Acquired Vitamin B12 Deficiency in Newborns: Positive Impact on Newborn Health through Early Detection

The early diagnosis of and intervention in vitamin B12 deficiency in exclusively breastfed infants by mothers with low vitamin B12 is crucial in preventing possible irreversible neurologic damage, megaloblastic anemia, and failure to thrive. We assess the usefulness of the early detection of asymptomatic B12 deficiency related to acquired conditions and highlight the importance of monitoring serum vitamin B12 levels during pregnancy. We describe demographic, clinical, dietary, and biochemical data, including the evolution of a vitamin B12 deficiency’s functional biomarkers. We enrolled 12 newborns (5 males) with an age range of 1–2 months old that were exclusively breastfed and asymptomatic. These cases were referred to our metabolic unit due to alterations in expanded newborn screening: high levels of methylmalonic acid and/or total homocysteine (tHcy). All mothers were under a vegetarian diet except three who had abnormal B12 absorption, and all presented low or borderline serum B12 level and high plasma levels of tHcy. Supplementation with oral vitB12 re-established the metabolic homeostasis of the mothers. In infants, therapy with an intramuscular injection of 1.0 mg hydroxocobalamin led to the rapid normalization of the metabolic pattern, and a healthy outcome was observed. Acquired B12 deficiency should be ruled out before proceeding in a differential diagnosis of cobalamin metabolism deficits, methylmalonic acidemia, and homocystinuria.     

Varespladib in the Treatment of Snakebite Envenoming: Development History and Preclinical Evidence Supporting Advancement to Clinical Trials in Patients Bitten by Venomous Snakes

The availability of effective, reliably accessible, and affordable treatments for snakebite envenoming is a critical and long unmet medical need. Recently, small, synthetic toxin-specific inhibitors with oral bioavailability used in conjunction with antivenom have been identified as having the potential to greatly improve outcomes after snakebite. Varespladib, a small, synthetic molecule that broadly and potently inhibits secreted phospholipase A2 (sPLA2s) venom toxins has renewed interest in this class of inhibitors due to its potential utility in the treatment of snakebite envenoming. The development of varespladib and its oral dosage form, varespladib-methyl, has been accelerated by previous clinical development campaigns to treat non-envenoming conditions related to ulcerative colitis, rheumatoid arthritis, asthma, sepsis, and acute coronary syndrome. To date, twenty-nine clinical studies evaluating the safety, pharmacokinetics (PK), and efficacy of varespladib for non-snakebite envenoming conditions have been completed in more than 4600 human subjects, and the drugs were generally well-tolerated and considered safe for use in humans. Since 2016, more than 30 publications describing the structure, function, and efficacy of varespladib have directly addressed its potential for the treatment of snakebite. This review summarizes preclinical findings and outlines the scientific support, the potential limitations, and the next steps in the development of varespladib’s use as a snakebite treatment, which is now in Phase 2 human clinical trials in the United States and India.     

High intrapatient variability of tacrolimus exposure associated with poorer outcomes in liver transplantation

Tacrolimus (TAC) is a dose‐dependent immunosuppressor with considerable intrapatient variability (IPV) in its pharmacokinetics. The aim of this work is to ascertain the association between TAC IPV at 6 months after liver transplantation (LT) and patient outcome. This single‐center cohort study retrospectively analyzed adult patients who underwent transplantation from 2015 to 2019 who survived the first 6 months with a functioning graft. The primary end point was the patient’s probability of death and the secondary outcome was the loss of renal function between month 6 and the last follow‐up. TAC IPV was estimated by calculating the coefficient of variation (CV) of the dose‐corrected concentration (C₀/D) between the third and sixth months post‐LT. Of the 140 patients who underwent LT included in the study, the low‐variability group (C₀/D CV < 27%) comprised 105 patients and the high‐variability group (C₀/D CV ≥ 27%) 35 patients. One‐, 3‐, and 5‐year patient survival rates were 100%, 82%, and 72% in the high‐variability group versus 100%, 97%, and 93% in the low‐variability group, respectively (p = 0.005). Moreover, significant impaired renal function was observed in the high‐variability group at 1 year (69 ± 16 ml/min/1.73 m² vs. 78 ± 16 ml/min/1.73 m², p = 0.004) and at 2 years post‐LT (69 ± 17 ml/min/1.73 m² vs. 77 ± 15 ml/min/1.73 m², p = 0.03). High C₀/D CV 3–6 months remained independently associated with worse survival (hazard ratio = 3.57, 95% CI = 1.32–9.67, p = 0.012) and loss of renal function (odds ratio = 3.47, 95% CI = 1.30–9.20, p = 0.01). Therefore, high IPV between the third and sixth months appears to be an early and independent predictor of patients with poorer liver transplant outcomes.

Abbreviations

BPAR

Biopsy proven acute rejection

BMI

Body mass index

CKD‐EPI

chronic kidney disease epidemiology collaboration

CV

coefficient of variation

C₀/D

dose‐corrected concentration

CMV

cytomegalovirus

eGFR

estimated glomerular filtration rate

HR

hazard ratio

HCC

hepatocellular carcinoma

ICU

intensive care unit

IPV

intrapatient variability

i.v.

intravenously

LC–MS/MS

liquid chromatography‐ tandem mass spectrometry

LT

liver transplantation

MELD

model for end‐stage liver disease

MMF

mycophenolate mofetil

NASH

Non‐Alcoholic Steatohepatitis

OR

odds ratio

PCR

polymerase chain reaction

SD

Standard Deviation

TAC

tacrolimus

3–6 M

three–six months

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

There is high intrapatient variability of tacrolimus and its correlation with liver transplantation (LT) outcomes.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Could the intrapatient variability of tacrolimus between months 3 and 6 post‐LT be a potential prognostic tool for poor outcomes?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Those patients with dose‐corrected concentration coefficient of variation greater than or equal to 27% between months 3 and 6 post‐LT have worst overall survival and impaired renal function.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

If we promptly identify those patients, a closer therapeutic drug monitoring program should be imperative with the possibility to make therapeutic interventions to improve outcomes.     

Chinikomycins A and B: isolation, structure elucidation, and biological activity of novel antibiotics from a marine Streptomyces sp. isolate M045

In our screening of marine Streptomycetes for bioactive principles, two novel antitumor antibiotics designated as chinikomycins A (2a) and B (2b) were isolated together with manumycin A (1), and their structures were elucidated by a detailed interpretation of their spectra. Chinikomycins A (2a) and B (2b) are chlorine-containing aromatized manumycin derivatives of the type 64-pABA-2 with an unusual para orientation of the side chains. They exhibited antitumor activity against different human cancer cell lines, but were inactive in antiviral, antimicrobial, and phytotoxicity tests.     

New Compounds Hybrids 1H‐1,2,3‐Triazole‐Quinoline Against Plasmodium falciparum

Malaria is one of the most prevalent parasitic diseases in the world. The global importance of this disease, current vector control limitations, and the absence of an effective vaccine make the use of therapeutic antimalarial drugs the main strategy to control malaria. Chloroquine is a cost‐effective antimalarial drug with a relatively robust safety profile, or therapeutic index. However, chloroquine is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of chloroquine‐resistant strains, which have also been reported for Plasmodium vivax. However, the activity of 1,2,3‐triazole derivatives against chloroquine‐sensitive and chloroquine‐resistant strains of P. falciparum has been reported in the literature. To enhance the anti‐P. falciparum activity of quinoline derivatives, we synthesized 11 new quinoline‐1H‐1,2,3‐triazole hybrids with different substituents in the 4‐positions of the 1H‐1,2,3‐triazole ring, which were assayed against the W2‐chloroquine‐resistant P. falciparum clone. Six compounds exhibited activity against the P. falciparum W2 clone, chloroquine‐resistant, with IC₅₀ values ranging from 1.4 to 46 μm . None of these compounds was toxic to a normal monkey kidney cell line, thus exhibiting good selectivity indexes, as high 351 for one compound ( 11 ).     

Autoimmune Primary Adrenal Insufficiency in Children

Objective:Primary adrenal insufficiency (PAI) is a rare condition in children, and is potentially life-threatening. The most common cause is congenital adrenal hyperplasia, and autoimmune etiology is the most frequent acquired cause in this age group. Symptoms are usually non-specific and, when suspected, investigation should include adrenocorticotropin hormone (ACTH) and morning serum cortisol measurement and, in some cases, a cosyntropin test to confirm the diagnosis. Prompt treatment is essential to prevent an adverse outcome.Methods:We retrospectively collected clinical and laboratory data from adrenal insufficiency due to autoimmune adrenalitis, observed from 2015 to 2020 in a pediatric endocrinology department of a tertiary care hospital.Results:Eight patients were identified, seven males and one female, with age at diagnosis between 14 and 17 years. The symptoms at presentation ranged from non-specific symptoms, such as chronic fatigue and weight loss, to a severe presentation, with altered mental status and seizures. The median duration of symptoms was 4.5 months. The diagnosis was confirmed by serum cortisol and plasma ACTH measurement and all were confirmed to have autoimmune etiology (positive anti-adrenal antibodies). At diagnosis, the most common laboratory abnormality was hyponatremia. All patients were treated with hydrocortisone and fludrocortisone. One patient presented with evidence of type 2 autoimmune polyglandular syndrome.Conclusion:PAI is a rare condition in the pediatric age group. Due to non-specific symptoms, a high index of suspicion is necessary to establish a prompt diagnosis. Once an autoimmune etiology is confirmed, it is important to initiate the appropriate treatment and search for signs and symptoms of other autoimmune diseases during follow-up.     

Abrupt loss and uncertain recovery from fires of Amazon forests under low climate mitigation scenarios

Tropical forests contribute a major sink for anthropogenic carbon emissions essential to slowing down the buildup of atmospheric CO₂ and buffering climate change impacts. However, the response of tropical forests to more frequent weather extremes and long-recovery disturbances like fires remains uncertain. Analyses of field data and ecological theory raise concerns about the possibility of the Amazon crossing a tipping point leading to catastrophic tropical forest loss. In contrast, climate models consistently project an enhanced tropical sink. Here, we show a heterogeneous response of Amazonian carbon stocks in GFDL-ESM4.1, an Earth System Model (ESM) featuring dynamic disturbances and height-structured tree–grass competition. Enhanced productivity due to CO₂ fertilization promotes increases in forest biomass that, under low emission scenarios, last until the end of the century. Under high emissions, positive trends reverse after 2060, when simulated fires prompt forest loss that results in a 40% decline in tropical forest biomass by 2100. Projected fires occur under dry conditions associated with El Niño Southern Oscillation and the Atlantic Multidecadal Oscillation, a response observed under current climate conditions, but exacerbated by an overall decline in precipitation. Following the initial disturbance, grassland dominance promotes recurrent fires and tree competitive exclusion, which prevents forest recovery. EC-Earth3-Veg, an ESM with a dynamic vegetation model of similar complexity, projected comparable wildfire forest loss under high emissions but faster postfire recovery rates. Our results reveal the importance of complex nonlinear responses to assessing climate change impacts and the urgent need to research postfire recovery and its representation in ESMs.

Tropical forests are a major reservoir of biodiversity that contribute key ecosystem services to the regulation of Earth’s climate and carbon cycle. Recent studies raise concerns about the ability of tropical forests to sustain these services in the face of global change. For example, forest inventories provide direct evidence of a slowing sink in intact tropical forests (1, 2). This trend may be further aggravated in areas affected by land degradation, deforestation, and long-recovery disturbances associated with the increased frequency of weather extremes (3). The widespread and intense droughts observed in South America in recent years—2005, 2010, and 2015 to 2016—sparked severe, primarily intentional fires associated with land management (4) that burned millions of hectares of primary forests in the drier portions of the Amazon Basin and released vast amounts of CO₂ to the atmosphere (5 –7). It is unclear whether such extreme disturbances represent an actual threat to the resilience of tropical forests, but they add to growing concerns about the possibility of a tipping point for the Amazon system (8) beyond which the remaining forest would dry out, turning forest to savanna (9).The literature on Amazonian tipping points is in disagreement, with alternative bodies of evidence making opposite predictions. Empirical relationships between annual rainfall and vegetation type (forest vs. savanna vs. grassland) and simple models of tree–grass competition and fire suggest that tree vs. grass cover represents alternative stable states (10, 11). Savanna grasses favor the occurrence of fires by retaining highly flammable erect leaves and stems through the dry season (rather than their abscission) (12). Fire kills tree saplings that would eventually overtop the grasses and prevents competitive exclusion. Trees are much less flammable and decrease the likelihood of fires, granting saplings the time needed to replace trees that die and to fill gaps in the forest canopy. However, in an extremely dry year, forest patches can burn and rapidly convert to grassland, and a string of unusually wet years can allow saplings to overtop grasses and slowly convert savanna back to forest (13) (Fig. 1). These ecological mechanisms anticipate the possibility of a tipping point in the near future—a large loss of up to 20 to 40% of tropical forest (14) under rainfall regimes projected by climate models. Regional ecosystem–fire models further stress how drought-induced fires threaten the stability of Amazon forests (15), and how fragmentation and changes in land use might enhance the impact of fires under future drier conditions (16). However, these projections do not account for physiological factors such as CO₂ fertilization that may benefit trees and prevent a tropical-forest tipping point.Open in a separate windowFig. 1.Emergence of alternative states and hysteresis in the structure of tropical vegetation along a gradient of water availability. The schematic highlights key mechanisms implemented in the dynamic land model LM4.1 embedded in GFDL-ESM4.1. Low precipitation regimes favor the dominance of grasslands and savannas where seasonal fuel accumulation promotes recurrent fires that keep a state of arrested succession. High precipitation regimes converge toward a high tree cover state where the closed tree canopy inhibits grasses, reduces evaporative water loss, and increases transpiration to enhance moisture recycling at regional scales. Fire and humidity feedback mechanisms reinforce the resilience of each state and result in their coexistence at intermediate precipitation levels, where the dominant formation becomes contingent to past conditions. After a string of wet years, trees may be able to displace grasses, form a closed canopy, and reach a new alternative equilibrium. As conditions become drier, a closed forest canopy resiliently keeps humidity and prevents its own collapse until disturbances like fires prompt an abrupt transition to the low cover state.Modern Earth System Models (ESMs), which include CO₂ fertilization and climate–vegetation feedbacks often missing from ecological models, come to the opposite conclusion. Although the first comprehensive ESM with dynamic vegetation projected large-scale dieback of the Amazon under rapid climate warming (17), recent ESMs consistently projected that tropical forests will thrive through the century (18, 19), maintaining both the “natural” tropical carbon sink and the viability of emission reduction initiatives based on reforestation [e.g., the Bonn Challenge (20)]. However, the computational burden of simulating coupled global climate and the carbon cycle often results in the adoption of a relatively simple representation of land vegetation (21). These ESMs do not include the ecological mechanisms responsible for the tipping point predicted by the ecological literature, but increasingly do project the drying that causes it, particularly in the Amazon (22 –24).In this paper, we bring these two bodies of work together by analyzing an ESM that includes the mechanisms present in both the alarming ecological literature (e.g., height-structured plant competition, grass fire feedbacks, and tree shade–fire suppression) and the reassuring climatological literature (CO₂ fertilization and large-scale climate–vegetation feedbacks; see also Fig. 1). Specifically, we analyze recent trends and future projections of tropical forest biomass and fire carbon emissions using GFDL-ESM4.1 (25), a fully coupled global climate and carbon cycle model contributing to Phase 6 of the Coupled Model Intercomparison Project (CMIP6) (26). The terrestrial biosphere component of GFDL-ESM4.1 (LM4.1) simulates vegetation dynamics by following the fate of individual demographic cohorts of multiple, competing vegetation types (27), including tropical trees and grasses. Realistic patch dynamics emerge through the simulation of multiple tiles within each ESM grid cell and subgrid scale disturbances like fires (28, 29). The outcome of height-structured competition among vegetation types and fires results in a mosaic of patches (tiles) with a varying degree of tree dominance, ranging from pure grasslands to forests through savanna landscapes. We focused on the response of tropical vegetation during global simulations for the 21st century under the low- and high-end emission forcing from the plausible Shared Socioeconomic Pathways (30) (SSP1-2.6 and SSP5-8.5, respectively) and briefly comment on results for intermediate emission scenarios. We first examined divergent responses in projected trends of tropical vegetation biomass across biogeographical realms. We analyzed the role of climate-induced fires as a driver of projected declines in the Amazon under high emissions. Finally, we used both the present-day observations and simulation results to assess the robustness of GFDL-ESM4.1 projections. We analyzed the subset of CMIP6 ESMs featuring dynamic vegetation and fires, conducting a more detailed comparison of ESM4.1 and EC-Earth3-Veg (31) projections, the two ESMs implementing complex vegetation dynamics.