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The article presents information on the analysis of a skeleton of a little girl dating from the 2nd and 3rd centuries found on an archaeological excavation site in 1997. Particular focus is given to the fact that the examination of her tailbone showed that she was suffering from urolithiasis, a condition where urinary calculi are formed in the urinary tract. A discussion on the potential causes of this condition is proposed, reflecting on the historical context of this period in terms of hygiene and nutritional deficiencies.

Abstract Background The amount of lead in the environment has decreased significantly in recent years, and so did exposure. However, there is no known safe exposure level and, therefore, the exposure of children to lead, although low, remains a major public health issue. With the lower levels of exposure, it is becoming more difficult to identify lead sources and new approaches may be required for preventive action. This study assessed the usefulness of lead isotope ratios for identifying sources of lead using data from a nationwide sample of French children aged from six months to six years with blood lead levels ≥25 μg/L. Methods Blood samples were taken from 125 children, representing about 600,000 French children; environmental samples were taken from their homes and personal information was collected. Lead isotope ratios were determined using quadrupole ICP-MS (inductively coupled plasma - mass spectrometry) and the isotopic signatures of potential sources of exposure were matched with those of blood in order to identify the most likely sources. Results In addition to the interpretation of lead concentrations, lead isotope ratios were potentially of use for 57% of children aged from six months to six years with blood lead level ≥ 25 μg/L (7% of overall children in France, about 332,000 children), with at least one potential source of lead and sufficiently well discriminated lead isotope ratios. Lead isotope ratios revealed a single suspected source of exposure for 32% of the subjects and were able to eliminate at least one unlikely source of exposure for 30% of the children. Conclusions In France, lead isotope ratios could provide valuable additional information in about a third of routine environmental investigations.

Background: The EyeCee ® ONE intraocular lens (Nidek, Gamagori, Japan) has been withdrawn from the market due to a high number of reports of severe ocular hypertension (OHT) following phacoemulsification with implantation of this intraocular lens (IOL). In this case series, we report the results of a toxicological analysis and the surgical management of five patients with severe OHT following the implantation of defective EyeCee ® ONE IOLs during cataract surgery., Cases Presentation: Five patients developed early, severe OHT refractory to maximal medical therapy following uneventful phacoemulsification (PCE) cataract surgery with implantation of an EyeCee ® ONE IOL from a defective lot. Glaucoma filtering surgeries were required to control intraocular pressure (IOP). Toxicological analyses were carried out on the aqueous humor of one patient. IOP levels were monitored during postoperative follow-up, but three patients required postoperative adjustments (reintroduction of IOP-lowering therapy, goniopuncture or needling) in order to maintain IOP at satisfactory levels. Toxicological analysis revealed a high concentration of silicon in the aqueous humor of the patient from whom the sample was obtained., Conclusions: These cases of OHT following cataract surgery with a defective IOL were of early onset severe, all requiring filtering surgery. The exact mechanism of this OHT has not been determined, but we did find high concentrations of silicon in the aqueous humor of one of these patients. Patients who received EyeCee ® ONE IOLs during the same period of time should have their IOP and optic nerve monitored to detect any potential OHT or glaucoma that might appear over time., Competing Interests: Declarations. Ethical approval: The study was made in accordance with the principles of the Declaration of Helsinki. Consent for publication: Written informed consent was obtained from all patients for the publication of this case series, after an explanation of the study design and purpose by their treating physician. Patients’ confidentiality was ensured. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Surgeons may discover perioperative clinical situations associated with an increased risk of peritoneal carcinomatosis recurrence after primary resection. We developed a thermogel that can be used as a drug carrier to deliver an anticancer agent in the peritoneal cavity as a rescue solution. The spatial distribution of the thermogel and pharmacokinetics of chemotherapy have been studied in pigs. The safety of the thermogel was assessed based on the healing of bowel sutures., Methods: Nine pigs received gel with oxaliplatin at 130 mg/200 mL (TG-Ox group), and 4 pigs received the gel alone (TG group). Digestive tract and bladder wounds were made and sutured. Pigs were sacrificed at different times after surgery to monitor the distribution of the thermogel and to detect the occurrence of bowel fistulas. Oxaliplatin plasma and tissue concentrations were determined via mass spectrometry., Results: After 3 h, 100 % of the regions of interest were covered by the gel, 78 % were covered after 2 days, and 38 % were covered after 4 days. The thermogel delayed the release of oxaliplatin into the systemic circulation and significantly prolonged tissue impregnation. Anastomotic fistulas were observed in the TG-Ox group (10 %) versus 0 % in the TG group (p = 0.31)., Conclusions: A homogeneous distribution of the thermogel throughout the peritoneal cavity was observed, and the thermogel fulfilled its functions as a drug carrier, including ensuring safety and delaying chemotherapy delivery. Treatment-induced toxicity due to oxaliplatin was identified. The concept of a rescue solution being available in operating rooms was demonstrated., Competing Interests: Declaration of competing interest Others authors did not reported any conflict of interest., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Psoriasis is a multifactorial, chronic inflammatory skin disease with unresolved questions on its primary events. Iron overload has been described in the epidermis of psoriasis patients, but its relevance remains unknown. We found that the key iron regulatory hormone hepcidin was highly expressed in the epidermis of psoriasis patients, especially the pustular variants resistant to treatments. In a murine model of acute skin inflammation, keratinocyte-derived hepcidin was required for iron retention in keratinocytes, leading to hyperproliferation of the epidermal layer and neutrophil recruitment, two main features of psoriatic skin lesions. Keratinocytes overexpressing hepcidin were sufficient to elicit these psoriasiform features in a transgenic mouse model. Furthermore, transcriptome analysis of these keratinocytes revealed canonical pathways found in human psoriasis, pointing to a causal role for hepcidin in the pathogenesis of the disease. Altogether, our data suggest that hepcidin could be an actionable target for skin psoriasis treatment, in addition to current therapeutics, or targeted as maintenance therapy during remission to prevent recurrence., (© 2024. The Author(s).)

Lithium induces nephrogenic diabetes insipidus (NDI) and microcystic chronic kidney disease (CKD). As previous clinical studies suggest that NDI is dose-dependent and CKD is time-dependent, we investigated the effect of low exposition to lithium in a long-term experimental rat model. Rats were fed with a normal diet (control group), with the addition of lithium (Li + group), or with lithium and amiloride (Li + /Ami group) for 6 months, allowing obtaining low plasma lithium concentrations (0.25 ± 0.06 and 0.43 ± 0.16 mmol/L, respectively). Exposition to low concentrations of plasma lithium levels prevented NDI but not microcystic dilations of kidney tubules, which were identified as collecting ducts (CDs) on immunofluorescent staining. Both hypertrophy, characterized by an increase in the ratio of nuclei per tubular area, and microcystic dilations were observed. The ratio between principal cells and intercalated cells was higher in microcystic than in hypertrophied tubules. There was no correlation between AQP2 messenger RNA levels and cellular remodeling of the CD. Additional amiloride treatment in the Li + /Ami group did not allow consistent morphometric and cellular composition changes compared to the Li + group. Low exposition to lithium prevented overt NDI but not microcystic dilations of the CD, with differential cellular composition in hypertrophied and microcystic CDs, suggesting different underlying cellular mechanisms., (© 2024 The Authors. Archiv der Pharmazie published by Wiley‐VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

Background: G-quadruplex DNA (G4) is a non-canonical structure forming in guanine-rich regions, which play a vital role in cancer biology and are now being acknowledged in both nuclear and mitochondrial (mt) genome. However, the impact of G4-based targeted therapy on both nuclear and mt genome, affecting mt function and its underlying mechanisms remain largely unexplored., Methods: The mechanisms of action and therapeutic effects of a G4-binding platinum(II) complex, Pt-ttpy, on mitochondria were conducted through a comprehensive approaches with in vitro and in vivo models, including ICP-MS for platinum measurement, PCR-based genetic analysis, western blotting (WB), confocal microscope for mt morphology study, extracellular flux analyzer, JC1 and Annexin V apoptosis assay, flow cytometry and high content microscope screening with single-cell quantification of both ROS and mt specific ROS, as well as click-chemistry for IF study of mt translation. Decipher Pt-ttpy effects on nuclear-encoded mt related genes expression were undertaken via RNA-seq, Chip-seq and CUT-RUN assays., Results: Pt-ttpy, shows a highest accumulation in the mitochondria of A2780 cancer cells as compared with two other platinum(II) complexes with no/weak G4-binding properties, Pt-tpy and cisplatin. Pt-ttpy induces mtDNA deletion, copy reduction and transcription inhibition, hindering mt protein translation. Functional analysis reveals potent mt dysfunction without reactive oxygen species (ROS) induction. Mechanistic study provided first evidence that most of mt ribosome genes are highly enriched in G4 structures in their promoter regions, notably, Pt-ttpy impairs most nuclear-encoded mt ribosome genes' transcription through dampening the recruiting of transcription initiation and elongation factors of NELFB and TAF1 to their promoter with G4-enriched sequences. In vivo studies show Pt-ttpy's efficient anti-tumor effects, disrupting mt genome function with fewer side effects than cisplatin., Conclusion: This study underscores Pt-ttpy as a G4-binding platinum(II) complex, effectively targeting cancer mitochondria through dual action on mt and nuclear G4-enriched genomes without inducing ROS, offering promise for safer and effective platinum-based G4-targeted cancer therapy., (© 2024. The Author(s).)

TMEM165-CDG has first been reported in 2012 and manganese supplementation was shown highly efficient in rescuing glycosylation in isogenic KO cells. The unreported homozygous missense c.928G>C; p.Ala310Pro variant leading to a functional but unstable protein was identified. This patient was diagnosed at 2 months and displays a predominant bone phenotype and combined defects in N-, O- and GAG glycosylation. We administered for the first time a combined D-Gal and Mn 2+ therapy to the patient. This fully suppressed the N-; O- and GAG hypoglycosylation. There was also striking improvement in biochemical parameters and in gastrointestinal symptoms. This study offers exciting therapeutic perspectives for TMEM165-CDG., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The cause of death of Saint-Louis is not known, but recent findings indicated that he presented scurvy and inflammatory jaw disease, which has been associated with infection by oral commensals. Here, we have the exceptional opportunity to analyze the relics of the viscera of King Saint-Louis. A 4.3 g sample from the viscera relics of King Saint-Louis conserved in Versailles' cathedral was subjected to radiocarbon dating, electronic and optic microscopy, and elementary, palynological, molecular, proteomics and microbiological analyses including specific PCR and v3v4 16 S rRNA gene amplification prior to large-scale sequencing using an Illumina MiSeq instrument. The measured radiocarbon age was Cal 1290 CE-1400, which was compatible with that of the viscera of St Louis viscera, considering the addition of lime, incense and vegetables within the human organs. Elemental and palynological analyses confirmed a medieval embalming process. Proteomics analysis identified mainly human muscle and blood proteins. Specific PCR for plague, amoebiasis, shigellosis and typhoid fever was negative. C. sputigena was identified as the main pathogenic species representing 10.8 % of all microbial sequences. In contrast, C. sputigena was found in only 0.001 % of samples sequenced in our center, and the 23 positive human samples showed a dramatically lower abundance (0.02-2.6 %). In the literature, human infections with C. sputigena included odontitis, dental abscess, sinusitis, thoracic infections and bacteremia, particularly in immunocompromised patients with oral and dental diseases consistent with recent analysis of King Saint-Louis' jaw. C. sputigena, a commensal of the mouth that is potentially pathogenic and responsible for fatal bacteremia, may have been the cause of the king's death., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Bioactive NHC-transition metal complexes have shown promise as anti-cancer agents, but their potential use as radiosensitizers has been neglected so far. We disclose here a new series of bimetallic platinum(II) complexes displaying NHC-type bridging ligands, (bis-NHC)[ trans -Pt(RNH 2 )I 2 ] 2 , that have been synthesized via a simple, two-step procedure. They display cytotoxicity in the micromolar range on cancerous cell lines, accumulate in cells, and bind to genomic DNA, by inducing DNA damages. Notably, these bimetallic complexes demonstrate significant radiosensitizing effects on both ovarian cells A2780 and nonsmall lung carcinoma cells H1299. Further investigations revealed that bimetallic species make irradiation-induced DNA damages more persistent by inhibiting repair mechanisms. Indeed, a higher and persistent accumulation of both γ-H2AX and 53BP1 foci post-irradiation was detected, in the presence of the NHC-Pt complexes. Overall, we provide the first in vitro evidence for the radiosensitizing properties of NHC-platinum complexes, which suggests their potential use in combined chemo-radio therapy protocols.

Chronic graft-versus-host disease (cGVHD) occurs in 20% to 50% of recipients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Corticosteroids (CS) remain the first-line therapy but have suboptimal efficacy and carry a risk of long-term side effects. New agents with a better safety profile and higher efficacy are urgently needed. This study aimed to evaluate the efficacy and safety of a first-line combination of arsenic trioxide (ATO) and CS in adult patients with cGVHD requiring systemic therapy after first allo-HSCT for a hematologic disease. In this prospective national multicenter single-arm open-label Phase II study conducted in 5 university hospital centers in France, ATO was started within 10 days of CS at 1 mg/kg/day. Patients received 11 infusions per cycle of 28 days at a dose of .15 mg/kg per infusion. According to the clinical response and depending on the clinician's opinion, patients received 1 or 2 cycles of treatment. Cycles were separated by an 8- to 11-week interval from the first infusion of ATO. Patients were evaluated at 6 weeks, 14 weeks, 6 months, 9 months, and 12 months after the first ATO infusion, using the Chronic GVHD Activity Assessment Form A. The primary endpoint was preliminary efficacy based on the overall response rate (ORR; complete response [CR] or partial response [PR]) at 6 months. Response rates were estimated with 2-sided 95% exact confidence intervals (CIs). Twenty-one patients entered the study and received at least 1 ATO infusion (1 incomplete cycle for 1 patient, 1 complete cycle for 11 patients, and 2 complete cycles for 9). Six patients continued ongoing cyclosporine A (CsA) treatment after inclusion, and 4 other patients resumed CsA treatment during the study. The ORR at 6 months was 75.0% (95% CI, 50.9% to 91.3%), with CR in 35% and PR in 40%. Failure-free survival was 90.0% (95% CI, 65.6% to 97.4%) at 6 months and 65.0% (95% CI, 40.3% to 81.5%) at 12 months. The progression-free survival rate was 95.0% (95% CI, 69.5% to 99.3%) at 6 months and 83.8% (95% CI, 57.7% to 94.5%) at 12 months. The mean CS dose was decreased by 74.6 ± 32.7% from baseline to the 6-month visit and by 91.0 ± 14.6% from baseline to the 12-month visit. CS was definitively stopped in 30.0% of patients at the 6-month visit and in 47.4% at the 12-month visit. Two patients died, at 7 months and 12 months after the first ATO infusion from causes unrelated to ATO. One patient withdrew because of transient hepatotoxicity. The first-line combination of ATO and CS was associated with a high clinical response rate and rapid CS sparing in cGVHD after previous allo-HSCT., Competing Interests: Declaration of Competing Interest M.D. received consulting fees from Medsenic SAS for the statistical plan and overall analysis. C.L. received consulting fees for this work as the acting clinical medical officer of Medsenic SAS. D.R.G. and F.R. are employed by Medsenic SAS. J.P. and N.D.O. are employed AP-HP, Lariboisière Hospital., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Une femme de 63 ans rapporte avoir acheté une « pierre noire » pour se protéger de la Covid-19 à la suite de conseils trouvés sur des réseaux sociaux. Dans les 24 heures qui suivent l'absorption d'une cuillère à soupe d'un mélange de « pierre » avec du miel, apparaissent des myalgies puis une altération de l'état général qui la conduit à consulter aux urgences après 5 jours. L'examen clinique est sans autre particularité alors que le bilan biologique rapporte une insuffisance rénale aiguë et une rhabdomyolyse. L'évolution est marquée par une aggravation de l'insuffisance rénale nécessitant plusieurs séances d'hémodialyse. Les circonstances d'apparition des symptômes associées à la consommation de la « pierre » font suspecter une origine toxique. Un tube de sang et la « pierre » sont adressés au Laboratoire de toxicologie biologique pour analyses. La « pierre » friable, noire en surface, blanche en interne, est soluble dans les alcools et peu soluble dans l'eau. L'analyse par plasma à couplage inductif - spectrométrie de masse - ne retrouve ni éléments métalliques, ni métalloïdes. L'analyse par chromatographie gazeuse couplée à la spectrométrie de masse met en évidence un pic identifié comme de la paraphénylènediamine (PPD). Une analyse par spectroscopie UV permet d'estimer la pureté de la « pierre » à plus de 99 %. La PPD utilisée comme teinture capillaire noire ou adjuvant du henné est responsable d'intoxications graves, majoritairement volontaires, caractérisées par une détresse respiratoire, une rhabdomyolyse associée à des douleurs musculaires et à une insuffisance rénale. À l'exception de la détresse respiratoire, notre patiente a présenté tous les signes cliniques de l'intoxication. L'absence de détection de la PPD dans le plasma s'explique tant par la mise en œuvre de méthodes non adaptées à la détection de ce type de composés chimiques, que par le délai écoulé depuis la consommation de la « pierre ».

Pt-ttpy (tolyl terpyridin-Pt complex) covalently binds to G-quadruplex (G4) structures in vitro and to telomeres in cellulo via its Pt moiety. Here, we identified its targets in the human genome, in comparison to Pt-tpy, its derivative without G4 affinity, and cisplatin. Pt-ttpy, but not Pt-tpy, induces the release of the shelterin protein TRF2 from telomeres concomitantly to the formation of DNA damage foci at telomeres but also at other chromosomal locations. γ-H2AX chromatin immunoprecipitation (ChIP-seq) after treatment with Pt-ttpy or cisplatin revealed accumulation in G- and A-rich tandemly repeated sequences, but not particularly in potential G4 forming sequences. Collectively, Pt-ttpy presents dual targeting efficiency on DNA, by inducing telomere dysfunction and genomic DNA damage at specific loci., (© The Author(s) 2021. Published by Oxford University Press.)

To promote breast feeding and breast pumping is essential for the most vulnerable infants even if the current coronavirus disease 2019 (COVID-19) pandemic sanitary crisis imposes more stringent hygienic measures. As recommended by the Centers for Disease Control and Prevention, World Health Organization, and Milk Bank Association, "after each pumping session, all pump part that come into contact with breast milk should be appropriately disinfected." The present study proposed different methods than can be used and focus on the safety analysis of chlorine solution (CS) in terms of residual hypochlorous acid (HCA) and total trihalomethanes (THM). We also performed an efficacy testing of the CS approach to decontaminate the devices used to collect the milk (breast pumps and bottles). The bacteriologic results of 1,982 breast pump milk samples collected in three different settings showed a major decrease of the microbial contamination using either sterile device or decontamination with CS compared to a simple soap washing. The main messages from our study are to propose a guideline for the safe use of CS and to define situations when breast pump decontamination might be necessary: vulnerable babies for which sterile device is recommended; special circumstances, for example the current COVID-19 pandemic; special situations, for example women living in precarious conditions; or women pumping their milk at work but that would have low or no access to boiled water. Overall, cold decontamination reduced losses of milk for bacteriological reasons in human milk banks and may also be interesting to prevent horizontal contamination by virus like COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rigourd, Mouadh, Poupon, Langrand, Goutard, Droguet, Bille, Frange, Bahri, Pasquier, Lapillonne and Skurnik.)

Background: Lupus animal model has shown that arsenic trioxide (ATO), a treatment of acute promyelocytic leukaemia, could be effective in SLE. This is the first clinical study to determine the safety and efficacy of a short course of intravenous ATO in patients with active SLE., Methods: This phase IIa, open-label, dose-escalating study enrolled 11 adult SLE patients with a non-organ threatening disease, clinically active despite conventional therapy. Patients received 10 IV infusions of ATO within 24 days. The first group received 0.10 mg/kg per injection, with dose-escalating to 0.15 mg/kg in a second group, and to 0.20 mg/kg in a third group. The primary endpoint was the occurrence of adverse events (AEs) and secondary endpoints were the number of SLE Responder Index 4 (SRI-4) responders at week 24 and reduction of corticosteroid dosage. In an exploratory analysis, we collected long-term data for safety and attainment of lupus low disease activity state (LLDAS)., Results: Four serious AEs occurred (grade 3 neutropenia, osteitis, neuropathy), 2 of which were attributable to ATO (neutropenia in the 2 patients treated with mycophenolate). Two patients suffered a severe flare during the last 4 weeks of the trial. At W24, five patients among 10 were SRI-4 responders. Overall, mean corticosteroid dosage decreased from 11.25 mg/day at baseline to 6 mg/day at W24 (P < 0.01). In the long term, 6 patients attained LLDAS at W52, which continued at last follow-up (median LLDAS duration 3 years, range 2-4)., Conclusions: A short course of ATO has an acceptable safety profile in SLE patients and encouraging efficacy., Trial Registration: ClinicalTrials.gov, NCT01738360  registered 30 November 2012.

Background: Lithium (Li) is a first-line treatment for bipolar disorder (BD). To study its cerebral distribution and association with plasma concentrations, we used 7 Li magnetic resonance imaging at 7T in euthymic patients with BD treated with Li carbonate for at least 2 years., Methods: Three-dimensional 7 Li magnetic resonance imaging scans (N = 21) were acquired with an ultra-short echo-time sequence using a non-Cartesian k-space sampling scheme. Lithium concentrations ([Li]) were estimated using a phantom replacement approach accounting for differential T 1 and T 2 relaxation effects. In addition to the determination of mean regional [Li] from 7 broad anatomical areas, voxel- and parcellation-based group analyses were conducted for the first time for 7 Li magnetic resonance imaging., Results: Using unprecedented spatial sensitivity and specificity, we were able to confirm the heterogeneity of the brain Li distribution and its interindividual variability, as well as the strong correlation between plasma and average brain [Li] ([Li] B ≈ 0.40 × [Li] P , R = .74). Remarkably, our statistical analysis led to the identification of a well-defined and significant cluster corresponding closely to the left hippocampus for which high Li content was displayed consistently across our cohort., Conclusions: This observation could be of interest considering 1) the major role of the hippocampus in emotion processing and regulation, 2) the consistent atrophy of the hippocampus in untreated patients with BD, and 3) the normalization effect of Li on gray matter volumes. This study paves the way for the elucidation of the relationship between Li cerebral distribution and its therapeutic response, notably in newly diagnosed patients with BD., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Iron is required for the oxidative response of neutrophils to allow the production of reactive oxygen species (ROS). However, neutrophil function may be severely altered in conditions of iron overload, as observed in chronically transfused patients. Therefore, a tight regulation of neutrophil iron homeostasis seems to be critical for avoiding iron toxicity. Hepcidin is the key iron regulator in organisms; however, no studies have investigated its role in maintaining neutrophil iron homeostasis or characterized neutrophil function in patients with hereditary hemochromatosis (HH), a common iron overload genetic disorder that results from a defect in hepcidin production. To explore these issues, we studied 2 mouse models of iron overload: an experimentally induced iron overload model (EIO), in which hepcidin is increased, and a genetic HH model of iron overload with a deletion of hepatic hepcidin. We found that iron-dependent increase of hepatic hepcidin results in neutrophil intracellular iron trapping and consecutive defects in oxidative burst activity. In contrast, in both HH mouse models and HH patients, the lack of hepcidin expression protects neutrophils from toxic iron accumulation. Moreover, systemic iron overload correlated with a surprising neutrophil priming and resulted in a more powerful oxidative burst. Indeed, important factors in neutrophil priming and activation, such as tumor necrosis factor α (TNF-α), VCAM-1, and ICAM-1 are increased in the plasma of HH patients and are associated with an increase in HH neutrophil phagocytosis capacity and a decrease in L-selectin surface expression. This is the first study to characterize neutrophil iron homeostasis and associated functions in patients with HH., (© 2020 by The American Society of Hematology.)