A cross-sectional analysis of reporting guideline and clinical trial registration policies in nephrology journals.

OBJECTIVE: To determine the extent to which nephrology journals recommend and require reporting guideline adherence and clinical trial registration. BACKGROUND: Despite a rising disease burden, research published on chronic kidney disease (CKD) and the field of nephrology has failed to keep pace and is limited. To improve the quality of research in the field of nephrology, reporting guidelines have been developed to minimize such deficits in research quality. However, the extent to which nephrology journals require and use reporting guidelines in addition to clinical trial registration is unknown. METHODS: Sixty-two Nephrology journals were selected through the 2021 Scopus CiteScore tool. Each journal's Instructions for Authors was assessed to determine endorsement of study design-specific reporting guidelines or clinical trial registration. Researchers used R (version 4.2.1) and RStudio to create data summaries of descriptive statistics for nephrology journal reporting guidelines. RESULTS: Clinical trial registration was required by 52% (32/62) of nephrology journals within our sample. The reporting guideline for clinical trials, CONSORT, was required by 17.74% (11/62) of journals. The EQUATOR Network was mentioned by 46.77% (29/62) of journals, while 9.67% (6/62) failed to mention the ICMJE. The reporting guideline for systematic review, PRISMA, was only required by 12.90% (8/62) of journals. When contacting journal editors, 9.67% (6/62) responded and 4.83% (3/62) provided clarifying information. CONCLUSIONS: Reporting guidelines and clinical trial registration are suboptimally required and recommended by nephrology journals. Their adoption may decrease bias and increase research quality. Thus, nephrology journals should consider a more complete endorsement of these safeguards.

Assessing Patient Risk, Benefit, and Outcomes in Drug Development: A Decade of Lenvatinib Clinical Trials: A Systematic Review.

IMPORTANCE: Chemotherapy agents are typically initially tested in their most promising indications; however, following initial US FDA approval, new clinical trials are often initiated in less promising indications where patients experience a worse burden-benefit ratio. The current literature on the burden-benefit profile of lenvatinib in non-FDA-approved indications is lacking. OBJECTIVE: This study aimed to evaluate published clinical trials of lenvatinib in order to determine the burden-benefit profile for patients over time. EVIDENCE REVIEW: On 25 May 2023, we searched the Pubmed/MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov databases for clinical trials of lenvatinib used to treat solid cancers. Eligible articles were clinical trials, containing adult participants, published in English, and involving solid tumors. Screening and data collection took place in a masked, duplicate fashion. For each eligible study, we collected adverse event data, trial characteristics, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Trials were classified as positive when meeting their primary endpoint and safety, negative (not meeting either criteria), or indeterminate (lacking prespecified primary endpoint). FINDINGS: Expansion of clinical trial testing beyond lenvatinib's initial FDA indication demonstrated a consistent rise in cumulative adverse events, along with a decline in drug efficacy. Lenvatinib was tested in 16 cancer indications, receiving FDA approval in 4. A total of 5390 Grade 3-5 adverse events were experienced across 6225 clinical trial participants. Expanded indication testing further demonstrated widely variable ORR (11-69%), OS (6.2-32 months), and PFS (3.6-15.7 months) across all indications. After initial FDA approval, clinical trial results in expanded indications were less likely to meet their primary endpoints, particularly among non-randomized clinical trials. CONCLUSION AND RELEVANCE: Our paper evaluated the effectiveness of lenvatinib for its FDA-approved indications; however, expansion of clinical trials into novel indications was characterized by diminished efficacy, while patients experienced a high burden of adverse events consistent with lenvatinib's established safety profile. Furthermore, clinical trials testing in novel indications was marked by repeated phase I and II clinical trials along with a failure to progress to phase III clinical trials. Future clinical trials using lenvatinib as an intervention should carefully evaluate the potential benefits and burden patients may experience.

Trait Loss in Evolution: What Cavefish Have Taught Us about Mechanisms Underlying Eye Regression.

Reduction or complete loss of traits is a common occurrence throughout evolutionary history. In spite of this, numerous questions remain about why and how trait loss has occurred. Cave animals are an excellent system in which these questions can be answered, as multiple traits, including eyes and pigmentation, have been repeatedly reduced or lost across populations of cave species. This review focuses on how the blind Mexican cavefish, Astyanax mexicanus, has been used as a model system for examining the developmental, genetic, and evolutionary mechanisms that underlie eye regression in cave animals. We focus on multiple aspects of how eye regression evolved in A. mexicanus, including the developmental and genetic pathways that contribute to eye regression, the effects of the evolution of eye regression on other traits that have also evolved in A. mexicanus, and the evolutionary forces contributing to eye regression. We also discuss what is known about the repeated evolution of eye regression, both across populations of A. mexicanus cavefish and across cave animals more generally. Finally, we offer perspectives on how cavefish can be used in the future to further elucidate mechanisms underlying trait loss using tools and resources that have recently become available.

Constraints on the synchronization of entorhinal cortex stellate cells.

Synchronized oscillations of large numbers of central neurons are believed to be important for a wide variety of cognitive functions, including long-term memory recall and spatial navigation. It is therefore plausible that evolution has optimized the biophysical properties of central neurons in some way for synchronized oscillations to occur. Here, we use computational models to investigate the relationships between the presumably genetically determined parameters of stellate cells in layer II of the entorhinal cortex and the ability of coupled populations of these cells to synchronize their intrinsic oscillations: in particular, we calculate the time it takes circuits of two or three cells with initially randomly distributed phases to synchronize their oscillations to within one action potential width, and the metabolic energy they consume in doing so. For recurrent circuit topologies, we find that parameters giving low intrinsic firing frequencies close to those actually observed are strongly advantageous for both synchronization time and metabolic energy consumption.

Josephson junction simulation of neurons.

With the goal of understanding the intricate behavior and dynamics of collections of neurons, we present superconducting circuits containing Josephson junctions that model biologically realistic neurons. These "Josephson junction neurons" reproduce many characteristic behaviors of biological neurons such as action potentials, refractory periods, and firing thresholds. They can be coupled together in ways that mimic electrical and chemical synapses. Using existing fabrication technologies, large interconnected networks of Josephson junction neurons would operate fully in parallel. They would be orders of magnitude faster than both traditional computer simulations and biological neural networks. Josephson junction neurons provide a new tool for exploring long-term large-scale dynamics for networks of neurons.

Optimization of the leak conductance in the squid giant axon.

We report on a theoretical study showing that the leak conductance density, G{L} , in the squid giant axon appears to be optimal for the action potential firing frequency. More precisely, the standard assumption that the leak current is composed of chloride ions leads to the result that the experimental value for G{L} is very close to the optimal value in the Hodgkin-Huxley model, which minimizes the absolute refractory period of the action potential, thereby maximizing the maximum firing frequency under stimulation by sharp, brief input current spikes to one end of the axon. The measured value of G{L} also appears to be close to optimal for the frequency of repetitive firing caused by a constant current input to one end of the axon, especially when temperature variations are taken into account. If, by contrast, the leak current is assumed to be composed of separate voltage-independent sodium and potassium currents, then these optimizations are not observed.

Metabolic energy cost of action potential velocity.

The action potential of the unmyelinated nerve is metabolically expensive. Using the energetic cost per unit length for the biophysically modeled action potential of the squid giant axon, we analyze this cost and identify one possible optimization. The energetic cost arising from an action potential is divided into three separate components: 1) the depolarization of the rising phase; 2) the hyperpolarization of the falling phase; and 3) the largest component, the overlapping of positive and negative currents, which has no electrical effect. Using both the Hodgkin-Huxley (HH) model and an improved version of the HH model (HHSFL), we investigate the variation of these three components as a function of easily evolvable parameters, axon diameter and ion channel densities. Assuming conduction velocity is well designed for each organism, the energy component associated with the rising phase attains a minimum near the biological values of the diameter and channel densities. This optimization is explained by the membrane capacitance per unit length. The functional capacitance is the sum of the intrinsic membrane capacitance and the gating capacitance associated with the sodium channel, and this capacitance minimizes at nearly the same values of diameter and channel density. Because capacitance is temperature independent and because this result is independent of the assumed velocity, the result generalizes to unmyelinated mammalian axons. That is, channel density is arguably an evolved property that goes hand-in-hand with the evolutionary stability of the sodium channel.

Bounds on isocurvature perturbations from cosmic microwave background and large scale structure data.

We obtain very stringent bounds on the possible cold dark matter, baryon, and neutrino isocurvature contributions to the primordial fluctuations in the Universe, using recent cosmic microwave background and large scale structure data. Neglecting the possible effects of spatial curvature, tensor perturbations, and reionization, we perform a Bayesian likelihood analysis with nine free parameters, and find that the amplitude of the isocurvature component cannot be larger than about 31% for the cold dark matter mode, 91% for the baryon mode, 76% for the neutrino density mode, and 60% for the neutrino velocity mode, at 2sigma, for uncorrelated models. For correlated adiabatic and isocurvature components, the fraction could be slightly larger. However, the cross-correlation coefficient is strongly constrained, and maximally correlated/anticorrelated models are disfavored. This puts strong bounds on the curvaton model.