Summary
What is known and objective
Abundant clinical data now confirm that ketamine produces a remarkable rapid‐onset antidepressant effect – hours or days – in contrast to the delayed onset ...(typically weeks) of current antidepressant drugs. This surprising and revolutionary finding may lead to the development of life‐saving pharmacotherapy for depressive illness by reducing the high suicide risk associated with the delayed onset of effect of current drugs. As ketamine has serious self‐limiting drawbacks that restrict its widespread use for this purpose, a safer alternative is needed. Our objective is to review the proposed mechanism(s) of ketamine's rapid‐onset antidepressant action for new insights into the physiological basis of depressive illness that may lead to new and novel targets for antidepressant drug discovery.
Methods
A search was conducted on published literature (e.g. PubMed) and Internet sources to identify information relevant to ketamine's rapid‐acting antidepressant action and, specifically, to the possible mechanism(s) of this action. Key search words included ‘ketamine’, ‘antidepressant’, ‘mechanism of action’, ‘depression’ and ‘rapid acting’, either individually or in combination. Information was sought that would include less well‐known, as well as well‐known, basic pharmacologic properties of ketamine and that identified and evaluated the several hypotheses about ketamine's mechanism of antidepressant action.
Results
Whether the mechanistic explanation for ketamine's rapid‐onset antidepressant action is related to its well‐known antagonism of the NMDA (N‐Methyl‐d‐aspartate) subtype of glutamate receptor or to something else has not yet been fully elucidated. The evidence from pharmacologic, medicinal chemistry, animal model and drug‐discovery sources reveals a wide variety of postulated mechanisms.
What is new and conclusion
The surprising discovery of ketamine's rapid‐onset antidepressant effect is a game‐changer for the understanding and treatment of depressive illness. There is some convergence on NMDA receptor antagonism as a likely, but to date unproven, common mechanism. The surprising number of other mechanisms, and the several novel biochemical aetiologies of depression proposed, suggests exciting new drug‐discovery targets.
The discovery of ketamine's rapid‐onset antidepressant effect compared to conventional therapy is a game changer for an understanding and treatment of depressive illness. There is some convergence on NMDA receptor antagonism as a likely, but to date unproven, common mechanism. The surprising number of other mechanisms, and the several novel biochemical aetiologies proposed, suggests exciting new drug‐discovery targets.
With excellent energy resolution and ultralow-level radiogenic backgrounds, the high-purity germanium detectors in the Majorana Demonstrator enable searches for several classes of exotic dark matter ...(DM) models. In this work, we report new experimental limits on keV-scale sterile neutrino DM via the transition magnetic moment from conversion to active neutrinos ν_{s}→ν_{a}. We report new limits on fermionic dark matter absorption (χ+A→ν+A) and sub-GeV DM-nucleus 3→2 scattering (χ+χ+A→ϕ+A), and new exclusion limits for bosonic dark matter (axionlike particles and dark photons). These searches utilize the (1-100)-keV low-energy region of a 37.5-kg y exposure collected by the Demonstrator between May 2016 and November 2019 using a set of ^{76}Ge-enriched detectors whose surface exposure time was carefully controlled, resulting in extremely low levels of cosmogenic activation.
Coronavirus disease 19 (COVID-19) has played a pivotal role in changing medical care around the world. During the pandemic, the operating rooms (ORs) were closed to elective surgery. Since breast ...cancer surgery is not regarded as an emergent procedure, there was an adoption of treatment regimen modification due to delays in treatment. Therefore, a decision was made to bridge early-stage HER2-positive breast cancer patients with neoadjuvant treatment to postpone surgery. Consequently, to reduce the frequency of dosing and the number of visits, as well as avoid steroid premedication, these patients were treated with ado-trastuzumab emtansine (T-DM1) every three weeks as opposed to weekly taxol and herceptin (TH).BackgroundCoronavirus disease 19 (COVID-19) has played a pivotal role in changing medical care around the world. During the pandemic, the operating rooms (ORs) were closed to elective surgery. Since breast cancer surgery is not regarded as an emergent procedure, there was an adoption of treatment regimen modification due to delays in treatment. Therefore, a decision was made to bridge early-stage HER2-positive breast cancer patients with neoadjuvant treatment to postpone surgery. Consequently, to reduce the frequency of dosing and the number of visits, as well as avoid steroid premedication, these patients were treated with ado-trastuzumab emtansine (T-DM1) every three weeks as opposed to weekly taxol and herceptin (TH).Five patients with early-stage HER2-positive cancer were treated with neoadjuvant T-DM1 3.6 mg/kg IV every three weeks. Three of the five patients developed cancer progression identified by their physical exam and/or imaging. T-DM1 was discontinued, and all three patients underwent immediate surgery. The remaining two patients, 4 and 5, had a complete and partial pathological response, respectively. All five patients received adjuvant therapy after surgery, and currently, none of these patients show evidence of disease on follow-up.Case DescriptionFive patients with early-stage HER2-positive cancer were treated with neoadjuvant T-DM1 3.6 mg/kg IV every three weeks. Three of the five patients developed cancer progression identified by their physical exam and/or imaging. T-DM1 was discontinued, and all three patients underwent immediate surgery. The remaining two patients, 4 and 5, had a complete and partial pathological response, respectively. All five patients received adjuvant therapy after surgery, and currently, none of these patients show evidence of disease on follow-up.Our findings underscore the obstacles and treatment challenges encountered during the COVID-19 pandemic while preventing the spread of the virus and cancer progression. Furthermore, the use of T-DM1 for neoadjuvant treatment remains controversial, particularly when T-DM1 is used as a bridge to surgery during critical times. Perhaps better patient selection or a different drug regimen could have resulted in a better outcome in our study.ConclusionsOur findings underscore the obstacles and treatment challenges encountered during the COVID-19 pandemic while preventing the spread of the virus and cancer progression. Furthermore, the use of T-DM1 for neoadjuvant treatment remains controversial, particularly when T-DM1 is used as a bridge to surgery during critical times. Perhaps better patient selection or a different drug regimen could have resulted in a better outcome in our study.
$^{180m}$$\mathrm{Ta}$ is a rare nuclear isomer whose decay has never been observed. Its remarkably long lifetime surpasses the half-lives of all other known $β$ and electron capture decays due to ...the large K-spin differences and small energy differences between the isomeric and lower-energy states. Detecting its decay presents a significant experimental challenge but could shed light on neutrino-induced nucleosynthesis mechanisms, the nature of dark matter, and K-spin violation. For this study, we repurposed the Majorana Demonstrator, an experimental search for the neutrinoless double-beta decay of $^{76}$$\mathrm{Ge}$ using an array of high-purity germanium detectors, to search for the decay of $^{180m}$$\mathrm{Ta}$. Here, more than 17 kg, the largest amount of tantalum metal ever used for such a search, was installed within the ultralow-background detector array. In this Letter, we present results from the first year of Ta data taking and provide an updated limit for the $^{180m}$$\mathrm{Ta}$ half-life on the different decay channels. In conclusion, with new limits up to $\mathrm{1.5 × 10^{19} yr}$, we improved existing limits by 1–2 orders of magnitude which are the most sensitive searches for a single $β$ and electron capture decay ever achieved. Over all channels, the decay can be excluded for $T_\frac{1}{2} < 0.29 × 10^{18}$$\mathrm{yr}$.
P-type point contact (PPC) high-purity germanium detectors are an important technology in astroparticle and nuclear physics due to their superb energy resolution, low noise, and pulse shape ...discrimination capabilities. Analysis of data from the Majorana Demonstrator, a neutrinoless double-β decay experiment deploying PPC detectors enriched in 76Ge, has led to several novel improvements in the analysis of PPC signals. In this work we discuss charge trapping in PPC detectors and its effect on energy resolution. Small dislocations or impurities in the crystal lattice result in trapping of charge carriers from an ionization event of interest, attenuating the signal, and degrading the measured energy. We present a modified digital pole-zero correction to the signal energy estimation that counters the effects of charge trapping and improves the energy resolution of the Majorana Demonstrator by approximately 30 % to around 2.4 keV full width at half-maximum at 2039 keV, the 76Ge Q value. An alternative approach achieving similar resolution enhancement is also presented.
Constraints on the Decay of Ta 180 m Arnquist, I. J.; Avignone, F. T.; Barabash, A. S. ...
Physical review letters,
10/2023, Letnik:
131, Številka:
15
Journal Article
The MAJORANA DEMONSTRATOR is a leading experiment searching for neutrinoless double-beta decay with high purity germanium (HPGe) detectors. Machine learning provides a new way to maximize the amount ...of information provided by these detectors, but the data-driven nature makes it less interpretable compared to traditional analysis. An interpretability study reveals the machine’s decision-making logic, allowing us to learn from the machine to feed back to the traditional analysis. In this work, we present the first machine learning analysis of the data from the MAJORANA DEMONSTRATOR; this is also the first interpretable machine learning analysis of any germanium detector experiment. Two gradient boosted decision tree models are trained to learn from the data, and a game-theory-based model interpretability study is conducted to understand the origin of the classification power. By learning from data, this analysis recognizes the correlations among reconstruction parameters to further enhance the background rejection performance. Here, by learning from the machine, this analysis reveals the importance of new background categories to reciprocally benefit the standard MAJORANA analysis. This model is highly compatible with next-generation germanium detector experiments like LEGEND since it can be simultaneously trained on a large number of detectors.
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