Capivasertib and fulvestrant for patients with hormone receptor-positive advanced breast cancer: characterization, time course, and management of frequent adverse events from the phase III CAPItello-291 study.

BACKGROUND: Capivasertib is a potent, selective pan-AKT inhibitor. In CAPItello-291, the addition of capivasertib to fulvestrant resulted in a statistically significant (P < 0.001) improvement in progression-free survival over fulvestrant monotherapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer and disease progression on or after aromatase inhibitor-based therapy. Characterization of the capivasertib-fulvestrant adverse event (AE) profile as managed in CAPItello-291 can inform future management guidance and optimize clinical benefit. PATIENTS AND METHODS: Seven hundred and eight patients were randomized 1 : 1 to capivasertib (400 mg twice daily; 4 days on, 3 days off) or placebo, plus fulvestrant, on a 4-week cycle. Dose reductions/interruptions for capivasertib/placebo were permitted (up to two dose reductions). Safety analyses included exposure, AE, and clinical laboratory data and were conducted in patients who received at least one dose of capivasertib, fulvestrant, or placebo. Frequent AEs associated with phosphoinositide 3-kinase (PI3K)/protein kinase (AKT) pathway inhibition (diarrhea, rash, hyperglycemia) were characterized using group terms. AEs were summarized using descriptive statistics; time-to-event analyses were conducted. RESULTS: Safety analyses included 705 patients: capivasertib-fulvestrant (n = 355) and placebo-fulvestrant (n = 350). Frequent any-grade AEs with capivasertib-fulvestrant were diarrhea (72.4%), rash (38.0%), and nausea (34.6%); frequent grade ≥3 AEs were rash (12.1%), diarrhea (9.3%), and hyperglycemia (2.3%). Diarrhea, rash, and hyperglycemia occurred shortly after starting capivasertib-fulvestrant [median days to onset (interquartile range) of any grade: 8 (2-22), 12 (10-15), and 15 (1-51), respectively], and were managed with supportive medications, dose reductions, interruptions, and/or discontinuation. Discontinuation rates were 2.0%, 4.5%, and 0.3%, respectively. Overall, 13.0% discontinued capivasertib due to AEs. CONCLUSIONS: Frequent AEs associated with PI3K/AKT pathway inhibition occurred early and were manageable. The low rate of treatment discontinuations suggests that, when appropriately managed, these AEs do not pose a challenge to clinical benefit.

Retention of the posterior cruciate ligament stabilizes the medial femoral condyle during kneeling using a tibial insert with ball-in-socket medial conformity.

PURPOSE: Resecting the posterior cruciate ligament (PCL) increases posterior laxity and increases the flexion gap more than the extension gap in the native (i.e. healthy) knee. These two effects could lead to significant anterior displacement of the medial femoral condyle in kneeling following total knee arthroplasty even when using a tibial insert with a high degree of medial conformity. Using an insert with ball-in-socket medial conformity and a flat lateral articular surface, the primary purpose was to determine whether the medial femoral condyle remained stable with and without PCL retention during kneeling. METHODS: Two groups of patients were studied, one with PCL retention (22 patients) and the other with PCL resection (25 patients), while kneeling at 90º flexion. Following 3D model-to-2D image registration, A-P displacements of both femoral condyles were determined relative to the dwell point of the medial socket. RESULTS: With PCL resection versus PCL retention, the medial femoral condyle was 5.1 ± 3.7 mm versus 0.8 ± 2.1 mm anterior of the dwell point (p < 0.0001). Patient-reported function scores were comparable (p ≥ 0.1610) despite a significantly shorter follow-up of 7.8 ± 0.9 months with PCL retention than 19.6 ± 4.9 months with PCL resection (p < 0.0001). Range of motion was 126 ± 8° versus 122 ± 6° with and without PCL retention, respectively (p = 0.057). CONCLUSION: Surgeons that use a highly conforming tibial insert design can stabilize the medial femoral condyle during kneeling by retaining the PCL. In patients with PCL resection, the 9 mm high anterior lip of the insert with ball-in-socket medial conformity was insufficient to prevent significant anterior displacement of the medial femoral condyle when weight-bearing on the anterior tibia.

The peak force to push a trial tibial insert into position cannot be used to select the correct thickness in total knee arthroplasty.

An objective of a total knee arthroplasty (TKA) is to restore native (i.e. healthy) function, and a crucial step is determining the correct insert thickness for each patient. If the insert is too thick, then stiffness results, and if too thin, then instability results. Two methods to determine the insert thickness are by manually assessing the joint laxity and by using a trial insert with goniometric markings that measures the internal-external rotation of the trial with respect to a mark on the femoral component. The former is qualitative and depends on the surgeon's experience and 'feel' and while the latter is quantitative, it can be used only with an insert with medial ball-in-socket conformity. An unexplored method is to measure the force required to push a trial insert into position. To determine whether this method has merit, the push force was measured in 30 patients undergoing unrestricted kinematically aligned TKA using an insert with ball-in-socket medial conformity, a flat lateral surface, and retention of the posterior cruciate ligament. During surgery, the surgeon determined three appropriate thicknesses to test from a selection ranging from 10 mm to 14 mm in 1 mm increments. The peak push forces going from an insert 1 mm thinner than the correct thickness as determined by an insert goniometer and from the correct thickness to 1 mm thicker were measured. Mean peak forces for the different insert thicknesses were 127 ± 104 N, 127 ± 95 N, and 144 ± 96 N for 1 mm thinner, correct, and 1 mm thicker, respectively, and did not differ (p = 0.3210). As a result, measurement of peak force during trial positioning of a tibial insert cannot be used to identify the correct thickness for all insert designs.

Appreciating the links between heart failure and depression.

Depression and heart failure frequently occur together, symptoms overlap and the prognosis is worsened. Both conditions share biopsychosocial risk factors and are accompanied by behavioural/lifestyle, neurohormonal, inflammatory and autonomic changes that are implicated aetiologically. Depression has been conceptualized as a decompensated response to allostatic overload, wherein adaptive psychological, behavioural and physiological responses to chronic and/or severe stress, become unsustainable. Heart failure can similarly be viewed as a decompensated response to circulatory overload, wherein adaptive functional (neurohormonal effects on circulation, inotropic effects on heart) and structural (myocardial remodelling) changes, become unsustainable. It has been argued that the disengaged state of depression can initially be protective, limiting an individual's exposure to external challenges, such that full recovery is often possible. In contrast, heart failure, once past a tipping-point, can progress relentlessly. Here, we consider the bidirectional interactions between depression and heart failure. Targeted treatment of depression in the context of heart failure may improve quality of life, yet overall benefits on mortality remain elusive. However, effective treatment of heart failure typically enhances function and improves key psychological and behavioural determinants of low mood. Prospectively, research that examines the mechanistic associations between depression and heart failure offers fresh opportunity to optimize personalized management in the advent of newer interventions for both conditions.

Posterior cruciate ligament retention with medial ball-in-socket conformity promotes internal tibial rotation and knee flexion while providing high clinical outcome scores.

BACKGROUND: Although retaining the posterior cruciate ligament (PCL) is advantageous in unrestricted kinematically aligned TKA, it is often excised with a medial stabilized implant. The primary objectives were to determine whether PCL retention using an insert with ball-in-socket (B-in-S) medial conformity to maximize A-P stability promotes internal tibial rotation and flexion while providing high patient-reported outcome scores. METHODS: Two cohorts of 25 patients each were treated with unrestricted kinematically aligned (KA) TKA using a tibial insert with B-in-S medial conformity and a flat lateral articular surface. One cohort retained the PCL; the other had it excised. Patients performed deep knee bend and step-up exercises during fluoroscopic imaging. Following 3D model-to-2D image registration, anterior-posterior (A-P) positions of the femoral condyles and tibial rotation were determined. RESULTS: For deep knee bend, mean internal tibial rotation with PCL retention was significantly greater at maximum flexion (17.7° ± 5.7° versus 10.4° ± 6.5°, p < 0.001) and significantly greater at 30°, 60°, and 90° flexion as well (p ≤ 0.0283). For step-up, mean internal tibial rotation with PCL retention was significantly greater at at 15°, 30°, and 45° flexion (p ≤ 0.0049) but was marginally not significantly greater at 60° (i.e. maximum) flexion (12.3° ± 4.4° versus 10.1° ± 5.4°, p = 0.0794). Mean flexion during active knee flexion with PCL retention was significantly greater (127° ± 8° versus 122° ± 6°, p = 0.0400). Both cohorts had high median Oxford Knee, WOMAC, and Forgotten Joint Scores that were not significantly different (p = 0.0918, 0.1448, and 0.0855, respectively) CONCLUSION: Surgeons that perform unrestricted KA TKA should retain the PCL with an insert that has B-in-S medial conformity, as this maintains extension and flexion gaps while also promoting internal tibial rotation and knee flexion as well as providing high clinical outcome scores.

Process, structural, and outcome quality indicators to support perioperative opioid stewardship: a rapid review.

Opioids are effective analgesics but can cause harm. Opioid stewardship is key to ensuring that opioids are used effectively and safely. There is no agreed set of quality indicators relating to the use of opioids perioperatively. This work is part of the Yorkshire Cancer Research Bowel Cancer Quality Improvement programme and aims to develop useful quality indicators for the improvement of care and patient outcomes at all stages of the perioperative journey.A rapid review was performed to identify original research and reviews in which quality indicators for perioperative opioid use are described. A data tool was developed to enable reliable and reproducible extraction of opioid quality indicators.A review of 628 abstracts and 118 full-text publications was undertaken. Opioid quality indicators were identified from 47 full-text publications. In total, 128 structure, process and outcome quality indicators were extracted. Duplicates were merged, with the final extraction of 24 discrete indicators. These indicators are based on five topics: patient education, clinician education, pre-operative optimization, procedure, and patient-specific prescribing and de-prescribing and opioid-related adverse drug events.The quality indicators are presented as a toolkit to contribute to practical opioid stewardship. Process indicators were most commonly identified and contribute most to quality improvement. Fewer quality indicators relating to intraoperative and immediate recovery stages of the patient journey were identified. An expert clinician panel will be convened to agree which of the quality indicators identified will be most valuable in our region for the management of patients undergoing surgery for bowel cancer.

Dermatopathology and the Diagnosis of Fungal Infections.

Diagnosis of superficial/cutaneous fungal infections from skin, hair and nail samples is generally achieved using microscopy and culture in a microbiology laboratory, however, any presentation that is unusual or subcutaneous is sampled by taking a biopsy. Using histological techniques a tissue biopsy enables a pathologist to perform a full examination of the skin structure, detect any inflammatory processes or the presence of an infectious agent or foreign body. Histopathological examination can give a presumptive diagnosis while a culture result is pending, and may provide valuable diagnostic information if culture fails. This review demonstrates how histopathology contributes to the diagnosis of fungal infections from the superficial to the life threatening.

Evolving relationship of Nares Strait ice arches on sea ice along the Strait and the North Water, the Arctic's most productive polynya.

Nares Strait, the waterway that separates northwest Greenland from Ellesmere Island, is a major pathway along which sea ice leaves the Arctic, including the planet's oldest and thickest sea ice that is experiencing an accelerated loss. Ice arches that develop during the winter at the Strait's northern or southern terminus can remain stable for months at a time during which the transport of sea ice ceases. The Arctic's most productive polynya, the North Water (NOW) or Pikialasorsuaq (West Greenlandic for 'great upwelling') forms at the Strait's southern end. There is evidence that a warming climate and the concomitant thinning of Arctic sea ice is weakening the arches and it has been proposed that this may impact the stability of NOW and the complex ecosystem that it sustains. Here we employ a categorization of recent winters with respect to the presence or absence of ice arches to explore their impact on sea ice along the Strait and over the NOW. We find that winters during which a southern ice arch is absent are associated with a reduced and thinner ice cover along the Strait with ice conditions over the NOW similar to that during winters with a southern arch. In winters, without a southern arch, there is also an acceleration of the winds along the Strait that contributes to the presence of reduced ice cover. Ocean color remote sensing data suggests that current levels of primary productivity over the NOW are independent of the presence or absence of an ice arch. The results suggest more research is needed to assess the stability of the NOW, with respect to reduced ice cover and primary productivity, in a future where ice arches cease to form along Nares Strait.

Finding Order in Chaos: Quantitative Predictors of Chaos Terrain Morphology on Europa.

The mechanisms for chaos terrain formation on Europa have long been a source of debate in the scientific community. There exist numerous theoretical and numerical models for chaos formation, but to date there has been a lack of quantifiable observations that can be used to constrain models and permit comparison to the outputs of these chaos models. Here, we use mapping and statistical analysis to develop a quantitative description of chaos terrain and their observed morphologies. For nine chaos features, we map every block, or region of pre-existing terrain within disrupted matrix. We demonstrate that chaos terrains follow a continuous spectrum of morphologies between two endmembers, platy and knobby. We find that any given chaos terrain's morphology can be quantified by means of the linearized exponential slope of its cumulative block area distribution. This quantitative metric provides a new diagnostic parameter in future studies of chaos terrain formation and comparison.

Anomalous collapses of Nares Strait ice arches leads to enhanced export of Arctic sea ice.

The ice arches that usually develop at the northern and southern ends of Nares Strait play an important role in modulating the export of Arctic Ocean multi-year sea ice. The Arctic Ocean is evolving towards an ice pack that is younger, thinner, and more mobile and the fate of its multi-year ice is becoming of increasing interest. Here, we use sea ice motion retrievals from Sentinel-1 imagery to report on the recent behavior of these ice arches and the associated ice fluxes. We show that the duration of arch formation has decreased over the past 20 years, while the ice area and volume fluxes along Nares Strait have both increased. These results suggest that a transition is underway towards a state where the formation of these arches will become atypical with a concomitant increase in the export of multi-year ice accelerating the transition towards a younger and thinner Arctic ice pack.

Perspectives on the fellowship training in cardiac, thoracic, and vascular anesthesia and critical care in Europe from program directors and educational leads around europe

ABSTRACT:This article reviews fellowship training in adult cardiac, thoracic, and vascular anesthesia and critical care from the perspective of European program initiators and educational leaders in these subspecialties together with current training fellows. Currently, the European Association of Cardiothoracic Anaesthesiology (EACTA) network has 20 certified fellowship positions each year in 10 hosting centers within 7 European countries, with 2 positions outside Europe (São Paulo, Brazil). Since 2009, 42 fellows have completed the fellowship training. The aim of this article is to provide an overview of the rationale, requirements, and contributions of the fellows, in the context of the developmental progression of the EACTA fellowship in adult cardiac, thoracic, and vascular anesthesia and critical care from inception to present. A summary of the program structure, accreditation of host centers, requirements to join the program, teaching and assessment tools, certification, and training requirements in transesophageal electrocardiography is outlined. In addition, a description of the current state of EACTA fellowships across Europe, and a perspective for future steps and challenges to the educational program, is provided. (AU)

Prospective observational cohort study of the association between antiplatelet therapy, bleeding and thrombosis in patients with coronary stents undergoing noncardiac surgery.

BACKGROUND: The perioperative management of antiplatelet therapy in noncardiac surgery patients who have undergone previous percutaneous coronary intervention (PCI) remains a dilemma. Continuing dual antiplatelet therapy (DAPT) may carry a risk of bleeding, while stopping antiplatelet therapy may increase the risk of perioperative major adverse cardiovascular events (MACE). METHODS: Occurrence of Bleeding and Thrombosis during Antiplatelet Therapy In Non-Cardiac Surgery (OBTAIN) was an international prospective multicentre cohort study of perioperative antiplatelet treatment, MACE, and serious bleeding in noncardiac surgery. The incidences of MACE and bleeding were compared in patients receiving DAPT, monotherapy, and no antiplatelet therapy before surgery. Unadjusted risk ratios were calculated taking monotherapy as the baseline. The adjusted risks of bleeding and MACE were compared in patients receiving monotherapy and DAPT using propensity score matching. RESULTS: A total of 917 patients were recruited and 847 were eligible for inclusion. Ninety-six patients received no antiplatelet therapy, 526 received monotherapy with aspirin, and 225 received DAPT. Thirty-two patients suffered MACE and 22 had bleeding. The unadjusted risk ratio for MACE in patients receiving DAPT compared with monotherapy was 1.9 (0.93-3.88), P=0.08. There was no difference in MACE between no antiplatelet treatment and monotherapy 1.03 (0.31-3.46), P=0.96. Bleeding was more frequent with DAPT 6.55 (2.3-17.96) P=0.0002. In a propensity matched analysis of 177 patients who received DAPT and 177 monotherapy patients, the risk ratio for MACE with DAPT was 1.83 (0.69-4.85), P=0.32. The risk of bleeding was significantly greater in the DAPT group 4.00 (1.15-13.93), P=0.031. CONCLUSIONS: OBTAIN showed an increased risk of bleeding with DAPT and found no evidence for protective effects of DAPT from perioperative MACE in patients who have undergone previous PCI.

Intravenous tranexamic acid and lower limb arthroplasty-a randomised controlled feasibility study.

Tranexamic acid (TA) is widely reported to reduce bleeding and the risk of blood transfusion in patients undergoing lower limb arthroplasty. No study in this setting has had adequate power to examine for the effect of TA on either uncommon, but clinically important, adverse events or patient-centric endpoints. A large randomised controlled trial (RCT) is required to address these questions. As a preliminary feasibility study, we conducted an investigator-initiated, prospective, randomised, double blind placebo-controlled trial in 140 patients, aged 45 years or older, undergoing elective primary or revision hip or knee joint replacement. Subjects were randomised to receive intravenous (IV) TA or a placebo. The primary endpoints were the proportion of patients receiving allogenic blood transfusion and the feasibility of extending our trial methodology to a large trial of TA in this population. Secondary endpoints included a range of adverse clinical and surgical events as well as several patient-centric questionnaires. Red blood cell transfusion occurred in 15% of all patients prior to discharge from hospital. Transfusion rates were significantly different between the TA and placebo groups (8.5% versus 21.7%, P=0.03). Three out of four feasibility endpoints were met, with recruitment being slower than expected. No significant differences were seen between groups in the secondary endpoints. Despite a lower rate of transfusion than that widely reported, IV TA reduced transfusion in patients undergoing lower limb arthroplasty. Our trial methodology would be feasible in the setting of a large multicentre study to investigate whether TA is safe and reduces bleeding in lower limb arthroplasty.

Paediatric antiepileptic polytherapy: systematic review of efficacy and neurobehavioural effects and a tertiary centre experience.

AIM: This paper presents the prevalence of antiepileptic polytherapy at a single tertiary institution and systematically reviews the evidence base for its efficacy and neurobehavioural safety in children. METHOD: Prevalence of antiepileptic polypharmacy was determined from pharmacy dispensing records at a paediatric tertiary hospital and neurobehavioural comorbidities quantified through casenote review; comparison is made with studies evaluating the neurobehavioural safety of antiepileptic polytherapy, identified via systematic literature review. RESULTS: Amongst 262 patients at the hospital, 117 (44.7%) were prescribed polytherapy; with patients having an intellectual disability statistically more likely to be prescribed polytherapy than those without (70.5% vs 40.6%; p < 0.0001). Systematic review identified no trials addressing the efficacy or neurobehavioural outcomes of polytherapy as a primary outcome. Several observational studies identified associations between polytherapy and neurobehavioural adverse outcomes such as anxiety and behavioural disturbance. Observational studies also suggest that a reduction in polytherapy load is generally not associated with worsening seizure control. CONCLUSION: Whilst antiepileptic polytherapy is common practice within paediatric epilepsy cohorts attending tertiary care institutions, evidence is lacking to support its efficacy. There are significant practical difficulties to undertaking randomised controlled trials within this population. Nonetheless, clinicians must consider that adverse neurobehavioural consequences of polytherapy might outweigh benefits to seizure control.