In the US, there are no effective regulations controlling how much the price of a medication can increase. A patchwork of studies examining the reasons for soaring prices has focused on medications ...that have received considerable media attention, like insulin, epinephrine, and colchicine.
To identify the 50 medications with the greatest increase in average spending per beneficiary and the 50 medications with the greatest decrease in average spending per beneficiary, and to identify the factors associated with spending increases.
This cross-sectional study used publicly available data from the Medicare Part D Prescription Drug Program from 2014 to 2020. We included drugs dispensed to > 1000 beneficiaries in each study year and excluded those primarily administered intravenously.
Percentage change in average spending per beneficiary from 2014 to 2020 was calculated for each drug. For each drug, we extracted the number of beneficiaries, the number of manufacturers, and the drug-specific total annual spending reported in the Medicare Part D data set. An online database search was conducted to identify the primary clinical indication, the availability of any generic versions, and the date of FDA approval for each drug.
The 50 medications with the greatest increase in spending per beneficiary had a median increase of 362.4% (interquartile range IQR: 286.6%-563.0%), with a cumulative spending of almost $5 billion in 2020 alone. Most drugs with the greatest increases in spending per beneficiary had generic versions available (68%) and were approved by the FDA over 10 years ago (66%). Medications with the greatest increase in spending per beneficiary had a median of 1 manufacturer (IQR: 1-2), while medications with the greatest decrease in spending per beneficiary had a median of 9.5 manufacturers (IQR: 5-14).
This study identified rapidly increasing costs of medications under Medicare Part D. Our findings demonstrate that off-patent medications can skyrocket in price, especially when there are few manufacturers of a given medication.
Primary progressive aphasia (PPA) is associated with progressive loss of language functions in the context of irreversible neurodegeneration, for which there is no cure. Speech-language therapy can ...help preserve language abilities, and most promisingly, interventions like transcranial direct current stimulation (tDCS) have been shown to augment the effectiveness of therapy. However, the underlying mechanism for this enhancement is unknown.
We evaluated the behavioural and physiological (using resting-state magnetoencephalography rsMEG) effects of contemporary naming treatment provided with tDCS in a patient with an advanced case of nonfluent variant PPA (P01; 67 year old male). P01 was mute but had preserved written abilities, which we aimed to enhance with written naming therapy and excitatory or anodal-tDCS. We hypothesized greater improvement in written performance, particularly immediate gains, maintenance, and generalization, after anodal- than sham-tDCS. Additionally, reductions in oscillatory abnormal activity, as indicated by rsMEG, were expected after repeated sessions of anodal-tDCS with the naming treatment.
A written picture naming therapy was paired with five sessions of anodal and five sessions of sham high-definition tDCS over two weeks. Anatomical and neurophysiological abnormalities were mapped with structural-MRI and rsMEG, respectively. TDCS was targeted towards an anatomically intact left supramarginal gyrus. The therapy-induced changes in written performance were evaluated on both trained and untrained pictures using Levenshtein Distances (LD). The neurophysiological changes were evaluated by comparing spectral relative power estimates in frequency bands ranging from delta to low-gamma (1-50 Hz), before and after therapy. All evaluations were completed immediately after therapy with sham- and anodal-tDCS, and at a 3-month follow-up.
Compared to sham-tDCS, anodal-tDCS augmented the immediate therapy-induced gains on trained items, as indicated by reductions in LD scores, reflecting improvement in written performance, particularly for more difficult target words. Neural activity at the stimulation spot and in surrounding and remote regions exhibited reduced oscillatory slowing, both immediately after one session (short-term) and after completion of five sessions (long-term) of anodal-tDCS compared to sham-tDCS. This is manifested as decreased theta (1-4 Hz) and increased beta and low-gamma (15-50 Hz) power. No additional gains with anodal-tDCS were found on untrained items (generalization) or at 3-month follow-up (maintenance).
Our findings suggest that five sessions of anodal-tDCS can improve written performance by partially reversing abnormal neural activity and thus boosting the functional capacity of the structurally intact cortex. Longer duration of treatment may be needed for additional gains in maintenance and generalization with anodal-tDCS.
Sodium glucose co-transporter-2 inhibitors (SGLT-2i) are increasingly being used among hospitalized patients. Our objective was to assess the risk of diabetic ketoacidosis (DKA) among hospitalized ...patients receiving an SGLT-2i.
We conducted a multicentre cohort study of patients hospitalized at 19 hospitals. We included patients over 18 years of age who received an SGLT-2i or a dipeptidyl peptidase-4 inhibitor (DPP-4i) in hospital. The primary outcome was the risk of DKA during their hospitalization.
61,517 patients received a DPP-4i and 11,061 received an SGLT-2i. The risk of inpatient DKA was 0.07 % (N = 41 events) among adults who received a DPP-4i and 0.18 % (N = 20 events) among adults who received an SGLT-2i; adjusted odds ratio of 3.30 (95 % CI: 1.85–5.72).
In hospitalized patients, the absolute risk of DKA was 0.2 %, which corresponded to a three-fold higher relative risk.
•We conducted a multicentre cohort study of hospitalized adults to examine the risk of diabetic ketoacidosis (DKA) among patients who received an SGLT2 inhibitor in hospital (SGLT-2i).•The absolute risk of DKA with SGLT-2i was 0.2%, results consistent with a recent meta-analysis of SGLT-2i use in the outpatient setting.
Importance
Results from high-profile randomized controlled trials (RCTs) are routinely reported through press release months prior to peer-reviewed publication. There are potential benefits to press ...releases (e.g., knowledge dissemination, ensuring regulatory compliance), but also potential drawbacks (e.g., selective reporting, positive “spin”).
Objective
To characterize the practice of press release predating the publication of a drug-related RCT in a peer-reviewed journal (“preemptive press release”), including factors associated with this practice.
Design, Setting, and Participants
We systematically reviewed all RCTs of medications published between 2015 and 2019 in the
New England Journal of Medicine
(
NEJM
),
Journal of the American Medical Association
(
JAMA
), and
Lancet
. Press releases were identified using a systematic search of the grey literature (e.g., press release databases, study sponsor websites). An RCT was considered to have a preemptive press release if the press release was published at least three months (90 days) prior to the date of publication in a peer-reviewed journal.
Main Outcomes and Measures
Presence of preemptive press release, defined as a press-release at least 90 days prior to the date of publication in a peer-reviewed journal. As secondary measures for dissemination, we also assessed citation count and Altmetric score.
Results
We identified 988 RCTs, of which 172 (17%) had a press release published at least 90 days before the date of peer-reviewed publication. Press releases were published a median of 246 days (interquartile range IQR 169–366 days) before publication in a peer-reviewed journal. In the multivariable logistic regression model, the strongest predictor of having a preemptive press release was funding by a pharmaceutical company (odds ratio 13, 95% CI 7, 25). Approximately 85% of RCTs with preemptive press releases had a positive primary outcome and, concordantly, 81% of the corresponding press releases had a positive headline. Multivariable regression models identified studies with a preemptive press release had a similar Altmetric score (median − 15, 95% CI − 33, 12) and higher median citation count (median 22 95% CI 10 to 33 compared to studies without a preemptive press release.
Conclusions and Relevance
Preemptive press releases were common, most often issued for trials funded by a pharmaceutical company, and typically preceded publication in a peer-reviewed journal by approximately eight months.
Widespread structural brain abnormalities have been consistently reported in schizophrenia, but their relation to the heterogeneous clinical manifestations remains unknown. In particular, it is ...unclear whether anatomical abnormalities in discrete regions give rise to discrete symptoms or whether distributed abnormalities give rise to the broad clinical profile associated with schizophrenia. Here, we apply a multivariate data-driven approach to investigate covariance patterns between multiple-symptom domains and distributed brain abnormalities in schizophrenia. Structural magnetic resonance imaging and clinical data were derived from one discovery sample (133 patients and 113 controls) and one independent validation sample (108 patients and 69 controls). Disease-related voxel-wise brain abnormalities were estimated using deformation-based morphometry. Partial least-squares analysis was used to comprehensively map clinical, neuropsychological, and demographic data onto distributed deformation in a single multivariate model. The analysis identified 3 latent clinical-anatomical dimensions that collectively accounted for 55% of the covariance between clinical data and brain deformation. The first latent clinical-anatomical dimension was replicated in an independent sample, encompassing cognitive impairments, negative symptom severity, and brain abnormalities within the default mode and visual networks. This cognitive-negative dimension was associated with low socioeconomic status and was represented across multiple races. Altogether, we identified a continuous cognitive-negative dimension of schizophrenia, centered on 2 intrinsic networks. By simultaneously taking into account both clinical manifestations and neuroanatomical abnormalities, the present results open new avenues for multi-omic stratification and biotyping of individuals with schizophrenia.
Abstract
Negative symptoms such as anhedonia and apathy are among the most debilitating manifestations of schizophrenia (SZ). Imaging studies have linked these symptoms to morphometric abnormalities ...in 2 brain regions implicated in reward and motivation: the orbitofrontal cortex (OFC) and striatum. Higher negative symptoms are generally associated with reduced OFC thickness, while higher apathy specifically maps to reduced striatal volume. However, it remains unclear whether these tissue losses are a consequence of chronic illness and its treatment or an underlying phenotypic trait. Here, we use multicentre magnetic resonance imaging data to investigate orbitofrontal-striatal abnormalities across the SZ spectrum from healthy populations with high schizotypy to unmedicated and medicated first-episode psychosis (FEP), and patients with chronic SZ. Putamen, caudate, accumbens volume, and OFC thickness were estimated from T1-weighted images acquired in all 3 diagnostic groups and controls from 4 sites (n = 337). Results were first established in 1 discovery dataset and replicated in 3 independent samples. There was a negative correlation between apathy and putamen/accumbens volume only in healthy individuals with schizotypy; however, medicated patients exhibited larger putamen volume, which appears to be a consequence of antipsychotic medications. The negative association between reduced OFC thickness and total negative symptoms also appeared to vary along the SZ spectrum, being significant only in FEP patients. In schizotypy, there was increased OFC thickness relative to controls. Our findings suggest that negative symptoms are associated with a temporal continuum of orbitofrontal-striatal abnormalities that may predate the occurrence of SZ. Thicker OFC in schizotypy may represent either compensatory or pathological mechanisms prior to the disease onset.
Abstract
Background
Although widespread structural brain abnormalities have been consistently reported in schizophrenia, their relation to the heterogeneous clinical manifestations is not well ...understood. Multivariate methods are needed to uncover covariance patterns between multiple symptom dimensions and system-wide brain imaging data.
Methods
This cross-sectional study used structural magnetic resonance imaging and neuropsychological data from 133 patients with chronic schizophrenia (48 female, 34.8±13.2 years) from the Northwestern University Schizophrenia Data and Software Tool (NUSDAST). We estimate disease-related voxel-wise tissue volume loss using deformation-based morphometry (DBM) of T1 weighted images. In patients with schizophrenia, multiple clinical dimensions including positive/negative symptoms and cognitive deficits, demographic data as well as individual tissue volume loss (DBM) were included in the multivariate model. Clinical-anatomical phenotypes were identified using partial least squares analysis.
Results
Multivariate analysis revealed three distinct clinical-anatomical phenotypes accounting for 27.5%, 15%, and 13% of the shared covariance between clinical-behavioural data and tissue volume loss (total of 55.5%). The first clinical-anatomical phenotype encompassed cognitive impairments, severity of negative symptoms and tissue volume loss within the default mode network and visual network. The second clinical-anatomical phenotype was associated with additional cognitive impairments and tissue volume loss within the frontoparietal and ventral attention network, while the third clinical-anatomical phenotype encompassed a mixed positive and negative symptoms phenotype and tissue volume loss within the dorsal attention network. Critically, the pattern of volume loss within the first most prevalent clinical-anatomical phenotype mediated (a*b) the effect of socioeconomic status on clinical outcome (cognitive performance and negative symptoms) (a*b=-0.033(0.008); P<1.0×〖10〗^(-4); 95% CI -0.049, -0.018). Finally, we partly replicated the first clinical-anatomical phenotype in an independent sample of patients with schizophrenia (n=108).
Discussion
The heterogeneous clinical manifestation of schizophrenia can be significantly explained by three clinical-anatomical phenotypes. Despite their distributed topography, each phenotype is centered on a specific, well-defined set of intrinsic networks.
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