Negative Phase Research Articles

The Effects of Bipolar Cancellation Phenomenon on Nano-Electrochemotherapy of Melanoma Tumors: In Vitro and In Vivo Pilot.

The phenomenon known as bipolar cancellation is observed when biphasic nanosecond electric field pulses are used, which results in reduced electroporation efficiency when compared to unipolar pulses of the same parameters. Basically, the negative phase of the bipolar pulse diminishes the effect of the positive phase. Our study aimed to investigate how bipolar cancellation affects Ca2+ electrochemotherapy and cellular response under varying electric field intensities and pulse durations (3-7 kV/cm, 100, 300, and 500 ns bipolar 1 MHz repetition frequency pulse bursts, n = 100). As a reference, standard microsecond range parametric protocols were used (100 µs × 8 pulses). We have shown that the cancellation effect is extremely strong when the pulses are closely spaced (1 MHz frequency), which results in a lack of cell membrane permeabilization and consequent failure of electrochemotherapy in vitro. To validate the observations, we have performed a pilot in vivo study where we compared the efficacy of monophasic (5 kV/cm × ↑500 ns × 100) and biphasic sequences (5 kV/cm × ↑500 ns + ↓500 ns × 100) delivered at 1 MHz frequency in the context of Ca2+ electrochemotherapy (B16-F10 cell line, C57BL/6 mice, n = 24). Mice treated with bipolar pulses did not exhibit prolonged survival when compared to the untreated control (tumor-bearing mice); therefore, the bipolar cancellation phenomenon was also occurrent in vivo, significantly impairing electrochemotherapy. At the same time, the efficacy of monophasic nanosecond pulses was comparable to 1.4 kV/cm × 100 µs × 8 pulses sequence, resulting in tumor reduction following the treatment and prolonged survival of the animals.

Non‐Synchronization of the Decadal Transition in Winter Near‐Surface Wind Speed Across Northern and Southern China

AbstractDecadal variations in near‐surface wind speed (NSWS) and their causes are poorly understood. We found that the decadal transition of winter NSWS in northern China (NC) was 10 years earlier than in southern China (SC), which could be linked to the changes in intensities of the eastward wave‐activity flux and Siberian High (SH) induced by the Warm Arctic‐Cold Eurasia (WACE) dipole pattern. From 1973 to 1990, the WACE pattern from positive to negative phases confined the eastward wave trains to high latitudes with a decreasing SH, inducing an NSWS reduction. From 1991 to 2000, the WACE strengthened from negative to positive phases, causing a decadal transition in NSWS first in NC. After 2000, accompanied by the strengthening of the positive WACE, the eastward wave trains propagated downstream to lower latitudes, the SH and the meridional pressure gradient enhanced. Therefore, the transition of decadal NSWS occurred in SC until 2000.

Holocene extreme flood events in the middle reaches of the Lancang‒Mekong River basin recorded by a high-altitude lake in southwestern China

The Lancang‒Mekong River (LMR) basin is a region particularly susceptible to floods induced by extreme precipitation. However, owing to limited historical flood records, it is difficult to understand the processes and mechanisms of extreme floods in the LMR basin. In the present study, sediments from a high-altitude lake (Lake Baima, 4700 m above sea level) located in the upper-middle reaches of the LMR are used to reconstruct climate and hydrology variability since the last deglaciation based on a range of climate proxies and methods, including loss-on-ignition, grain size, X-ray diffraction, and X-ray fluorescence. Through the investigation of modern and historical floods in the LMR basin, we combine the climate proxies with hydrological frequency curves to reconstruct the paleoflood sequence during the Holocene. Our results suggest that the temperature and precipitation in southwestern China increased during the Holocene compared to the last deglaciation, indicating a response to changes in Northern Hemisphere summer solar insolation. In addition, Holocene sediments of Lake Baima are primarily composed of brown background layers and numerous light yellow/gray event layers. These event layers are further identified as flood events based on sedimentary facies, redness, and main exogenous elements content and their rate of change. The results show that extreme flood events in the LMR basin occurred more frequently during the early and late Holocene, with seven once-in-1000-year floods during the two intervals; while there were low-frequency flood periods during the mid-Holocene. The occurrence of Holocene floods may be related to external forcing, such as the abrupt changes in total solar irradiance (TSI) and volcanic activity, as well as the internal variability of the wider climate system including the Pacific Decadal Oscillation (PDO) and El Niño‒Southern Oscillation (ENSO). When the TSI was low, the Intertropical Convergence Zone (ITCZ) in the Northern Hemisphere shifted northward, and the Western Pacific Subtropical High (WPSH) moved eastward, accompanied with a negative phase of the PDO and La Niña-like phase of the ENSO. The air-sea interactions increased sea surface temperatures, leading to high precipitation and increasing flood risk in the LMR basin.

Interdecadal shifts of ENSO influences on Spring Central Asian precipitation

Spring Central Asian precipitation (SCAP) holds significant implications for local agriculture and ecosystems, with its variability mainly modulated by El Niño–Southern Oscillation (ENSO). The ENSO–SCAP relationship has experienced pronounced interdecadal shifts, though mechanisms remain elusive. Based on observations and climate model simulations, these shifts may result from transitions in ENSO-induced meridional circulation and Rossby wave trains triggered by North Atlantic (NA) sea surface temperature (SST) anomalies. During high (low) correlation periods, ENSO induces strong (weak) vertical motion anomalies over Central Asia, while NA SST anomalies exert a weak (strong) counteracting effect, modulated by the Pacific decadal oscillation (PDO). In the positive (negative) phase of PDO, a slow (fast) decaying ENSO triggers a strong (weak) NA horseshoe-like SST anomaly in the post-ENSO spring, affecting the ENSO–SCAP relationship. Our study identifies a strengthening trend in the ENSO–SCAP relationship since the 2000s, indicating improved predictability for SCAP in recent decades.

Predictability of the early summer surface air temperature over Western South Asia

Variability of the Surface Air Temperature (SAT) over the Western South Asia (WSA) region leads to frequent heatwaves during the early summer (May-June) season. The present study uses the European Centre for Medium-Range Weather Forecast’s fifth-generation seasonal prediction system, SEAS5, from 1981 to 2022 based on April initial conditions (1-month lead) to assess the SAT predictability during early summer season. The goal is to evaluate the SEAS5’s ability to predict the El Niño-Southern Oscillation (ENSO) related interannual variability and predictability of the SAT over WSA, which is mediated through upper-level (200-hPa) geopotential height anomalies. This teleconnection leads to anomalously warm surface conditions over the region during the negative ENSO phase, as observed in the reanalysis and SEAS5. We evaluate SEAS5 prediction skill against two observations and three reanalyses datasets. The SEAS5 SAT prediction skill is higher with high spatial resolution observations and reanalysis datasets compared to the ones with low-resolution. Overall, SEAS5 shows reasonable skill in predicting SAT and its variability over the WSA region. Moreover, the predictability of SAT during La Niña is comparable to El Niño years over the WSA region.

Increasing WNP tropical cyclone-related extreme precipitation over East Asia during boreal summer associated with PDO shift

Over the past two decades, there has been a significant shift in tropical cyclone (TC) activity in the western North Pacific (WNP) basin during the boreal summer. Our analysis of data spanning from 1979 to 2021 reveals significant shifts in the WNP TC characteristics and rainfall pattern variation. To deepen our understanding of TC-related precipitation dynamics, we expressly address the difference between TC-related core precipitation (TCP) and remote precipitation (TRP). The results show that TRP significantly impacts the East Asian (EA) continent, especially on the Korean Peninsula. Notably, TCP exhibits decadal variability, with a pronounced negative correlation identified between it and the Pacific decadal oscillation (PDO) following a strong climate shift. This pivotal shift was marked by the PDO first transitioning to its negative phase in 1997, a notable change since 1979, resulting in a marked increase in TC-related extreme rainfall over the EA area. Concurrently, the rising sea surface temperatures (SSTs) over the WNP have intensified the western Pacific subtropical high (WPSH) circulation. The easterly steering flow associated with the WPSH then strengthened, leading to the continental migration of TC trajectories, thereby intensifying TC-related extreme precipitation.

On the association of Pacific Decadal Oscillation with the interdecadal variability in Asian-Pacific Oscillation

The Asian-Pacific Oscillation (APO), featuring a seesaw pattern in the upper-tropospheric temperatures between Asia and the North Pacific, plays profound roles in the Northern Hemispheric climate anomalies. So, its variability and associated physical mechanisms are of great interest. Although progress has been achieved for the APO variability at the interannual time scale, the understanding of its interdecadal variability remains relatively poor. Based on the twentieth-century reanalysis and the simulations of the preindustrial control, Pacific pacemaker, and large ensemble experiments, this study reports a salient contribution of the Pacific Decadal Oscillation (PDO) to the interdecadal variability of the APO during summer, featured as a warm (cold) PDO phase accompanying a negative (positive) APO polarity. During the warm PDO phase, the sea surface temperature (SST) warming over the eastern Pacific is conducive to local ascending anomalies, which teleconnect with descending anomalies over the Tibetan Plateau through zonal vertical circulations. The anomalous ascent (descent) over the eastern Pacific (Tibetan Plateau) tends to strengthen (weaken) the atmospheric heating, beneficial for a warming (cooling) of the troposphere in situ. In addition, the PDO-related meridional SST gradient anomalies favor a southward shift of the subtropical jet stream, weakening the South Asian high and the North Pacific trough in the upper troposphere, which corresponds to the atmospheric situation of a negative APO phase. Quantitative analysis from the large ensemble simulations indicates that the PDO may contribute to approximately 48% of recent APO interdecadal variation from the negative phase to the positive phase in the late 1990s.

Threshold Interphase Delay for Bipolar Pulses to Prevent Cancellation Phenomenon during Electrochemotherapy.

Electroporation-based procedures employing nanosecond bipolar pulses are commonly linked to an undesirable phenomenon known as the cancelation effect. The cancellation effect arises when the second pulse partially or completely neutralizes the effects of the first pulse, simultaneously diminishing cells' plasma membrane permeabilization and the overall efficiency of the procedure. Introducing a temporal gap between the positive and negative phases of the bipolar pulses during electroporation procedures may help to overcome the cancellation phenomenon; however, the exact thresholds are not yet known. Therefore, in this work, we have tested the influence of different interphase delay values (from 0 ms to 95 ms) using symmetric bipolar nanoseconds (300 and 500 ns) on cell permeabilization using 10 Hz, 100 Hz, and 1 kHz protocols. As a model mouse hepatoma, the MH-22a cell line was employed. Additionally, we conducted in vitro electrochemotherapy with cisplatin, employing reduced interphase delay values (0 ms and 0.1 ms) at 10 Hz. Cell plasma membrane permeabilization and viability dependence on a variety of bipolar pulsed electric field protocols were characterized. It was shown that it is possible to minimize bipolar cancellation, enabling treatment efficiency comparable to monophasic pulses with identical parameters. At the same time, it was highlighted that bipolar cancellation has a significant influence on permeabilization, while the effects on the outcome of electrochemotherapy are minimal.

Climatic influence of the Antarctic ozone hole on the East Asian winter precipitation

The Antarctic ozone hole exerts a substantial impact on the climate of the Southern Hemisphere, yet research exploring its potential influence on the Northern Hemisphere climate is limited. This study unveils a significant positive relationship between interannual variations of Antarctic total column ozone (TCO) during September–October and East Asian precipitation in the subsequent boreal winter. Specifically, ~10% of the East Asian winter precipitation variability is attributed to Antarctic TCO during September–October. Both observational data and model results indicate that the increased Antarctic TCO during September–October triggers a simultaneous meridional southern Indian Ocean tripole sea surface temperature anomalies (SSTA) through the negative phase of the Southern Annular Mode. This SSTA pattern persists from September–November through the boreal winter, subsequently weakening the local-scale zonal-vertical circulation anomalies in the Indian Ocean. The process leads to positive outgoing longwave radiation (OLR) anomalies over the southern Marine Continent. As a result, the linear response of wind anomalies at 850 hPa over East Asia to the OLR-induced diabatic heating anomalies exhibits southwesterlies, as demonstrated by a linear baroclinic model. These anomalous winds facilitate the transport of abundant moisture from the tropics to East Asia, favoring the formation of winter precipitation. We employ the Specified-Chemistry version of the Whole Atmosphere Community Climate Model to validate that the increase of September–October Antarctic ozone substantially enhances East Asian precipitation during boreal winter. Importantly, the relationship between Antarctic ozone and East Asian winter precipitation is found to be independent of El Niño-Southern Oscillation and the Indian Ocean Dipole Mode. Our findings provide a fresh insight into the prediction of the East Asian winter precipitation.

Lapsed El Niño impact on Atlantic and Northwest Pacific tropical cyclone activity in 2023

A typical El Niño event often results in suppressed tropical cyclone (TC) genesis frequency (TCGF) over the North Atlantic (NA) and a distinct northwest-southeast dipole pattern in TCGF anomaly over the western North Pacific (WNP). The 2023 saw a strong El Niño event but surprisingly active NA and suppressed WNP TC activities. Here, we present that these unprecedented deviations were driven by the record-warm NA, a record-breaking negative phase of the Pacific Meridional Mode (PMM), and background global warming. Results from high-resolution global model experiments demonstrate that extraordinary Atlantic warming dominated the increased NA TCGF and contributed equally with the PMM to the suppressed WNP TCGF, overshadowing El Niño’s impact. Global warming also contributed to the observed TCGF anomalies. Our findings demonstrate that the typical influence of strong El Niño events on regional TC activity could be markedly altered by other climate modes, highlighting the complexity of TC genesis in a warming world.

Multidecadal variations in North Atlantic SSTs modulate the relationship between ENSO and the South Atlantic Subtropical Dipole since 1900

Abstract This study investigates the long-term variability of the relationship between the El Niño South/Oscillation (ENSO) and the South Atlantic Subtropical Dipole (SASD), and their connection to multidecadal variations in the North Atlantic sea surface temperature (MDV-SST). Using a century’s worth of SST and atmospheric data and the Community Atmosphere Model version 5, the study found significant interdecadal variability in the correlation between the Niño3.4 index and the SASD index. This variability is closely linked to the North Atlantic MDV-SST, often interpreted as Atlantic Multidecadal Oscillation (AMO). This is demonstrated by significant ENSO-SASD correlations during warm (positive) phases of MDV-SST (1930–1960 and 2001–2020) and insignificant correlations during cold (negative) phases (1900–1929 and 1961–2000). Through a Gill-type response, MDV-SST excites Rossby wave over the tropical Pacific Ocean, influencing surface wind, SST, convective activities and upper-level zonal wind over the Pacific Ocean. During warm MDV-SST phases, the more eastward positioned Rossby wave source (RWS), triggered by SST and precipitation anomalies over the South Pacific Ocean, along with a stronger, more northward subtropical jet stream, propagates the wavetrain more eastwards into the South Atlantic Ocean, thereby strengthening the SST anomalies in the SASD. Conversely, during the cold MDV-SST phases, the more westward-positioned ENSO-related RWS and a stronger mid-latitude jet stream guide the wavetrain southeastwards into the southeastern Pacific Ocean, exerting less influence on the SST anomalies in the SASD. The Ekman pumping caused by anomalous surface pressure and the associated surface wind field as well as surface turbulent heat flux also affect the SST anomalies in the SASD and the ENSO-SASD relation.

Impaired HBsAg release and antiproliferative/antioxidant cell regulation by HBeAg-negative patient isolates reflects an evolutionary process.

The hepatitis B e antigen (HBeAg)-negative infection Phase 3 is characterized by no or minimal signs of hepatic inflammation and the absence of hepatic fibrosis. However, underlying molecular mechanisms leading to this benign phenotype are poorly understood. Genotype A, B and D HBeAg-negative patient isolates with precore mutation G1896A from Phase 3 were analysed in comparison with respective HBeAg-positive rescue mutant and HBeAg-positive wild-type reference genomes regarding differences in viral replication, morphogenesis, infectivity and impact on NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE)-dependent gene expression and cellular kinome. In comparison with reference genomes, the patient isolates are characterized by a lower intra- and extracellular hepatitis B surface antigen (HBsAg)-amount, and HBsAg-retention in the endoplasmic reticulum. Rescue of HBeAg expression increased HBsAg-amount but not its release. Expression of the isolated genomes is associated with a higher Nrf2/ARE-dependent gene expression as compared to reference genomes independent of HBeAg expression. Kinome analyses revealed a decreased activity of receptors involved in regulation of proliferative pathways for all patient isolates compared to the reference genomes. No specific conserved mutations could be found between all genomes from Phase 3. HBeAg-negative genomes from Phase 3 exhibit distinct molecular characteristics leading to lower HBsAg synthesis and release, enhanced oxidative stress protection and decreased activity of key kinases, triggering an antiproliferative stage, which might contribute to the lower probability of hepatocellular carcinoma. The observed differences cannot be associated with loss of HBeAg or specific mutations common to all analysed isolates, indicating the phenotype of Phase 3 derived genomes to be the result of a multifactorial process likely reflecting a conserved natural selection process.

Evidence of low velocity layers at the top and bottom of the Mantle Transition Zone (MTZ) below the Uttarakhand Himalaya, India

The Mantle Transition Zone (MTZ) beneath the Uttarakhand Himalaya has been modelled using Common Conversion Point (CCP) stacking and depth-migration of radial P-receiver functions. In the Uttarakhand Himalaya region, the depths of the 410-km discontinuity (d410) and the 660-km discontinuity (d660) are estimated to be approximately 406 ± 8 km and 659 ± 10 km, respectively. Additionally, the thickness of the mantle transition zone (MTZ) is modelled to be 255 ± 7 km. The average arrival times for d410 and d660 conversions are (44.47 ± 1.33) s and (71.08 ± 1.29) s, respectively, indicating an undisturbed slightly deeper d410 and a deformed noticeably deeper d660 in the area. The model identifies the characteristics of the d410 and d660 mantle discontinuities beneath the Lesser Himalayan region, revealing a thickening of the MTZ towards northeast, which could be due to gradual cooling or thickening of the Indian lithosphere towards its northern limit. We simulate a low-velocity layer (perhaps partially molten) above the d410 discontinuity at depths of 350 to 385 km, indicating the presence of a hydrated MTZ beneath the area. We also interpret a negative phase at d660 as a low-velocity layer between 590 and 640 km depths, which could be attributed to the accumulation of old subducted oceanic materials or increased water content at the bottom of the MTZ. Our results suggest the presence of residues from paleo-subducted lithospheric slabs in and below the mantle transition zone underlying the Uttarakhand Himalayas.

The impact of intra-annual temperature fluctuations on agricultural temperature extreme events and attribution analysis in mainland China

Daily temperature variations, which tend to exhibit non-constant and non-linear patterns, are often characterized by intra-annual fluctuations that cause severe and frequent extreme temperature events that have an enormous impact on agricultural production. However, the quantitative relationship between intra-annual temperature fluctuations and extreme agricultural temperatures remains unclear. We aimed to investigate intra-annual temperature fluctuation changes based on daily meteorological data in nine agricultural regions across China from 1960 to 2022 and quantify the impact of temperature fluctuations on extreme agricultural temperatures during crop growth periods. Moreover, an attribution analysis of intra-annual temperature fluctuations was performed using climate indicators. Main results showed: (1) intra-annual temperature fluctuations in each region exhibited a certain decrease, and the spatial distribution showed a significant decreasing trend from north to south. (2) Intra-annual temperature fluctuations have moderately exacerbated extreme agricultural hot and cold events during growth periods, which have brought serious challenges to agriculture owing to advances in phenology and unsynchronized rain heat compared to climate warming. The proportion of positive correlations between temperature fluctuations and extreme temperatures was much larger than that of the negative correlations in nearly all of China (percentage of stations: 20.5 %), and the negative correlation was concentrated only in southern China (percentage of stations: 3.7 %). (3) Hydrothermal coupling and elevation moderately affected intra-annual temperature fluctuations. Average temperature, relative humidity, and elevation had negative correlations with intra-annual temperature fluctuations, the correlation coefficients (R) were − 0.62, −0.42 and − 0.12, respectively; however, reference crop evapotranspiration (ET0) exhibited a positive correlation (R: 0.29), and all reached highly significant levels (P < 0.01). Climate indicators mainly affected intra-annual temperature fluctuations in eastern China. Specifically, the El Niño-Southern Oscillation (ENSO), unstable Asia Polar Vortex, and increased Western Pacific Subtropical High have enhanced temperature fluctuations. The deepened East Asian Trough and Arctic Oscillation of the negative phase weakened the intra-annual temperature fluctuations. This investigation highlights the crucial function of temperature fluctuation in intensifying extreme temperature occurrences and provides a more reasonable scientific foundation for extreme event prediction and agricultural planning.

Positive feedback between the negative phase of interannual component of the Pacific Decadal Oscillation and La Niña

Positive feedback between the negative phase of interannual component of the Pacific Decadal Oscillation and La Niña

The relationship between Antarctic sea-ice extent change and the main modes of sea-ice variability in austral winter

Accompanying global warming, Antarctic sea-ice extent shows a somewhat increasing trend from 1979 to 2014, followed by an abrupt decrease after 2016. Our previous study examined the change of Antarctic sea-ice extent in austral summer, autumn and spring. In this study, we turn our attention to the austral winter, relating the main modes of sea-ice variability to sea-ice extent in the Pacific, Atlantic and Indian sectors of the Southern Ocean. We find that the modes with the strongest correlation with the sea-ice extent are the third, first and first modes in the Pacific, Atlantic and Indian sectors, respectively. Atmospheric circulation anomalies of zonal wavenumber three over the Southern Ocean, related to planetary wave trains induced by the SST anomalies over the south-western Pacific and the southern Indian oceans, can explain sea-ice concentration anomalies of the third mode in the Pacific sector through thermodynamic and dynamic processes. Sea-ice anomalies of the first modes in the Atlantic and Indian sectors result from atmospheric circulation anomalies of a positive and negative phases of the Southern Annular Mode, respectively. The anomalous Southern Annular Mode is also associated with wave trains over the Southern Ocean excited by SST anomalies over the southern Indian Ocean and the south-western Pacific Ocean. The relationship between SST anomalies and Antarctic sea-ice anomalies can provide a reference for the prediction of Antarctic sea-ice anomalies in austral winter on interannual and decadal timescales.

Preclinical Development of a Romidepsin Nanoparticle Demonstrates Superior Tolerability and Efficacy in Models of Human T-Cell Lymphoma and Large Granular Lymphocyte Leukemia.

Histone deacetylase (HDAC) inhibitors are a widely recognized and valued treatment option for patients with relapsed or refractory peripheral T cell lymphomas (PTCL). Romidepsin is a relatively selective Class I HDAC inhibitor originally approved for patients with relapsed or refractory (R/R) cutaneous T cell lymphoma (CTCL) and subsequently R/R PTCL. Unfortunately, the FDA approval of romidepsin for R/R PTCL was withdrawn due to a negative Phase 4 post-marketing requirement (PMR), diminishing further the treatment options for patients with PTCL. Herein we describe the development of a first-in-class polymer nanoparticle of romidepsin (Nanoromidepsin) using an innovative amphiphilic di-block copolymer-based nanochemistry platform. Nanoromidepsin exhibited superior pharmacologic disposition, with improved tolerability and safety in murine models of T-cell lymphoma. Nanoromidepsin also exhibited superior anti-tumor efficacy in multiple models including in vitro T cell lymphoma (TCL) cell lines, ex vivo LGL leukemia primary patient samples, and murine TCL xenografts. Nanoromidepsin demonstrated greater accumulation in tumors and a statistically significant improvement in overall survival (OS) compared to romidepsin in murine xenograft models. These findings collectively justify the clinical development of Nanoromidepsin in patients with T-cell malignancies.

Personalized PLGA/BCL Scaffold with Hierarchical Porous Structure Resembling Periosteum-Bone Complex Enables Efficient Repair of Bone Defect.

Using bone regeneration scaffolds to repair craniomaxillofacial bone defects is a promising strategy. However, most bone regeneration scaffolds still exist some issues such as a lack of barrier structure, inability to precisely match bone defects, and necessity to incorporate biological components to enhance efficacy. Herein, inspired by a periosteum-bone complex, a class of multifunctional hierarchical porous poly(lactic-co-glycolic acid)/baicalein scaffolds is facilely prepared by the union of personalized negative mold technique and phase separation strategy and demonstrated to precisely fit intricate bone defect cavity. The dense up-surface of the scaffold can prevent soft tissue cell penetration, while the loose bottom-surface can promote protein adsorption, cell adhesion, and cell infiltration. The interior macropores of the scaffold and the loaded baicalein can synergistically promote cell differentiation, angiogenesis, and osteogenesis. These findings can open an appealing avenue for the development of personalized multifunctional hierarchical materials for bone repair.

Unusually low dust activity in North Africa in June 2023: Causes, impacts and future projections

Dust activity during the pre-monsoon season in Africa has an impact on the monsoon circulation and the Atlantic hurricane season. During early June 2023 the atmosphere was relatively clear over West Africa and the eastern tropical Atlantic, in contrast with the dustier June 2020. The negative phase of the North Atlantic Oscillation suppressed dust lifting, with an equatorward shifted African Easterly Jet limiting its downstream advection. On the other hand, dust accumulated in the atmosphere over northeastern Africa, with the negative dust aerosol optical depth (DAOD) anomalies over western Africa and the positive anomalies over eastern Africa more than two standard deviations away from the climatological mean. The lack of dust led to an up to 55 W m−2 increase in the surface downward shortwave radiation flux and a 35 W m−2 decrease in the longwave flux, and is in line with the record-breaking sea surface temperatures over the eastern tropical Atlantic and the active start to the Atlantic hurricane season. In order to explore future projections of DAOD, a multi-model ensemble (MME) is constructed from 29 models that integrate the sixth phase of the Coupled Model Intercomparison Project (CMIP6). It captures the positive trend in the June DAOD over the eastern tropical Atlantic during 1980–2014, although the amplitude is roughly a factor of six smaller than the 0.0017 year−1 in the reanalysis dataset. The CMIP6 MME projects a further increase in DAOD in the region at a rate of up to 0.0003 year−1 in the most extreme climate change scenario for 2066–2100, which is comparable to that seen during the historical period, even though the mean values are projected to decrease by 0.03–0.06. While lower dust loadings may lead to improved air quality, they will likely further fuel pre-season and early season storms in the North Atlantic, which have become more frequent in recent decades.

Prevalence and Impact of Bypassing or Overriding Phase 2 Trials in Neurologic Drug Development.

Pivotal trials for neurologic drugs in clinical development are often initiated without a phase 2 trial ("bypass") or despite a negative phase 2 efficacy result ("override"). Such practices may degrade the risk/benefit ratio of phase 3 trials. The aim of this study is to estimate the proportion of phase 3 trials for 10 neurologic diseases started without a positive phase 2 trial, to identify factors associated with this practice, and to investigate any association with unfavorable phase 3 trial outcomes. We searched ClinicalTrials.gov for phase 3 trials completed during 2011-2021, with at least 1 research site in the United States, Canada, the European Union, the United Kingdom, or Australia, and investigating drugs or biologics for treatment of 10 neurologic conditions. Our primary objective was to assess the prevalence of phase 2 bypass/override by searching for preceding phase 2 trials. We used Fisher exact tests to determine whether phase 3 trial characteristics and trial results were associated with phase 2 bypass/override. Of the 1,188 phase 3 trials captured in our search, 113 met eligibility for inclusion. Of these, 46% were not preceded by a phase 2 trial that was positive on an efficacy endpoint (31% bypassed and 15% overrode phase 2 trial). Phase 2 bypass/override was not associated with industry funding (77% vs 89%, 95% CI 0.75-7.55, p = 0.13) or testing already approved interventions (23% vs 15%, 95% CI 0.60-5.14, p = 0.33). Overall, phase 3 trials based on phase 2 bypassed/override were statistically significantly less likely to be positive on their primary outcome (31% vs 57%, respectively, 95% CI 1.21-6.92, p = 0.01). This effect disappeared when indications characterized by nearly universal positive or negative results were excluded. Trials that bypassed/overrode phase 2 trials were not statistically significantly more likely to be terminated early because of safety or futility (29% vs 15%, respectively, 95% CI 0.15-1.18, p = 0.11) and did not show increased risk of adverse events in experimental arms (RR = 1.46, 95% CI 1.19-1.79, vs RR = 1.36, 95% CI 1.10-1.69, respectively, p = 0.65). Almost half of the neurologic disease phase 3 trials were initiated without the support of a positive phase 2 trial. Although our analysis does not establish harm with bypass/override, its prevalence and the scientific rationale for phase 2 trial testing favor development of criteria defining when phase 2 bypass/override is justified.