In this paper we prove sharp regularity for a differential inclusion into a set
K
⊂
R
2
×
2
that arises in connection with the Aviles–Giga functional. The set
K
is not elliptic, and in that sense our ...main result goes beyond Šverák’s regularity theorem on elliptic differential inclusions. It can also be reformulated as a sharp regularity result for a critical nonlinear Beltrami equation. In terms of the Aviles–Giga energy, our main result implies that zero energy states coincide (modulo a canonical transformation) with solutions of the differential inclusion into
K
. This opens new perspectives towards understanding energy concentration properties for Aviles–Giga: quantitative estimates for the stability of zero energy states can now be approached from the point of view of stability estimates for differential inclusions. All these reformulations of our results are strong improvements upon a recent work by the last two authors, Lorent and Peng, where the link between the differential inclusion into
K
and the Aviles–Giga functional was first observed and used. Our proof relies moreover on new observations concerning the algebraic structure of entropies.
In early clinical development, randomized controlled trials (RCT) or single‐arm trials with external controls (SATwEC) are design options, which allow adjustment for confounding: RCT via design, ...SATwEC via analysis using propensity score methods. SATwEC requires less investment than RCT. However, if the confounder space substantially differs between the experimental and external control group, the SATwEC might lead to inappropriate decisions for further development. We develop an adaptive two‐stage design (ATD) for early clinical development that reduces the risk of unreliable decision‐making at the end of a SATwEC. In Stage I, subjects are solely assigned to the experimental group. If at the interim the propensity score distributions of internal and external data are comparable based on the preference score, the subjects in stage II will again be solely assigned to the experimental arm; if not, a randomized stage II will be conducted. In a simulation study guided by a motivating example, data is generated using a time‐to‐event model with observable and unobservable confounders. The confounder space is varied to investigate the impact on false go/stop probabilities as well as a loss function, which reflects the quality of treatment effect estimates and decision‐making. The proposed ATD provides a compromise between optimizing quality (as expressed by false go/stop probabilities and the loss function) and investment (defined by sample size and trial duration).
For a smooth bounded domain
G
⊂
R
3
, we consider maps
n
:
R
3
\
G
→
S
2
minimizing the energy
E
(
n
)
=
∫
R
3
\
G
|
∇
n
|
2
+
F
s
(
n
⌊
∂
G
)
among
S
2
-valued map such that
n
(
x
)
≈
n
0
as
|
x
|
→
...∞
. This is a model for a particle
G
immersed in nematic liquid crystal. The surface energy
F
s
describes the anchoring properties of the particle and can be quite general. We prove that such minimizing map
n
has an asymptotic expansion in powers of 1/
r
. Further, we show that the leading order 1/
r
term is uniquely determined by the far-field condition
n
0
for almost all
n
0
∈
S
2
, by relating it to the gradient of the minimal energy with respect to
n
0
. We derive various consequences of this relation in physically motivated situations: when the orientation of the particle
G
is stable relative to a prescribed far-field alignment
n
0
; and when the particle
G
has some rotational symmetries. In particular, these corollaries justify some approximations that can be found in the physics literature to describe nematic suspensions via a so-called electrostatics analogy.
Although depression and cognitive dysfunction are connected, limited tools exist to capture the patient's perspective on cognitive dysfunction and its impact on major depressive disorder (MDD). We ...report results of a psychometric validation of the Perceived Deficits Questionnaire-Depression (PDQ-D), a self-report measure of cognitive dysfunction for use in MDD.
A non-interventional, prospective, panel-recruited, online survey was conducted using the PDQ-D in adults with and without MDD in the US and UK. Respondents were assessed at baseline and after 6 weeks (MDD only) (baseline: US n=418, UK n=437, 49% MDD; follow-up: US n=169, UK n=153, all MDD). The criterion measures included: Medical Outcomes Study Cognitive Functioning Scale-Revised-acute form (MOS COG-R), Patient Health Questionnaire-9 (PHQ-9), Patient Global Impression of Severity scale (PGI-Severity), Sheehan Disability Scale (SDS), Work Productivity and Activity Impairment Questionnaire: Specific-Health Problem (WPAI:SHP), and modified Lam Employment Absence and Productivity Scale (LEAPS). US and UK data were analyzed separately.
Internal consistency was high for PDQ-D total scale and four subscales (Cronbach's alpha 0.81-0.96). Convergent validity was good, with strong concordance with MOS COG-R and moderate/small correlations with PHQ-9, SDS, WPAI:SHP, LEAPS, and PGI-Severity. Significant differences (all
<0.001) existed for all PDQ-D subscale and total scores between MDD/non-MDD samples. The PDQ-D was responsive to changes in depression symptom severity. Confirmatory factor analysis supported scoring of a global overall scale for perceived cognitive dysfunction.
The PDQ-D provides a reliable and valid measure of subjective cognitive dysfunction in patients with MDD.
We consider a nematic liquid crystal occupying the three-dimensional domain in the exterior of a spherical colloid particle. The nematic is subject to Dirichlet boundary conditions that enforce ...orthogonal attachment of nematic molecules to the surface of the particle. Our main interest is to understand the behavior of energy-critical configurations of the Landau–de Gennes
Q
-tensor model in the limit of vanishing correlation length. We demonstrate existence of configurations with a single Saturn-ring defect approaching the equator of the particle and no other line or point defects. We show this by analyzing asymptotics of energy minimizers under two symmetry constraints: rotational equivariance around the vertical axis and reflection across the horizontal plane. Energy blow-up at the ring defect is a significant obstacle to constructing well-behaved comparison maps needed to eliminate the possibility of point defects. The boundary estimates we develop to address this issue are new and should be applicable to a wider class of problems.
Background
Limited data are available regarding second‐line (2 L) treatment for advanced or metastatic biliary tract cancers (BTC) in the US real‐world setting. This study explores the rapidly ...evolving and growing treatment landscape in the 2 L setting for advanced or metastatic BTC with a large cohort of patients treated in a community oncology setting.
Methods
Adult patients with BTC initiating 2 L treatment after a platinum‐containing first‐line between 1/1/10‐ and 6/30/19 were identified from the US Oncology Network electronic healthcare record database and followed through 12/31/19. Baseline patient and treatment characteristics were analyzed descriptively, including overall response rate (ORR) in the real‐world clinical setting. Kaplan–Meier methods were used to measure duration of response, progression‐free survival (PFS), and overall survival (OS).
Results
The overall population (N = 160) included 74 patients (46.3%) with intrahepatic cholangiocarcinoma, 41 (25.6%) with extrahepatic cholangiocarcinoma, and 45 (28.1%) with gallbladder cancer. Thirty unique 2 L regimens were recorded for the study population, with folinic acid, fluorouracil and oxaliplatin (FOLFOX, 34.4%) and capecitabine monotherapy (20.0%) being the most common. ORR was 7.5% (95% CI, 3.9%–12.7%). From 2 L initiation, median PFS was 2.8 months (95% CI, 2.4–3.3 months), and median OS was 5.2 months (95% CI, 4.2–6.7 months).
Conclusion
Results from this study provide real‐world evidence that although patients treated in the community oncology setting receive a wide variety of 2 L treatments, the regimens are consistent with those recommended by guidelines. Although responses are observed with 2 L treatment, duration is brief and associated with poor OS in patients with advanced or metastatic disease.
High‐dose corticosteroids have been associated with increased risk of serious infection in patients with metastatic melanoma treated with immune checkpoint inhibitors targeting cytotoxic T‐lymphocyte ...antigen 4. This potential association needs to be examined further among patients with other cancer types and for other immune checkpoint inhibitors. We examined whether receipt of high‐dose corticosteroids was associated with increased rates of hospitalization for infection among 981 Danish renal, urothelial, and lung cancer patients followed from first administration of programmed death receptor 1 (PD‐1)/programmed death ligand 1 (PD‐L1) immune checkpoint inhibitors. Our cohort analysis was based on the information from national medical registries. During follow‐up, 522 patients (53.2%) initiated treatment with high‐dose corticosteroids and 317 patients (32.3%) experienced at least one hospitalization for infection. In analyses adjusted for age, sex, and previous use of chemotherapy/targeted therapy, initiation of high‐dose systemic corticosteroids was associated with increased rate of hospitalization for infections (hazard ratio (HR) = 2.96, 95% confidence interval (CI) = 2.41–3.65) even in patients not receiving any chemotherapy/targeted therapy (HR = 3.66, 95% CI = 2.25–5.96). Our findings showed that high‐dose corticosteroid initiation is associated with hospitalization for infection in patients treated with PD‐1/PD‐L1 immune checkpoint inhibitors. Clinicians and patients should be aware of this risk of infection when initiating treatment with high‐dose corticosteroids.
High‐dose corticosteroids have been associated with increased risk of serious infection in metastatic melanoma patients treated with immune checkpoint inhibitors (ICIs) targeting cytotoxic T‐lymphocyte antigen 4. The present study adds that use of high‐dose corticosteroids is also associated with increased rate of hospitalization for infection among lung, kidney, and urothelial cancer patients treated with ICIs targeting programmed death receptor 1 or programmed death ligand 1 even in patients who did not receive chemotherapy/targeted therapy.
Patients who require a switch in their antidepressant therapy may have different clinical profiles and treatment needs compared with patients initiating or maintaining a first-line antidepressant ...therapy.
The Prospective Epidemiological Research on Functioning Outcomes Related to Major depressive disorder (MDD) (PERFORM) study was a 2-year observational cohort study in outpatients with MDD in five European countries. Enrolled patients were either initiating or undergoing the first switch to an antidepressant monotherapy. Baseline data on patients' clinical status, functioning, productivity, quality of life and medical-resource use were compared in a cross-sectional baseline analysis.
A total of 1402 patients were enrolled, of whom 1159 (82.7%) provided analysable baseline data. The majority (78.7%) of the analysable population were initiating antidepressant treatment and most (83.6%) were enrolled and followed up by general practitioners. Compared with patients initiating antidepressants, those switching antidepressants (21.3%) tended to have more severe depressive symptoms, greater anxiety, worse health-related quality of life, greater functional impairment, greater medical-resource use and had a different medical history. Limitations included an over-representation of switches due to lack of efficacy among patients who were switching treatment, as patients were selected based on presence of depressive symptoms.
Patients with MDD who are switching treatment for the first time have a different profile and different depression-associated health needs compared with those initiating treatment. Therapeutic management should therefore be adapted for patients who switch.
ClinicalTrials.gov NCT01427439 ; Retrospectively registered 26 August 2011.
Background Detailed epidemiologic descriptions of large populations of advanced stage ovarian cancer patients have been lacking to date. This study aimed to describe the patient characteristics, ...treatment patterns, survival, and incidence rates of health outcomes of interest (HOI) in a large cohort of advanced stage ovarian cancer patients in the United States (US). Methods This cohort study identified incident advanced stage (III/IV) ovarian cancer patients in the US diagnosed from 2010 to 2018 in the HealthCore Integrated Research Database (HIRD) using a validated predictive model algorithm. Descriptive characteristics were presented overall and by treatment line. The incidence rates and 95% confidence intervals for pre-specified HOIs were evaluated after advanced stage diagnosis. Overall survival, time to treatment discontinuation or death (TTD), and time to next treatment or death (TTNT) were defined using treatment information in claims and linkage with the National Death Index. Results We identified 12,659 patients with incident advanced stage ovarian cancer during the study period. Most patients undergoing treatment received platinum agents (75%) and/or taxanes (70%). The most common HOIs (> 24 per 100 person-years) included abdominal pain, nausea and vomiting, anemia, and serious infections. The median overall survival from diagnosis was 4.5 years, while approximately half of the treated cohort had a first-line time to treatment discontinuation or death (TTD) within the first 4 months, and a time to next treatment or death (TTNT) from first to second-line of about 6 months. Conclusions This study describes commercially insured US patients with advanced stage ovarian cancer from 2010 to 2018, and observed diverse treatment patterns, incidence of numerous HOIs, and limited survival in this population. Keywords: Epidemiology, Ovarian Cancer, Advanced stage, Treatment patterns, Health outcome of interest, Survival
BACKGROUND Different pharmaceutical forms of oral tacrolimus allow tailored administration. The granular formulation facilitates accurate dose adjustment of tacrolimus according to patient ...characteristics, such as weight, or potential concomitant drug interactions. Currently, there are no data describing the use of tacrolimus granules in transplant recipients in France. MATERIAL AND METHODS OPTIMOD was a 6-month prospective, observational multicenter study that aimed to describe patient characteristics and conditions of use of tacrolimus granules. The 25 participating centers enrolled patients at time of tacrolimus granules initiation and were to collect patient and treatment data at initiation and after 6 months of follow-up. All analyses were descriptive. RESULTS Of 61 patients included, 55.7% were children (mainly kidney graft recipients) and 44.3% were adults (mostly lung graft recipients). Overall, 24.6% of patients (all children) initiated tacrolimus granules immediately post-transplant; the remaining 75.4% converted to tacrolimus granules from ciclosporin or immediate-release tacrolimus hard capsules. The main reasons for initiating tacrolimus granules, irrespective of whether first- or second-line therapy, were to offset potential drug-drug interactions in adults by adjusting dose, and to adapt to the particular needs of children as patients. Most patients (78.7%) underwent ≥1 dose modification during follow-up. Eleven rejection episodes occurred during follow-up, of which none led to graft loss. The adverse-event profile of the tacrolimus granules was similar to that of other tacrolimus formulations and 7 treatment-related adverse events were recorded. CONCLUSIONS Results suggest that tacrolimus granules are well tolerated and effective in preventing transplant rejection when administered in routine practice in France.
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