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New surgical procedures can expose patients to harm and should be carefully evaluated before widespread use. The InSpace balloon (Stryker, USA) is an innovative surgical device used to treat people with rotator cuff tears that cannot be repaired. We aimed to determine the effectiveness of the InSpace balloon for people with irreparable rotator cuff tears.We conducted a double-blind, group-sequential, adaptive randomised controlled trial in 24 hospitals in the UK, comparing arthroscopic debridement of the subacromial space with biceps tenotomy (debridement only group) with the same procedure but including insertion of the InSpace balloon (debridement with device group). Participants had an irreparable rotator cuff tear, which had not resolved with conservative treatment, and they had symptoms warranting surgery. Eligibility was confirmed intraoperatively before randomly assigning (1:1) participants to a treatment group using a remote computer system. Participants and assessors were masked to group assignment. Masking was achieved by using identical incisions for both procedures, blinding the operation note, and a consistent rehabilitation programme was offered regardless of group allocation. The primary outcome was the Oxford Shoulder Score at 12 months. Pre-trial simulations using data from early and late timepoints informed stopping boundaries for two interim analyses. The primary analysis was on a modified intention-to-treat basis, adjusted for the planned interim analysis. The trial was registered with ISRCTN, ISRCTN17825590.Between June 1, 2018, and July 30, 2020, we assessed 385 people for eligibility, of which 317 were eligible. 249 (79%) people consented for inclusion in the study. 117 participants were randomly allocated to a treatment group, 61 participants to the debridement only group and 56 to the debridement with device group. A predefined stopping boundary was met at the first interim analysis and recruitment stopped with 117 participants randomised. 43% of participants were female, 57% were male. We obtained primary outcome data for 114 (97%) participants. The mean Oxford Shoulder Score at 12 months was 34·3 (SD 11·1) in the debridement only group and 30·3 (10·9) in the debridement with device group (mean difference adjusted for adaptive design -4·2 [95% CI -8·2 to -0·26];p=0·037) favouring control. There was no difference in adverse events between the two groups.In an efficient, adaptive trial design, our results favoured the debridement only group. We do not recommend the InSpace balloon for the treatment of irreparable rotator cuff tears.Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health and Care Research partnership.

The purpose of this article was to assess the effectiveness of ozone therapy as an adjunct to mechanical therapy in periodontitis patients. Thirty-two patients diagnosed with generalized periodontitis were selected, with a total of 655 teeth examined. Each patient’s mouth was divided into four quadrants (the split-mouth model) to be randomly treated with four sessions of gaseous ozone or air. The following clinical variables were recorded: the gingival index, the periodontal clinical attachment loss, the Miller’s mobility index and the clinical improvements, as assessed through the visual analog scale (VAS). In addition, the microorganisms were qualitatively compared. After four weeks of treatment, the teeth of the ozone-treated quadrants showed statistically significant reductions in the gingival index and an improvement in the clinical attachment (p < 0.0001). The same treatment also significantly improved mobility by between 70% and 86% compared to the control group (p < 0.0001). Statistically significant differences were also recorded for the VAS (p < 0.0001). In the qualitative study of the subgingival flora, significant differences were observed (p < 0.0001). The overall results of this trial support the view that ozone treatment is effective and well tolerated in cases of generalized chronic periodontitis.

Introduction Despite the known benefit to patients and families, discussions about goals, values and preferences for medical care in advancing serious illness often do not occur. Many system and clinician factors, such as patient and clinician reticence and shortage of specialty palliative care teams, contribute to this lack of communication. To address this gap, we designed an intervention to promote goals-of-care conversations and palliative care referrals in the hospital setting by using trained palliative care educators and video decision aids. This paper presents the rationale, design and methods for a trial aimed at addressing barriers to goals-of-care conversations for hospitalised adults aged 65 and older and those with Alzheimer’s disease and related Dementias, regardless of age. Methods and analysis The Video Image about Decisions to Improve Ethical Outcomes with Palliative Care Educators is a pragmatic stepped wedge, cluster randomised controlled trial, which aims to improve and extend goals-of-care conversations in the hospital setting with palliative care educators trained in serious illness communication and video decision aids. The primary outcome is the proportion of patients with goals-of-care documentation in the electronic health record. We estimate that over 9000 patients will be included. Ethics and dissemination The Institutional Review Board (IRB) at Boston Medical Center will serve as the single IRB of record for all regulatory and ethical aspects of this trial. BMC Protocol Number: H-41482. Findings will be presented at national meetings and in publications. This trial is registered at ClinicalTrials.gov. Trial registration number NCT04857060 ; ClinicalTrials.gov

Objetivos. Evaluar el efecto antiinflamatorio del extracto etanólico de hojas de Chromolaena leptocephala (DC) R.M. King & H. Rob. “chilca negra” e identificar los metabolitos secundarios presentes. Materiales y métodos. Se realizó una identificación de sus metabolitos secundarios mediante un tamizaje fitoquímico y se evaluó el efecto antiinflamatorio del extracto mediante el modelo de edema subplantar en ratas a la dosis suministrada (diclofenaco 50 mg/kg, C. leptocephala 100 mg/kg y 400 mg/kg). Resultados. Dentro de los metabolitos secundarios se encontraron flavonoides, compuestos fenólicos, alcaloides, entre otros. Con respecto al efecto antiinflamatorio del extracto de la planta, se encontró efecto en la concentración de 100 y 400 mg/kg. Conclusión. El extracto etanólico de hojas de Chromolaena leptocephala (DC) R.M. King & H. Rob. “chilca negra” presentó flavonoides, compuestos fenólicos y alcaloides, que ejercerían efecto antiinflamatorio en la concentración de 100 y 400 mg/kg.

An ultrahigh performance liquid chromatography-tandem mass spectrometry method for the identification and quantification of neurotransmitters, metabolites and precursors at different stages in zebrafish life was developed. Betaine, glutamine, glutamic acid, γ-aminobutyric acid, phosphocholine, glycerophosphocholine, cytidine 5'-diphosphocholine, choline, acetylcholine, dopamine, norepinephrine, serotonin, tyrosine, epinephrine, tryptophan, 5-hydroxyindolacetic acid and agmatine were selected as analytes. The method consisted of a simple deproteinization of samples using methanol and formic acid, subsequent injection onto the chromatographic equipment and quantification with a triple quadrupole mass spectrometer detector using an electrospray ionization interface in positive mode. Limits of detection ranged from 0.02 to 11ngmL(-1) and limits of quantification from 0.1 to 38ngmL(-1), depending on the analyte. The method was validated according to US Food and Drugs Administration (FDA) guideline for bioanalytical assays. Precision, expressed as relative standard deviation (%RSD), was lower than 15% in all cases, and the determination coefficient (R(2)) was equal or higher than 99.0% with a residual deviation for each calibration point lower than ±25%. Mean recoveries were between 85% and 115%. The method was applied to determine of these compounds in zebrafish from early stages of development to adulthood and showed the time-course of neurotransmitters and others neurocompounds through the life cycle. The possibility of measuring up to 17 compounds related with the main neurotransmitter systems in a simple analytical method will complement and reinforce the use of zebrafish in multiple applications in the field of neurosciences. The proposed method will facilitate future studies related with brain development.

The main objective of this work was to develop a method to measure Leucine (Leu) and β-hydroxymethylbutyrate (HMB) at basal levels in serum, urine, milk and brain microdialysates in rats. Ultrahigh performance liquid chromatography–electrospray-tandem mass spectrometry (UHPLC-ESI-MS/MS) was used as analytical technique. The sample treatment was simple and consisted of dilution with methanol and centrifugation for serum and urine, dilution with water and filtration with an Amicon filter for milk, and treatment with formic acid with no further dilution for microdialyzates. The procedures for sampling and the UHPLC-MS/MS parameters were accurately optimized to achieve the highest recoveries and to enhance the analytical characteristics of the method. For chromatographic separation, an Acquity UPLC BEH Amide column using acetonitrile-water gradient with formic acid as additive was used. The total run time was 4 min. The analytical characteristics (accuracy, selectivity and sensitivity) of the proposed method were evaluated. The limits of detection (LODs) obtained ranged from 0.4 to 7 ng mL −1 and the limits of quantification (LOQs) from 1 to 22 ng mL −1 . Precision, expressed as relative standard deviation (% RSD), was lower than 15% in all cases, and the determination coefficient ( R 2 ) was equal or higher than 99.0% with a residual deviation for each calibration point lower than ±25%. Mean recoveries were between 85 and 115%. The method was successfully applied to these matrices being able to detect significant differences between physiological situations, strains and stages of life.

The administration of high-dose continuous intravenous infusion interleukin-2 (IL-2) is able to induce the presence of lymphokine-activated killer (LAK) cells. LAK are able to nonspecifically lyse tumor cells. They are also able to lyse endothelial cells, which accounts for, at least in part, the capillary leak syndrome seen as one of the toxicities with this therapy. A pulmonary manifestation of capillary leak syndrome is the presence of pulmonary edema. We postulated that capillary leak may also be a mechanism by which LAK could conceivably reach pulmonary metastases or could be a reflection of damage of endothelial cells in vasculature supplying metastases and that capillary leak syndrome may actually correlate with the response of pulmonary metastases. We examined our database of patients with lung metastases treated with high-dose continuous infusion IL-2 (18 MIU/m(2)/day for 3 days) regimens. Eighteen patients had the following characteristics: melanoma (11), renal cancer (7), median age of 67 years (range, 28-79 years), and males (15). All patients were treated by oncology nurses on either the stem cell transplant unit or oncology ward. Pulmonary edema was defined as the presence of pleural fluid on a chest X-ray, computed tomography (CT) scan, and/or as noted on a physical examination by at least 2 observers. No patients required endotracheal intubation, mechanical ventilation, or an intensive care unit transfer. The median number of cycles received was 6 (range, 1-13). All 8 responding patients (6 patients with melanoma, 2 patients with kidney cancer) manifested pulmonary edema during interleukin-2 therapy. Four patients with pulmonary edema were nonresponders. The presence of pulmonary edema correlated with the response to therapy (p = 0.01). The median duration of response of pulmonary nodules was 5 months (range, 1-16 months). There is a correlation between the development of pulmonary edema and the response of pulmonary metastases in patients with melanoma and kidney cancer treated with high-dose continuous infusion interleukin-2.

High-dose continuous infusion interleukin-2 (IL-2) regimens generate a higher degree of lymphokine activated killer cell (LAK) cytotoxicity when tested against tumor cells in vitro and a higher rebound lymphocytosis in vivo than do bolus IL-2 regimens. Lymphocytes initially activated by continuous infusion IL-2 have increased cytotoxicity against cancer cells when they are subsequently pulsed with additional IL-2. Famotidine may enhance LAK cytolytic ability. Six patients with kidney cancer have been treated with a combination of famotidine 20 mg intravenous bid and continuous infusion IL-2 (18 MIU/sq m/24 hours) for 72 hours, followed by a 24-hour rest, then IL-2 18 MIU/sq m over 15-30 minutes. The most common metastatic sites were the lung, lymph node, and bone. Median number of cycles received = 5 (range, 3-8). The most common toxicities were fever, rigors, nausea/emesis, hypophosphatemia, hypotension, elevated creatinine, and metabolic acidosis. There were no treatment-related deaths, and no patients required intensive care admission. Two partial responses (33% response rate) have been seen. Median survival has not been reached at greater than 8 months. The combination of high-dose continuous infusion plus pulse IL-2 and famotidine is active in metastatic kidney cancer. An accrual of additional patients is needed to better assess the response rate.

High-dose, continuous infusion interleukin-2 (IL-2) regimens generate greater Lymphokine Activated Killer cell (LAK) cytotoxicity in vitro and a higher rebound lymphocytosis in vivo than do bolus IL-2 regimens. Lymphocytes initially activated by continuous infusion IL-2 then subsequently pulsed with IL-2 have increased cytotoxicity against cancer cells. Famotidine may enhance the lysis of tumors by cytotoxic lymphocytes. Fourteen patients with melanoma were treated with famotidine 20 mg intravenously twice per day and continuous infusion IL-2 (18 MIU/sq m/24 hours) for 72 hours, followed by a 24-hour rest, then IL-2 18 MIU/sq m over 15-30 minutes for 1 dose (12 patients) or daily for 3 doses (2 patients). Most common toxicities were fever, nausea/emesis, hypophosphatemia, hypomagnesemia, and rigors. Nine partial responses (64% response rate; 95% Confidence Interval: 39%-84%) have been seen. Median survival has not been reached at greater than 10 months. Two patients responding to therapy showed an increase in detectable CD 56(+) cells in serial subcutaneous or lymph node biopsies, while 1 patient undergoing progression of disease had no such infiltrate. High-dose, 72-hour continuous infusion plus pulse interleukin-2 with famotidine has activity in melanoma. CD 56(+) cells may play a role in responding patients.

We studied 19 peripartum patients with acute respiratory failure associated with pregnancy. Although it is an uncommon event, noncardiogenic pulmonary edema is the most common cause of respiratory failure in the peripartum period. This acute lung injury syndrome was observed to be associated with a variety of complications of pregnancy including premature labor, the use of tocolytics, infection, hypertension, leukoagglutinin reactions, aspiration, abruptio placentae, and amniotic fluid embolism. From 1989 through 1992 there were 10,852 deliveries and 19 patients with noncardiogenic pulmonary edema at our institution. Analyzing these cases has led us to favor the hypothesis that the respiratory failure associated with the various complications of pregnancy primarily represents the fatal and nonfatal cases of amniotic fluid embolism that Steiner and Lushbaugh initially believed undoubtedly to exist. Moreover, we suggest, as have others, that the nonspecific symptom complex of inflammation, coagulopathy, and cardiopulmonary failure represents the release of soluble mediators into the maternal circulation. It is not clear what the predominant mediator is, but we have focused on platelet activating factor. It is also not established whether the mediator(s) is of amniotic fluid origin or a result of maternal anaphylactoid-type of response to a fetal or amnioplacental antigen. In conclusion, monitoring maternal oxygenation either directly or indirectly by oximetry should be considered routinely in the peripartum period, especially in complicated pregnancies, to detect at an early stage "asymptomatic" or preclinical cases of noncardiogenic pulmonary edema, in hopes of then modifying management to prevent their progression.

Lymphokine-activated killer (LAK) cells generated by high-dose continuous infusion interleukin-2 (IL-2) are able to nonspecifically lyse melanoma and kidney cancer cells. In vitro famotidine enhances cytotoxicity of LAK against tumor cells, possibly by increasing IL-2 uptake at the IL-2 receptor on lymphocytes. Outpatient IL-2 regimens typically have response rates of 15% or less, with most patients eventually experiencing progressive disease. Second-line therapy is, therefore, needed. We treated 11 patients (6 with metastatic melanoma; 5 having metastatic kidney cancer) who had previously experienced progressive disease on prior IL-2 regimens, with a combination of famotidine 20 mg intravenously (i.v.) twice per day and continuous-infusion IL-2 18 MIU/M2/24 hours x 72 hours, followed 24 hours later by a pulse IL-2 dose (18 MIU/M2 over 15 minutes). Cycles were repeated every 3 weeks. Patient characteristics were: 9 males, median age 63 years (range, 57-75), median Eastern Cooperative Oncology Group (ECOG) performance status: 1; most common metastatic sites: lungs, lymph nodes, and soft tissue/subcutaneous (s.c.); median number of cycles received: 4; most common toxicities were fever, nausea/emesis, hypophosphatemia, and hypomagnesemia. Five (5) patients (3 with melanoma, 2 with kidney cancer) have had partial responses. Two (2) patients with kidney cancer have been converted to complete responders with resection of residual disease, remaining without relapse at 5+ and 20+ months. Responding sites are lungs, lymph nodes, abdominal mass, and s.c. Median duration of response was 9.5 months. Median survival was 12 months. This combination has activity in patients with metastatic kidney cancer or melanoma who have received prior IL-2.

High-dose bolus or continuous infusion interleukin-2-based therapy can cause capillary leak syndrome. Significant cardiovascular/hemodynamic events, including myocardial infarction, hypotension, pulmonary edema, and cardiac arrhythmia, have been described with such therapy. Concern over the toxicity of highdose interleukin-2 (IL-2) therapy has led to some clinicians excluding patients 70 years of age or over. We have treated 15 patients 70 years of age or over having an Eastern Conference Oncology Group (ECOG) performance status of 0 or 1, with therapy based on continuous infusion IL-2 18 MIU/sq m/24 hours for 72 hours. All patients underwent a pretreatment evaluation of cardiac status with a low-level stress or adenosine stress test. Cycles were typically repeated every 3 weeks for 4 cycles, then every 3-4 weeks thereafter. Patients were treated by oncology nurses in either the stem cell transplant (intermediate unit) or the oncology inpatient unit. Patient characteristics were: median age, 72 years (range, 70-83 years); tumor types: melanoma (10), kidney cancer (5); most common sites of disease: lung (11), lymph nodes (6), subcutaneous (3), liver (2); prior therapy included: none (8), outpatient IL-2 (5), other immunotherapy (4). Median number of cycles received: 3 (1-10). Most common toxicities were: fever, rigors, nausea, emesis, hypophosphatemia, and hypomagnesemia. Three patients required the use of dopamine for blood pressure support. Two patients declined further therapy. There were no treatment-related deaths. No patients required endotracheal intubation or transfer to an intensive care unit. One complete and 8 partial responses (60% response rate) have been seen. Responding sites include the lung, lymph node, intact kidney primary, and liver. Median survival has not been reached at over 14 months (range 3+-26+ months). Patients who are 70 years of age and older with an ECOG performance status of 0 or 1 are able to tolerate high-dose continuous infusion IL-2-based therapy and may respond to such treatment.

Objectives. —To validate the Braunwald classification of unstable angina as a predictor of in-hospital cardiac complications; to determine which factors of the Braunwald classification contributed significantly to this prediction; and to devise a method of combining these predictive factors into an overall odds ratio for complications. Design. —A validation cohort of consecutive patients followed prospectively for in-hospital cardiac complications including myocardial infarction and death. Setting. —A community-based academic medical center. Patients. —A total of 393 patients admitted consecutively to the coronary care and intermediate care units with unstable angina. Main Outcome Measures. —Major cardiac complications including death, myocardial infarction, congestive heart failure, cardiogenic shock, and severe ventricular dysrhythmias. Results. —Multiple logistic regression analysis identified four clinical factors used in the Braunwald classification that predicted the in-hospital occurrence of major cardiac complications: (1) myocardial infarction within less than 14 days (odds ratio [OR], 5.72; 95% confidence interval [CI], 1.92 to 16.97); (2) need for intravenous nitroglycerin (OR, 2.33; 95% CI, 1.31 to 4.17); (3) lack of β-blocker or calcium channel blocker prior to admission (OR, 3.83; 95% CI, 1.55 to 9.42); and (4) baseline ST depression (OR, 2.81; 95% CI, 1.45 to 5.47). Two other clinical factors, diabetes and age, were also significant predictors. Validation of this model using parametric and nonparametric bootstrap techniques revealed excellent agreement between the CIs for adjusted ORs derived from the multiple logistic regression and those derived from the bootstrap. Conclusions. —The classification of unstable angina proposed by Braunwald includes four factors that predict risk of major in-hospital cardiac complications. Specific factors used in this classification can be combined with diabetes and age to better stratify risk of major cardiac complications in this disorder using a simpler model. (JAMA. 1995;273:136-141)