Introduction
Medications are compounded when a formulation of a medication is needed but not commercially available. Regulatory oversight of compounding is piecemeal and compounding errors have ...resulted in patient harm. We review compounding in the United States (US), including a history of compounding, a critique of current regulatory oversight, and a systematic review of compounding errors recorded in the literature.
Methods
We gathered reports of compounding errors occurring in the US from 1990 to 2020 from PubMed, Embase, several relevant conference abstracts, and the US Food and Drug Administration “Drug Alerts and Statements” repository. We categorized reports into errors of “contamination,” suprapotency,” and “subpotency.” Errors were also subdivided by whether they resulted in morbidity and mortality. We reported demographic, medication, and outcome data where available.
Results
We screened 2155 reports and identified 63 errors. Twenty-one of 63 were errors of concentration, harming 36 patients. Twenty-seven of 63 were contamination errors, harming 1119 patients. Fifteen errors did not result in any identified harm.
Discussion
Compounding errors are attributed to contamination or concentration. Concentration errors predominantly result from compounding a prescription for a single patient, and disproportionately affect children. Contamination errors largely occur during bulk distribution of compounded medications for parenteral use, and affect more patients. The burden falls on the government, pharmacy industry, and medical providers to reduce the risk of patient harm caused by compounding errors.
Conclusion
In the US, drug compounding is important in ensuring access to vital medications, but has the potential to cause patient harm without adequate safeguards.
Neuropathic pain, caused by various central and peripheral nerve disorders, is especially problematic because of its severity, chronicity and resistance to simple analgesics. The condition affects ...2%-3% of the population, is costly to the health care system and is personally devastating to the people who experience it. The diagnosis of neuropathic pain is based primarily on history (e.g., underlying disorder and distinct pain qualities) and the findings on physical examination (e.g., pattern of sensory disturbance); however, several tests may sometimes be helpful. Important pathophysiologic mechanisms include sodium-and calcium-channel upregulation, spinal hyperexcitability, descending facilitation and aberrant sympathetic-somatic nervous system interactions. Treatments are generally palliative and include conservative nonpharmacologic therapies, drugs and more invasive interventions (e.g., spinal cord stimulation). Individualizing treatment requires consideration of the functional impact of the neuropathic pain (e.g., depression, disability) as well as ongoing evaluation, patient education, reassurance and specialty referral. We propose a primary care algorithm for treatments with the most favourable risk-benefit profile, including topical lidocaine, gabapentin, pregabalin, tricyclic antidepressants, mixed serotonin-norepinephrine reuptake inhibitors, tramadol and opioids. The field of neuropathic pain research and treatment is in the early stages of development, with many unmet goals. In coming years, several advances are expected in the basic and clinical sciences of neuropathic pain, which will provide new and improved therapies for patients who continue to experience this disabling condition.
Cancer incidence increases with age and is a leading cause of death. Caloric restriction (CR) confers benefits on health and survival and delays cancer. However, due to CR's stringency, dietary ...alternatives offering the same cancer protection have become increasingly attractive. Short cycles of a plant-based diet designed to mimic fasting (FMD) are protective against tumorigenesis without the chronic restriction of calories. Yet, it is unclear whether the fasting time, level of dietary restriction, or nutrient composition is the primary driver behind cancer protection. Using a breast cancer model in mice, we compare the potency of daily CR to that of periodic caloric cycling on FMD or an isocaloric standard laboratory chow against primary tumor growth and metastatic burden. Here, we report that daily CR provides greater protection against tumor growth and metastasis to the lung, which may be in part due to the unique immune signature observed with daily CR.
During sleep, the widespread coordination of neuronal oscillations across both cortical and subcortical brain regions is thought to support various physiological functions. However, how sleep-related ...activity within the brain's largest sensorimotor structure, the cerebellum, is multiplexed with well-described sleep-related mechanisms in regions such as the hippocampus remains unknown. We therefore simultaneously recorded from the dorsal hippocampus and three distinct regions of the cerebellum (Crus I, lobule VI, and lobules II/III) in male mice during natural sleep. Local field potential (LFP) oscillations were found to be coordinated between these structures in a sleep stage-specific manner. During non-REM sleep, prominent δ frequency coherence was observed between lobule VI and hippocampus, whereas non-REM-associated hippocampal sharp-wave ripple activity evoked discrete LFP modulation in all recorded cerebellar regions, with the shortest latency effects in lobule VI. We also describe discrete phasic sharp potentials (PSPs), which synchronize across cerebellar regions and trigger sharp-wave ripple suppression. During REM, cerebellar δ phase significantly modulated hippocampal theta frequency, and this effect was greatest when PSPs were abundant. PSPs were phase-locked to cerebellar δ oscillation peak and hippocampal theta oscillation trough, respectively. Within all three cerebellar regions, prominent LFP oscillations were observed at both low (δ, <4 Hz) and very high frequencies (∼250 Hz) during non-REM and REM sleep. Intracerebellar cross-frequency analysis revealed that δ oscillations modulate those in the very high-frequency range. Together, these results reveal multiple candidate physiological mechanisms to support "offline," bidirectional interaction within distributed cerebello-hippocampal networks.
Sleep is associated with widespread coordination of activity across a range of brain regions. However, little is known about how activity within the largest sensorimotor region of the brain, the cerebellum, is both intrinsically organized and links with higher-order structures, such as the hippocampus, during sleep. By making multisite local field potential recordings in naturally sleeping mice, we reveal and characterize multiple sleep stage-specific physiological mechanisms linking three distinct cerebellar regions with the hippocampus. Central to these physiological mechanisms is a prominent δ (<4 Hz) oscillation, which temporally coordinates both intracerebellar and cerebello-hippocampal network dynamics. Understanding this distributed network activity is important for gaining insight into cerebellar contributions to sleep-dependent processes, such as memory consolidation.
State-of-the-art radial-velocity (RV) exoplanet searches are currently limited by RV signals arising from stellar magnetic activity. We analyze solar observations acquired over a 3 yr period during ...the decline of Carrington Cycle 24 to test models of RV variation of Sun-like stars. A purpose-built solar telescope at the High Accuracy Radial-velocity Planet Searcher for the Northern hemisphere (HARPS-N) provides disk-integrated solar spectra, from which we extract RVs and log R HK ′ . The Solar Dynamics Observatory (SDO) provides disk-resolved images of magnetic activity. The Solar Radiation and Climate Experiment (SORCE) provides near-continuous solar photometry, analogous to a Kepler light curve. We verify that the SORCE photometry and HARPS-N log R HK ′ correlate strongly with the SDO-derived magnetic filling factor, while the HARPS-N RV variations do not. To explain this discrepancy, we test existing models of RV variations. We estimate the contributions of the suppression of convective blueshift and the rotational imbalance due to brightness inhomogeneities to the observed HARPS-N RVs. We investigate the time variation of these contributions over several rotation periods, and how these contributions depend on the area of active regions. We find that magnetic active regions smaller than 60 Mm2 do not significantly suppress convective blueshift. Our area-dependent model reduces the amplitude of activity-induced RV variations by a factor of two. The present study highlights the need to identify a proxy that correlates specifically with large, bright magnetic regions on the surfaces of exoplanet-hosting stars.
The importance of ice cliffs for glacier-scale ablation on debris-covered glaciers is now widely recognised. However, a paucity of data exists to describe the spatio-temporal distribution of ice ...cliffs. In this study we analysed the position and geometry of 8229 ice cliffs and 5582 supraglacial ponds on 14 glaciers in the Everest region between 2000 and 2015. We observed notable ice cliff and pond spatial coincidence. On average across our study glaciers, 77% of supraglacial pond area was associated with an adjacent ice cliff, and 49% of ice cliffs featured an adjacent supraglacial pond. The spatial density of ice cliffs was not directly related to glacier velocity, but did peak within zones of active ice. Furthermore, we found that ice cliff density was glacier-specific, temporally variable, and was positively correlated with surface lowering and decreasing debris thickness for individual glaciers. Ice cliffs predominantly had a north-facing (commonly north-westerly) aspect, which was independent of glacier flow direction, thereby signifying a strong solar radiation control on cliff evolution. Independent field observations indicated that cliff morphology was related to aspect, local debris thickness, and presence of a supraglacial pond, and highlighted the importance of surface runnel formation, which acts as a preferential pathway for meltwater and debris fluxes. Overall, by coupling remote sensing and in-situ observations it has been possible to capture local and glacier-scale ice cliff dynamics across 14 glaciers, which is necessary if explicit parameterisation of ice cliffs in dynamic glacier models is to be achieved.
•We analysed ice cliffs and supraglacial ponds on 14 glaciers (2000–2015).•Ice cliffs predominantly had north-facing aspects, independent of glacier flow direction.•Ice cliff density was positively correlated with surface lowering.•Ice cliff density peaked within zones of active ice flow.•49% of ice cliffs featured an adjacent supraglacial pond.
Black and Hispanic/Latinx cisgender men who have sex with men (MSM), transgender women, transgender men, and gender nonbinary (TGNB) individuals have been historically underrepresented in HIV ...pre-exposure prophylaxis (PrEP) clinical trials. There is an urgent need for ongoing engagement with communities that have been the most impacted by HIV and diverse representation in clinical trials. Here we describe strategic approaches undertaken in the PURPOSE 2 trial to optimize engagement of underrepresented individuals.
PURPOSE 2 is an ongoing Phase 3 trial evaluating the safety and efficacy of lenacapavir as PrEP in cisgender MSM and TGNB individuals. In PURPOSE 2, we used a multipronged approach aimed at enriching participation of underrepresented individuals. We conducted a review to identify evidence-informed recommendations from literature, engaged with stakeholders, and established the Global Community Advisory and Accountability Group (GCAG) to represent the needs of the community. Insights from stakeholders and GCAG members resulted in an expansion of the study population to include transgender men, gender nonbinary persons, and adolescents, and evaluation of population-specific outcomes. Feedback from stakeholders and GCAG members also informed investigator and site selection; these were selected based on prior experience working with persons from diverse racial, ethnic and gender identities, and estimates of local HIV incidence. Site selection was also expanded to include community-based clinics with services tailored towards Black, Hispanic/Latinx, and TGNB populations. We established a study-wide recruitment goal of 50% Black MSM and 20% Hispanic/Latinx MSM in US sites and 20% transgender women globally. Site-specific recruitment goals were also developed based on local demographics and HIV incidence. Mandatory trainings included Good Participatory Practice guidelines, gender inclusivity, and antiracism.
While further work is needed to achieve equitable representation, the strategies we describe may serve as a framework for future clinical trials.
Clinical Trial Number: NCT04925752.
Thermal inversions have long been predicted to exist in the atmospheres of ultra-hot Jupiters. However, the detection of two species thought to be responsible – titanium oxide and vanadium oxide – ...remains elusive. We present a search for TiO and VO in the atmosphere of the ultra-hot Jupiter WASP-121b (
T
eq
≳ 2400 K), an exoplanet with evidence of VO in its atmosphere at low resolution which also exhibits water emission features in its dayside spectrum characteristic of a temperature inversion. We observed its transmission spectrum with the UV-Visual Echelle Spectrograph at the Very Large Telescope and used the cross-correlation method – a powerful tool for the unambiguous identification of the presence of atomic and molecular species – in an effort to detect whether TiO or VO were responsible for the observed temperature inversion. No evidence for the presence of TiO or VO was found at the terminator of WASP-121b. By injecting signals into our data at varying abundance levels, we set rough detection limits of VO ≲−7.9 and TiO ≲−9.3. However, these detection limits are largely degenerate with scattering properties and the position of the cloud deck. Our results may suggest that neither TiO or VO are the main drivers of the thermal inversion in WASP-121b; however, until a more accurate line list is developed for VO, we cannot conclusively rule out its presence. Future works will consist of a search for other strong optically-absorbing species that may be responsible for the excess absorption in the red-optical.
The ability of medium-resolution (10–30 m) satellite imagery to delineate the size and persistence of ponds on debris-covered glaciers is a topic of recent interest as it has become apparent through ...the use of fine-resolution products that smaller ponds have often been neglected. In this study, we performed a quantitative analysis of pond detection using a normalised difference water index (NDWI) applied to several widely used satellite sensors, which offer multispectral information at high radiometric precision. These data include: RapidEye (5 m spatial resolution), Sentinel-2 Multispectral Instrument (MSI) (10–20 m), and Landsat 8 Operational Land Imager (OLI) multispectral imagery (30 m). We demonstrate a method to derive an optimum NDWI value for pond classification using a subset reference dataset of 285 ponds classified using fine-resolution (0.5 m) imagery. We then applied the optimised NDWI (NDWI-O) to the remaining images to assess pond classification accuracy against a broader reference dataset of 898 ponds. NDWI values calculated using Sentinel-2 imagery showed the best spectral contrast between water and surrounding debris cover, and the strongest relationship with pixel water content (R2 = 0.56), followed by the RapidEye NDWI (R2 = 0.45). We conclude that RapidEye and Sentinel-2 imagery is best suited for accurate pond classification using a multispectral classification approach, which is important for quantifying their role in glacier ablation, meltwater regulation, and lake development. By comparison, the impact of using coarse-resolution Landsat 8 imagery to characterise surface water dynamics is minimised when applied to large glacier lakes, where the area-to-perimeter ratio is greater.
•NDWI was optimised with a fine-resolution reference dataset of supraglacial ponds.•Sentinel-2 NDWI showed the best contrast between water and debris cover.•Landsat 8 pond classification had large omissions and commissions.•≤10 m resolution imagery is well suited for supraglacial pond classification.
Painful neuropathy is one of the most common long-term complications of diabetes mellitus and often proves difficult to relieve.
Patients with diabetic neuropathy with moderate or greater pain for at ...least 3 months, were evaluated for efficacy, safety and health-related quality of life (QOL) while receiving controlled-release (CR) oxycodone (OxyContin) or active placebo. Patients underwent washout from all opioids 2-7 days before randomization to 10 mg CR oxycodone or active placebo (0.25 mg benztropine) q12h. The dose was increased, approximately weekly, to a maximum of 40 mg q12h CR oxycodone or 1 mg q12h benztropine, with crossover to the alternate treatment after a maximum of 4 weeks. Acetaminophen, 325-650 mg q4-6h prn was provided as rescue.
Thirty-six patients were evaluable for efficacy (21 men, 15 women, mean age 63.0+/-9.4 years). CR oxycodone resulted in significantly lower (P=0.0001) mean daily pain (21.8+/-20.7 vs. 48.6+/-26.6 mm VAS), steady pain (23.5+/-23.0 vs. 47.6+/-30.7 mm VAS), brief pain (21.8+/-23.5 vs. 46.7+/-30.8 mm VAS), skin pain (14.3+/-20.4 vs. 43.2+/-31.3 mm VAS), and total pain and disability (16.8+/-15.6 vs. 25.2+/-16.7; P=0.004). Scores from 6 of the 8 SF-36 domains and both summary scales, Standardized Physical Component (P=0.0002) and Standardized Mental Component (P=0.0338) were significantly better during CR oxycodone treatment. The number needed to treat to obtain one patient with at least 50% pain relief is 2.6 and clinical effectiveness scores favoured treatment with CR oxycodone over placebo (P=0.0001).
CR oxycodone is effective and safe for the management of painful diabetic neuropathy and improves QOL.
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