We present the results of our experience in the diagnosis of inborn errors of metabolism (IEM) since the Expanded Newborn Screening was implemented in our Region. Dried blood samples were collected 48 h after birth. Amino acids and acylcarnitines were quantitated by mass spectrometry (MS)/MS. Newborns with alterations were referred to the clinical centers for follow‐up. Biochemical and molecular genetic studies for confirmation of a disease were performed. In the period 2011 to 2019, 592 822 children were screened: 902 of them were referred for abnormal results. An IEM was confirmed in 222 (1/2670): aminoacidopathies: 89 hyperphenylalaninemia (HPA) , 6 hypermethioninemia, 3 tyrosinemia type 1 (TYR‐1), 1 TYR‐3, 4 maple syrup urine disease (MSUD), 2 branched‐chain amino acid transferase 2 deficiency, 2 homocystinuria, 1 cystinuria, 2 ornithine transcarbamylase (OTC) deficiency, 2 citrullinemia type I (CTLN1); FAO defects: 43 medium‐chain acyl‐CoA dehydrogenase deficiency (MCADD), 13 very long‐chain acyl‐CoA dehydrogenase deficiency, 2 long‐chain 3‐hydroxyacyl‐CoA dehydrogenase deficiency (LCHADD), 1 multiple acyl‐coA dehydrogenation deficiency, 11 systemic primary carnitine deficiency, 2 carnitine palmitoyltransferase type 2 (CPT‐II) deficiency, 1 CPT‐I deficiency; organic acidurias: 12 glutaric aciduria type 1 (GA‐1), 4 methylmalonic acidemia (MMA), 7 MMA including combined cases with homocystinuria (MMAHC), 6 propionic acidemia (PA), 7 3‐methylcrotonyl‐CoA carboxylase, 1 3‐hydroxy‐3‐methylglutaryl‐CoA lyase deficiency lyase deficiency. Only 19 infants (8.5%) were symptomatic at newborn screening result . No false negative cases were identified. Genetic diagnosis was conclusive in all biochemically confirmed cases, except for two infants with HPA, identifying pathogenic variants in 32 different genes. The conditions with the highest incidence were HPA (1/6661) and MCAD deficiencies (1/13 787). After the expanded newborn screening, 222 inborn errors of metabolism have been diagnosed in the Madrid Region, 203 of them in a presymptomatic phase.1Newborn screening (NBS) started in the early 1960s with Robert Guthrie.2Metabolic disorders included in our ENBS program were: benign hyperphenylalaninemia (HPA)/ PKU, tyrosinemia type 1 (Tyr‐1), maple syrup urine disease (MSUD), MCADD, LCHADD, very long‐chain acyl‐CoA dehydrogenase deficiency, systemic primary carnitine deficiency (SPCD), 3‐hydroxy‐3‐methylglutaryl‐CoA lyase deficiency (HMG‐CoA lyase deficiency), GA‐1, methylmalonic acidemia (MMA) including combined cases with homocystinuria (MMAHC), propionic acidemia (PA), isovaleric acidemia, and beta‐ketothiolase deficiency. Furthermore, the different metabolites analyzed allows the identification of other IEM, such as homocystinuria, tyrosinemia type III, 3‐methylcrotonyl‐CoA carboxylase deficiency (MCG‐3), and some urea cycle defects, which are reported when detected, although not included “per se” in the program.Dried blood samples were collected 48 h after birth and dried at room temperature. Amino acids, acylcarnitines, and succinylacetone were quantitated by NeoBase non‐derivatized MS/MS kit  from March 2011 to August 2018 and NeoBase 2 non‐derivatized MS/MS kit (PerkinElmer) from that moment to December 2019. Tandem mass spectrometer employed was an Acquity TDQ UPLC/MS  system. For data acquisition and processing, the applications MassLynx (Waters), Neolynx and Specimen Gate MSMS Data Suite (PerkinElmer) were used. Our program analytes and ratios were selected following the Clinical and Laboratory Standards Institute recommendation.In this study, we have included all the patients diagnosed with an IEM, who were referred to the clinical units for an abnormal screening between March 8, 2011 when ENBS was established in the Community of Madrid, and December 31, 2019.Demographic and clinical conditions of the patients were registered, including sex, gestational age, presence or not of consanguinity, parents' country of origin, presence or not of symptoms at the time of the NBS result, biochemical and molecular diagnose, and if death occurred due to their pathology.All these data were statistically analyzed with SPSS Statistics 24.3During the period included, 592.822 children were included in the ENBS program, 902 of them were referred due to an abnormal screening result. An IEM was confirmed in 222 cases Table , which mIEM diagnosis included in the NBS program were 89 HPA , 3 Tyr‐1, 4 MSUD, 43 MCADD, 2 LCHADD, 13 VLCAD, 11 SPCD, 12 GA‐1, 4 MMA, 7 MMAHC , 6 PA, and 1 HMG‐CoA lyase deficiency. No cases of isovaleric acidemia nor beta‐ketothiolase deficiency were detected. Other metabolic conditions detected were: 6 hypermethioninemia, 1 tyrosinemia type 3, 2 branched‐chain amino acid transferase 2 deficiencies (BCAT‐2), 2 homocystinuria (cystathionine beta‐synthase deficiencies), 1 cystinuria, 2 ornithine transcarbamylase (OTC) deficiencies, 2 citrullinemia type I (CTLN1), 1 multiple acyl‐coA dehydrogenation deficiency (MADD), 2 carnitine palmitoyltransferase type 2 (CPT‐II) deficiency, 1 CPT 1 deficiency (CPT‐I), and 7 MCG‐3 . Median time to consultation in the clinical centers was 11 days of life (interquartile range: 8–17), being different according to the different pathologies as shown in Table Only 19 infants (8.5%) were symptomatic at the time of the NBS result , displaying different clinical presentations and evolutions ,ACADM gene, which has been associated with more severe cases and higher levels of neonatal C8 and urinary acylglycines.Most of the cases benefited from presymptomatic diagnosis. Only 19 patients (8.5%) displayed symptoms before the result of the NBS was available. However, for some fatty acid oxidations disorders, organic acidemias and urea cycle disorders, at least half of the patients presented with clinical symptoms . Only one patient with MCADD, who presented with remarkable high octanoylcarnitine (C8) levels, displayed clinical symptoms (hypoglycemia and hypotonia). He harbored a homozygous pathogenic variant c.985A > G in the For PA and MMA (including MMAHC) several cases presented with neurological deterioration in the first‐second weeks of life. It is well known that their clinical course generally starts with an acute metabolic decompensation in the neonatal period,Mean time to clinical referral varied notably among the different IEMs. As shown in Table The death rate in our population was 1.3% (3/222), a bit lower than observed in other series.In our program, genetic diagnosis not only has confirmed all the biochemical cases (except for two) but also has allowed to detect novel IEM, as HPA due to DNAJC12 pathogenic variants and BCAT‐2 deficiency. These new two entities present with a heterogeneous clinical spectrum,For HPA, as it has been previously described,Concerning MCADD, the most common variant was c.985A > G, found in 59 of 86 alleles (66%). In Galicia, the proportion was higher with a prevalence of 86% .In conclusion, in 9 years, 222 IEM have been detected with a large clinical, biochemical, and molecular heterogeneity. Most of the cases benefited from presymptomatic diagnosis but with quite notable differences among the different disorders and 27 novel variants have been reported.The authors declare no potential conflict of interest.Consuelo Pedrón‐Giner: Had the original idea and contributed to planning the research design, methods, and preparation of manuscript. Álvaro Martín‐Rivada and Laura Palomino Pérez: Contributed to data acquisition, carrying out aspects of the methods and statistical analysis, and writing the draft of the manuscript. Belén Pérez: Performed, reviewed, and discussed data concerning molecular and genetic diagnosis. All authors have been involved in drafting the article and have expressed their agreement to submission.All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation  and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.Supplementary Material S1 Novel variants detected after the Implementation of Expanded Newborn Screening in Madrid.dbSNP: Database for Single Nucleotide PolymorphismsPhiloPGVGD: Grantham Variation ‐ Grantham DeviationSIFT: Scale‐invariant feature transformCSVS: Collaborative Spanish Variant ServerMAF: Minimum allele frequencyGnomAD: Genome Aggregation DatabaseACMG: American College of Medical GeneticsClick here for additional data file.Supplementary Material S2 Novel variants affecting intronic sites detected after the Implementation of Expanded Newborn Screening in Madrid.SSF: Splicing Sequences FinderMaxEnt: Maximum Entropy ModelingNNSPLICE: Splice Site Prediction by Neural NetworkCSVS: Collaborative Spanish Variant ServerMAF: Minimum allele frequencyGnomAD: Genome Aggregation DatabaseACMG: American College of Medical GeneticsClick here for additional data file.


In addition, some new organosulfur compounds are developed. The reversible sulfur—sulfur (S—S) bond breakage/formation of organosulfur in batteries makes them applicable as functional materials in batteries. In this review, new organosulfur materials including molecules, polymers, and composites are introduced. In the following, organosulfur‐inorganic hybrid materials are discussed, which have shown unique redox process and enhanced battery performance. In the third part, organosulfur additives are used in Li‐S batteries, which can improve the formation of solid‐electrolyte interphase (SEI) and alter the redox pathways of sulfur cathodes. In the fourth part, organosulfur materials used in other metal batteries are introduced. Lastly, a summary and some perspectives are given. This review presents an overview of the recent advances of organosulfur materials in batteries and provides guidance for the future development of these materials.Battery materials have become a hotspot in the academic research. Organosulfur compounds are considered as a promising class of cathode materials for rechargeable metal batteries. They have attracted increasing attention in recent years after a long‐term stagnancy since 1980s. Recent studies have focused on the understanding of redox mechanism of linear organosulfur molecules R‐S In this review, recent understanding and developments of organosulfur for rechargeable lithium batteries are summarized, including molecules, polymers, composites, and organosulfur‐inorganic hybrid materials. In addition, organosulfur as electrolyte additives in Li‐S battery and other metal batteries are covered. Finally, some perspectives are given. This review provides guidance for the future development of organosulfur materials for batteries. The current cathode materials are mainly crystal materials such as layered LiCoO2, spinel LiMn2O4, and olivine LiFePO4. Their structures allow reversible lithium ion intercalation/deintercalation, offering long cycle life for practical application. However, the theoretical specific capacities and energies of these materials are limited to below 250 mAh g−1 and 800 Wh kg−1, respectively. To further increase these values, alternative electrode materials with higher specific capacities are needed. Significant efforts are being focused on transition metal oxides, e.g., high‐nickel‐layered oxide cathodes. In recent years, rechargeable lithium metal batteries have attracted tremendous interests because of the high capacity of lithium metal anode (3862 mAh g−1). To couple with lithium metal anode, lithium‐free cathode materials such as sulfur, oxygen, and organic compounds can be used. Although there are many challenges associated with the lithium metal anode, such as dendrite formation and safety concern, these rechargeable lithium metal batteries are definitely promising to overcome the energy limits of Li‐ion batteries. A lot of efforts are being focused on solving the issues of lithium metal anodes. At the same time, alternative lithium‐free cathode materials are also attracting persistent attention.Lithium‐ion (Li‐ion) batteries have dominated the power supply market of portable electronics and electric vehicles because of their high specific energy (Wh kg LiFePO4.1 Thei−1 leading to the high specific energy of 2600 Wh kg−1 of lithium‐sulfur (Li‐S) batteries. In a Li‐S battery, many challenges exist facing the lithium metal anode as well as the sulfur cathode. There have been several thorough and in‐depth reviews about the issues and possible solutions for Li‐S batteries. As a class of sulfur derivatives, organosulfur as cathode materials has attracted much attention.Figure  not much progress has been made. In recent years, growing interest in organosulfur materials for rechargeable metal batteries has emerged. The linear organosulfur compounds R‐Sn‐R (n = 2–8) have become models for understanding the redox mechanism because of their defined structure. The R group have profound effects on the electrochemical and physical properties of organosulfur molecules. The studies on organosulfur materials not only expand the sulfur cathode family, but also improve our understanding of electrochemistry. The gains from these studies also help develop advanced materials for practical applications.Among the various cathode materials, elemental sulfur is one of the most promising candidates because of the high capacity of 1675 mAh gatteries.8 As aIn this review, we summarize the recent advances of organosulfur materials in rechargeable lithium batteries mostly after year 2019. In the first section, the newly developed organosulfur molecules and polymers are presented. They include 1,4‐bis(diphenylphosphanyl) tetrasulfide synthesized by an electrochemical method and hyperbranced polymer based on the condensation reaction between 1,3,5‐benzentrithiol and elemental sulfur. Two organosulfide–metal complexes are introduced. To enhance the conductivity and improve the cycling stability of organosulfur electrodes, some strategies to incorporate carbon materials are discussed. In the second section, several organosulfur–inorganic hybrid cathodes are described in detail, in which organosulfur plays an important role and interesting redox processes are revealed. In the third section, organosulfur materials used as additives in Li‐S batteries are described. In the last section, organosulfur materials used in other battery systems are briefly introduced, such as redox flow batteries and sodium (Na)/magnesium (Mg) batteries. Finally, a summary and some perspectives about the future development of organosulfur materials are given.2n‐, where n > 2. The specific capacity of organosulfur lies in the number of S—S bonds and sulfur contents in the structure. Our previous paper provides a comprehensive review on organosulfur (organosulfides) as cathode materials for rechargeable lithium batteries in 2019. Some small molecules such as dimethyl and diphenyl polysulfides, thiuram polysulfides, and selenium‐containing organosulfides have been covered. In this section, we only focus on organosulfur materials recently developed. In addition, some organosulfide–metal complexes show unique physical and electrochemical properties. Moreover, the efforts to enhance the conductivity of organosulfur electrodes by introducing different carbon materials are covered as well.Organosulfur consists of organic groups R which are bonded with S—S bonds. Sulfur could be bonded with the R group via di, tri, or even multiple sites, making organosulfur materials highly diversified. They can be small molecules, linear, or hyperbranched polymers. Between R groups, there could be single S—S bonds or a sulfur chain ‐S2.1n > 2). In addition, some of them are not stable in air, posing challenges for handling these chemicals. In addition, the electrochemical conversion processes of organosulfur molecules in rechargeable batteries are usually quite complex, making the characterization difficult. Below we list some organosulfur molecules investigated in rechargeable batteries recently.There are few organosulfur molecules that have been studied in rechargeable lithium batteries since 2019. First of all, it is quite challenging to synthesize pure or even analytical pure organosulfur molecules, in particular organosulfur molecules with long sulfur chains  isomers, i.e., 1,2‐LBDT, 1,3‐LBDT, and 1,4‐LBDT.13 The The lone pair of electrons on N atoms has strong electrostatic interaction with lithium ions, changing the behavior of discharged products in batteries. To reveal the effect of N‐heterocycles, dipyridyl disulfide (DpyDS) was investigated in comparison with diphenyl disulfide (DPDS) by Wang et al. With only two carbon replaced by N atoms, DpyDS shows significantly improved performance in terms of discharge voltage  for 10 days, only 6.3% of DPyDS is reduced by Li‐CP, but 58.7% of DPDS is reduced. This comparison reveals another reason behind the ultrastable cycling performance of DPyDS in rechargeable lithium metal batteries. Therefore, it can serve as an active material in the catholyte of a membrane‐free redox flow battery, leading to stable cycling performance.Organosulfur molecules containing N‐heterocycles such as thiuram polysulfides have shown unique electrochemical behavior in lithium batteries.15 The The target molecule is dipyridyl trisulfide Py2S3, however, a series of dipyridyl polysulfides including tri, tetra, penta, hexa, hepta, and octasulfides are detected in the synthesized catholyte. The Li cell shows a long discharge voltage plateau at 2.45 V followed by a sulfur‐like discharge voltage profile. After recharge, similar dipyridyl polysulfides are formed based on the high‐performance liquid chromatography‐quadrupole‐time of flight mass spectroscopy (HPLC‐QTof‐MS) analysis. The cell shows a superlong cycle life of 1200 cycles with >70% capacity retention at 1 C rate . Two IM1s are dimerized to form BDPPTS. The obtained liquid product was characterized and confirmed by Fourier transform infrared (FTIR), Raman spectroscopy, NMR, and MS analysis. The synthesized BDPPTS was evaluated in a Li cell, which shows a high discharge voltage plateau at ≈2.9 V followed by sulfur‐like voltage profile  tetrasulfide (BDPPTS) via an electrochemical synthesis method, as shown in Figure 19 Dipe Figure . It is bd Figure . The midd Figure . When th Each DIXPS molecule can take 10 Li+ and e− as shown in Figure −1 and specific energy of 1546 Wh kg−1. In a Li cell, it exhibits three discharge voltage plateaus at 2.61, 2.30, and 2.08 V with the initial discharge specific capacity of 628 mAh g−1  at C/10 rate  stability at 4 C rate. In a pouch cell, it shows quite stable performance when tested under high‐loading  and lean‐electrolyte  conditions. In addition to the outstanding performance, DIXPS is proved to be a promising sustainable material for high‐energy lithium batteries, which is in sharp contrast to the materials currently used in Li‐ion batteries, e.g., Co and Ni with potential supply shortage.Another two organosulfur model compounds are diisopropyl xanthogen disulfide (DIXDS) and diisopropyl xanthogen polysulfide (DIXPS) studied by Bhargav and Manthiram.20 Eace Figure , offerin Single crystals of TTT and HTP were synthesized in a zone‐melting chemical‐vapor‐transport apparatus by a solvent‐free and continuous synthetic protocol. They show quite different discharge/charge behavior  and hexathiapentacene (HTP) as shown in Figure 21 Sinr Figure  and cyclIn a short summary, organosulfur molecules are feasible model compounds for understanding their electrochemical behavior in rechargeable batteries. The heteroatoms in them have profound effects on their electronic structures and battery performance. The nitrogen and phosphorous atoms can act as bonding bridges in organosulfur molecules introducing various organic groups. For example, thiuram sulfides or disulfides consist of many structures, e.g., tetramethylthiuram sulfide and di(n‐propyl)thiuram disulfide. These compounds are waiting to be explored. Coupling organosulfur cathode materials with solid or polymer electrolyte would be a viable approach to enable practical battery performance with high mass loading and long cycle life of organosulfur active materials.2.2 Usually, they have flexible and transparent properties, making them suitable for flexible batteries and devices. However, they may not have good ionic and electronic conductivities, needing to be composited with carbon materials, e.g., carbon powder, carbon nanotubes (CNTs), and graphene, etc. Recently, some new organosulfur polymers with unique structures were synthesized, which have expanded the organosulfur family and improved our understanding of these polymers in rechargeable lithium batteries.Organosulfur polymers consist of many S—S bonds with organic groups R in the structure, leading to high theoretical specific capacities.23 UsuFigure  The obtained materials are rubber‐like polymers with different yellow color and they are insoluble in most solvents. The PPPS with the TBBT:S ratio of 1:4 could contain sulfur chains with multiple redox active sites, leading to a high theoretical capacity of 622.1 mAh g−1. All these polymers show a sloping discharge voltage region followed by a flat voltage plateau at 2.1 V in lithium batteries  and elemental sulfur with three different molar ratios of 1:1.5, 1:3.0, and 1:4.5 occur, leading to three polymers with hyperbranched structures (BTTP). These polymers are completely amorphous in the electrodes. In lithium batteries, they also show a sloping voltage region followed by a flat voltage part with overlapped voltage plateaus, which are due to the formation of PhS3Li3 and Li2S. In the cyclic voltammograms, three cathodic peaks can be seen, which are consistent with the voltage profiles. These polymers show relatively stable performance with high Coulombic efficiencies in batteries. The discharge capacities are in the range of 400–1000 mAh g−1, making them promising to be high‐capacity cathode materials for lithium batteries.Sang et al. synthesized a new class of polyphenyl polysulfides (PPPS) by condensation reactions between 4,4′‐thiobisbenzenethiol (TBBT) and elemental sulfur with molar ratios of 1:1, 1:2, 1:3, and 1:4, as shown in Figure 24 Thes Figure . The lows Figure . The sul The cyclic S8 opens at above 159 °C, which can react with cis‐1,4‐polyisoprene (RUB) molecular chains to form a highly crosslinking framework. The formed sulfur‐rich vulcanized clay rubber has a high sulfur content of 75 wt%. The experimental results and DFT calculations show a new mechanism based on Li2S3 and Li2S6 intermediates. The Li cell shows a high capacity of 780 mAh g−1 at 1 C rate and stable cycling performance of 300 cycles at room temperature. At −40 °C, the discharge capacity is ≈67% of that at room temperature. Li et al. used the ring opening S to copolymerize with triallyl isocyanurate (TAIC), as shown in Figure  The formed S‐triallyl isocyanurate organosulfur polymer (STI) consists of ultrafine monoclinic S particles embedded in the organosulfur polymer matrix, therefore a high S content of 90 wt% is obtained. The STI cathode shows a high initial capacity of 904 mAh g−1 at 0.5 C and a low capacity decay rate of 0.017% over 350 cycles at 1 C rate. Kim et al. incorporated 1D charged polypyrrole into a 2D covalent triazine framework (cPpy‐S‐CTF) synthesized in the presence of elemental sulfur. A high sulfur content of 83 wt% is achieved and cPpy enables a 3D nanochannel formation in the composite with high‐affinity anchoring sites toward LiPSs. The cPpy‐S‐CTF cathode shows a high discharge capacity of 1203.4 mAh g−1 at 0.05 C and a capacity retention of 86.8% after 500 cycles. The incorporation of charged conducting polymers is a promising strategy to enable high‐performance organosulfur polymer cathode.Recently, Wang et al. fabricated a sulfur‐rich polymer which enables all the discharged intermediates in amorphous state, promoting the battery performance at low temperature, e.g., −40 °C, as shown in Figure 26 TheAs can be seen from the above studies, most organosulfur polymers are insoluble in organic solvents, making their processability difficult. Therefore, the precursors need to be injected in porous conductive substrates before they can react to form polymers. Upon cycling, the discharged and recharged products are held in the substrates leading to stable battery performance. Therefore, the substrates are critical for the battery performance of organosulfur polymers. They need to be porous to hold active materials, at the same time, they need to be very conductive.2.34, to produce orgnaosulfide–metal complexes, like Cu‐BDT. When SnCl4 was used, Sn‐(BDT)2 can be synthesized. Their mass densities are about 2 mg cm−3, which are much higher than that (1.2 mg cm−3) of 1,2‐benzenedithiol. The Li/Sn‐(BDT)2 cell exhibits two overlapped discharge voltage plateaus and delivers a capacity of 221.2 mAh g−1 offering a high volumetric energy density of 973.2 Wh L−1. In contrast, the Li/Cu‐BDT cell exhibits four stepped discharge voltage plateaus and delivers a capacity of 234.2 mAh g−1 offering a high volumetric energy density of 1044.5 Wh L−1. Both show promising cycling stability. The charge storage occurs based on the reversible breakage/formation of sulfur–metal bonds accompanying valence changes of the metal ions. This work successfully demonstrates a plausible strategy to complex organosulfide and metal ions, which has a quite open space for further exploration.As electrode materials, organosulfur compounds use to have low densities, making them have low volumetric energy densities. To improve this, they need to be composited with dense materials, like metals. Another approach is to complex organosulfide with metal ions. Li et al. developed a simple method to make these complexes. Organothiols like 1,2‐benzenedithiol can react with a salt, e.g., CuSOe Cu‐BDT.29 Whe2.4 Close‐to‐theoretical specific capacity can be achieved, which allows analysis of the cycled products and revealing the redox mechanism.Organosulfur compounds usually are not electronically conductive, like elemental sulfur, which is due to the lack of conjugated structures, neither do the reduced products in batteries. To improve their conductivity, a variety of carbon materials can be composited with them, like carbon powder, CNTs, and graphene, etc. One of the successful approaches was developed by our group. We used a binder‐free CNT paper as a host/current collector for soluble organosulfur molecules. The CNT paper can be self‐weaved or purchased from commercial. It is composed of nanoscaled conductive network which is highly efficient for electron transport. In addition, they can adsorb the dissolved species including the organosulfur molecules and cycled products, making their rechargeability highly reversible. This approach is suitable for electrolyte‐soluble molecules such as dimethyl trisulfide, diphenyl trisulfide, diphenyl polysulfides, dipyridyl polysulfide, organosulfur polymers, etc.33 CloFigure  in which rGO nanosheets can improve electronic conductivity and the bonding between sulfur chain and rGO reduces the formation of high‐order LiPSs and therefore the shuttle effect. By coupling with a coated separator with nitrogen and sulfur co‐doped rGO, the cell shows a high initial discharge capacity of 1364 mAh g−1 at 0.2 C and a reversible discharge capacity of 750 mAh g−1 at 1 C after 700 cycles. Recently, our group found phenyl tetrasulfide can be cycled close to 1000 times when worked with a composite electrode consisting of rGO and MoS2. The π–π stacking between the phenyl groups and rGO can significantly enhance the battery cycling performance. He et al. developed a 3D nitrogen‐doped graphene sponge decorated with Fe3O4 nanoparticles (3DFNG) as a host for dimethyl trisulfide (DMTS), as shown in Figure 3O4 in the composite can effectively anchor DMTS and its discharged products because of their chemical interactions. Graphene and Fe3O4 provide electron transport pathways. In lithium batteries, 3DFNG is demonstrated to be a promising host for DMTS, leading to significantly improved cycling performance compared with 3DNG (3D nitrogen‐doped graphene sponge) and 3DG (3D graphene sponge)  and grafted on the carbon chain, as shown in Figure −1 based on the whole composite and excellent cycling life with a capacity retention of >91% after 620 cycles at 1 C rate. Recently, Chang et al. synthesized sulfurized carbon nanotube@aminophenol‐formaldehyde with covalently linked short‐chain sulfur. It is in the form of mesoporous yolk‐shell organosulfur nanotubes which can effectively accommodate the volume change, expose active sites, and improve the transport of charges, leading to excellent reaction kinetics (a specific capacity of 841 mAh g−1 and a capacity decay of 0.06% per cycle within 500 cycles at 5 C). Hu et al. grafted organic polysulfane on porous graphene as an organosulfur electrode material. The mesoporous graphene provides good electrical conductivity and the organic polysulfane bonded with it shows good structural stability, leading to promising battery performance.In addition to carbon matrix or additives, chemical bonding approaches have also been developed by aid of the organic groups. For example, Li et al. developed a novel cathode consisting of linear sulfur covalently attached to thiol‐rich reduced graphene oxide (rGO) as shown in Figure 30 in ) Figure . Another3In the process of organosulfur conversion reaction, RSLi and intermediate LiPSs are produced. To make the conversion more controllable, it is necessary to precisely locate lithiation sites during its redox process, detect specific products, and use bonding activity of the organic groups by introducing hybrid components such as inorganic nanomaterials. Through this approach, the interesting properties of organosulfur are combined with the functionalized utility of inorganic materials, leading to excellent electrochemical performance. The hybrid of organo‐inorganic covers rechargeable organosulfur, as well as a variety of inorganic nanomaterials, including metal oxides, metal sulfides, and elemental materials. The hybrid based on interatomic force also provides a facile and practical solution for promoting and boosting the electrochemical performance of batteries. In this section, we focus on hybrid cathodes composed of organosulfur and inorganic nanomaterials. In addition, the unique electrochemical properties enhanced by different interatomic forces are discussed as well.3.1 Se nanowires were mixed with CNTs to render a self‐weaving substrate, then DPTS was introduced to form a composite electrode. The hybrid electrode shows new redox reaction mechanisms involving S—Se bonds, enhancing the specific capacity and cycling stability. The assembled organic–inorganic hybrid electrode with the advantages of conductive Se and reduction of LiPSs form several diphenyl sulfoselenide compounds containing dynamic S—Se bonds during charge process, as shown in Figure 2Se, Li2S, and PhSLi are delithiated, ∙Se∙, ∙S∙, PhS∙ radicals are combined in pairs to form new products. A portion of ∙Se∙ is reconfigured into the diphenyl sulfoselenide compounds through dynamic S—Se bonds, avoiding the formation of long‐chain lithium polyselenides, which are easy to lose through the dissolution and diffusion. After the first 50 cycles, the diphenyl sulfoselenide compounds are fully formed. The Se atoms fixed in insoluble diphenyl sulfoselenide can remain electrochemically stable over prolonged cycles. The Li/DPDS‐Se battery shows a high initial discharge capacity of 471.1 mAh g−1 and retains a specific capacity of 325.8 mAh g−1 after 250 cycles. The Li/DPDS‐Se battery also shows a high Coulombic efficiency of over 99% after 250 cycles due to inhibiting the shuttle effect. In addition to organosulfide, diphenyl diselenide has also been proved to be effective to improve the Li‐Se performance by altering the redox chemistry of Se by the same research group. The effective combination of the organosulfide or organoselenide and Se is a promising approach to develop hybrid electrodes with superior battery performance.Zhao et al. reported a hybrid cathode composed by organosulfur diphenyl trisulfide (DPTS) and inorganic selenium (Se) nanowire.37 Se 3.2n‐R, n ≥ 3) with long sulfur chains can enhance the discharge voltage by flexibly adjusting the functional groups, own high specific energies, and achieve low electrolyte/active material ratios. However, there are still intermediate LiPSs during the discharge process. In addition, the discharged product RSLi has the high solubility in the ether electrolyte. Hence, many organosulfur materials show unsatisfactory cycling stability and Coulombic efficiency. In regard to tackle the problems, it is vital to anchor RSLi and LiPSs and accelerate the reduction reactions within the cathode by using novel electrode configuration, such as introducing inorganic nanomaterials. 2D layered transition metal disulfides with high conductivity, large polar surface, and high catalytic activity could be good choices. TiS2, an ideal transporter for both lithium ion and electron, is able to facilitate reaction kinetics and adsorb LiPSs. Constructing a hybrid cathode of TiS2 with PTS is a effective method to promote and boost electrochemical performance of battery by Fan et al. The self‐woven hybrid substrate provides enough pores for physical confinement through weak binding as shown in Figure 2  and Li2S. This process consists of two parts: lithium intercalation reactions at ≈1.9 V versus Li/Li+ and conversion reactions at below 1.0 V versus Li/Li+. It is found that bis(trifluoromethanesulfonyl) imide (TFSI−) anions can be intercalated into VS4 at 3.0 V in the charge process, then triggering S evolution. To avoid the escaping S changing to LiPSs, diphenyl disulfide (DPDS) was used as a sulfur receptor to capture these sulfur atoms. Hence, during the charge, DPDS changes to diphenyl trisulfide (DPTS) after S atom is evolved from VS4. The whole process is illustrated in Figure −1 after 300 cycles at the current density of 240 mA g−1.The above works focus on assisting organosulfur through the introduction of inorganic nanomaterials. When focusing on the active materials of metal polysulfides, Wang et al. found more interesting phenomena assisted by organosulfur.40 Amo4A Li‐S battery consists of a lithium‐metal anode and an elemental sulfur cathode. During the conversion‐type reaction, Li‐S battery suffers from a number of problems, including LiPSs dissolution and migration, the instability of Li anode and SEI on it. Efforts on Li‐S battery have made great strides to conquer these issues over the years. Recently, understanding the underlying chemistry is the new target for fundamental research. By truly unlocking the potential of the Li‐S battery, the practical application of Li‐S battery will forward a solid step.4.12S on the cathode are two key issues for the rapid capacity fading of Li‐S battery. Although tremendous approaches have been made to tackle them, new approaches are still needed. Chen et al. reported a functional electrolyte system using a liquid organosulfur compound, dimethyl disulfide (DMDS), as a co‐solvent for Li‐S battery. Through the reversible cleavage/reformation of S—S bonds in DMDS, DMDS can afford a theoretical capacity of 570 mAh g−1, which helps achieve high energy density of Li‐S battery. In addition, the DMDS‐containing electrolyte enables a new electrochemical reduction pathway for sulfur cathodes, leading to improved redox kinetics and rechargeability. These effects are reflected in the performance of the battery with lower charge overpotential, as shown in Figure 1H NMR, scanning electron microscopy (SEM), X‐ray diffraction, and XPS, a new redox pathway is obtained, which is about the formation and subsequent reduction of soluble dimethyl polysulfide (DMPS) species. In particular, during the subsequent reduction, DMPS forms MeSLi, LiPSs, and lithium sulfide (Li2S), which are beneficial to the reaction kinetics and cycling performance. This work thus provides a strategy from the aspect of co‐solvent for improving the practical energy density of Li‐S batteries.The dissolution of LiPSs in liquid electrolytes and the irreversible deposition of Li battery.41 Thr4.2 BTB provides an organosulfur‐containing SEI for shielding LiPSs and protecting Li metal anode as shown in Figure −2), low E/S radio (5.0 µL mg−1), and an ultrathin Li anode (50 µm).To solve the problems brought by the dissolution–precipitation redox reactions of the S cathode and the corrosion reaction on the Li metal, 3,5‐bis(trifluoromethyl) thiophenol (BTB) as an electrolyte additive is introduced into Li‐S battery by Wei et al.42 BTB The thiol groups can react with Li metal and elemental sulfur  bonds formation and interfacial electrochemical transformation, this work demonstrates a strategy to solve the intrinsic problems from a more chemical perspective. In addition, Lian et al. report a class of electrolyte additives, i.e., benzenedithiols (BDTs), which have three isomeric structures, including 1,2‐BDT, 1,3‐BDT, and 1,4‐BDT. Different conjugate diprotic structures are bridged with sulfur as different building blocks, which are analyzed by UPLC‐QTOF‐MS. After distinguishing the electrochemical performances of different concentrations for different isomer electrolytes, 0.15 m 1,4‐BDT is the best choice of the three isomers due to its high capacity for bonding sulfur and stable cycles. Figure −1 and stability by 909.3 mAh g−1 after 500 cycles at C/2 rate. The capacity fading rate is as low as 0.065% per cycle. The Li‐S pouch cell with 1,4‐BDT exhibits a capacity of 2223.9 mAh after 26 cycles. The only disadvantage of using organothiols in Li‐S batteries is that they react with Li metal and sulfur cathode releasing hydrogen and hydrogen sulfide gases, respectively. These gases can be quickly released after the electrolyte injection, which has been dealt with a gas bag in the pouch cell assembly.The interfacial instability of the Li metal anode and shuttling of soluble intermediate LiPSs in Li‐S batteries plague its applications. Most efforts have only focused on one side. Simultaneous formation of interfaces on both anode and cathode are promising solutions to fully satisfy the requirements. Guo et al. reported organothiol as a functional electrolyte additive which has thiol groups.43 Ther Figure , and con3TFA) as an electrolyte additive in Li‐S batteries. It can react with LiPSs in situ to form lithium trifluoroacetate (LiTFA) and DMPS. The TFA anion changes solution coordination behavior, thus reducing polarization and improving discharge kinetics. At the same time, the derivatization to DMPS improves the solubility of intermediate species, enhancing the utilization of sulfur under lean‐electrolyte conditions. The theorized improvements are illustrated in Figure Recently, Gupta et al. used methyl trifluoroacetate . The pyridine in SPAN acts as a lithiophilic matrix which synergistically works with the robust SEI to form an ultrathick Li metal anode, as shown in Figure −2, the cell shows stable cycling under a lean electrolyte of 2.2 µL mg−1 and low negative‐to‐positive (N/P) capacity ratio of 1.3. For the sulfur cathode, Xie et al. used a polymer organosulfur additive of di(tri)sulfide polyethylene glycol (PESn) as sulfur containers to regulate the PS intermediates in a working sulfur electrode, as shown in Figure  It can reversibly store sulfur species by forming organosulfur during charge and release them during discharge, improving reaction kinetics and cycling performance. Chen et al. developed an in situ solidification strategy by using 2,5‐dichloro‐1,4‐benzoquinone (DCBQ) as an electrolyte additive. It can covalently bond with LiPSs via nucleophilic substitution reactions forming a solid S‐DCBQ organosulfur polymer which can effectively impede the polysulfide dissolution and migration, as shown in Figure To form stable SEI on lithium metal anode and reduce shuttle effect of LiPSs of the sulfur cathode, other organosulfur materials have also been utilized. For the Li metal anode, Boateng et al. used garlic, which consists of a variety of organosulfur compounds as shown in Figure 46 Theg Figure . Jiang e5Orgnosulfur materials have been extensively studied in rechargeable lithium batteries. Their intriguing redox mechanisms and the effects of different functional groups R on their electrochemical behaviors have been revealed. Based on the previous understanding, interests in their applications in other battery systems have grown obviously. Interesting phenomena have been observed and they have shown unique properties in improving battery performance. Below we list a few examples, which can serve as the beginning of application of organosulfur materials in the wide battery systems.5.1 However, perhaps due to the shuttle of active materials or the irreversible chemical reaction between organosulfur lithium compound (discharged product) and carbonate electrolyte, the Li‐organosulfur RFB shows rapid decay of capacity. Recently, Zhang et al. use tetraethylthiuram disulfide (TETD) as an active material for nonaqueous RFBs. Comparing with TMTD, TETD has high solubility  in the symmetric organodisulfides (R‐S‐S‐R) is replaced with an allyl (A) to form asymmetric organosulfides (R‐Sn‐A). The R‐Sn‐A can be simply prepared in the supporting electrolyte by mixing phenyl disulfides  with allyl‐based organosulfur (DDS and DTS), as shown in Figure − . Tetramethylthiuram disulfide (TMTD) with relatively low molecular weight was first adopted as the active material of a nonaqueous Li‐organosulfur RFB by Wang et al.50 How% Figure . To impr− Figure . Further Some sulfur atoms can be inserted into the organodisulfide/diselenide structures to generate new active materials (RSSSR/RSSSeR) during the discharge–charge process. The inserted sulfur atoms can be transformed into Li2S directly in the absence of long LiPSs , which accelerate redox kinetics of sulfur and improve the sulfur material utilization. In addition, this strategy can effectively remove the passivation of Li metal anode via self‐healing process due to the presence of DpyDS and PhSeSePh in the circulating catholyte. Because of the above reasons, a superior sulfur utilization of 92% (1543 mAh g−1 based sulfur mass) is achieved in a continuous Li‐S RFB  as adjuvants into a Li‐S RFB Figure .53]5356[53Zr2Si2PO12 ceramics, Miao et al. reported a green and simple powder polishing method to modify the pyrolytic PAN (pPAN) intermediate layer on the surface of Na superionic conductor (NASICON) ceramics. The introduced sulfur can trigger the dehydrogenation and cyclization of PAN, thus rendering SPAN layer on the surface of NASICON particles  as the carbonate‐based electrolyte additives,58 whi5.4−1) and volumetric (3833 mAh cm−3) capacity and the low reduction potential. However, traditional magnesium‐sulfur (Mg‐S) batteries suffer from poor cycling stability and reversibility. Very few studies were carried out on the application of organosulfur materials in Mg batteries. Kaland et al. reported the dipentamethylene thiuram tetrasulfide (PMTT) as the cathode, which exhibits a high discharge capacity of 295 mAh g−1 in Mg battery. During the reduction process of PMTT, the S—S bonds are preferentially attacked and broken, then the structure of Mg pentamethylene dithiocarbamate (Mg‐(PMDTC)2) is formed. In addition, the PMTT‐derived sulfur/mesoporous carbon composite also was prepared that displays excellent rate performance (185 mAh g−1 at 500 mA g−1) and 76% capacity retention after 100 cycles.Magnesium (Mg) metal anode has several benefits: 1) dendrite growth on Mg metal anode has little or no risk; 2) abundant Mg resources and low cost; 3) the high specific  design and synthesize novel organosulfur molecules with defined structures, e.g., novel organosulfur molecules with more active sites for high specific capacity. In addition, new synthetic methods are needed to afford large‐scale synthesis; 2) apply advanced characterization techniques to clarify the redox mechanism of organosulfur. Up to now, the redox intermediates of organosulfur are still difficult to capture. Therefore, in order to better understand their reaction mechanism, more advanced characterization techniques such as in situ spectroscopies are needed; 3) investigate organosulfur in various battery systems, such as zinc, aluminum, and calcium batteries. They have clear advantages of low cost and high capacity/energy density. To date, only limited efforts have been focused on other metal batteries; 4) develop solid‐state batteries with organosulfur materials. Some organosulfur molecules can be adapted in solid‐state batteries to improve interfacial properties. For example, DEEs could be used as conductive glues in solid‐state battery electrodes. In addition, the discharged products of organosulfur can conduct ions, which can be used as salt additives in solid‐state electrolytes; 5) hybrid organosulfur with other inorganic and organic materials. It has been confirmed that organosulfur can be involved in the redox process of metal polysulfides. However, only few inorganic materials have been studied in the hybrids. Other metal polysulfides like MoSOrganosulfur possesses many advantages and the family of organosulfur is large. Their potential has been shown in this review and more endeavors need to be made in this area. It is believed more interesting results and intriguing mechanisms will be discovered. There is still some way to go before organosulfur materials can be used in commercial batteries. During the application process, two outstanding issues need to be considered. For organosulfur molecules as cathode materials, solid or polymer electrolytes are needed, which can block their crossover and reduce the risk. In addition, since organosulfur materials are not lithiated, therefore Li metal anodes are needed which add additional challenges for the practical application of organosulfur. In order to replace the unsafe lithium metal anode, it is also necessary to consider the development of suitable electrolytes to enable organosulfur be paired with lithiated graphite anode. For other battery systems, such as Li‐S batteries, the commercial use of organosulfur is also promising. Maybe organothiols used as electrolyte additives could become the first trials in commercial batteries. In addition, the introduction of Se—S bonds could bring unexpected benefits. Although some challenges need to be overcome, we believe organosulfur will play a critical and diverse role in the future battery systems and beyond.The authors declare no conflict of interest.


Previous studies have shown that natriuretic peptide levels are increased in patients with restrictive cardiomyopathy (RCM) but not in constrictive pericarditis (CP). We performed a systematic review and meta‐analysis to evaluate the diagnostic utility of B‐type natriuretic peptide (BNP) and N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) to differentiate CP and RCM. We searched electronic databases from inception to January 07, 2021. Studies involving adult patients that assessed the utility of natriuretic peptides to differentiate CP and RCM were included. All meta‐analyses were performed using a random‐effects model. Seven studies (four case‐control and three cohorts) involving 204 patients were included. The mean age ranged between 25.7 and 64.1 years and 77% of patients were men. BNP levels were significantly lower  in patients with CP compared to RCM. The pooled area under the curve (AUC) of the BNP level was 0.81 . NT‐proBNP  and log NT‐proBNP  levels were significantly lower in patients with CP compared to RCM. Our review shows that BNP and NT‐proBNP levels were significantly lower in patients with CP compared to RCM. The pooled AUC of BNP level showed a good diagnostic accuracy to differentiate both conditions. The search was conducted from inception to January 07, 2021. The complete search strategy is available in Table 2.2Studies involving adult patients (≥18 years old) that evaluated the utility of natriuretic peptides to differentiate CP and RCM were included. We excluded conference abstracts, animal studies, editorials, commentaries, systematic reviews, and narrative reviews.2.3We downloaded all articles from electronic search to EndNote X8 software and duplicate records were removed. Titles and abstracts were independently screened by two review authors (CDA and JSC) to identify relevant studies. The same review authors (CDA and JSC) independently evaluated the full text of the articles. Any disagreement on title/abstract and full‐text selection was resolved through consensus.2.4The data from each study were independently extracted by two review authors (CDA and JSC) using standardized data extraction and any disagreement was resolved through consensus. If additional data was needed, the corresponding author was contacted through email. We extracted the following information: first author name, year of publication, country, study design, population, sample size, age, sex, etiology, and diagnosis of CP and RCM, and natriuretic peptide levels.2.5The Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS‐2) tool was used to evaluate the quality of diagnostic accuracy studies.2.6χ2 test (threshold p < .10) and I² statistic. Heterogeneity was defined as low if I2 < 30%, moderate if I2 = 30%–60%, and high if I² > 60%. Meta‐analyses were conducted using the software R 3.6.3 and the web IPD Meta‐Analysis of Diagnostic Accuracy.p < .05 was considered statistically significant.For diagnostic accuracy studies, when individual patient data were available, we displayed a receiver operating characteristic (ROC) curve for each study. In addition, we used a random‐effects model to calculate the pooled area under the curve (AUC) with their 95% confidence interval (CI) of BNP level. For case‐control studies, the Dersimonian‐Laird random‐effects model was performed to pool standardized mean difference (SMD) with their 95% CIs of BNP, NT‐proBNP, and log NT‐proBNP levels. The SMD was chosen because there was variation in the type of assay used for the measurement of natriuretic peptides. Log NT‐proBNP represents the logarithmic transformation of the NT‐proBNP levels reported in the studies. We pooled NT‐proBNP and log NT‐proBNP separately because some studies only reported log NT‐proBNP and it was not possible to convert to NT‐proBNP. Heterogeneity among studies was evaluated using the 33.1Our electronic search retrieved 162 articles. After the removal of duplicates, 83 articles were screened by title/abstract, and of those, 70 were excluded. After a full‐text assessment of 13 remaining articles, six were excluded due to other populations (4), conference abstract (1), and commentary (1). Finally, seven articles3.2n = 204) are shown in Table The characteristics of the seven included studies , postcardiac surgery (27%), and tuberculosis (20%) across six studies. In two studies, the diagnosis of RCM was defined according to cardiac catheterization findings. In rest of the studies, it was based on echocardiography and/or endomyocardial biopsy. The etiology of RCM was reported in three studies. Endomyocardial fibrosis (40%) and cardiac amyloidosis (37%) were the most frequent etiological diagnosis. Only one study reported data on the impact of kidney function on natriuretic peptide levels.3.3The QUADAS‐2 scores for the risk of bias and applicability concerns are shown in Figure 3.4n = 97), the BNP levels were significantly lower  in patients with CP compared to RCM , the NT‐proBNP levels were significantly lower  in patients with CP compared to RCM , the log NT‐proBNP levels were significantly lower  in patients with CP compared to RCM  that could affect the determination of natriuretic peptides have not been adequately evaluated in the included studies. Fourth, women were underrepresented across included studies. Thus, our results may not generalizable to the female population. Fifth, heterogeneity was moderate for pooled BNP levels across studies. Finally, given that our study included a small sample size for BNP and NT‐proBNP assays, limiting the generalizability of our findings.5Our review shows that plasma concentrations of BNP and NT‐proBNP were significantly lower in patients with CP compared to RCM. The pooled AUC of BNP level showed a good diagnostic accuracy to differentiate both conditions. However, further studies with a larger sample size using standardized measurements of natriuretic peptides are required to confirm our results.The authors declare that there are no conflict of interests.Carlos Diaz‐Arocutipa and Jose Saucedo‐Chinchay were involved in concept/design and in data acquisition. Carlos Diaz‐Arocutipa, Jose Saucedo‐Chinchay, Massimo Imazio, and Edgar Argulian were involved in data analysis/interpretation. Carlos Diaz‐Arocutipa drafted the article. Jose Saucedo‐Chinchay, Massimo Imazio, and Edgar Argulian critically revised the article. Carlos Diaz‐Arocutipa, Jose Saucedo‐Chinchay, Massimo Imazio, and Edgar Argulian approved the article.Supporting information.Click here for additional data file.


CH was negatively associated with glomerular filtration rate estimated from cystatin-C , but not with eGFR estimated from creatinine, and was specifically associated with CKD defined by eGFR.cys < 60 . In participants without prevalent myeloid neoplasms, eGFR.cys was associated with myeloid mCA  and somatic driver mutations  associated with myeloid neoplasia (myeloid CH), specifically mutations in CBL, TET2, JAK2, PPM1D and GNB1 but not DNMT3A or ASXL1. In participants with no history of cardiovascular disease or myeloid neoplasms, myeloid CH increased the risk of adverse outcomes in CKD  compared to those without myeloid CH. Mendelian randomisation analysis provided suggestive evidence for a causal relationship between CH and CKD (P = 0.03). We conclude that CH, and specifically myeloid CH, is associated with CKD defined by eGFR.cys. Myeloid CH promotes adverse outcomes in CKD, highlighting the importance of the interaction between intrinsic and extrinsic factors to define the health risk associated with CH.We sought to determine the relationship between age-related clonal hematopoiesis (CH) and chronic kidney disease (CKD). CH, defined as mosaic chromosome abnormalities (mCA) and/or driver mutations was identified in 5449 (2.9%) eligible UK Biobank participants ( Clonal hematopoiesis (CH) is an age-related phenomenon characterised by a gradual replacement of polyclonal leucocytes by one or more clones marked by somatic mutations , 2 or moChronic kidney disease (CKD) is a common worldwide health problem defined by low estimated glomerular filtration rate (eGFR) and/or elevated urine albumin to creatinine ratio (uACR) . PatientLike CH, CKD is associated with an elevated risk of CVD and mortality . Atherosn = 200,361; median age = 58 years, median follow up = 11 years) . However, this relationship failed to reach significance (P = 0.81) in a more conservative analysis that applied stricter threshold (P < 1 × 10–5) to select 28 SNPs associated with CH   were use< 0.001) . Only th P = 0.02. HoweverAs expected, established risk factors  were associated on univariate analysis with an adverse outcome as defined by a composite endpoint of death, MI, or stroke (Supplementary Table n = 320) or any prior history of CVD (n = 8459). Initially, Cox proportional-hazard analysis was used to identify risk factors unrelated to CH and CKD (Supplementary Table n = 1180/6970) compared to CKD free participants  (Supplementary Table P = 1.4 × 10–11) in cases with myeloid CH (n = 338/3078) compared to myeloid CH-free participants . Testing each component of adverse outcomes confirmed the previously reported features of UKB cohort [P = 2.5 × 10–10) but did not reach significance for MI  or stroke  considered independently, in accordance with previous findings [To understand the influence of myeloid CH and CKD on adverse outcomes, we focused on participants without prevalent myeloid neoplasms  for participants with moderate CKD (n = 59/226 with myeloid CH compared to n = 1121/6744 without myeloid CH) .To further investigate the relationship between CH and adverse outcome in participants with CKD, we stratified the cohort , into participants with moderate renal impairment (eGFR.cys ≥15 to <60), mild impairment (eGFR.cys ≥60 to <90) and normal kidney function (eGFR.cys ≥90). We then tested the effect of CH in each subset using Kaplan–Meier survival analysis. CH increased the risk of adverse outcome in all groups but was particularly marked  of participants with eGFR.cys/eGFR.creat ratio > 0.6 , but after eliminating these cases myeloid CH was still associated with an adverse prognosis in CKD  and remained most pronounced for participants with moderate renal impairment  UKB participants with potential SPS (eGFR.cys/eGFR.creat ratio ≤0.6). Of these, 58 (6.0%) had myeloid CH compared to 2.9% n = 591 of parDNMT3A or ASXL1, two of the most common drivers of clonality, although there was an overall association with clone size. These findings confirm previous observations that that not all CH is equal [In this study we identified that CH, and specifically myeloid CH, is associated with CKD. The association was not seen with all markers of CH and, strikingly, not with mutations in is equal , 25, 31,We found that myeloid CH is specifically associated with eGFR.cys but not eGFR.creat and only marginally with eGFR.cys.creat. Similarly, recent studies have reported the superior utility of eGFR.cys in predicting the incidence of CVD and mortality in patients with CKD , 48, 49.The finding that myeloid CH is associated with eGFR.cys also provides further evidence for the importance of chronic inflammation in CH-related disorders. Levels of cystatin C correlate generally with oxidative stress and inflammation , 50, a wP = 0.03), but this link was not supported by a more conservative analysis of 28 SNPs that are more strongly associated with CH. Given that two of the most common CH genes (DNMT3A and ASXL1) were not associated with CKD, and that the 380 SNPs only explain 3.6% of the heritability of CH [MR uses genetic variation as a natural experiment to estimate causality in observational data  and has,ty of CH , the useIn summary, the role of CH in the pathogenesis of benign diseases varies widely and depends on intrinsic factors that define the clone as well as extrinsic factors that impact the inflammatory environment , 56. In Supplementary Methods and FiguresSupplementary Tables


LCD score was assessed by a 147‐ item semi‐quantitative food frequency questionnaire (FFQ). The Pittsburgh Sleep Quality Index (PSQI) was used to assess the sleep quality. FFQ and PSQI questionnaires are completed simultaneously by the participants. Biochemical indicators (inflammatory markers) were measured and anthropometric components were evaluated. The relationship between sleep quality and LCD with quantitative variables was assessed by independent sample t‐test and with qualitative variables by chi‐square test. Binary logistic regression was used to estimate confounding variables including age, job, stress, weight to investigate the relationship between LCD and sleep. Following of LCD had a significant negative relationship with PSQI score. It can be said that with increasing LCD adherence, the possibility of poor sleep quality decrease . It was also showed, hs‐CRP  and TAC , eliminated the significance of the association and it is possible that they play a mediating role in this relationship Following the LCD can have a positive effect on improving PSQI scores by reduction in inflammatory markers levels.Poor sleep quality can lead to increased obesity. Low carbohydrate diet (LCD) is considered as an approach for sleep quality and obesity improvement. The aim of this investigation is to evaluate the relationship between LCD and sleep quality with the mediatory effect of inflammatory markers including transforming growth factor‐β (TGF‐β), high‐sensitivity C‐reactive protein (hs‐CRP), total antioxidant capacity: In our cross‐sectional study, 304 obese women aged from 19 to 50 years were enrolled. Body mass index (BMI) in these women ranged from 25.2 to 48.3 kg/m Poor sleep quality can lead to increased obesity. Low carbohydrate diet (LCD) is considered as an approach for sleep quality and obesity improvement. The purpose of this study is to examine the association between adherence of LCD and sleep quality by the mediatory effect of inflammatory markers including high‐sensitivity C‐reactive protein (hs‐CRP), transforming growth factor‐β (TGF‐β), total antioxidant capacity (TAC) and interleukin‐1β (IL‐1β) in women with overweight and obesity. Excess energy intake, which is usually shown as a positive energy balance that leads to an increase in body fat, can be considered as a nutritional factor for weight gain, hs‐CRP, IL‐1β and TGF‐β in obese and overweight women. Our hypothesis in this study is that following a low‐carbohydrate diet may be associated with poor sleep quality due to increased inflammatory markers in women.22.1n = [(Z 1‐α + Z 1‐β) × √1‐ r2]/r) 2 + 2), where α = 0.05, β = 0.95, r = 0.25. All participants were randomly selected from those who referred to health centers in Tehran. Inclusion criteria indicated as: aged 19 to 50 years and being overweight or obese (BMI ≥25 kg/m2); exclusion criteria indicated as: pregnant or lactation or being at menopausal period, chronic diseases such as diabetes mellitus, kidney and liver diseases, cardiovascular diseases such as hypertension, addiction to drugs and alcohol, regular use of medications except contraceptives, body weight changes in the last year so that the weight changes were more than 5%, weight loss surgery, and weight loss diets. All women signed a consent form, and our study was confirmed by the local Ethics Committee of Tehran University of Medical Sciences (IR.TUMS.VCR.REC.1397.804).In this cross‐sectional study, 304 overweight and obese 19‐ to 50‐year‐old women were participated. Sample size was calculated based on the following formula: 2.22).Participants’ anthropometric components including obesity degree percentage (ODP), fat‐free mass (FFM), visceral fat area (VFA), body fat percentage (BFP), and body fat mass (BFM) were determined by body composition analyzer . In this assessment, participants had to be free of any metal objects and without shoes or socks according to the instructions. Assessments were not performed after extreme exercise, individuals rested for at least twenty minutes before the measurements, and the evaluations were conducted 2 hr after the last meal  kit  was assessed. Total cholesterol (TC), triglyceride (TG), low‐density lipoprotein cholesterol (LDL‐C), and high‐density lipoprotein cholesterol (HDL‐C) were measured by Pars Azemun, Iran kits, autoanalyzer approach. hs‐CRP was assessed with the use of the immunoturbidimetric assay, IL‐1β was evaluated by IL‐1β Quantikine ELISA kit, R&D System, USA, and TGF‐β by HUMAN TGF‐BETA, and TAC was measured by ZellBio (cat. No: ZB‐TAC‐A96), GmBh (cat. No:ZB_TAC‐A48) kit.2.4For assessing the sleep quality over the women, PSQI was confirmed. This questionnaire includes 18 questions related to seven components including sleep quality, sleep disorders, sleep duration, delay in falling asleep, SE, use of sleeping pills, disturbances in daily activities due to poor sleep quality. Moreover, there are five questions in this questionnaire that are answered by someone who lives with the participant, which are not considered in scoring. The total score range is from 0 to 21 that resulting from seven components mentioned above, and each item has between 0 and 3 points. A score higher than five indicates poor sleep quality .2.6.2z‐scores were used to define differences  questionnaire with twenty‐one‐item self‐reported was confirmed for depression, anxiety, and stress evaluation in the last week. Calculating of the total scores for each subscale, a responder shows a four‐point scale with the degree according to which each item was applied during the last week, and also, 2.6.3It was a cofounder variable in our study. International physical activity questionnaires, the complex questionnaires, that are specially used for research purposes were used for physical activity assessments. Nine items were used for weekly physical activity assessments according to metabolic equivalent (MET) scores for each item of activity  was used that adjusted for job, weight, and physical activity. Binary logistic regression was used to estimate confounding variables including age, job, stress, and weight to investigate the relationship between LCD and sleep quality in this modeling; the groups of “good sleep quality” and “low adherence of LCD” were considered as reference. In this study, the mediating role of inflammatory factors  in the relationship between LCD and sleep quality was also investigated that for this purpose, we entered each of these factors into the final model separately as a confounding variable, and each of them, which destroyed the significance of the model, was considered a mediating factor. Statistical analyses were performed using IBM SPSS version 25.0 . p value ≤ 0.05 was considered as acceptable level of significance.The normal distribution of data was checked by the Kolmogorov–Smirnov test. We used mean and standard deviation to describe quantitative variables and reported number and percentage for describing of qualitative data. Quartiles were made for assessing LCD score; then, we divided them into two groups: first which contained first and second quartiles and second which contained third and fourth quartiles. First group indicates low adherence of LCD and second group indicates high adherence of LCD. To assess the quality of sleep, individuals were divided into two groups according to the scores of the PSQI with cut points: 0–5 as good quality and 6 to 21 as poor quality. The relationship between sleep quality and LCD with quantitative variables was assessed by independent‐sample 33.12 in the study population. In this investigation, the mean (SD) BMI, weight, height, age, LCD score, and sleep quality were, 30.83 (3.71) kg/m2, 77.81 (11.51) kg, 160.78 (6.02) cm, 35.69 (7.88) years, 33.98 (9.91), and 5.76 (3.55), respectively, and the number (percentage) marriage, job situation, and education were 230 (78%) single and 65 (22%) married, 95 (67%) unemployed and 96 (33%) employed, 43 (14.6%) illiterate and 87 (29.5%) diploma and 165 (55.9%) university educated; respectively. Table p =.001), weight (p =.02), FFM (p =.004), WC (p =.02), WHR (p =.005), job situation (p =.002), and LCD have a significant relationship, and after adjustment, a significant association between LCD and age (p =.04), height (p =.02), BMI (p =.02), ODP (p =.05), fat mass index (FMI) (p =.03), and the significance for job situation became stronger (p =.001). Also, there was a marginal significance with body weight (p =.06), TC (p =.08), LDL (p =.07), hs‐CRP (p =.07) and IL‐1β (p =.07). Age and FMI were higher in the high adherence group, and body weight, BMI, ODP, and both unemployed and employed groups were higher in the low adherence group. Only GL (p =.001) of LCD components had a significant relationship with LCD groups, the mean of which was higher in the lower adherence group . In the final model, after adjusting the confounding variables including job, age, stress, and weight, the relationship between high LCD adherence and sleep quality became significant . We found that by increasing the following LCD compared to low adherence of it, the odds of poor sleep quality compared to good sleep quality decreased  and TAC , destroyed the significant relationship between LCD and sleep quality, so they were considered as mediating factors in this relationship (Table 3).In this study, the mediating role of inflammatory factors  in a significant relationship between LCD and sleep quality was investigated. The results of previous investigations have found that eating less carbohydrate can reduce some inflammatory markers such as IL‐6, hs‐CRP, and IL‐8, and it can increase the concentration of adiponectin as an anti‐inflammatory marker in the problem of overweight and obesity among women.It was showed that LCD was significantly associated with sleep quality. Our findings suggested that increasing LCD scores or intake of LC can reduce the odds of poor sleep quality by 43% compared to good sleep quality group. In fact, a negative association between LCD scores and the PSQI scores was found. Moreover, inflammatory factors, TAC, and hs‐CRP may have mediatory roles in this correlation. A significant association between sleep quality and variables including TGF‐β, WC, WHR, and marriage status was found. They were positively correlated with PSQI scores, and their means were higher in poor quality group. So, it may be found that individuals with sleep quality disorders had a higher odd for becoming obese. However, a significant correlation between LCD and age and FMI was also found that they were higher in the low adherence group and height, BMI and ODP and job situation that were higher in the low adherence group. So, participants that had higher scores of LCDs may had a lower risk of being obese.Findings show that the LCD produced clinically significant reductions in body weight (6% from baseline), LDL cholesterol, blood pressure, and fasting insulin levels  were considered as possible mediating factors in this association.6Subjects signed a written informed consent.The authors declare that there is no conflict of interest in this study.Atefeh Tavakoli: Conceptualization ; Investigation ; Methodology ; Writing‐original draft . Atieh Mirzababaei: Data curation ; Writing‐review & editing . Khadijeh Mirzaei: Supervision .The study protocol was approved by the ethics committee of Tehran University of medical sciences (IR.TUMS.VCR.REC.1397.804) and is acknowledged by authors. All participants signed a written informed consent.


Actinomyces oris, Candida albicans, Fusobacterium nucleatum, Streptococcus oralis, and Streptococcus mutans) as well as to each microorganism. A culture method was used to assess the anti‐biofilm effects and two different agar diffusion assays were performed for testing the antimicrobial effect on each microorganism. The measurements of the culture and diffusion analyses were statistically normalized and compared and toothpastes were ranked according to their antimicrobial efficacy. The results of both agar diffusion assays showed a high correlation across all tested species (Spearman correlation coefficients ρs > 0.95). The results of the multispecies biofilm model, however, substantially differed in its assessment of antibacterial properties (ρs ranging from 0.22 to 0.87) compared to the results of both diffusion assays. Toothpastes with amine fluoride (with and without stannous fluoride), and toothpastes with triclosan resulted in the highest antimicrobial efficacy. Activated carbon supplements in toothpastes were comparable in their antimicrobial action to the negative control NaCl. The appropriate selection of a broad range of oral microorganisms seems crucial when testing the chemical impact of toothpaste and toothpaste supplements.Antibacterial properties of toothpastes enable chemical plaque control in limited‐access tooth regions that are mechanically not sufficiently reached by toothbrushes. Therefore, this study aimed to compare different microbial methods to assess antimicrobial toothpaste properties and evaluate different toothpastes in terms of their antibacterial efficacy against different oral microorganisms in an in vitro setting. Six toothpaste suspensions with varying antibacterial supplements were applied to a multispecies biofilm model ( The appropriate selection of a broad range of oral microorganisms seems crucial when testing the chemical impact of toothpaste and toothpaste supplements. This study aimed first to compare diffusion assays and a multispecies biofilm experiment to assess antimicrobial toothpaste properties and later evaluate different toothpastes on their antibacterial efficacy against different oral microorganisms in vitro. Biofilm formation was based on previous studies as already described in detail  and then mixed in equal volumes to produce the inoculum. Hydroxyapatite discs  were preconditioned with whole unstimulated saliva for 4 h to induce pellicle formation according to Guggenheim et al.  were prepared from the bacterial suspensions using 0.9% NaCl, of which 50 µl aliquots were plated out on different agar plates using a spiral diluter . Columbia blood agar plates , enriched with 5% whole human blood (Blood Donation Swiss Red Cross), were used to determine total colony‐forming unit (CFU) counts. Selective agar plates were used to determine the CFU counts of each biofilm species, as described elsewhere  supplemented with 0.001% (w/v) sodium tellurite). C. albicans was quantified on BIGGY Agar plates . The CBA plates were anaerobically incubated at 37°C, while MITIS and BIGGY plates were aerobically incubated at 37°C. After 72 h of incubation, CFU counts were determined on the plates, differentiating the species by colony morphology . Serial dilutions  with 300 ml Aqua dest.The mFUM agar plates were produced by mixing the medium with 1% agar . The resulting mFUM agar solution was autoclaved  and cooled to 50°C before filling the plates  with 40 ml of the agar solution. A selective agar was used for A. oris, C. albicans, F. nucleatum, S. oralis, and S. mutans) were inoculated as described above to reach comparable optical densities of OD550 = 1.0. Each microbial suspension was dispensed on the freshly produced agar plates. Five sterile filter paper discs  were applied on each plate and immediately covered with 100 µl of each test solution. Toothpaste suspensions (1:2 in NaCl) were tested in triplets per species and triplets per plate (n = 9). Each selective plate comprised a three times test solution, the positive control, and the negative control. Incubation followed at 37°C for 24 h  and 48 h  anaerobically in jars with gas‐paks . After incubation, zones of inhibition around the discs were measured on the tightest diameter using a digital caliper (Holex Electronic AG).Before experimentation, precultures of each bacterial species . Five plugs were cut into each plate using a sterile punch (Ø 9 mm)  and 48 h  of cultivation under anaerobic conditions, the zones of inhibition around the plugs were measured as described above.The agar plug diffusion assay was applied analog to the agar disc diffusion assay. Freshly produced plates (mFUM agar and Fastidious Anaerobe agar) were covered with each of the bacterial suspensions  and the resampling rate is greater than 95% (proportion of significant test results over 1000 resamples). For the comparison of methods, the data of the culture analyses and the agar diffusion methods were scaled to a consistent range; that is, biofilm data were first log10(x + 1) transformed, and then all data were normalized and transformed to numbers between 0 and 1, with 0 being the lowest antibacterial efficacy and 1 the highest per method across all species. The coefficient of variation was calculated for each species and toothpaste overall assays. The methods were further compared by applying a standardized ranking of the antimicrobial efficacy  of distinct toothpastes for each species and total CFU (multiple observations for the same toothpaste were aggregated by the median). The Spearman correlation coefficient ρs of the standardized ranking between different assays was then calculated for each species and total CFU. Furthermore, multidimensional scaling (based on Euclidean distances) on the standardized ranking of the three assays was applied separately for each species and presented as a two‐dimensional chart. All calculations were performed with the statistical software R . The highest antimicrobial efficacy was shown for the AmF‐TP and triclosan‐TP, followed by the AmF/SnF2‐TP , the triclosan‐TP, and the positive control (0.2% CHX). The activated carbon‐TP did not significantly differ from the negative control (0.9% NaCl). Similarly, low antimicrobial efficacies were shown for the essential oil‐TP and sodium fluoride toothpaste (NaF‐TP). Comparing the total CFU counts to a species‐specific level, all toothpastes exhibited similar antimicrobial efficacy on both P Figure . The resmF‐TP, th3.22‐TP. Species‐specific results for the biofilm experiment reflected the following pattern: A. oris, C. albicans, S. oralis, and S. mutans showed similar antimicrobial effects after treatment with 0.2% CHX, triclosan‐TP, AmF‐TP, and AmF/SnF2, while F. nucleatum showed inconsistent outcomes after AmF/SnF2‐TP exposure, resulting in high interquartile ranges. Moderate antimicrobial efficacy was shown for the essential oil‐TP and NaF‐TP. However, analysis of species‐specific CFU data for A. oris and C. albicans revealed higher antimicrobial efficacy compared with that against S. oralis and S. mutans. The essential oil‐TP showed a moderate antimicrobial efficacy against F. nucleatum, while NaF‐TP demonstrated high efficacy against F. nucleatum. The negative control (0.9% NaCl) and the activated carbon‐TP exhibited no antimicrobial efficacy in the biofilm experiments for most species and the total CFU counts. Activated carbon‐TP yielded a moderate antimicrobial efficacy against C. albicans.To enable interassay comparisons, all data were transformed and standardized to values between 0 and 1 . The standardized outcomes of all assays were compared graphically Figure . The tot2‐TP: both toothpastes exhibited strong antibacterial actions against F. nucleatum, but not equally strong against other species , highlighting their overall close relation regarding outcomes.The diffusion assays revealed comparable antimicrobial actions, showing high efficacy for CHX, triclosan‐TP, while less pronounced antimicrobial efficacy was measured for the essential oil‐TP and NaF‐TP. Different trends were observed for AmF‐TP and AmF/SnFA. oris , C. albicans , S. oralis , and F. nucleatum  depicted strong variations in the biofilm experiments. Similarly, strong variations of coefficients were found in the diffusion assays for F. nucleatum (agar disc diffusion assay) and S. mutans (agar plug diffusion assay) after exposure to AmF‐TP and essential oil‐TP.The precision of the assays is presented graphically in Figure 3.32‐TP) and essential oils . Comparing the antimicrobial actions as revealed by the biofilm experiments to the antimicrobial efficacy estimated by both diffusion assays resulted in the following differences detected regarding toothpastes and species: AmF/SnF2‐TP, essential oil‐TP, and NaF‐TP differed in their antimicrobial efficacy against A. oris (correlation coefficient ρs of 0.75); AmF‐TP, AmF/SnF2‐TP, and essential oil‐TP against C. candida (ρs of O.71) and S. oralis (ρs of 0.56 biofilm/disc and ρs of 0.41 biofilm/plug); AmF/SnF2‐TP and the essential oil‐TP against F. nucleatum (ρs of 0.87); and AmF/SnF2‐TP, essential oil‐TP, and triclosan‐TP against S. mutans (ρs of 0.23 biofilm/disc and ρs of 0.22 biofilm/plug). The weakest correlation between the methods was therefore measured between the assays regarding S. mutans  and the activated carbon‐TP also appeared close to each other, indicating similar antimicrobial efficacy in most of the tested species  to evaluate the antimicrobial potential of six different toothpastes revealed similar antimicrobial trends against the tested oral microorganisms correlating with the chemical properties of the toothpastes. Interestingly, discrepancies of the toothpaste antimicrobial efficacy were found at a species‐specific level within the same microbial assays. However, the interdiffusion‐array comparison suggested a comparable toothpaste ranking of antimicrobial efficacy. Thus, the null hypothesis was rejected.S. mutans. This seems to hold strong importance because S. mutans is frequently used in microbial analyses of antimicrobial agents using single‐species diffusion assays , which would produce more accurate data; however, live and dead cells are both detectable with qPCR. Therefore, this method cannot efficiently answer the primary question of the present report. Another more general limitation in the methodology is the application of different diffusion assays for the testing of toothpastes. It remains unclear whether all active toothpaste ingredients diffuse homogeneously through the discs and agar.Clinical studies on the chemical effectiveness of toothpastes are rare and most notably due to frequent changes in the products and their formulations often become antiquated as soon as they are published. Thus, laboratory analyses are preferentially applied to screen diverse toothpaste properties, besides their mechanical action. Unfortunately, the lack of standardized procedures for quality control limits the interpretation and comparison of different studies in this field. Applied laboratory methods to evaluate the antimicrobial properties of toothpastes vary to a strong degree  ; writing—original draft (lead); writing—review and editing . Lamprini Karygianni: Conceptualization ; writing—original draft (supporting); writing—review and editing . Julien Kneubuehler: Writing—review and editing . Lorenzo Fiscalini: Writing—review and editing . Daniel B. Wiedemeier: Formal analysis ; writing—review and editing . Marcel Müller: Formal analysis ; writing—review and editing . Thomas Attin: Conceptualization , writing—review, and editing . Thomas Thurnheer: Conceptualization , writing—review, and editing .