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Paediatric cardiovascular diseases have been referred to as diseases of injustice as access to care is inequitable globally. For example, Africa only has 78 cardiac centres, with 22 located in Sub-Saharan Africa. Most of these centres rely on visiting surgical teams to provide clinical care. While visiting surgical teams provide essential care, building a sustainable and locally run cardiac workforce in Africa is critical to addressing these inequities in access to care. This paper considers the role of south-to-south partnerships in building sustainable surgical programmes using Rwanda’s paediatric cardiac surgery programme as an example.

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Summary: Mammals typically heal with fibrotic scars, and treatments to regenerate human skin and hair without a scar remain elusive. We discovered that mice lacking C-X-C motif chemokine receptor 2 (CXCR2 knockout [KO]) displayed robust and complete tissue regeneration across three different injury models: skin, hair follicle, and cartilage. Remarkably, wild-type mice receiving plasma from CXCR2 KO mice through parabiosis or injections healed wounds scarlessly. A comparison of circulating proteins using multiplex ELISA revealed a 24-fold higher plasma level of granulocyte colony stimulating factor (G-CSF) in CXCR2 KO blood. Local injections of G-CSF into wild-type (WT) mouse wound beds reduced scar formation and increased scarless tissue regeneration. G-CSF directly polarized macrophages into an anti-inflammatory phenotype, and both CXCR2 KO and G-CSF-treated mice recruited more anti-inflammatory macrophages into injured areas. Modulating macrophage activation states at early time points after injury promotes scarless tissue regeneration and may offer a therapeutic approach to improve healing of human skin wounds.

Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures. This report describes two siblings in a family with late-onset forms of HCS deficiency. The younger sister presented at the age of 11 years and manifested as acute metabolic acidosis, which promptly resolved following rehydration and biotin administration. The results of the organic urine profile confirmed multiple carboxylase deficiency, and genetic testing revealed a novel pathogenic variant in the HLCS gene (NM_000411.8) in the homozygous state: c.995A>G; p. (Gln332Arg). No further decompensation was observed for her during the 3-year follow-up period. His older brother was diagnosed at the age of 23 years-old through biochemical tests, without any history of acidotic decompensation. A mini-review of HCS deficiency with late onset (>1 year) or early onset (

Severe floods and landslides in Eastern Northeast Brazil in May 2022 led to severe impacts with human losses and material damage. These disasters were a direct consequence of extremely heavy rainfall days. A rapid attribution study was performed to assess the role of anthropogenic climate change in 7 and 15-day mean rainfall over this region. A dense network of 389 weather stations was analysed resulting in 79 selected stations containing consistent and spatially well-distributed data over the study region with records starting in the 1970s. Daily rainfall from a multi-model ensemble of climate simulations were also examined to investigate the role of climate change in modifying the likelihood of such extreme events over the studied region. However, such an analysis was hindered by the fact that most investigated models have deficiencies in representing convection associated with warm rains, which are key for the manifestation of such extreme events associated with Easterly Wave Disturbances. From the observational analysis, both 7 and 15-day mean events in 2022 were found to be exceptionally rare, with an approximately 1-in-500 and 1-in-1000 chance of happening in any year in today's climate, respectively. Even though both events were located far outside the previously observed records, because of the short observational record and associated uncertainties it was not possible to quantify how much climate change made these events more likely to happen. The performed analysis also revealed that global warming increased the intensity of such extreme rainfall: rainfall events as rare as those investigated here occurring in a 1.2 °C cooler climate would have been approximately a fifth less intense. Combining observations with the physical understanding of the climate system, this study showed that human-induced climate change is, at least in part, responsible for the increase in likelihood and intensity of heavy rainfall events as observed in May 2022. Besides, the extreme nature, as a result of such events, made it so extraordinary that population exposure and vulnerability was identified as the main driver for the observed impacts, although long-term impacts and recovery will likely be mediated by socio-economic, demographic and governance factors.

Abstract Gram-negative bacteria (GNB) are a major cause of neonatal sepsis in low- and middle-income countries (LMICs). Although the World Health Organization (WHO) reports that over 80% of these sepsis deaths could be prevented through improved treatment, the efficacy of the currently recommended first- and second-line treatment regimens for this condition is increasingly affected by high rates of drug resistance. Here we assess three well known antibiotics, fosfomycin, flomoxef and amikacin, in combination as potential antibiotic treatment regimens by investigating the drug resistance and genetic profiles of commonly isolated GNB causing neonatal sepsis in LMICs. The five most prevalent bacterial isolates in the NeoOBS study (NCT03721302) are Klebsiella pneumoniae, Acinetobacter baumannii, E. coli, Serratia marcescens and Enterobacter cloacae complex. Among these isolates, high levels of ESBL and carbapenemase encoding genes are detected along with resistance to ampicillin, gentamicin and cefotaxime, the current WHO recommended empiric regimens. The three new combinations show excellent in vitro activity against ESBL-producing K. pneumoniae and E. coli isolates. Our data should further inform and support the clinical evaluation of these three antibiotic combinations for the treatment of neonatal sepsis in areas with high rates of multidrug-resistant Gram-negative bacteria.

Abstract Cryotherapy is an ablative therapy that can be used to treat localized prostate cancer. In case of recurrence, treatment options are not well-defined, and their outcomes are unknown. We therefore collected all patients treated with radiotherapy after cryotherapy for prostate cancer recurrence in Nantes (France) between 2012 and 2019. We identified ten patients. After a median follow-up of 5 years, two patients presented late grade 3 toxicities; one patient presented a grade 3 rectal hemorrhage, and one had a grade 3 hematuria. Two patients relapsed at 61 and 62 months, and three patients died of other causes. Radiotherapy to treat local prostate cancer recurrence after cryotherapy seems feasible and effective in local control. These results do not allow us to recommend this technique in current practice but are encouraging for the conduct of prospective trials.

Abstract Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson’s disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p

Abstract Background Infliximab is currently recommended as a third-line treatment for refractory sarcoidosis. Data in function of clinical phenotype are currently lacking. We evaluated patients’ characteristics and responses to infliximab according to their GenPhenReSa cluster. Methods We evaluated clinical and biological characteristics of patients diagnosed with sarcoidosis who received infliximab between September 2008 and April 2019 at our centre. Results Fifty-five patients (median disease duration, 87 months) received infliximab: 48 (87%) as a second- or third-line treatment, and 7 (13%) as a first-line treatment. After a median duration of 12 months, 24 (45%) and 14 (25%) patients achieved complete and partial responses, respectively, together with a significant decrease in the number of affected organs and tapering of steroid doses. All patients with neurosarcoidosis (OR 17), 90% in group 2 (ocular-cardiac-cutaneous-CNS, OR 7.4), and approximately two-thirds of those in groups 1 (abdominal organs), 4 (pulmonary-lympho-nodal), and 5 (extrapulmonary), achieved a response, whereas patients in group 3 (musculoskeletal-cutaneous) had a treatment-failure OR of 9. Infliximab could be stopped after complete remission was achieved in 7 patients: 4 relapsed after a median of 6 months. Overall, 36% of patients experienced serious adverse events, mainly infections, which led to treatment cessation in 29% of patients and caused two deaths. Conclusions Other than patients with musculoskeletal-cutaneous involvement (group 3), infliximab led to a good response for patients with CNS (group 2) and liver (group 1) organ-predominant sarcoidosis. However, it led to serious infections and merely suspended sarcoidosis, so further research on factors predictive of relapse is needed.

Abstract The ketogenic diet (KD) has been shown to be effective in refractory epilepsy after long-term administration. However, its interference with short-term brain metabolism and its involvement in the early process leading to epilepsy remain poorly understood. This study aimed to assess the effect of a short-term ketogenic diet on cerebral glucose metabolic changes, before and after status epilepticus (SE) in rats, by using [18F]-FDG PET. Thirty-nine rats were subjected to a one-week KD (KD-rats, n = 24) or to a standard diet (SD-rats, n = 15) before the induction of a status epilepticus (SE) by lithium-pilocarpine administrations. Brain [18F]-FDG PET scans were performed before and 4 h after this induction. Morphological MRIs were acquired and used to spatially normalize the PET images which were then analyzed voxel-wisely using a statistical parametric-based method. Twenty-six rats were analyzed (KD-rats, n = 15; SD-rats, n = 11). The 7 days of the KD were associated with significant increases in the plasma β-hydroxybutyrate level, but with an unchanged glycemia. The PET images, recorded after the KD and before SE induction, showed an increased metabolism within sites involved in the appetitive behaviors: hypothalamic areas and periaqueductal gray, whereas no area of decreased metabolism was observed. At the 4th hour following the SE induction, large metabolism increases were observed in the KD- and SD-rats in areas known to be involved in the epileptogenesis process late—i.e., the hippocampus, parahippocampic, thalamic and hypothalamic areas, the periaqueductal gray, and the limbic structures (and in the motor cortex for the KD-rats only). However, no statistically significant difference was observed when comparing SD and KD groups at the 4th hour following the SE induction. A one-week ketogenic diet does not prevent the status epilepticus (SE) and associated metabolic brain abnormalities in the lithium-pilocarpine rat model. Further explorations are needed to determine whether a significant prevention could be achieved by more prolonged ketogenic diets and by testing this diet in less severe experimental models, and moreover, to analyze the diet effects on the later and chronic stages leading to epileptogenesis.

Abstract Background The terms syndemic and infodemic have both been applied to the COVID-19 pandemic, and emphasize concurrent socio-cultural dynamics that are distinct from the epidemiological outbreak itself. We argue that the COVID-19 pandemic has exposed yet another important socio-political dynamic that can best be captured by the concept of a quandemic – a portmanteau of “quantification” and “pandemic”. Main text The use of quantifiable metrics in policymaking and evaluation has increased throughout the last decades, and is driven by a synergetic relationship between increases in supply and advances in demand for data. In most regards this is a welcome development. However, a quandemic, refers to a situation where a small subset of quantifiable metrics dominate policymaking and the public debate, at the expense of more nuanced and multi-disciplinary discourse. We therefore pose that a quandemic reduces a complex pandemic to a few metrics that present an overly simplified picture. During COVID-19, these metrics were different iterations of case numbers, deaths, hospitalizations, diagnostic tests, bed occupancy rates, the R-number and vaccination coverage. These limited metrics came to constitute the internationally recognized benchmarks for effective pandemic management. Based on experience from the Nordic region, we propose four distinct dynamics that characterize a quandemic: 1) A limited number of metrics tend to dominate both political, expert, and public spheres and exhibit a great deal of rigidity over time. 2) These few metrics crowd-out other forms of evidence relevant to pandemic response. 3) The metrics tend to favour certain outcomes of pandemic management, such as reducing hospitalization rates, while not capturing potential adverse effects such as social isolation and loneliness. 4) Finally, the metrics are easily standardized across countries, and give rise to competitive dynamics based on international comparisons and benchmarking. Conclusion A quandemic is not inevitable. While metrics are an indispensable part of evidence-informed policymaking, being attentive to quandemic dynamics also means identifying relevant evidence that might not be captured by these few but dominant metrics. Pandemic responses need to account for and consider multilayered vulnerabilities and risks, including socioeconomic inequities and comorbidities.

The teaching of medical humanities is increasingly being integrated into medical school curricula. We developed a podcast called Le Serment d’Augusta (Augusta’s Oath), consisting of six episodes tackling hot topics in the modern world of healthcare related to the patient-doctor relationship, professionalism, and ethics. This podcast aimed to provide scientific content in an entertaining way, while promoting debate among medical students. The Le Serment d’Augusta podcast was proposed as one of the various optional modules included in the second- to fifth-year curriculum at the School of Medicine of Sorbonne University (Paris). We asked students to report their lived experience of listening to the podcast. We then used a text-mining approach focusing on two main aspects: i) students’ perspective of the use of this educational podcast to learn about medical humanities; ii) self-reported change in their perception of and knowledge about core elements of healthcare after listening to the podcast. 478 students were included. Students were grateful for the opportunity to participate in this teaching module. They greatly enjoyed this kind of learning tool and reported that it gave them autonomy in learning. They appreciated the content as well as the format, highlighting that the topics were related to the very essence of medical practice and that the numerous testimonies were of great added value. Listening to the podcast resulted in knowledge acquisition and significant change of perspective. These findings further support the use of podcasts in medical education, especially to teach medical humanities, and their implementation in the curriculum.

Acute hepatic porphyrias are inherited metabolic disorders of heme biosynthesis characterized by the accumulation of toxic intermediate metabolites responsible for disabling acute neurovisceral attacks. Givosiran is a newly approved siRNA-based treatment of acute hepatic porphyria targeting the first and rate-limiting δ-aminolevulinic acid synthase 1 (ALAS1) enzyme of heme biosynthetic pathway. We described a 72-year old patient who presented with severe inaugural neurological form of acute intermittent porphyria evolving for several years which made her eligible for givosiran administration. On initiation of treatment, the patient developed a major hyperhomocysteinemia (>400 μmol/L) which necessitated to discontinue the siRNA-based therapy. A thorough metabolic analysis in the patient suggests that hyperhomocysteinemia could be attributed to a functional deficiency of cystathionine β-synthase (CBS) enzyme induced by givosiran. Long-term treatment with vitamin B6, a cofactor of CBS, allowed to normalize homocysteinemia while givosiran treatment was maintained. We review the recently published cases of hyperhomocysteinemia in acute hepatic porphyria and its exacerbation under givosiran therapy. We also discuss the benefits of vitamin B6 supplementation in the light of hypothetic pathophysiological mechanisms responsible for hyperhomocysteinemia in these patients. Our results confirmed the importance of monitoring homocysteine metabolism and vitamin status in patients with acute intermittent porphyria in order to improve management by appropriate vitamin supplementation during givosiran treatment.

Abstract Over the past years, poly(lactic acid) or polylactide (PLA) is commonly researched as a possible replacement for traditional fossil‐based polymers because of its compostability, biocompatibility, and high mechanical properties. PLA has a variety of applications in packaging, biomedical, and structural. However, PLA has limitations, such as high brittleness, low thermal stability, and a slow crystallization rate, which limits the wide range of applications. To overcome these limitations, the literature reports that blending PLA with other polymers, such as poly(ε‐caprolactone) (PCL), is an economically viable approach. Although blending PLA with PCL is considered a feasible approach, the blend system still suffers from immiscibility, depending on the blend composition. This review aims to highlight recent developments from 2014 to date on the processing of PLA/PCL blends, including their composites, with a primary focus on morphological characteristics and mechanical and thermal properties, including their potential applications in various sectors.

Abstract Polycaprolactone (PCL) is one of the durable polymers with potential in a plethora of healthcare applications. Its biological properties, degradability, chemical properties, and mechanical properties can further be modified to manufacture desired products for modern biomedical applications. Electrospinning of PCL offers the opportunity to design treatment materials that resemble human tissues and facilitate regeneration at the target site. The resultant materials can also be modified by loading other active functional materials to broaden their applications. Herein, the recent advances in the preparation and modification of PCL‐based materials for healthcare applications are elucidated. The challenges and future trends for its application in modern biomedical applications are also outlined.

Healthcare facilities in isolated rural areas of sub-Saharan Africa face challenges in providing essential health services due to unreliable energy access. This study examines the use of hybrid renewable energy systems consisting of solar PV, wind turbines, batteries, and hydrogen storage for the electrification of rural healthcare facilities in Nigeria and South Africa. The study deployed the efficacy of Hybrid Optimization of Multiple Energy Resources software for techno-economic analysis and the Evaluation based on the Distance from Average Solution method for multi-criteria decision-making for sizing, optimizing, and selecting the optimal energy system. Results show that the optimal configurations achieve cost-effective levelized energy costs ranging from $0.336 to $0.410/kWh for both countries. For the Nigeria case study, the optimal energy system includes 5 kW PV, 10 kW fuel cell, 10 kW inverter, 10 kW electrolyzer, and 16 kg hydrogen tank. South Africa’s optimal configuration has 5 kW PV, 10 kW battery, 10 kW inverter, and 7.5 kW rectifier. Solar PV provides more than 90 % of energy, with dual axis tracking yielding the highest output: 8,889kWh/yr for Nigeria and 10,470kWh/yr for South Africa. The multi-criteria decision-making analysis reveals that Nigeria’s preferred option is the hybrid system without tracking. In contrast, the horizontal axis, weekly adjustment tracking configuration is optimal for South Africa, considering technical, economic, and environmental criteria. The findings highlight the importance of context-specific optimization for hybrid renewable energy systems in rural healthcare facilities to accelerate Sustainable Development Goals 3 and 7.

The cytosolic enzymes N-Acetyl Transferases 1 and 2 (NATs) transfer an acetyl group from acetyl-CoA to a xenobiotic substrate. NATs are regulated at the genetic and epigenetic levels by deacetylase enzymes such as sirtuins. The enzymatic expression of NAT1, NAT2, and SIRT1 was evaluated by flow cytometry, as well as the enzymatic activity of NATs by cell culture and HPLC analysis. Six SNPs were determined through genotyping. T2D patients (n = 29) and healthy subjects (n = 25) with a median age of 57 and 50, respectively, were recruited. An increased enzyme expression and a diminished NAT2 enzymatic activity were found in cells of T2D patients compared to the control group, while NAT1 was negatively correlated with body fat percentage and BMI. In contrast, Sirtuin inhibition increased NAT2 activity, while Sirtuin agonism decreased its activity in both groups. The analysis of NAT2 SNPs showed a higher frequency of rapid acetylation haplotypes in T2D patients compared to the control group, possibly associated as a risk factor for diabetes. The enzymatic expression of CD3+NAT2+ cells was higher in the rapid acetylators group compared to the slow acetylators group. The levels and activity of NAT1 were associated with total cholesterol and triglycerides. Meanwhile, CD3+NAT2+ cells and NAT2 activity levels were associated with HbA1c and glucose levels. The results indicate that NAT2 could be involved in metabolic processes related to the development of T2D, due to its association with glucose levels, HbA1c, and the altered SIRT-NAT axis. NAT1 may be involved with dyslipidaemias in people who are overweight or obese.

Abstract 2D magnetic materials offer the opportunity to study and manipulate emergent collective excitations. Among these, spin–phonon coupling is one of the most important interactions correlating charge, spin and lattice vibrations. Understanding and controlling this coupling is important for spintronics applications, control of magnons and phonon by THz radiation, and for strain‐driven magnetoelastic applications. Here, a resonant mode‐selective spin–phonon coupling in several magnetic 2D metal thiophosphates (NiPS3, FePS3, CoPS3 and MnPS3) through multi‐excitation and temperature‐dependent Raman scattering measurements is uncovered. The phonon mode, which is a Raman‐active out‐of‐plane vibrational mode (∼250 cm−1 or 7.5 THz), exhibits an asymmetric Fano lineshape where its asymmetry is proportional to the spin–phonon coupling. The measurements reveal the coupling to be the highest in NiPS3, followed by FePS3 and CoPS3, and least in MnPS3. These differences are attributed to the metal–sulfur interatomic distances, which are the lowest in NiPS3, followed by CoPS3, FePS3 and MnPS3. Finally, the spin–phonon coupling is also observed in exfoliated materials, with a slight reduction between 20 and 30% in the thinnest flakes compared to the bulk crystals.