete inhibition of the total complement activity. Nine patients had adverse events; two were severe events, and one patient had an adverse event considered related to pozelimab. INTERPRETATION: Pozelimab inhibits complement overactivation and resolves the clinical and laboratory manifestations of CHAPLE disease. Pozelimab is the only currently approved therapeutic drug for patients with this life-threatening, ultra-rare condition. In patients with protein-losing enteropathy where known causes have been excluded, testing for a CD55 deficiency should be contemplated. A diagnosis of CHAPLE disease should lead to early consideration of treatment with pozelimab. FUNDING: Regeneron Pharmaceuticals and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls.

BACKGROUND: Type 1 spinal muscular atrophy (SMA) is a progressive neuromuscular disease characterized by an onset at 6 months of age or younger, an inability to sit without support, and deficient levels of survival of motor neuron (SMN) protein. Risdiplam is an orally administered small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein in blood. METHODS: We conducted an open-label study of risdiplam in infants with type 1 SMA who were 1 to 7 months of age at enrollment. Part 1 of the study (published previously) determined the dose to be used in part 2 (reported here), which assessed the efficacy and safety of daily risdiplam as compared with no treatment in historical controls. The primary end point was the ability to sit without support for at least 5 seconds after 12 months of treatment. Key secondary end points were a score of 40 or higher on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND; range, 0 to 64, with higher scores indicating better motor function), an increase of at least 4 points from baseline in the CHOP-INTEND score, a motor-milestone response as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2), and survival without permanent ventilation. For the secondary end points, comparisons were made with the upper boundary of 90% confidence intervals for natural-history data from 40 infants with type 1 SMA. RESULTS: A total of 41 infants were enrolled. After 12 months of treatment, 12 infants (29%) were able to sit without support for at least 5 seconds, a milestone not attained in this disorder. The percentages of infants in whom the key secondary end points were met as compared with the upper boundary of confidence intervals from historical controls were 56% as compared with 17% for a CHOP-INTEND score of 40 or higher, 90% as compared with 17% for an increase of at least 4 points from baseline in the CHOP-INTEND score, 78% as compared with 12% for a HINE-2 motor-milestone response, and 85% as compared with 42% for survival without permanent ventilation (P<0.001 for all comparisons). The most common serious adverse events were pneumonia, bronchiolitis, hypotonia, and respiratory failure. CONCLUSIONS: In this study involving infants with type 1 SMA, risdiplam resulted in higher percentages of infants who met motor milestones and who showed improvements in motor function than the percentages observed in historical cohorts. Longer and larger trials are required to determine the long-term safety and efficacy of risdiplam in infants with type 1 SMA. (Funded by F. Hoffmann-La Roche; FIREFISH ClinicalTrials.gov number, NCT02913482.).

Historical controls in clinical trials: a note on linking Pocock's model with the robust mixture priors.

Several Bayesian methods have been proposed to borrow information dynamically from historical controls in clinical trials. In this note, we identify key features of the relationship between the first method proposed, the bias-variance method, which is strongly related to the commensurate prior approach, and a more recent and widely used approach called robust mixture priors (RMP). We focus on the two key terms that need to be chosen to define the RMP, namely $w$, the prior probability that the new trial differs systematically from the historical trial, and $s_v^2$, the variance of the vague component of the RMP. The relationship with Pocock's prior reveals that different combinations of these two terms can express similar prior beliefs about the amount of information provided by the historical data. This demonstrates the value of fixing $s_v^2$, e.g., so the vague component is "worth one subject." Prior belief about the relevance of the historical data is then driven by a single value, the prespecified weight $w$.

Combination therapy with anti-HIV-1 antibodies maintains viral suppression.

Individuals infected with HIV-1 require lifelong antiretroviral therapy, because interruption of treatment leads to rapid rebound viraemia. Here we report on a phase 1b clinical trial in which a combination of 3BNC117 and 10-1074, two potent monoclonal anti-HIV-1 broadly neutralizing antibodies that target independent sites on the HIV-1 envelope spike, was administered during analytical treatment interruption. Participants received three infusions of 30 mg kg-1 of each antibody at 0, 3 and 6 weeks. Infusions of the two antibodies were generally well-tolerated. The nine enrolled individuals with antibody-sensitive latent viral reservoirs maintained suppression for between 15 and more than 30 weeks (median of 21 weeks), and none developed viruses that were resistant to both antibodies. We conclude that the combination of the anti-HIV-1 monoclonal antibodies 3BNC117 and 10-1074 can maintain long-term suppression in the absence of antiretroviral therapy in individuals with antibody-sensitive viral reservoirs.

Efficacy and Safety of Nifurtimox in Pediatric Patients with Chagas Disease: Results at 4-Year Follow-Up in a Prospective, Historically Controlled Study (CHICO SECURE).

Nifurtimox is recommended for the treatment of Chagas disease; however, long-term follow-up data are scarce. This prolonged follow-up phase of the prospective, historically controlled, CHICO clinical trial evaluated seronegative conversion in pediatric patients aged <18 years with Chagas disease who were followed for 4 years after nifurtimox treatment. Patients were randomly assigned 2:1 to nifurtimox 60-day or 30-day regimens comprising 10 to 20 mg/kg/day for patients aged <12 years and body weight <40 kg, and 8 to 10 mg/kg/day for those aged ≥12 years and body weight ≥40 kg. Anti-Trypanosoma cruzi antibodies decreased during the study period, achieving seronegative conversion in 16 (8.12%) and 8 (8.16%) patients in the 60-day and 30-day nifurtimox regimens, respectively, with corresponding incidence rates per 100 patients/year of seronegative conversion of 2.12 (95% confidence interval [CI]: 1.21 to 3.45) and 2.11 (95% CI: 0.91 to 4.16). Superiority of the 60-day nifurtimox regimen was confirmed by the lower limit of the 95% CI being higher than that (0%) in a historical placebo control group. Children aged <2 years at baseline were more likely to reach seronegative conversion during the 4-year follow-up than older children. At any annual follow-up visit, >90% of evaluable patients had persistently negative quantitative PCR results for T. cruzi DNA. No adverse events potentially related to treatment or caused by protocol-required procedures were documented for either treatment regimen. This study confirms the effectiveness and safety of a pediatric formulation of nifurtimox administered in an age- and weight-adjusted regimen for 60 days to treat children with Chagas disease.

A regimen with caplacizumab, immunosuppression, and plasma exchange prevents unfavorable outcomes in immune-mediated TTP.

The anti-von Willebrand factor nanobody caplacizumab was licensed for adults with immune-mediated thrombotic thrombocytopenic purpura (iTTP) based on prospective controlled trials. However, few data are available on postmarketing surveillance. We treated 90 iTTP patients with a compassionate frontline triplet regimen associating therapeutic plasma exchange (TPE), immunosuppression with corticosteroids and rituximab, and caplacizumab. Outcomes were compared with 180 historical patients treated with the standard frontline treatment (TPE and corticosteroids, with rituximab as salvage therapy). The primary outcome was a composite of refractoriness and death within 30 days since diagnosis. Key secondary outcomes were exacerbations, time to platelet count recovery, the number of TPE, and the volume of plasma required to achieve durable remission. The percentage of patients in the triplet regimen with the composite primary outcome was 2.2% vs 12.2% in historical patients (P = .01). One elderly patient in the triplet regimen died of pulmonary embolism. Patients from this cohort experienced less exacerbations (3.4% vs 44%, P < .01); they recovered durable platelet count 1.8 times faster than historical patients (95% confidence interval, 1.41-2.36; P < .01), with fewer TPE sessions and lower plasma volumes (P < .01 both). The number of days in hospital was 41% lower in the triplet regimen than in the historical cohort (13 vs 22 days; P < .01). Caplacizumab-related adverse events occurred in 46 patients (51%), including 13 major or clinically relevant nonmajor hemorrhagic events. Associating caplacizumab to TPE and immunosuppression, by addressing the 3 processes of iTTP pathophysiology, prevents unfavorable outcomes and alleviates the burden of care.

HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption.

Interruption of combination antiretroviral therapy in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117,a broad and potent neutralizing antibody against the CD4 binding site of the HIV-1 Env protein, during analytical treatment interruption in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Results show that two or four 30 mg kg(-1) 3BNC117 infusions,separated by 3 or 2 weeks, respectively, are generally well tolerated.Infusions are associated with a delay in viral rebound of 5-9 weeks after two infusions, and up to 19 weeks after four infusions, or an average of 6.7 and 9.9 weeks, respectively, compared with 2.6 weeks for historical controls (P < 0.00001). Rebound viruses arise predominantly from a single provirus. In most individuals,emerging viruses show increased resistance, indicating escape.However, 30% of participants remained suppressed until antibody concentrations waned below 20 µg ml(-1), and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks.We conclude that the administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during analytical treatment interruption in humans.

Improved management of placenta accreta spectrum disorders: experience from a single institution.

OBJECTIVES: To assess the applicability of a standardized multidisciplinary protocol for managing placenta accreta spectrum (PAS) disorders and its impact on the outcomes. METHODS: We compared patients with PAS manage by a standardized multidisciplinary protocol (T2) to historic controls managed on a case-by-case basis by individual physicians between (T1). The primary outcome is composite maternal morbidity. Secondary outcomes were the rates of surgical complications, estimated blood loss, number of blood products transfused, intensive care unit admissions, ventilator use, and birth weight. Multivariate logistic analysis was used to identify independent predictors of composite maternal morbidity. RESULTS: During T1 and T2, we managed 39 and 36 patients with confirmed PAS, respectively. During T2, the protocol could be implemented in 21 cases (58%). Compared to T1, patients managed during T2 had 70% less composite maternal morbidity (95% CI: 0.11-0.82) and lower blood loss (median, 2,000 vs. 1,100 mL, p=0.008). Also, they were 68% less likely to require transfusion of blood products (95% CI: 0.12-0.81; p=0.01), including fewer units of packed red blood cells (median, 2 vs. 0, p=0.02). Management following the protocol was the only independent factor associated with lower composite maternal morbidity (OR: 0.22; 95% CI: 0.05-0.95; p=0.04). Selected maternal and neonatal outcomes were not different among 12 and 15 patients with suspected but unconfirmed PAS disorders managed during T1 and T2, respectively. CONCLUSIONS: Most patients can be managed under a standardized multidisciplinary protocol for PAS disorders, leading to improved outcomes.

Study of Intraventricular Cerliponase Alfa for CLN2 Disease.

BACKGROUND: Recombinant human tripeptidyl peptidase 1 (cerliponase alfa) is an enzyme-replacement therapy that has been developed to treat neuronal ceroid lipofuscinosis type 2 (CLN2) disease, a rare lysosomal disorder that causes progressive dementia in children. METHODS: In a multicenter, open-label study, we evaluated the effect of intraventricular infusion of cerliponase alfa every 2 weeks in children with CLN2 disease who were between the ages of 3 and 16 years. Treatment was initiated at a dose of 30 mg, 100 mg, or 300 mg; all the patients then received the 300-mg dose for at least 96 weeks. The primary outcome was the time until a 2-point decline in the score on the motor and language domains of the CLN2 Clinical Rating Scale (which ranges from 0 to 6, with 0 representing no function and 3 representing normal function in each of the two domains), which was compared with the time until a 2-point decline in 42 historical controls. We also compared the rate of decline in the motor-language score between the two groups, using data from baseline to the last assessment with a score of more than 0, divided by the length of follow-up (in units of 48 weeks). RESULTS: Twenty-four patients were enrolled, 23 of whom constituted the efficacy population. The median time until a 2-point decline in the motor-language score was not reached for treated patients and was 345 days for historical controls. The mean (±SD) unadjusted rate of decline in the motor-language score per 48-week period was 0.27±0.35 points in treated patients and 2.12±0.98 points in 42 historical controls (mean difference, 1.85; P<0.001). Common adverse events included convulsions, pyrexia, vomiting, hypersensitivity reactions, and failure of the intraventricular device. In 2 patients, infections developed in the intraventricular device that was used to administer the infusion, which required antibiotic treatment and device replacement. CONCLUSIONS: Intraventricular infusion of cerliponase alfa in patients with CLN2 disease resulted in less decline in motor and language function than that in historical controls. Serious adverse events included failure of the intraventricular device and device-related infections. (Funded by BioMarin Pharmaceutical and others; CLN2 ClinicalTrials.gov numbers, NCT01907087 and NCT02485899 .).

Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma.

BACKGROUND: Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma. Complete response rates of 21% have been observed for each agent when administered as long-term continuous therapy. Preclinical models predict synergy in combination. METHODS: We conducted a single-group, phase 2 study of daily oral ibrutinib and venetoclax in patients, as compared with historical controls. Patients commenced ibrutinib monotherapy at a dose of 560 mg per day. After 4 weeks, venetoclax was added in stepwise, weekly increasing doses to 400 mg per day. Both drugs were continued until progression or an unacceptable level of adverse events. The primary end point was the rate of complete response at week 16. Minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and by allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in blood. RESULTS: The study included 24 patients with relapsed or refractory mantle-cell lymphoma (23 patients) or previously untreated mantle-cell lymphoma (1 patient). Patients were 47 to 81 years of age, and the number of previous treatments ranged from none to six. Half the patients had aberrations of TP53, and 75% had a high-risk prognostic score. The complete response rate according to computed tomography at week 16 was 42%, which was higher than the historical result of 9% at this time point with ibrutinib monotherapy (P<0.001). The rate of complete response as assessed by positron-emission tomography was 62% at week 16 and 71% overall. MRD clearance was confirmed by flow cytometry in 67% of the patients and by ASO-PCR in 38%. In a time-to-event analysis, 78% of the patients with a response were estimated to have an ongoing response at 15 months. The tumor lysis syndrome occurred in 2 patients. Common side effects were generally low grade and included diarrhea (in 83% of the patients), fatigue (in 75%), and nausea or vomiting (in 71%). CONCLUSIONS: In this study involving historical controls, dual targeting of BTK and BCL2 with ibrutinib and venetoclax was consistent with improved outcomes in patients with mantle-cell lymphoma who had been predicted to have poor outcomes with current therapy. (Funded by Janssen and others; AIM ClinicalTrials.gov number, NCT02471391 .).

A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403.

Retrospective studies have suggested that older adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) have better survival rates when treated using a pediatric ALL regimen administered by pediatric treatment teams. To address the feasibility and efficacy of using a pediatric treatment regimen for AYA patients with newly diagnosed ALL administered by adult treatment teams, we performed a prospective study, CALGB 10403, with doses and schedule identical to those in the Children's Oncology Group study AALL0232. From 2007 to 2012, 318 patients were enrolled; 295 were eligible and evaluable for response. Median age was 24 years (range, 17-39 years). Use of the pediatric regimen was safe; overall treatment-related mortality was 3%, and there were only 2 postremission deaths. Median event-free survival (EFS) was 78.1 months (95% confidence interval [CI], 41.8 to not reached), more than double the historical control of 30 months (95% CI, 22-38 months); 3-year EFS was 59% (95% CI, 54%-65%). Median overall survival (OS) was not reached. Estimated 3-year OS was 73% (95% CI, 68%-78%). Pretreatment risk factors associated with worse treatment outcomes included obesity and presence of the Philadelphia-like gene expression signature. Use of a pediatric regimen for AYAs with ALL up to age 40 years was feasible and effective, resulting in improved survival rates compared with historical controls. CALGB 10403 can be considered a new treatment standard upon which to build for improving survival for AYAs with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00558519.

Placenta Accreta Spectrum Treatment With Intraoperative Multivessel Embolization: the PASTIME protocol.

BACKGROUND: Multidisciplinary care of placenta accreta spectrum cases improves pregnancy outcomes, but the specific components of such a multidisciplinary collaboration varies between institutions. As experience with placenta accreta spectrum increases, it is crucial to assess new surgical techniques and protocols to help improve maternal outcomes and to advocate for hospital resources. OBJECTIVE: This study aimed to assess a novel multidisciplinary protocol for the treatment of placenta accreta spectrum that comprises cesarean delivery, multivessel uterine embolization, and hysterectomy in a single procedure within a hybrid operative suite. STUDY DESIGN: This was a matched prepost study of placenta accreta spectrum cases managed before (2010-2017) and after implementation of the Placenta Accreta Spectrum Treatment With Intraoperative Multivessel Embolization protocol (2018-2021) at a tertiary medical center. Historical cases were managed with internal iliac artery balloon placement in selected cases with the decision to inflate the balloons intraoperatively at the discretion of the primary surgeon. Intraoperative Embolization cases were compared with historical cases in a 1:2 ratio matched on the basis of placenta accreta spectrum severity and surgical urgency. The primary outcome was a requirement for transfusion with packed red blood cells. Secondary outcomes included estimated surgical blood loss, operative and postoperative complications, procedural time, length of stay, and neonatal outcomes. RESULTS: A total of 15 Placenta Accreta Spectrum Treatment With Intraoperative Multivessel Embolization cases and 30 matched historical cases were included in the analysis. There were no demographic differences noted between the groups. A median (interquartile range) of 0 units (0-2 units) of packed red blood cells were transfused in the Intraoperative Embolization group compared with 2 units (0-4.5 units) in the historical group (P=.045); 5 of 15 (33.3%) Intraoperative Embolization cases required blood transfusions compared with 19 of 30 (63.3%) cases in the historical group (P=.11). The estimated blood loss was significantly less in the Intraoperative Embolization group with a median (interquartile range) of 750 mL (450-1050 mL) compared with 1750 mL (1050-2500 mL) in the historical group (P=.003). There were no cases requiring massive transfusion (≥10 red blood cell units in 24 hours) in the Intraoperative Embolization group compared with 5 of 30 (16.7%) cases in the historical group (P=.15). There were no intraoperative deaths from hemorrhagic shock using the Intraoperative Embolization protocol, whereas this occurred in 2 of the historical cases. The mean duration of the interventional radiology procedure was longer in the Intraoperative Embolization group (67.8 vs 34.1 minutes; P=.002). Intensive care unit admission and postpartum length of stay were similar, and surgical and postoperative complications were not significantly different between the groups. The gestational age and neonatal birthweights were similar; however, the neonatal length of stay was longer in the Intraoperative Embolization group (median duration, 32 days vs 15 days; P=.02) with a trend toward low Apgar scores. Incidence of arterial umbilical cord blood pH <7.2 and respiratory distress syndrome and intubation rates were not statistically different between the groups. CONCLUSION: A multidisciplinary pathway including a single-surgery protocol with multivessel uterine embolization is associated with a decrease in blood transfusion requirements and estimated blood loss with no increase in operative complications. The Placenta Accreta Spectrum Treatment With Intraoperative Multivessel Embolization protocol provides a definitive surgical method that warrants consideration by other centers specializing in placenta accreta spectrum treatment.

Feasibility and efficacy of modified fixed citrate concentration protocol using only commercial preparations in critically ill patients: a prospective cohort study with a historical control group.

BACKGROUND: The cumbersome program and the shortage of commercial solution hindered the regular application of regional citrate anticoagulation (RCA). It is urgent to simplify the protocol using only commercial preparations. The aim of this study was to explore the feasibility and efficacy of the modified protocol for continuous veno-venous hemofiltration (CVVH) in unselected critically ill patients. METHODS: A prospective cohort study was conducted in 66 patients who received a new protocol combining fixed citrate concentration with modified algorithm for supplements (i.e., fixed protocol), and compared the efficacy, safety and convenience for this group to a historical control group with a traditional protocol (n = 64), where citrate was titrated according to the circuit ionized calcium concentration (i.e., titrated protocol). The convenience was defined as the demand for monitoring test and dose adjustment of any supplement. RESULTS: The filter lifespan was 63.2 ± 16.1 h in the fixed group and 51.9 ± 17.7 h in the titrated group, respectively. Kaplan-Meier survival analysis demonstrated longer circuit lifetime for fixed group (log-rank, p = 0.026). The incidence of circuit clotting was lower in the fixed protocol (15.2% vs. 29.7% in the titrated protocol, p = 0.047). Moreover, compared with the titrated group, patients with fixed protocol had less demand for monitoring test and dose adjustment of any supplement (the number of times per person per day) (3.3 [IQR 2.3-4.5] vs. 5.7 [IQR 3.3-6.9], p = 0.001 and 1.9 [IQR 0.5-2.7] vs. 6.3 [IQR 4.2-7.9], p < 0.001; respectively). No new onset bleeding complications occurred in all patients. The overall incidence of suspected citrate accumulation was 4.6% and there was no difference between the two groups (p = 0.969), yet a lower rate of metabolic alkalosis was found in the fixed group (3.0% vs. 14.1%, p = 0.024). CONCLUSIONS: Our modified fixed citrate concentration protocol is feasible, safe and effective to enhance the circuit lifespan and the convenience of implementation while maintaining a similar safety when compared to the traditional protocol. Using only commercial preparations may be helpful for widespread application of RCA. TRIAL REGISTRATION: Clinicaltrials.gov. NCT02663960 . Registered 26 January 2016.

The traditional experience strategy (TES) and combined ultrasonography examination (CUE) for the treatment of lateral compression type 1 pelvic fractures: a historical control study.

BACKGROUND: It is difficult to judge the stability of lateral compression type-1 (LC-1) pelvic fracture, as it is often based on static images of the pelvis. Compared with the traditional experience strategy, ultrasonography examination may be able to distinguish operative and conservative patients before definitive treatment. However, in previous studies, we have not compared the outcomes between traditional experience strategy (TES group) and combined ultrasonography examination (CUE group). Thus, the aim of the study is comparing the differences between TES and CUE strategy, to identify the value of ultrasonography examination. METHODS: Medical records system for patients with LC-1 pelvic fractures who were treated with TES and CUE strategy were included. Patients' baseline characteristics, treatment strategy, and function were recorded at follow-up. Functional outcomes were evaluated using the Majeed grading system. RESULTS: In total, 77 patients with LC-1 pelvic fractures were included in the study. There were 42 and 35 patients in TES and CUE group, respectively. Compared to TES group (69 %), there were less proportion patients chosen the operative treatment in CUE group (43 %, P = 0.021). The volume of intraoperative blood loss in CUE operative group was more than TES operative group (P = 0.037). There were more patients with complete sacral fracture in CUE operative group than TES operative group (P = 0.002). The Majeed scores in CUE conservative group was higher than TES conservative group (P = 0.008). The overall Majeed scores in CUE group was higher than that in TES group (P = 0.039). CONCLUSIONS: The ultrasonography examination could relatively accurately identify the unstable LC-1 pelvis than the traditional experience strategy, the operative rate could be reduced and the overall function of LC-1 patients could be improved under the ultrasonography examination. LEVEL OF EVIDENCE: Level III.

Evaluating the Effect of Pravastatin in Early-Onset Fetal Growth Restriction: A Nonrandomized and Historically Controlled Pilot Study.

OBJECTIVE: This study aimed to analyze the effect of pravastatin on angiogenic factors, feto-maternal Doppler findings and pregnancy outcomes in women with early-onset fetal growth restriction (FGR) treated with pravastatin compared with nontreated controls. STUDY DESIGN: This was a pilot study conducted between March 2016 and September 2017. Women with single pregnancies and FGR diagnosed at ≤ 28 weeks of gestation were offered 40 mg of pravastatin daily. Doppler progression, soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) values, and pregnancy outcomes were assessed and compared with consecutive historical controls. Controls were matched to treated women for gestational age, maternal characteristics, maternal and obstetric history, Doppler severity classification, and angiogenic factors at diagnosis. The sFlt-1/PlGF was measured in maternal serum at two different times: before pravastatin was started (ratio M0) and during pravastatin treatment (ratio M1). Doppler severity was classified into four categories: normal, mild, moderate, and severe. RESULTS: A total of 38 women were enrolled in this study. No differences were observed in baseline characteristics between groups. However, when compared with the ratio M0, M1 was increased by a median (interquartile range) of 67.0 (-34.8 to 197.3) in the control group but decreased by a median (interquartile range) of -10.1 (-53.1 to -0.07) in the pravastatin treated group (p < 0.001). No significant differences were observed in Doppler progression throughout pregnancy. Median interval from diagnosis to delivery was extended by 16.5 days, the median newborn birthweight was increased from 1,040 to 1,300 g, and the number of women with preeclampsia decreased from 9 (47.4%) to 6 (31.6%) in treated women; however, these trends were not statistically significant. CONCLUSION: In women with early-onset FGR, treatment with pravastatin 40 mg daily was associated with significant improvement in the angiogenic profile. Additionally, median pregnancy duration and median birthweight increased and the incidence of PE was reduced in treated women. Nevertheless, since this pilot study was underpowered, none of these differences were statistically significant. KEY POINTS: · Pravastatin improves sFlt-1/PlGF in FGR.. · Pregnancy duration tended to be greater in treated women.. · Birthweight tended to be greater in treated women..

Designing historical control studies with survival endpoints using exact statistical inference.

Historical control trials compare an experimental treatment with a previously conducted control treatment. By assigning all recruited samples to the experimental arm, historical control trials can better identify promising treatments in early phase trials compared with randomized control trials. Existing designs of historical control trials with survival endpoints are based on asymptotic normal distribution. However, it remains unclear whether the asymptotic distribution of the test statistic is close enough to the true distribution given relatively small sample sizes in early phase trials. In this article, we address this question by introducing an exact design approach for exponentially distributed survival endpoints, and compare it with an asymptotic design in both real examples and simulation examples. Simulation results show that the asymptotic test could lead to bias in the sample size estimation. We conclude the proposed exact design should be used in the design of historical control trials.

An enhanced recovery programme improves the comfort and outcomes in children with obstructive sleep apnoea undergoing adenotonsillectomy: A retrospective historical control study.

OBJECTIVE: To explore the effects of an enhanced recovery after surgery (ERAS) programme on postoperative rehabilitation in children with obstructive sleep apnoea (OSA) during the perioperative period of adenotonsillectomy. DESIGN: A retrospective historical control study. SETTING: Service improvement project. PARTICIPANTS: The study included 394 children with OSA (207 males, 187 females; age range, 2.5 years to 14 years) who underwent adenotonsillectomy. MAIN OUTCOME MEASURES: The children who had undergone adenoidal ablation and bilateral tonsillectomy were divided into an ERAS group (208 patients) treated with the combined optimisation measures and a control group (186 patients) treated with traditional measures during the perioperative period. The postoperative incidence of complications, pain scores, anxiety scores and postoperative diets in the two groups were assessed. RESULTS: Patients in the ERAS group had significantly a lower overall complication rate and incidence of fever for 2 weeks of follow-up when compared to patients in the control group through the application of perioperative optimisation measures. Furthermore, patients in the ERAS group had less post-surgical pain, had better dietary intake at days 1, 3 and 7 after surgery and had lower preoperative anxiety scores after admission education and while waiting in the operation room. CONCLUSION: The ERAS programme consisting of combined optimisation measures can reduce physical and psychological trauma during the perioperative period of adenotonsillectomy performed for children with OSA.

Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy.

BACKGROUND: Spinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for mechanical ventilation by 2 years of age. We studied functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in this disease. METHODS: Fifteen patients with SMA1 received a single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA encoding the missing SMN protein. Three of the patients received a low dose (6.7×1013 vg per kilogram of body weight), and 12 received a high dose (2.0×1014 vg per kilogram). The primary outcome was safety. The secondary outcome was the time until death or the need for permanent ventilatory assistance. In exploratory analyses, we compared scores on the CHOP INTEND (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders) scale of motor function (ranging from 0 to 64, with higher scores indicating better function) in the two cohorts and motor milestones in the high-dose cohort with scores in studies of the natural history of the disease (historical cohorts). RESULTS: As of the data cutoff on August 7, 2017, all 15 patients were alive and event-free at 20 months of age, as compared with a rate of survival of 8% in a historical cohort. In the high-dose cohort, a rapid increase from baseline in the score on the CHOP INTEND scale followed gene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3 months, as compared with a decline in this score in a historical cohort. Of the 12 patients who had received the high dose, 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently. Elevated serum aminotransferase levels occurred in 4 patients and were attenuated by prednisolone. CONCLUSIONS: In patients with SMA1, a single intravenous infusion of adeno-associated viral vector containing DNA coding for SMN resulted in longer survival, superior achievement of motor milestones, and better motor function than in historical cohorts. Further studies are necessary to confirm the safety and efficacy of this gene therapy. (Funded by AveXis and others; ClinicalTrials.gov number, NCT02122952 .).

Implications of Obesity for the Management of Severe Coronavirus Disease 2019 Pneumonia.

OBJECTIVES: To investigate patients' characteristics, management, and outcomes in the critically ill population admitted to the ICU for severe acute respiratory syndrome coronavirus disease 2019 pneumonia causing an acute respiratory distress syndrome. DESIGN: Retrospective case-control study. SETTING: A 34-bed ICU of a tertiary hospital. PATIENTS: The first 44 coronavirus disease 2019 acute respiratory distress syndrome patients were compared with a historical control group of 39 consecutive acute respiratory distress syndrome patients admitted to the ICU just before the coronavirus disease 2019 crisis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Obesity was the most frequent comorbidity exhibited by coronavirus disease 2019 patients (n = 32, 73% vs n = 11, 28% in controls; p < 0.001). Despite the same severity of illness and level of hypoxemia at admission, coronavirus disease 2019 patients failed more high flow oxygen via nasal cannula challenges (n = 16, 100% vs n = 5, 45% in controls; p = 0.002), were more often intubated (n = 44, 100% vs n = 22, 56% in controls; p < 0.001) and paralyzed (n = 34, 77% vs n = 3, 14% in controls; p < 0.001), required higher level of positive end-expiratory pressure (15 vs 8 cm H2O in controls; p < 0.001), more prone positioning (n = 33, 75% vs n = 6, 27% in controls; p < 0.001), more dialysis (n = 16, 36% vs n = 3, 8% in controls; p = 0.003), more hemodynamic support by vasopressors (n = 36, 82% vs n = 22, 56% in controls; p = 0.001), and had more often a prolonged weaning from mechanical ventilation (n = 28, 64% vs n = 10, 26% in controls; p < 0.01) resulting in a more frequent resort to tracheostomy (n = 18, 40.9% vs n = 2, 9% in controls; p = 0.01). However, an intensive management requiring more staff per patient for positioning coronavirus disease 2019 subjects (6 [5-7] vs 5 [4-5] in controls; p < 0.001) yielded the same ICU survival rate in the two groups (n = 34, 77% vs n = 29, 74% in controls; p = 0.23). CONCLUSIONS: In its most severe form, coronavirus disease 2019 pneumonia striked preferentially the vulnerable obese population, evolved toward a multiple organ failure, required prolonged mechanical ventilatory support, and resulted in a high workload for the caregivers.

Historically controlled comparison of glucocorticoids with or without tocilizumab versus supportive care only in patients with COVID-19-associated cytokine storm syndrome: results of the CHIC study.

OBJECTIVES: To prospectively investigate in patients with severe COVID-19-associated cytokine storm syndrome (CSS) whether an intensive course of glucocorticoids with or without tocilizumab accelerates clinical improvement, reduces mortality and prevents invasive mechanical ventilation, in comparison with a historic control group of patients who received supportive care only. METHODS: From 1 April 2020, patients with COVID-19-associated CSS, defined as rapid respiratory deterioration plus at least two out of three biomarkers with important elevations (C-reactive protein >100 mg/L; ferritin >900 µg/L; D-dimer >1500 µg/L), received high-dose intravenous methylprednisolone for 5 consecutive days (250 mg on day 1 followed by 80 mg on days 2-5). If the respiratory condition had not improved sufficiently (in 43%), the interleukin-6 receptor blocker tocilizumab (8 mg/kg body weight, single infusion) was added on or after day 2. Control patients with COVID-19-associated CSS (same definition) were retrospectively sampled from the pool of patients (n=350) admitted between 7 March and 31 March, and matched one to one to treated patients on sex and age. The primary outcome was ≥2 stages of improvement on a 7-item WHO-endorsed scale for trials in patients with severe influenza pneumonia, or discharge from the hospital. Secondary outcomes were hospital mortality and mechanical ventilation. RESULTS: At baseline all patients with COVID-19 in the treatment group (n=86) and control group (n=86) had symptoms of CSS and faced acute respiratory failure. Treated patients had 79% higher likelihood on reaching the primary outcome (HR: 1.8; 95% CI 1.2 to 2.7) (7 days earlier), 65% less mortality (HR: 0.35; 95% CI 0.19 to 0.65) and 71% less invasive mechanical ventilation (HR: 0.29; 95% CI 0.14 to 0.65). Treatment effects remained constant in confounding and sensitivity analyses. CONCLUSIONS: A strategy involving a course of high-dose methylprednisolone, followed by tocilizumab if needed, may accelerate respiratory recovery, lower hospital mortality and reduce the likelihood of invasive mechanical ventilation in COVID-19-associated CSS.