Anemia, which is a condition with reduced healthy red blood cells, is reported to be closely related to the development of infectious diseases. We aimed to investigate the association between history of anemia and 12-year mortality rate due to infections, and compare it with that among non-anemic individuals.Data from the National Health Insurance Service Health Screening Cohort were used in this population-based cohort study. Adults who underwent standardized medical examination between and 2002–2003 were included, and the mortality rate due to infection between 2004 and 2015 was analyzed. Individuals were considered to have a history of anemia if the serum hemoglobin level in 2002–2003 was < 12 g/dL for women and < 13 g/dL for men. The severity of anemia at that time was categorized as mild (12 g/dL > hemoglobin ≥11 g/dL in women and 13 g/dL > hemoglobin ≥11 g/dL in men), moderate (hemoglobin 8–10.9 g/dL), or severe (hemoglobin < 8 g/dL). Propensity score (PS) matching and Cox regression analysis were used as statistical methods.P < 0.001) than that in the non-anemic group. In the subgroup analysis, the mild and moderate anemia groups had 1.38-fold  and 2.02-fold  risk of mortality due to infection compared to that of the non-anemic group, respectively. The severe anemia group did not have a significantly different risk of mortality due to infection (P = 0.448).Overall, 512,905 individuals were included in this study. The mean age of the participants was 54.5 years old (range: 40–98), and 49,042 (9.6%) individuals were classified in the anemic group, which comprised of 36,383 (7.1%), 11,787 (2.3%), and 872 (0.2%) participants in the mild, moderate, and severe sub-groups, respectively. After PS matching, 49,039 individuals in each group were included in the analysis. The risk of mortality due to infection in the anemic group was 1.77-fold higher (hazard ratio [HR]: 1.77, 95% confidence interval [CI]: 1.52–2.60; History of anemia was associated with increased mortality rate due to infection at 12-year follow-up.The online version contains supplementary material available at 10.1186/s12879-021-06377-0. Infection is defined as the entrance and development of an infectious agent in a human, regardless of whether it develops into an infectious disease . As a maAnemia is a chronic disease in which a person’s hemoglobin levels are lower than required to meet their physiological needs, and affects roughly one-third of the global population .In South Korea, the total prevalence of anemia was 6.0%, and the prevalence of severe anemia was 0.92% . Since iTherefore, this study aimed to investigate the hypothesis that history of anemia might be an independent risk factor for higher mortality rate due to infection.This study involved human participants, and all procedures were conducted in accordance with the guidance provided by the relevant ethics boards. The Institutional Review Board (IRB) of Seoul National University Bundang Hospital  and the Health Insurance Review and Assessment Service (NHIS-2020-2-067) approved the study protocol. Informed consent was waived by IRB of Seoul National University Bundang Hospital, because data analyses were performed retrospectively using anonymized health records derived from the South Korean NHIS database. Data were extracted by an independent medical record technician at the NHIS center who was unaffiliated with this study.The NHIS-National Health Screening Cohort (NHIS-HEALS) was used in this study . As the All individuals were divided into two groups: the anemic (who had a history of anemia) and non-anemic groups. Individuals who had hemoglobin levels < 12 g/dL for women and < 13 g/dL for men, during 2003–2003, were considered to have anemia based on the World Health Organization (WHO) criteria. The severity of anemia at that time was categorized as mild (12 g/dL > hemoglobin ≥11 g/dL in women and 13 g/dL > hemoglobin ≥11 g/dL in men), moderate (hemoglobin 8–10.9 g/dL), or severe (hemoglobin < 8 g/dL), using the WHO criteria . Serum hIn this study, mortality due to a primary infection was considered as the study endpoint. The NHIS database provided data on the death date and main cause of death for all individuals. Mortality rate due to infection was evaluated for a period of 12-years, from January 1, 2004 to December 31, 2015. The specific diagnoses for mortality due to infection are presented as ICD-10 codes in 2). The national income level was registered in the NHIS database to determine the insurance premium of all individuals. Annual income level was divided into five groups using quintile ratio , and underlying disability was divided into two groups . In South Korea, all physical disabilities should be registered in the NHIS to receive various benefits, and are divided into six levels considering their severity. Thus, in this study, disabilities in the 1st (most severe) to 3rd levels were classified in the severe disability group, while those in the 4th to 6th (most mild) levels were classified in the mild to moderate disability group. Smoking status was divided into four groups , and alcohol consumption was divided into six groups . Exercise frequency was divided into six groups . The Charlson comorbidity index was calculated using registered ICD-10 codes from to 2002–2003, as shown in The following variables were collected as covariates for this study: demographic information , socioeconomic status related information , comorbidity related information (underlying disability and Charlson comorbidity index), and lifestyle information . Residence was divided into three groups , and BMI was categorized into four groups  matching between the anemic group (those with a history of anemia) and non-anemic group to reduce confounders . For thiP < 0.05 was considered statistically significant.As a second sensitivity analysis, we constructed a multivariable Cox regression model for mortality due to infection using the entire cohort to determine: (1) whether the results obtained from the PS-matched cohort were generalizable to the entire cohort, and (2) the risk of mortality due to infection in the anemic group with other important covariates in context, and not in isolation. All covariates were included in the multivariate Cox model for adjustment. Using multivariable Cox regression modeling, we performed subgroup analyses to investigate whether mild, moderate, and severe anemia in the past, were associated with mortality due to infection compared to the non-anemic group. In addition, considering sex is associated with development of anemia , we perfIn the NHIS-HEALS data, a total of 514,795 individuals received standardized medical examination from 2002 to 2003. Among them, 1320 individuals were excluded due to death during 2002–2003, and 570 individuals were excluded due to missing data regarding hemoglobin level. Thus, a total of 512,905 individuals were included in this study. Among them, 49,042 individuals were classified as the anemic group (9.6%) using serum hemoglobin level, and 463,863 individuals (90.4%) were classified as the non-anemic group. After PS-matching, a total of 98,078 individuals  were included in the analysis  than that in the non-anemic group. The incidence of mortality due to infection in the two groups had a similar trend, as shown in Fig.P < 0.001) than that in the non-anemic group.Table P < 0.001; Model 1). In the subgroup analysis, the mild and moderate historical anemia groups had 1.38-fold  and 2.02-fold  higher mortality due to infection than the non-anemic group, respectively. However, the severe anemic group did not show a significant difference in mortality due to infection compared to that of the non-anemic group (P = 0.448). The C-index of the multivariable model was 0.85 (95% CI: 0.84 to 0.86). The Table n = 277,846) had a 1.57-fold higher mortality due to infection than the male non-anemic group . The female anemic group  had a 1.36-fold higher mortality due to infection than the female non-anemic group .Table up P = 0.48. The CThis population-based cohort study showed that history of anemia was independently associated with increased infectious mortality in South Korea. Interestingly, in the subgroup analyses, it was more evident in the mild and moderate anemic groups than the severe anemic group. We hypothesized that patients with a history of anemia have a higher risk of death due to infection during the long-term follow-up period. Considering that the prevalence of both anemia and infection was high in the low-income countries , our resAnemia, iron deficiency, and infections have been reported as three major causes of mortality and morbidity during childhood worldwide . These tHowever, a previous study reported that > 50% of anemia was developed due to other reasons such as deficiency of micronutrients  rather than IDA alone . The malHistory of anemia might also affect the prognosis of individuals after infection. Anemia has been reported to be common among hospitalized patients with acquired pneumonia, and it was associated independently with higher 90-day mortality . MoreoveA recent study has reported that the comorbid status of anemia is associated with an enhanced risk of severe COVID-19 infection, with an odds ratio of 2.44 (95% CI: 1.75 to 3.40) . In the The results of the subgroup analysis are notable: the severe anemic group (hemoglobin < 8 g/dL) was not associated with mortality due to infection; whereas, the mild and moderate anemic groups were associated with a higher risk of mortality due to infection. Anemia has been reported to increase hospitalization and mortality in older adults , and it Our study has some limitations. First, we did not distinguish the type of anemia in detail because we only used the measured hemoglobin level in the standardized medical examination. Furthermore, information on treatment of the anemia was not evaluated during follow-up period (2004–2015) in this study, and it might affect the result of this study. Second, PS-matching, and multivariable adjustment only adjusted for known confounders, and there might be unmeasured confounders that may have affected the results in this study. Third, we used ICD-10 codes to define comorbid status and calculate the Charlson comorbidity index, but actual underlying diseases might differ with the registered ICD-10 codes in this study. For example, if individuals with diabetes mellitus did not visit outpatient clinic due to mild symptom or poor accessibility to healthcare utilization, they were not registered as diabetes mellitus in the NHIS database in this study. Fourth, we did not exclude women who were pregnant during 2002–2003 in this study. However, since our inclusion criteria were adults ≥40 years old, we believe that the impact of pregnancy might be limited in this study. Fifth, lifestyle information was collected using a questionnaire, and there might be a selection bias due to non-response to the surveys in the standardized medical examination . Lastly,We showed that a history of anemia was associated with increased mortality due to infection among the adult South Korean population, and this was more evident in patients with mild to moderate anemia than those with severe anemia. However, considering the limitations of this study, further studies are warranted to confirm our findings.Additional file 1.Additional file 2.Additional file 3.


The different structures of the new materialslead to compounds with a range of band gaps with MXDBiI5 having the lowest at 2.15 eV. We have explored the tunabilty ofMXDBiI5 through halide substitution by preparing a seriesof samples with composition MXDBiIx5–Brx and determined the halide contentusing energy dispersive X-ray spectroscopy. A large range of solidsolution is obtained in MXDBiIx5–Brx, resulting in the formation of single-phasematerials for bromine contents from x = 0 to 3.71(iodine contents from 1.29 to 5). This highlights the fact that zero-dimensionalorganic–inorganic halides are highly tunable, in a similarmanner to the higher-dimensional perovskite counterparts. Such newmaterials open up the opportunity for further studies of the physicsand optoelectronic properties of these materials.Over the past decade,the efficiency of photovoltaic devices basedon CH 2PbI6, MXDBiI5 and MXD3Bi2Br12·2H2O have been determined. Halide substitution has been exploredin MXDBiIx5−Brx, and a large region of solid solution has been found. MXDBiI5 has short intercluster I−I distances and π−πstacking between the MXD cations while also possessing the lowestband gap of the materials studied here.The structures of MXD The structure consists of corner-sharing PbI6 octahedra, with the organic cation being disordered on theperovskite A-site at room temperature.6 As the size of the organic ammonium cation is increased, differentperovskite-related structure types can form.7 In particular, layered perovskites based on the Ruddlesden–Popperand Dion–Jacobson structure types have received considerableinterest. A notable breakthrough came when a power conversion efficiencyof 12.52% was achieved for (C4H9NH3)2(CH3NH3)3Pb4I13, which adopts the Ruddlesden–Popper structure.8 Very recently, the “Memory Seed Effect”has been reported, which involves dissolving presynthesized crystalsin solvents such as DMF, which enables the preparation of high-qualitythin films for a variety of layered perovskites.9 The solutions have been shown to retain “memoryseed” crystallites, which facilitates the production of phase-purelayered perovskites.9 The use of this “MemorySeed Effect” has led to solar cells with power conversion efficienciesof 17.1% for (C4H9NH3)2(CH3NH3)3Pb4I13.9CH10 The A, B, and X sites can bedoped in order to fine-tune the electronic structure and band gapfor a range of optoelectronic applications.11 In particular, as the electronic structureof organic–inorganic metal halides depends on the B-site cationand halide, halide substitution is an excellent way of tuning theband gap of these materials.13 For example, halidesubstitution in FAPbI3-xBrx (FA = formamidinium) resulted in the band gap being tunedfrom 1.48 to 2.23 eV.3 Unfortunately, photoinducedhalide segregation has been reported in CH3NH3PbIx3–Brx, yielding iodine- and bromine-rich domains in the thin films.14 Nevertheless, such tunability of the materialsis of interest, particularly in the fields of indoor photovoltaicsor tandem solar cells, which can utilize two perovskites with differentcompositions and band gaps.4 One methodof preventing halide segregation is to use multidentate ligands whichcreate interfaces with a low defect content.15Organic–inorganic halideperovskites exhibit great compositionalflexibility.meta-phenylenediammonium (mPDA).18 Several of these perovskitesadopt the Dion–Jacobson structure.17 Interestingly, the position of the aminomethyl group on the pyridiniumring in 4AMPY and 3AMPY influences the stacking of the inorganic layercontaining lead iodide octahedra and results in a decrease in bandgap when going from (4AMPY)(CH3NH3)n-1PbnIn+13 to (3AMPY)(CH3NH3)n-1PbnIn+13.16 (3AMPY)(CH3NH3)3Pb4I13 exhibited a power conversion efficiencyof 9.20%. In the (mPDA)(CH3NH3)n-1PbnIn+13 system, fabrication of phase pure thin films hasbeen challenging for some values of n.17 (PEA)2(CH3NH3)2Pb3I10 has been shown to haveenhanced moisture stability with respect to CH3NH3PbI3.18Recently, several new families of layered perovskites havebeenprepared which incorporate methylammonium in addition to cations whichcontain aromatic rings such as phenylethylammonium (PEA), 4-aminomethylpyridinium(4AMPY), 3-aminomethylpyridinium (3AMPY), or 6 or edge-sharing octahedra to make M2X10 or face-sharingoctahedra to make M2X9. Zero-dimensional materialsare already showing interesting properties; for example, 2Bi2I10·2H2O has beentested as a photodetector, and reproducible photocurrents could bedrawn from this material.19 (CH3NH3)3Bi2I9 shows highlyanisotropic photoluminescence and has shown evidence of quantum cutting.20 In addition, isovalent doping in the zero-dimensional(CH3NH3)3Bix2–SbxI9 hasshown a band-bowing phenomena.21 Zero-dimensionalall-inorganic halides such as A4PbX6 and Cs4SnX6  are alsoof interest, particularly for white light emission, and work by Mohammedet al. has recently found that the local octahedral distortions enabledthe formation of self-trapped states.22The term “zero-dimensionalperovskite” has been coinedfor organic–inorganic metal halides which consist of isolatedclusters of metal halide octahedra which are separated by organiccations, although strictly speaking these materials do not possessthe perovskite structure. Depending on the nature of the metal andhalide, different connectivities of octahedra may exist in the cluster,such as isolated MX18 alongwith the huge compositional and structural diversity of organic–inorganichalides, we have explored the synthesis and tunability of new organic–inorganichalides which use the meta-xylylenediammonium  cation.Motivated by reports of enhanced moisture stability when aromaticorganic ammonium cations are used,3NH3PbI3.23 The appropriate metal oxide was dissolved in 5 mL of HX and heatedto 80 °C. Separately, 0.5 mL of HX was added to 0.4 mL m-xylylenediamine, resulting in the formation of crystals.These crystals were heated until dissolved. The two solutions weremixed and stirred for 30 min. The solution was cooled to room temperature,and the resulting crystals were filtered. The crystals were driedin a vacuum oven at 80 °C for 2 h.The synthesis of all materials was based on modificationsof themethod reported by Poglitsch and Weber for the preparation of CHx5–Brx, 0.47 g Bi2O3 was added to a mixtureof HX acid . The volumetric ratioof HI:HBr used in the reactions are given in m-xylylenediamine(0.14 mL) was added to the solution, and the mixture was stirred for30 min. After cooling to room temperature, the crystals were filteredoff and left to dry in the fume hood.For the synthesis ofMXDBiIα1 radiation in Bragg–Brentanogeometry. Data were collected from 5° to 70° with a stepsize of 0.017° and a time per step of 0.94 s. PXRD data wereanalyzed using Topas Academic ver. 6.24Powder X-ray diffractiondata were collected on a Panalytical EmpyreanDiffractometer using CuK25 Thedata was processed using CrysAlisPro software.26 Structure solution was carried out using SHELXT,27 and structure refinement by full matrix least-squaresagainst F2 was carried out with SHELXL (2018/3).28 Non-hydrogen atoms were refined anisotropically,and carbon-bound hydrogens were refined using a riding model. Ammoniumhydrogens were located from the difference Fourier map and refinedisotropically subject to distance restraints. Selected crystallographicdata are presented in 2151572–2151574 contains the supplementary crystallographic datafor this paper. These data are provided free of charge by the jointCambridge Crystallographic Data Centre and FachinformationszentrumKarlsruhe Access Structures service www.ccdc.cam.ac.uk/structures.Single crystal diffraction data were recorded at either 173or293 K using a Rigaku FR-X Ultrahigh brilliance Microfocus RA generator/confocaloptics and Rigaku XtaLAB P200 diffractometer [Mo Kα radiation(λ = 0.71073 Å)]. Intensity data was collected using ωsteps accumulating area detector images spanning at least a hemisphereof reciprocal space .2 Jeol DrySD EDS detector anda Jeol JSM 5600. UV–vis diffuse reflectance spectra were collectedon a Jasco V650 spectrophotometer equipped with an integrating sphere,in the wavelength range 190–900 nm. BaSO4 was usedas a reference.Scanning electron microscopystudies were carried out using a JSMIT200 equipped with a 25 mm2O3 and HI or HBr, along with PbO and HI,produced the crystalline products MXDBiI5, MXD3Bi2Br12·2H2O, and MXD2PbI6. Their structures were determined from single-crystalX-ray diffraction data, and selected parameters are tabulated in The reactions of MXD with eitherBi2PbI6 consists of isolated PbI6 octahedra separated by MXD cations  to 3.2443(2) Å PbI4 recentlyreported.17 The aromatic core of the MXDcation is not directly above adjacent MXD cations but is offset. Theorientations of the adjacent MXD cations result in NH3 groupspointing in three different directions to give a Y-shaped arrangementof the NH3 groups, with one pair of NH3 groupsbeing almost eclipsed (3 hydrogens and iodinefrom the PbI6 octahedra range from 3.546(2) to 3.718(2)Å. Figure S1 shows the PXRD data ofthe bulk sample. Pawley fits were carried out using the unit cellparameters and space group obtained from single-crystal diffraction.Twelve Chebyshev background parameters, sample displacement, and profileparameters were also refined. The resulting fit is shown in Figure S1, and this confirms the phase purityof the sample.The structureof MXD cations 1. Althou443(2) Å 3. The I–eclipsed 1c. Hydro2PbI6,which contains isolated PbI6 octahedra, the structure ofMXDBiI5 consists of BiI6 octahedra, which shareedges to form Bi2I10 dimers (31 The Bi2I10 units are separated by the MXDcations. The Bi–I bond lengths range from 2.9710(5) to 3.2459(6)Å (trans positions and from 85.756(15)°to 94.581(17)° in the cis position. The Bi octahedrashow some distortion, with a bond length distortion of 10.39 and bondangle variance of 13.13. The orientation of the MXD cation plays animportant role in holding the structure together. The aromatic ringsof adjacent MXD cations are strictly parallel and have a centroid–centroiddistance of 3.509(5) Å. The close register of the rings forcesthe ammonium groups to point to the same side of the ring for eachcation, so when considered for each pair of cations, all four NH3 groups point in opposite directions. The I1–I4 interclusterdistance is 4.1357(6) Å, and this is of particular note, as thisis comparable to the short interlayer I–I distances of 4.00and 4.04 Å, which were reported in (H3NC6H4NH3)(CH3NH3)Pb2I7 and (H3NC6H4NH3)(CH3NH3)2Pb3I10, respectively.17 Althoughthese are thought to be the shortest interlayer iodine–iodinedistances in Dion–Jacobson perovskites, we note that in zero-dimensionalorganic−inorganic halides, short intercluster distances of3.7253(16) Å have been reported in (H3NC6H4NH3)2Bi2I10·4H2O, while short interchain distances of 3.871(10)Å have been reported in (H3NC6H4NH3)Bi2I8·I2.32 Hydrogen bonds between NH3 hydrogens and iodine in the Bi2I10 unitsranged from 3.712(5) to 3.812(6) Å. Figure S2 shows the PXRD data of the bulk MXDBiI5 sample.Pawley fits were carried out using the cell parameters and space groupobtained from single crystal diffraction MXDBiI5 and thesame nonstructural parameters that were described for MXD2PbI6. The resulting fit is shown in Figure S2, and this confirms the phase purity of the sample.In contrast to the structure of MXD0 dimers 2. This k459(6)Å 3. TheI–3Bi2Br12·2H2O consists of isolated BiBr6 octahedra, with theasymmetric unit containing two inequivalent BiBr6 octahedra(cis bond angles and 170.57(2)° to 176.29(3)° for trans angles, while for Bi(2), the bond angles range from 174.21(2)°to 177.20(3)° for trans bond angles and 85.46(2)°to 95.13(2)° for cis bond angles. Calculationof the bond length distortion and bond angle variance show that theBiBr6 octahedra exhibit different levels of distortion,with Bi(1) showing the greater angular variance than the Bi(2), whileBi(1) shows less distortion of bond lengths than Bi(2)  in the structure. They are also significantly smaller thanthe bond angle variance reported for (mPDA)PbI4, but arecomparable to those reported for some quinoline and isoquinoline leadhalides.33 The shortest hydrogen bonds are formed betweenthe NH3 and H2O, with N···O distancesof 2.757(12) Å and 2.822(10) Å. Figure S3 shows the PXRD data of the bulk MXD3Bi2Br12·2H2O sample. Pawley fits were carriedout using the cell parameters and space group obtained from singlecrystal diffraction and parameters described for MXD2PbI6. The resulting fit is shown in Figure S3, and this confirms the phase purity of the sample. SEM imagesof MXD2PbI6, MXDBiI5, and MXD3Bi2Br12·2H2O are shownin The structure of MXDctahedra3. For thctahedra3. In addan Bi(2) 3. The bo2PbI6, MXDBiI5, and MXD3Bi2Br12·2H2O are shown in 2PbI6 displays aggregates of crystals,with a needle-like morphology, of dimensions of approximately 600μm by 40 μm. Crystallites of MXDBiI5 also showa needle-like morphology, although the crystals are much shorter thanthose reported for the MXD2PbI6, with dimensionsof approximately 50–75 μm by 20 μm. The MXD3Bi2Br12·2H2O sampleconsists of much thinner crystallites with a narrow, plate-like morphology.A range of crystallite sizes can be observed, with typical dimensionsbeing around 50 μm by 100–200 μm. Although thecontrol of morphology was not considered in this study, this willbe of interest in the future, when manufacturing these materials intothin films, as any pinholes in thin films as a result of surface morphologycan influence factors such as device performance in photovoltaicsor LEDs.SEM images of MXD34 Therefore, isovalent doping on the anion site,e.g., replacing I– with Br–, isa particularly useful technique to tune the band gap of the CH3NH3PbI3 perovskites.35 This is often termed halide substitution and results in the creationof materials with compositions such as CH3NH3PbIx3–Brx. Zero-dimensional inorganic–organic halides commonlyexhibit a similar electronic structure to the 3D analogues, but withgreater orbital decoupling;36 therefore,we decided to probe halide substitution in MXDBiIx5–Brx, in order to determinethe doping limit of Br– in the MXDBiI5 structure type. A photograph of the MXDBiIx5–Brx samples is shownin Figure S5).36 We note that similar phenomena havebeen reported when two different cations are used in the synthesisof Ruddlesden–Popper phases, as nonstoichiometric ratios ofreagents must be used to isolate the phase pure product.37 In addition, in the synthesis of Cs2SnX6  mixed halides, the products werefound to be richer in the Cl or Br than would be expected given theratios in the precursors, and this has been attributed to the differencein solubility of halides in solution.38It is well-known that the valenceband and conduction bands in organic–inorganic halides compriseorbital contributions from both the halide and the inorganic cation.x5–Brx samples are shown in 4.11Br0.89 is shown in Figure S5. As can be seen, the 100% Br sample exhibits a completelydifferent PXRD pattern to the other samples prepared in this series,which indicates that it adopts a completely different structure type,MXD3Bi2Br12·2H2O(vide supra). However, with only a small amount of HI in the precursorsolution , the MXDBiI5 structure type is adopted, and all peaks can be indexed to a monoclinicunit cell in space group I2/m. Thisstructure type is adopted for all MXDBiIx5–Brx compositions which have a brominecontent, x, between 0 and 3.71 . In order to determine the extent ofthe solid solution in MXDBiIx5–Brx, Pawley refinements were carriedout. During the refinements, 12 Chebyshev polynomial terms were usedto fit the background, and in addition, unit cell parameters, profileparameters, and specimen displacement were all refined. The resultingvariation of unit cell volume with iodine content is shown in Supporting Information . As can be seen from x) and unit cell volume,in agreement with Vegard’s law, with the exception of a slightleveling off at the lowest bromine contents. This shows that thereis a large region of solid solution in the MXDBiIx5–Brx system. This regionof solid solution ranges from a bromine content, x, of 0 to 3.71, and it is likely that a full solid solution couldbe obtained with further optimization of synthetic conditions. Asthe bromine content increases, the β angle increases, but thereis a leveling off at the highest iodine contents (which correspondsto the lowest bromine contents). The a, b, and c unit cell parameters all show a linear relationshipwith bromine content and exhibit a smaller leveling off at the lowestbromine contents. The decrease in unit cell parameters with increasingbromine content is expected due to the smaller size of Br– (1.96 Å) with respect to I– (2.20 Å).39The PXRD data of MXDBiIx5–Brx samples and MXD3Bi2Br12·2H2O are shown in 2PbI6 spectrum is shown in Figure S7. Two absorption features are observed in the spectra forMXDBiIx5–Brx. For MXDBiIx5–Brx, the first feature is in the 2.36–2.06 eVrange (corresponding to 525–600 nm) and the second featureis centered around 1.9 eV (∼650 nm), while for MXD2PbI6, the peak occurs at ∼500 nm (2.5 eV) We notethat dual features have been observed in both UV–vis spectroscopyand photoluminescence measurements for both 2D, layered materials,and zero-dimensional materials.42 For example, Nag et al. noticeddual-emission in photoluminescence studies of single crystals of (PEA)2SnI4 (PEA = phenylethylammonium), which was alsoaccompanied by two absorption features in UV–vis absorptionspectra of the same material.41 A similarbehavior was also observed for (4-AMP)SnI4 (4-AMP = (4-aminomethyl)piperidinium).41 Dual PL emission has also been observed forthe zero-dimensional TPA2SbCl5 (TPA = tetrapropylammonium).42 To date, the presence of dual features in thephotoluminescence or absorption spectra has been attributed to differencesin the edge or bulk of the crystals or self-trapped excitons.42 As the bromide content is increased in MXDBiIx5–Brx, the absorption edgeshifts to larger energies, which is in agreement with an increasein band gap with increasing Br content. The resulting band gaps wereestimated using Tauc plots and are listed in 5 exhibiting thelowest band gap in the series (2.15 eV) and MXD3Bi2Br12·2H2O the largest (2.86 eV).In contrast, the band gap of MXD2PbI6 was determinedto be 2.33 eV. The variation of band gap with bromine content is shownin x5–Brx canbe tuned over a similar range to that observed for the FAPbIx3–Brx perovskites, whichallowed tuning of the band gap from 1.48 to 2.25 eV.3 The high crystallinity of these samples warrants furtherinvestigation into the photostability of MXDBiI5-xBrx, as in the mixed cation, mixed halideperovskites, CsyFAy1–PbIx3–Brx, a high level of crystallinity was found to suppresshalide segregation.43The Kubelka–Munk transformationsof the UV–vis diffusereflectance spectra of the MXDBiImeta-xylylenediammonium (MXD) cation: MXDBiI5, MXD3Bi2Br12·2H2O, and MXD2PbI6. MXDBiI5 has short intercluster I–Idistances and π–π stacking between the MXD cations,while also possessing the lowest band gap of the materials studiedhere. We explored the tunability of MXDBiI5 through halidesubstitution and found that a large region of solid solution existsin the MXDBiIx5–Brx system (where x = 0 to 3.71). Thiswork highlights the fact that zero-dimensional organic–inorganichalides are also highly tunable semiconductors and opens up the wayfor further studies of the physics and the long-term stability ofthese materials.Here, we have reported the synthesis and characterization of threenew organic–inorganic metal halides, using the


His bookLes démoniaques dans l'artis a representation of hysterical symptoms in religion and religious art. This paper aims to discuss Charcot's descriptions of hysteria in religion and his “hysterical saints”.Professor Jean-Martin Charcot was the founder of clinical neurology and one of the prominent researchers in the field of hysteria in the 19 Hysterikós, meaning “relative to the womb”. This correlation was established in ancient Greece because most cases of hysteria occurred in women, but only in the 16thcentury the term hysteria was regularly applied to designate such functional disorders.The term hysteria is derived from the Greek wordIn the middle age, hysteria gained a religious connotation, and the hysterical phenomenology was attributed to demonic possession or witchcraft. A similar situation to the one experienced by patients with other neurological conditions, such as stroke and epilepsy.thcentury, Jean-Martin Charcot (1825–1893) (In the 195–1893)  developLes démoniaques dans l'art. In this work, illustrated by Richer, they discussed how hysteria was represented in religious art, presenting works of art featuring some of the saints of the catholic church that were possibly presenting a hysterical event.Les démoniaques dans l'art, emphasizing Charcot's “hysterical saints.”This interest motivated Charcot to publish a book in 1887, alongside his pupil Paul Richer (1849–1933) :Les déIt is curious that Charcot took the burden of untangling the cloudy subject of hysteria since he had no prior interest in mental illnesses. His contact with the works of Pierre Janet and Briquet, besides the influence of Desirée Bourneville, one of the few of his pupils with experience with alienism, were determinants for his interest in hysteria.Charcot had strong political and religious standpoints. An anti-clerical and fierce defendant of laicism in all scientific investigations, Charcot opposed religious intervention in scientifical affairs.Permanent deformations of the hand from the point of view of medical semiotics, by Henri Meillet with drawings of Richer. Impressed by the quality of his art, Charcot invited Richer to join his service at theSalpêtrière. Richer's artistical prowess also contributed to his own thesis,Études cliniques sur l'hystéro-épilepsie ou grande histérie.Charcot was very fond of art, with a predilection for the classics. A gifted artist himself, he produced numerous self-portraits, drawings, and sketches.Les démoniaques dans l'artwas preceded by the start of Bourneville's work, theBibliothèque diabolique, nine books, published between 1882 and 1902.A brief discourse of a disease called the suffocation of the mother, in 1603. This book is considered a turning point in the understanding of hysteria, presenting it as a disease instead of a religious event.Another worthy contribution was Edward Jorden's publicationLes démoniaques dans l'art, Charcot presents his classical description of the grand hysterical attack, divided in four periods .Iconographie photographique de La Salpêtrière.Instigma. Hallucinations are common, often with a religious nature. This phenomenon is commonly described as an epiphanic, religious event, sometimes possessing an erotic connotation.Charcot describes a variant of the third period of the grand hysterical attack, with a predominance of the feeling and constant ecstatic facial expression. The patient is typically quiet, presenting a delusional speech, and might present negative sensorial symptoms, such as achromatopsia, blindness, and anesthesia. These sensorial symptoms are referred to asSainte Catherine de Sienne, providing a copied fragment of the fresco that decorates Saint-Dominique Church, in Sienna (Sainte Catherinein an attitude of ecstatic contemplation, with a facial expression of joy. Other representations of the “Hysterical saints” are mentioned by Charcot, such as “Saint François recevant les stigmates” (Sainte Marguerite de Cordoue en extase” (“Saint François en extase” (Charcot illustrates the ecstatic crisis with the case of Sienna . The pimates”  “Saintxtase” , and“Sxtase” , but thL'hystérie de Sainte-Thérèse, in hisBibliothèque diabolique, reinforcing the relevance of Bernini's work in depicting ecstatic phenomenology.A lacking honorable mention is Gian Lorenzo Bernini's sculpture “The Ecstasy of Saint Teresa” , the prThis sexual and orgasmic description is commonplace among the ecstatic religious events, as seen in the illustrations of Saint Catherine and Saint Francis. Charcot pointed this out, defining this uniformity as almost scientific, praising such artistic rigor.In modern times, these ecstatic events were also related to epileptic activity, typically secondary to non-dominant temporal lobe abnormalities, sometimes with a sexual and orgasmic phenomenology, giving rise to the term “Orgasmic epilepsy”La transfiguration, the opisthotonos of the clownism period in an image of Jesus performing an exorcism fromLa Bible de Picart, and the bizarre dystonic postures of the final delirium in a tableau from Saint-Ambroise church, at Genoa.Charcot and Richer also present examples of religious art illustrating the other periods of the grand hysterical attack, such as the limb circumduction movements of the epileptoid period in a fragment of Deodat Delmont'sth-century Parisian society, despite prior contributions in the literature. Charcot's publication ofLes démoniaques dans l'artis a tribute to laicism in science, demonstrating his unswerving respect for neurology.In conclusion, the depiction of religious events as a possible manifestation of functional disorders was unusual to the conservative 19


A 48-year-old woman was referred for a bone scan as an assessment of bone metastasis from breast cancer. Surprisingly, two hot spots of lung uptake were present in the left lung without any abnormality on CT slices. No history of pulmonary disease was observed. An optimized CT scan with fine slices performed the same day was strictly normal (without any micronodule). A lung ventilation/perfusion scintigraphy showed no significant perfusion defect. A follow-up bone scan performed eight months later was normal and without any lung uptake. After exclusion of the main etiologies described in the literature, such as amylosis, sarcoidosis, abscess, or hypercalcemia, radiotracer microembolism seems to be the most likely hypothesis in this patient.


Background: The infectious disease society of America (IDSA) recommends routine laboratory tests for all patients receiving outpatient parenteral antimicrobial therapy (OPAT) to monitor for adverse events. There are no data to support how often patients should take monitoring laboratory tests. In addition, the relevance of different laboratory tests commonly used for OPAT follow up is not clearly known. Methods: We conducted a retrospective observational cohort study over a 7-year study interval (1 January 2014 to 31 December 2021). Clinical data were obtained to identify the risk factors associated with abnormal laboratory tests and determine if abnormal laboratory tests led to antibiotic change or hospital readmission. Results: Two hundred and forty-six patients met the inclusion criteria for this study. In our multivariate analysis, the Charlson comorbidity index (CCI) of 0–4 , the use of ceftriaxone without vancomycin  and an OPAT duration of 2–4 weeks  were associated with a lower risk of OPAT complications. A CCI of 5 or more ) and an OPAT duration of 5 or more weeks  were associated with a higher risk of OPAT complications. An abnormal complete metabolic panel or vancomycin levels, but not an abnormal complete blood count, were associated with antibiotic change or readmission. Conclusion: Patients with fewer comorbidities, ceftriaxone and short OPAT durations are at lower risk for OPAT complications. These patients could be followed with less frequent laboratory monitoring. Outpatient parenteral antimicrobial therapy (OPAT) is a preferred method to administer long-term intravenous (IV) antibiotic therapy for various infections. OPAT reduces the length of hospital stays and costs while improving patient satisfaction ,2. The uThe IDSA OPAT guidelines on monitoring laboratory results for individual antibiotics are based on known adverse events associated with that antibiotic . The guiAfter reviewing the medical records of 326 patients, 246 eligible patients were included. A total of 116 patients had OPAT-related complications and 130 patients had no complications. Demographic and clinical data characteristics of the two groups of patients are shown in Infections with gram-positive bacteria other than MRSA and polymicrobial infections were the most common infections identified in 91/26 (37%) and 53/246 (21.5) patients, respectively. Beta-lactams with or without vancomycin were the most common antibiotics prescribed. Ceftriaxone and ertapenem were the most frequently used beta-lactams. Two-hundred and nineteen (89%) patients received one or two antibiotics for OPAT and 175/246 (71.1%) were receiving OPAT for 5 weeks or more. The majority of patients  received OPAT at home. Seventy-eight (67.3%) patients with complications and 102 (78.5%) without complications followed up in the outpatient clinic within the first 3 weeks of discharge. Anemia was the common baseline laboratory abnormality, seen in 85 (73.3) patients with complications and 86 (66.2%) patients without complications.There was no patient who had abnormal urinalysis results while receiving OPAT. We assessed the risk of readmission or antibiotic change based on laboratory abnormalities in our patient population. Fifty-two patients required readmission or antibiotic change . In a muOPAT is a health care cost-saving strategy for patients who require long-term parenteral antibiotics ,14. PatiIn our study, only 14 (5.7%) patients received OPAT at a skilled nursing facility (SNF). The risk of rehospitalization did not differ between the group who received OPAT at home and those receiving OPAT at SNF. This could be because of the small number of patients who had OPAT at SNF. A prior study showed that patients who received OPAT at SNF had a 46% increased risk of rehospitalization compared to patients who received OPAT at home ,19.Our results showed that patients with few comorbidities (CCL < 5), patients who used ceftriaxone alone and patients with an OPAT duration of 4 weeks or less could have laboratory monitoring less frequently than once a week. This study suggests that patients on ceftriaxone are less likely to experience OPAT complications and could require less frequent monitoring. Ertapenem was associated with more complications, but this could be incidental since it was more commonly used with vancomycin. Vancomycin use has a strong association with adverse events, as has been shown in multiple studies, so patients should have at least weekly vancomycin troughs and serum creatinine levels ,12.In our study, penicillin and semisynthetic penicillin were the most common causes of abnormal laboratory results. It has been previously reported that semisynthetic penicillins are associated with higher rates of adverse events compared to cephalosporins and ertapenem ,6,7,20. Metronidazole and rifampin were common oral antibiotics used with either vancomycin or beta-lactams for broader coverage and for a better activity in biofilm, respectively. Neither were associated with OPAT complications that warranted hospitalization, but two patients developed leukopenia while on rifampin. Metronidazole is generally safe for use during OPAT, and to our knowledge, there is only one report that showed an unexpected increase in AKI in patients receiving metronidazole, but these patients were also receiving vancomycin which was likely the main cause for AKI . RifampiIn addition to weekly laboratory follow ups, other different strategies have been employed to decrease rehospitalization rates. It has been reported that regular telephone calls after hospital discharge to ensure adherence is associated with lower readmission rates . BecauseIn our study, early clinic follow ups  were associated with fewer OPAT complications, whereas late clinic follow ups were associated with more OPAT complications. The time from discharge to clinic follow up is known to have an association with an increased risk of OPAT complications . PatientSettings: This study was conducted at Saint Louis University Hospital, a 350-bed tertiary academic medical center, over a 7-year interval (1 January 2014 to 31 December 2021). Patients that were discharged home and receiving OPAT received antibiotics from a home infusion company for self-administration. A home health care nurse visited weekly to maintain the peripherally inserted central catheter (PICC) line and obtain samples for weekly laboratory tests. In our center, we routinely order weekly CBCs with differential, CMPs and urine analyses (UA) with microscopy for all OPAT patients. In addition, we order specific serum drug levels for patients on vancomycin or aminoglycoside and creatinine kinase (CK) levels for patients on daptomycin weekly. Infectious disease (ID) fellows review laboratory results regularly and follow patients in the clinic under the supervision of ID attendings.Data collection: After approval from the Institutional Review Board, we collected clinical information from our institution’s electronic medical records. The data collected included age, gender, comorbidities, indications for OPAT, microbiology, prescribed antibiotics, OPAT duration, discharge location, time from discharge to outpatient clinic follow up, baseline laboratory abnormalities and the type and number of abnormal laboratory results while receiving OPAT. If patients were readmitted while receiving OPAT, we documented the date and reason for hospitalization. If the physician changed antibiotics, we documented the date of the change and reasons for the change.Inclusion and exclusion criteria: The patients included in this study were 18 years old or older, required two weeks or more of OPAT and was evaluated by an infectious diseases consult team while in the hospital. We excluded those that entered hospice care, had missing data and were readmitted for more than one week for causes not directly related to antibiotic treatment or abnormal OPAT follow-up results.Definitions and Variables: We separated patients into a cohort of OPAT patients with complications and patients with no complications. We defined an OPAT complication as a clinically significant laboratory abnormality, a need to change antibiotic class and hospital readmission for any reason. We defined immunosuppression as chronic glucocorticoid use, acquired immunodeficiency syndrome with CD4 < 200/mL, use of disease-modifying antirheumatic drugs (DMARD), solid organ transplant or bone marrow transplant. We used the Charlson comorbidity index (CCI) to estimate a 10-year mortality risk. The OPAT duration was the number of weeks from hospital discharge until the physician discontinued antibiotics. Laboratory values at initial discharge from the hospital were considered baseline. Clinically significant laboratory values included creatinine, sodium, potassium, aspartate aminotransferase, alanine transaminase, alkaline phosphatase, total white blood count, platelet count, absolute eosinophil count, vancomycin trough, CK and urinalysis.p value < 0.05 from the univariate analysis were included for the multivariable logistic regression model. We considered a p value  <  0.05 statistically significant for our regression model. IBM SPSS 26 was used for the analysis.Statistical Analysis: Continuous variables are reported in medians and interquartile ranges (IQRs). Nominal and categorical variables are reported as proportions and frequencies. Univariate analysis with Chi square test of independence was used to identify the risk factors of OPAT complications. Variables with a Complications are not uncommon in OPAT patients. Recognizing predictors of OPAT complications will help determine strategies to optimize care, increase patient satisfaction and potentially further decrease cost. The less frequent monitoring of laboratory values could be useful in OPAT patients at a lower risk of complications. Less-frequent laboratory testing could be important to reduce costs  and potentially increase patient satisfaction .


Staphylococcus aureus bacteremia enrolled in outpatient parenteral antibiotic therapy monitoring program (OPAT-MP) upon hospital discharge with patients not enrolled. OPAT-MP patients were more likely to attend infectious diseases follow-up appointments. OPAT-related emergency room visits and/or readmissions were more common among non–OPAT-MP patients, but differences were not statistically significant.We compared patients with  Outpatient parenteral antibiotic therapy (OPAT) has become an integral part of the treatment of deep-seated infections. Advantages of OPAT include cost-effectiveness, decreased exposure to hospital-acquired infections, and improved patient satisfaction; disadvantages include risk of readmission, catheter-related complications, and adverse drug events.Staphylococcus aureus bacteremia, which requires 2–6 weeks of intravenous antibiotic therapy. Many patients are therefore discharged from the hospital on intravenous anti-staphylococcal treatment. However, in the absence of appropriate laboratory monitoring, the available antibiotics  for S. aureus bacteremia are associated with significant and potentially life-threatening side effects. OPAT monitoring is therefore particularly applicable for this patient group. Given the persistent high morbidity and mortality of S. aureus bacteremia, new strategies to improve clinical outcomes are imperative.A notable indication for OPAT is We conducted a retrospective study to investigate whether a structured OPAT monitoring program (OPAT-MP) with dedicated faculty support improved outcomes among patients discharged after an episode of staphylococcal bacteremia.A formal OPAT-MP was established in July 2016 by the Division of Infectious Diseases at Columbia University Irving Medical Center (CUIMC), an academic, multicampus, acute-care hospital center in New York City. As part of the program, dedicated infectious diseases (ID) clinicians review weekly laboratory results collected by home infusion services (1) to adjust antibiotic levels and monitor antibiotic toxicity, (2) to troubleshoot issues regarding long-term intravenous lines to prevent emergency room (ER) visits and hospital readmissions, and (3) to coordinate with the primary ID physician to ensure proper completion of therapy.S. aureus bacteremia. Patients admitted between July 2016 and December 2017 and enrolled in the OPAT-MP at discharge were compared to those admitted between January 2015 and December 2017 who were not enrolled in OPAT-MP at discharge. Patients discharged to a short- or long-term rehabilitation center or nursing care facility were excluded. Outcomes included ID follow-up appointment attendance, OPAT-related hospital readmissions and ER visits, microbiological recurrences, and death. Readmissions and ER visits were deemed OPAT related if they were due to intravenous catheter complications , adverse drug reactions, new Clostridium difficile infection, or worsening of the primary infection after source control had previously been achieved.We conducted a retrospective chart review of patients discharged home on intravenous antibiotic therapy after a hospital admission at CUIMC for  tests or Fisher exact tests, as indicated. SAS version 9.4 software  was used for all analyses.Statistical measures included χThis study was approved by the Institutional Review Board of Columbia University Irving Medical Center.S. aureus bacteremia during the study period: 45 patients were included in the OPAT-MP cohort and 106 patients were discharged on OPAT without formal monitoring. The median age of patients was 55.8 years and did not significantly differ between the 2 groups (P = .34). Sex and race did not significantly differ between groups; more patients in the OPAT-MP group were Hispanic  (Table P = .03) and 27% versus 7% (P < .01), respectively. Also, 80% of the overall study cohort had an inpatient ID consultation; consultation was more common in the OPAT-MP group than in the unmonitored group . In the OPAT-MP group, at time of bacteremia, Pitt bacteremia scores ranged from 0 to 11 . In the non–OPAT-MP group, Pitt bacteremia scores ranged from 0 to 6 .Overall, 151 patients were discharged on intravenous anti-staphylococcal therapy for S. aureus (MSSA) bacteremia and 13 (29%) had methicillin-resistant S. aureus (MRSA) bacteremia. In the non–OPAT-MP group, 79 patients (75%) had MSSA bacteremia and 27 (25%) had MRSA bacteremia. Discharge regimens and sources of bacteremia are described in Table P = .55). At the time of discharge, the median planned duration of therapy was 4 weeks for the OPAT-MP group and 3 weeks for the non–OPAT-MP group.The median duration of admission was 16.1 days in the OPAT-MP group and 16.8 days in the unmonitored group. In the OPAT-MP group, 32 patients (71%) had methicillin-sensitive P = .04) (Table P = .11). Similarly, although OPAT-related readmissions within 30 days were more common in the non–OPAT-MP cohort, the trend was not statistically significant . Microbiological recurrence within 30 days was low . There were no deaths in the study cohort within the 30 days after discharge. Most patients completed therapy as planned: 64% in the OPAT-MP cohort and 57% in the non-OPAT-MP cohort (P = .37). There was no significant difference between the 2 groups regarding stopping therapy early (P = .23), changing or extending therapy (P = .08), or lack of documentation of therapy outcome (P = .07).Patients in the OPAT-MP cohort were more likely to attend an ID follow-up appointment  Table . AlthougAmong the 13 patients in the OPAT-MP cohort with MRSA bacteremia, 4 (31%) required changes in vancomycin dosing over the course of treatment. Of 23 patients in the OPAT-MP cohort with MSSA bacteremia on penicillin-based therapy, 4 (17%) developed drug rash, transaminitis, and/or acute interstitial nephritis. Of these 4 patients, 3 patients required antibiotic therapy changes, and 1 patient was monitored with continuation of therapy.S. aureus bacteremia, those who were followed by a formal OPAT-MP were significantly more likely to attend an ID follow-up appointment. We detected a nonsignificant trend toward fewer ER visits and readmissions among the patients in the monitored cohort.Among patients discharged on OPAT for This study had several limitations. The sample size was modest. This study was likely underpowered to detect differences in readmissions and ER visits between the 2 cohorts. Many patients who were not enrolled in OPAT-MP had limited follow-up documentation in the medical record after discharge. We detected a bias toward underdetection of adverse drug events and outside hospital readmissions and ER visits in this group. This group also had a higher percentage of patients with chronic or end stage renal disease, which may have predisposed them to having more readmissions or ER visits. Conversely, because patients in the monitored group were followed until the end of their course, they were more likely to have all adverse events captured appropriately. In our study, although we did not detect a significant difference in readmissions between the groups, patients in the OPAT-MP group were more likely to attend an ID appointment, and ID follow-up itself has been associated with a lower rate of 30-day readmission among OPAT patients.Although OPAT-related admissions were relatively low, overall readmissions within 30 days approached 30%, indicating that this is a high-risk group. Multiple studies have sought to elucidate the risk factors for readmission among patients on OPAT.Given the advantages of OPAT regarding efficient, effective, and patient-centered care, it is imperative to understand how best to keep patients safe while on OPAT and to further explore the potential benefits of OPAT-MP.


To determine whether a structured OPAT program supervised by an infectious disease physician and led by an OPAT nurse decreased hospital readmission rates and OPAT-related complications and whether it affected clinical cure. We also evaluated predictors of readmission while receiving OPAT.A convenience sample of 428 patients admitted to a tertiary-care hospital in Chicago, Illinois, with infections requiring intravenous antibiotic therapy after hospital discharge.2 test. Factors associated with readmission for OPAT-related problems at a significance level of P < .10 in univariate analysis were eligible for testing in a forward, stepwise, multinomial, logistic regression to identify independent predictors of readmission.In this retrospective, quasi-experimental study, we compared patients discharged on intravenous antimicrobials from an OPAT program before and after implementation of a structured ID physician and nurse-led OPAT program. The preintervention group consisted of patients discharged on OPAT managed by individual physicians without central program oversight or nurse care coordination. All-cause and OPAT-related readmissions were compared using the χP = .003). OPAT-related readmission reasons included infection recurrence or progression (53%), adverse drug reaction (26%), or line-associated issues (21%). Independent predictors of hospital readmission due to OPAT-related events included vancomycin administration and longer length of outpatient therapy. Clinical cure increased from 69.8% before the intervention to 94.9% after the intervention (P < .001).In total, 428 patients were included in the study. Unplanned OPAT-related hospital readmissions decreased significantly after implementation of the structured OPAT program (17.8% vs 7%; A structured ID physician and nurse-led OPAT program was associated with a decrease in OPAT-related readmissions and improved clinical cure. OPAT is not without limitations, however; unplanned 30-day hospital readmission rates as high as 26% have been reported. Moreover, intravascular catheters used for OPAT are associated with an increased risk for deep venous thrombosis and catheter-related infections.Outpatient parenteral antimicrobial therapy (OPAT) is a treatment option for medically stable patients who require intravenous (IV) antimicrobial therapy in an outpatient setting. It has been utilized since the 1970s. OPAT permits decreased length of hospital stay in patients who require IV antimicrobial therapy, reduces cost to both the patient and the healthcare system, and reduces the risk of nosocomial infections. Due to the need for multiple providers and institutions to be involved in the care of patients on OPAT, communication and care coordination is critical to the feasibility, safety, and success of OPAT programs in successful treatment and in reducing hospital readmission rates for OPAT-related complications. According to the Infectious Diseases Society of America (IDSA) guidelines on OPAT, an effective OPAT team encompasses the physician, nurse, pharmacist, and the patient. Each individual in this collaborative team plays a unique role in the planning and delivery of high-quality care for patients discharged home on OPAT. The presence of a formal OPAT care team has been reported as one of the most important quality indicators in optimal OPAT care. However, not every institution with an OPAT program has dedicated personnel or a complete OPAT team as recommended by IDSA guidelines. In a 2018 survey of 672 ID physicians in the Emerging Infectious Network (EIN), only 36% had a structured OPAT program at their institution. An explanation for this may be inadequate hospital administrative support of OPAT programs (as reported by 59.8% of providers) or financial support (as reported by 64.6%). Lack of evidence demonstrating the value of dedicated staff for a successful OPAT program may explain why more resources are not allocated to OPAT programs. Studies that compare OPAT outcomes in OPAT systems, which utilize various team models, provide much needed evidence and justification that these models are effective.OPAT programs require the involvement of multiple providers including infectious disease (ID) physicians and often pharmacists and nurses, in addition to care coordination between multiple institutions including hospitals, outpatient clinics, home health agencies, infusion companies, rehabilitation facilities, and skilled nursing facilities. ID consultation was not required for OPAT; however, most OPAT patients (69%) described in a cohort from 2012 to 2013 at UI Health had an ID physician involved in their care at the time of OPAT initiation. Individual physician management was problematic for several reasons: nonstandardized structure of the OPAT program, significant time coordinating care, competing responsibilities of physicians, and an increasing number of OPAT patients in the program. In August 2017, a dedicated  registered nurse with nursing education, health utilization management, and discharge planning expertise was hired to provide centralized and standardized care coordination, to support patient communication, and to facilitate and document laboratory and pharmaceutical management for our OPAT program. In addition, an ID physician was designated to oversee the program (0.1 FTE) and a requirement was enacted that all OPAT orders and patient management would be directed by the OPAT team and an ID physician. An inpatient ID pharmacist was available to support the OPAT program as needed, but no pharmacist FTE support was dedicated. In this study, we examined risk factors for readmission of patients receiving OPAT and assessed readmission rates before and after the implementation of a structured OPAT program as a key programmatic indicator of OPAT functioning at a large, academic, tertiary-care hospital.The University of Illinois Hospital and Health Sciences System  is a 463-bed tertiary-care academic hospital in Chicago. The evolution of the OPAT program at UI Health captures the spectrum of OPAT programs across the United States. Prior to hiring dedicated staff for the UI Health OPAT program, OPAT was managed by individual physicians who coordinated care individually without administrative support, dedicated care coordination, nor standardized management protocols. The postintervention group included patients discharged through the new structured OPAT program between October 1, 2017, and January 1, 2019. The structured OPAT program consisted of a full-time, dedicated nurse who provided care coordination and communication with home health agencies, infusion companies, patients, ID attending physicians and fellows, the ID clinic, and nursing and rehabilitation facilities. In addition, a dedicated ID physician served as the medical director by providing oversight for the program. This medical director developed laboratory monitoring protocols and management, and enhanced documentation standards. Although the medical director supervised the management of the entire program and oversight and support for the OPAT nurse, clinical decisions after hospital discharge were made by the supervising ID physician, often with an ID fellow, who cared for the patient while in the hospital and created the OPAT treatment plan. In most instances, the medical director and the supervising ID physician were not the same individual. The OPAT nurse utilized laboratory monitoring protocols for laboratory review, actions, and adjustment of dose and frequency, in coordination with the supervising ID physician. The primary end point of this study was unplanned, OPAT-related readmissions during receipt of OPAT. Readmissions deemed related to OPAT included treatment toxicities, complications of venous access devices , and relapse of infection being treated. Secondary end points included all-cause readmission during OPAT and treatment outcome (successful versus failed treatment). Successful treatment was defined as completion of planned duration of IV antimicrobial therapy or a transition from IV antimicrobials to oral antimicrobials. Failed treatment was defined as clinical signs or symptoms of infection with or without readmission to UI Health Hospital due to infection progression or recurrence while on OPAT. Predictors of OPAT-related readmission were also evaluated. Initial review was performed by a study team member, and an ID physician verified categorization of whether a readmission was related or not related to OPAT. The University of Illinois at Chicago Institutional Review Board approved this research study.This retrospective quasi-experimental study included patients aged ≥18 years who received an ID consultation and were discharged from UI Health on OPAT. The preintervention group included patients discharged from UI Health with OPAT recommendations from the ID consultation service between January 1, 2012, and August 1, 2013. This cohort was a subgroup of patients from our previously published study.Patients included in this study were retrospectively identified through the following sources: billing codes, orders for outpatient IV antimicrobials, a registry of patients who had a peripherally inserted central catheter (PICC) placed while in the hospital, and a registry of patients enrolled in the structured OPAT program. Patients must have received their medication through a PICC line for a minimum of 2 days for treatment of an infection as an outpatient to be included. Patients were included if they were receiving IV antimicrobials after hospital discharge in any setting except for those who were receiving IV antimicrobials during scheduled hemodialysis sessions who were excluded. Each patient was followed for the entire duration of their IV antimicrobial therapy even if it was completed outside the enrollment period.The UI Health electronic medical record  was utilized to collect patient information and data was stored using REDCap (Research Electronic Data Capture). Data abstracted included patient general characteristics such as age, sex, comorbidities, insurance status, presence of assigned primary care physician. In addition, healthcare utilization measures were collected, including hospital length of stay, previous hospitalizations for any cause within past 12 months, intensive care unit (ICU) stay during hospitalization, primary clinical team upon discharge, presence of ID consultation during hospitalization. Additional data included ID diagnosis, microbiology cultures, treatment information , total duration of antimicrobial therapy including number of inpatient days , and outpatient days . Further data were collected including frequency of dosing, location of OPAT administration , and outpatient follow-up appointment including with which specialty. Outcome data included unplanned OPAT-related readmission during OPAT, all-cause readmission during OPAT, reason for readmission, infection cure, infection relapse, and OPAT discontinuation due to OPAT related complication. The Charlson comorbidity index was calculated for each patient using collected clinical information. test. Continuous data were evaluated using the Mann-Whitney U test. Predictors of readmission were also evaluated; factors associated with readmission at a significance level of P < .10 in univariate analysis were eligible for testing in a forward, stepwise, multinomial, logistic regression to identify independent predictors of readmission. Data analysis was conducted with SPSS version 25 software .Comparisons of nominal data, such as patient demographics and readmission rates, were evaluated using the Fisher exact test or the χThis study included EMR data for 428 patients: 73 from the preintervention period and 355 from the postintervention period. Table P = .003). Reasons for readmissions due to OPAT-related complications included infection recurrence or progression , adverse drug reaction , or line-associated issues . The all-cause unplanned readmission rate decreased after the implementation of the structured program  compared to the preimplementation period ; however, this difference was not statistically significant (P = .165).After implementation of the structured OPAT program, the unplanned readmission rate due to OPAT-related complications significantly decreased from 17.8% (13 of 73) to 7.0% .Clinical cure or treatment failure was documented for 385 (90%) of 428 patients. Among them, clinical cure occurred in 91.4%. Clinical cure increased from 69.8% before the intervention to 94.9% after the intervention  for OPAT patients. Future studies should revisit the independent risk of readmission and vancomycin when monitored by AUC because AUC-based dosing may improve therapeutic target attainments and is now recommended instead of troughs.Beta-lactams and vancomycin were the 2 most-used OPAT drugs before and after the intervention. Patients who received vancomycin were more likely to be readmitted, which may in part be explained by the increased rates of adverse outcomes associated with vancomycin compared to other antimicrobials used in OPAT.In our study, longer OPAT duration was associated with a significant increased risk of unplanned readmission  compared with a relatively shorter OPAT duration . A strength of our study was that we were able to collect the completed duration of outpatient treatment, which may differ from the planned duration set at the time of hospital discharge. This finding reinforces the importance of regular monitoring for adverse events, especially as outpatient treatment length increases. we also found older age to be protective for readmission, supporting recommendations that elderly patients can be safely treated with OPAT. Several studies have found no association between age and readmission. We are uncertain why the younger age group  was more likely to be readmitted; we agree with Keller et al that younger patient populations may be more noncompliant with therapy. A survey of 65 adults discharged from a tertiary-care hospital on OPAT revealed that patient self-reported nonadherence to therapy was associated with younger age  as well as lack of time and low income. In addition to considering patient age and the potential risks of noncompliance, complexity of dosing regimen, social support, and convenience should all be assessed when prescribing OPAT.Similar to Keller et alWe did not find significant associations between readmission and Charlson comorbidity index, socioeconomic factors (utilizing insurance as a proxy), aminoglycoside use, or the presence of multidrug-resistant organisms. Inconsistent conclusions have been drawn regarding the association between readmission and these risk factors. and a follow-up OPAT clinic visit has been associated with a lower 30-day hospital readmission rate compared to no follow-up visit.Our study had several limitations. The retrospective study design may have introduced recall and selection bias. Our data only can capture what is documented in the medical record, and adverse events may have occurred that were not recorded. Our patient population was discharged from an urban, tertiary-care, academic medical center and may not reflect patients in other settings. Moreover, we had a greater number of patients with bone and joint disease which may not be generalizable to other patient populations. Several differences in baseline characteristics of the 2 groups could have affected outcomes, including more bone and joint infections, less culture positivity and culture-directed therapy, and more vancomycin and less β-lactam therapy in the preintervention group compared to the postintervention group. To mitigate these differences, our multivariate analysis included all factors potentially predictive of readmission that were identified in the univariate analyses. However, we were unable to capture readmissions to other hospitals. We did not include analysis of subsequent readmissions after the first readmission to allow for better comparison with our preintervention cohort and to avoid confounding factors. We defined successful treatment as completion of IV therapy regardless of whether the patient stopped all antibiotics at that point or was transitioned to oral therapy. Some patients may have relapsed with infection while on oral therapy after completion of IV therapy. Finally, we did not assess the impact of our structured OPAT program on outpatient ID follow-up rates or the availability of monitoring laboratories while on OPAT. Multidisciplinary OPAT teams have been associated with increased ID clinic follow-up rates,The implementation of an ID physician and nurse-led OPAT program significantly reduced unplanned OPAT-related hospital readmission rates and improved clinical cure rates, underscoring the importance of multidisciplinary teams. Enrollment in our strengthened OPAT program and older age were protective factors from readmission, whereas vancomycin administration and a longer outpatient treatment duration were associated with an increased risk of readmission.


Rapidly progressive crescentic glomerulonephritis associated with anti-neutrophil cytoplasmic antibodies (ANCA-GN) is a major cause of renal failure. Current immunosuppressive therapies are associated with severe side effects, intensifying the need for new therapeutic strategies. The activation of Mas receptor/Angiotensin-(1-7) axis exerted renoprotection in chronic kidney disease. Here, we investigated the effect of adding the lanthionine-stabilized cyclic form of angiotensin-1-7 [cAng-(1-7)] to cyclophosphamide in a rat model of ANCA-GN. At the onset of proteinuria, Wistar Kyoto rats with ANCA-GN received vehicle or a single bolus of cyclophosphamide, with or without daily cAng-(1-7). Treatment with cAng-(1-7) plus cyclophosphamide reduced proteinuria by 85% vs. vehicle, and by 60% vs. cyclophosphamide, and dramatically limited glomerular crescents to less than 10%. The addition of cAng-(1-7) to cyclophosphamide protected against glomerular inflammation and endothelial rarefaction and restored the normal distribution of parietal epithelial cells. Ultrastructural analysis revealed a preserved GBM, glomerular endothelium and podocyte structure, demonstrating that combination therapy provided an additional layer of renoprotection. This study demonstrates that adding cAng-(1-7) to a partially effective dose of cyclophosphamide arrests the progression of renal disease in rats with ANCA-GN, suggesting that cAng-(1-7) could be a novel clinical approach for sparing immunosuppressants. Pauci-immune crescentic glomerulonephritis is the most common form of rapidly progressive crescentic glomerulonephritis (RPGN), characterized by the lack of significant IgG deposits within glomeruli ,2. It isANCA-vasculitis is a life-threatening disease; its management consists of inducing remission with cyclophosphamide or rituximab, combined with glucocorticoids, followed by maintenance of remission to prevent relapse. However, this immunosuppressive approach is often associated with serious side effects, and 30–40% of patients may experience refractory disease or relapses , intensiob/ob mice with type 2 diabetic nephropathy by limiting albuminuria, inflammatory cell infiltration, podocyte injury and glomerular and peritubular capillary rarefaction [Angiotensin-converting enzyme 2 (ACE2)/angiotensin 1-7 (Ang-1-7)/Mas receptor axis is the counter-regulatory pathway of the harmful action of angiotensin II (Ang II), which is one of the major contributors to the progression of chronic kidney disease . ACE2 liefaction . In addiefaction .Here, we investigated the effect of treatment with cAng-(1-7) on top of cyclophosphamide in a rat model of MPO-ANCA-associated GN, which replicates the characteristic features of the disease in humans . CyclophMale Wistar Kyoto (WKY/NCrlBR) rats were purchased from Charles River Laboratories Italia  and maintained in a specific pathogen-free facility with a 12 h dark/12 h light cycle, in a constant temperature room and with free access to a standard diet and water.n = 5–6 rats/group) the following: vehicle ; the lanthipeptide cAng-(1-7)  plus cyclophosphamide (single bolus 50 mg/kg i.p.); or cyclophosphamide (50 mg/kg single bolus 50 mg/kg i.p.). Cyclophosphamide was administered in a single bolus on day 21. A group of unimmunized WKY rats (n = 5) served as controls. All animals were followed until day 35, when they were euthanized by CO2 inhalation.ANCA-associated crescentic glomerulonephritis was induced in WYK rats (180–220 g), as previously described . BrieflyTwenty-four-hour urine samples were collected using metabolic cages on days 21, 28, 35 post-immunization. Hematuria was assessed using dipstick Multistix . Urinary protein excretion was measured using the Coomassie method with a Miura one auto-analyzer . Renal function was assessed as blood urea nitrogen (BUN) in whole blood samples using the Reflotron test . Systolic blood pressure was measured with a computerized tail-cuff system in conscious rats .Duboscq-Brazil-fixed, paraffin-embedded renal sections (3 μm) were stained with periodic acid-Schiff reagent (PAS) , and Masson’s trichrome staining to analyze glomerular and tubular interstitial injury. The presence of at least two layers of proliferating cells in the Bowman’s space of the glomerular cross-sectional area was defined as a crescentic glomerular lesion. The mean percentage of glomeruli with crescents was estimated through the analysis of all glomeruli for each section. Tubular damage (atrophy and dilatation) was graded from 0 to 4+ . The number of tubular casts was counted in an average of 15 fields of interstitial areas (HPF/×200). All biopsy specimens were examined by two pathologists blind to treatment groups.For immunofluorescence experiments, OCT-frozen kidney sections (3 μm thick) were fixed with cold acetone and incubated with 1% BSA to block nonspecific sites. For the quantification of neutrophils, CD4+ T cells and endothelial rarefaction, the following primary antibodies were used: mouse anti-rat granulocytes (HIS48) , mouse monoclonal anti-rat CD4 , mouse monoclonal anti-rat RECA-1  followed by the specific Cy3-conjugated secondary antibodies. Claudin-1/NCAM double stainings were performed through incubation with rabbit anti-claudin-1 , mouse monoclonal anti-rat NCAM  followed by the specific FITC- or Cy3-conjugated secondary antibodies. Nuclei were stained with DAPI, and the renal structure with FITC-wheat germ agglutinin (WGA). Negative controls were obtained by omitting primary antibodies on adjacent sections. For the detection of claudin-1 and NCAM stainings, antigen retrieval with citrate buffer was performed to enhance the reactivity of antibodies to antigens. Fluorescence was examined using an inverted confocal laser-scanning microscope . At least 30 glomeruli were examined for each animal, and the extent of altered distribution of claudin-1 in the glomeruli was expressed as a score from 0 to 3 related to the percentage of the glomerular tuft area occupied by the claudin-1-positive cells . HIS48-positive neutrophils in the glomeruli, and CD4+ cells within glomeruli, were counted in an average of 25 glomeruli in each kidney sample and expressed as the average number of cells per glomerulus. RECA-1 staining of capillaries in the glomerular tuft was scored as previously described  as folloED-1 and CD8 stainings were performed using the immunoperoxidase method. Duboscq-Brazil-fixed, 3 μm paraffin-embedded kidney sections were incubated for 5 min with Peroxidazed 1  to quench endogenous peroxidase, after antigen retrieval in Rodent Decloaker . After blocking for 10 min with Rodent Block R , sections were incubated with mouse monoclonal antibody to monocyte/macrophage ED-1 surface antigen  or mouse anti-rat-CD8  followed by Rat HPR-Polymer  for 30 min. The stainings were visualized by the addition of the betazoid 3,3′diaminobenzidine chromogen kit solutions . Finally, slides were counterstained with Mayer hematoxylin and observed through light microscopy . Negative controls were obtained by omitting the primary antibody on adjacent sections. ED-1-positive monocytes/macrophages and CD8+ T cells within glomeruli were counted in an average of 25 glomeruli and expressed as the average number of cells per glomerulus.Fragments of kidney tissue were fixed overnight in 2.5% glutaraldehyde  in 0.1 M sodium cacodylate buffer (pH 7.4)  and washed repeatedly in the same buffer. After postfixation in 1% OsO4, specimens were dehydrated through ascending grades of alcohol and embedded in Epon resin. Ultrathin sections were stained with Uranyless (Electron Microscopy Sciences) and lead citrate (Electron Microscopy Sciences) and examined using a transmission electron microscopy .p < 0.05.Data are presented as the mean ± SEM. Data analysis was performed using Prism Software . Comparisons were made using ANOVA with the Tukey post hoc test or two-way ANOVA for repeated measures. Statistical significance was defined as Data on the systemic parameters evaluated at the end of the study (day 35) are reported in ANCA-GN was associated with the development of systemic hypertension, which was reduced significantly by treatment with cAng-(1-7) plus cyclophosphamide, but not with cyclophosphamide alone.Rats with ANCA-GN given vehicle exhibited kidney hypertrophy. A decrease in the kidney weight/body weight ratio was observed in both the combination therapy and the cyclophosphamide group, compared to the vehicle group. Notably, the kidney weights of rats treated with cAng-(1-7) plus cyclophosphamide were similar to those of control rats.p < 0.05). Indeed, the combined therapy afforded for a 60% reduction in proteinuria levels with respect to cyclophosphamide alone  (p < 0.05) lower compared to the vehicle group, but higher than the combination therapy group (p < 0.001) (p < 0.05 vs. cAng-(1-7) + cyclophosphamide)  B. Importvehicle) C. The pevehicle) B. ANCA-G< 0.001) B. These phamide) B,C.According to our previous observations , the glo+ T cells and CD8+ T cells in the glomerular tuft (+ T cells was prevented by the combination of cAng-(1-7) and cyclophosphamide, while CD8+ T cells were numerically limited compared to the vehicle group  plus cyclophosphamide was associated with an amelioration of glomerular endothelial damage. Electron microscopy analysis of glomeruli from rats with ANCA-GN that were on vehicle showed crescentic lesions closely resembling human pathology, as previously described . Fibrin p < 0.05) reduction in the number of proteinaceous casts (1.74 ± 0.16) was observed compared to vehicle; tubular dilatation (score: 0.60 ± 0.19) and atrophy (score: 0.70 ± 0.12) were no different from vehicle. In animals treated with a single bolus of cyclophosphamide, the number of proteinaceous casts averaged 2.37 ± 0.62 (NS vs. vehicle). Next, given the striking effect of the combined treatment on the glomerular capillary wall, we investigated whether a protective effect could be exerted on ultrastructural changes in post-glomerular vessels. The analysis of interstitial areas in rats with ANCA-GN on vehicle revealed swelling and loss of fenestrations of endothelial cells of peritubular capillaries associated with the accumulation of inflammatory cells, mainly monocytes/macrophages and lymphocytes , accompanied by tubular casts  A. In thephocytes B. In thephocytes B.In this study, we provide experimental evidence that daily treatment with the cyclic form of Ang-(1-7) on top of a single injection of cyclophosphamide has a deep renoprotective effect on rats with MPO-ANCA-associated crescentic GN. This therapeutic protocol blocked the rise of proteinuria and ameliorated renal function, dramatically reducing the number of glomeruli affected by crescents and limiting glomerular inflammation. Conversely, the administration of cyclophosphamide alone had partial effects on the course of the disease and pathology.ob/ob mice with diabetic nephropathy, in which the addition of cAng-(1-7) to ACE inhibitor therapy had a superior effect to ACE inhibitor alone, thanks to better preservation of podocytes and an improvement in glomerular endothelial damage [Here, the first remarkable finding is that combined therapy had a stable and pronounced effect on proteinuria, while evidence of a further rise in proteinuria at the end of the study in rats treated with cyclophosphamide alone indicates a tendency for the disease to relapse in the absence of co-administered cAng-(1-7). This may reflect the clinical condition of patients with ANCA-GN who do not completely respond to cyclophosphamide. Interestingly, the antiproteinuric effect of the combined treatment may be reminiscent of the data collected by our group from BTBR l damage . LikewisThe improvement in proteinuria after treating ANCA-GN rats with c-(Ang-1-7) plus cyclophosphamide was associated with a very strong reduction in the number of glomeruli affected by crescents and an increased number of normal glomeruli. The trigger event in crescent formation in ANCA-GN is the development of necrotizing and inflammatory injury to the glomerular capillary wall, leading to gaps in the GBM, extravasation of plasma proteins and red cells, and a severe inflammatory reaction ,24,25.Studies reported a pivotal and interconnected role for neutrophils and monocytes/macrophages in the acute phase of the disease ,27. ANCAIn the glomeruli of animals treated with combination therapy, we also found a reduced number of CD4+ T cells, which may be a consequence of the reduced number of neutrophils recruited to the glomerular tuft in response to therapy. Indeed, MPO released by activated neutrophils is known to act as planted antigen for anti-MPO effector CD4+ T cells  and, in Ultrastructural analysis also revealed that, according to our previous study , rats wiIn conclusion, the addition of cAng-(1-7) to cyclophosphamide enhanced the renoprotective effect of cyclophosphamide alone in an experimental model of ANCA-GN. The combination therapy, but not cyclophosphamide alone, interrupted the vicious cycle of inflammation initiated by neutrophil recruitment and degranulation, resulting in reduced glomerular accumulation of macrophages and CD4-positive T cells . This an