Asymptomatic Testing of Hospital Admissions for SARS-CoV-2: Is it OK to Stop?

Universal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing of all persons admitted to acute care hospitals has become common practice. We describe why 1 hospital discontinued this practice after weighing potential benefits against known harms. Considerations around the benefits shifted as we saw a decline in SARS-CoV-2 community transmission and coronavirus disease 2019 (COVID-19) severity of illness, increased availability of vaccines and treatments, and better understood the many other transmission pathways in the healthcare environment. Considerations around harms included the additional strain on laboratory and infection prevention resources, and several unintended adverse consequences of admission screening for patients, including unnecessary isolation, antiviral treatments, and delays in care delivery. Poor test performance for detection of infectiousness also played a significant role in determining to stop universal screening. No increase in hospital-onset COVID-19 has been documented since discontinuation of admission testing. We continue to apply other established layers of prevention while monitoring for any change in incidence of within-facility transmission of SARS-CoV-2.

Xenotransplantation experiments in brain-dead human subjects-A critical appraisal.

Brain-dead human subjects (decedents) were recently introduced as a potential preclinical experimental model in xenotransplantation. Brain death is associated with major pathophysiological changes, eg, structural injury and cell infiltration in vital organs, and major hormonal, metabolic, inflammatory, and hemodynamic changes. In 2 of the 3 initial experiments, the design of the experiments resulted in little or no new information becoming available. In the third, the experiment was unfortunately unsuccessful as neither of the 2 pig kidneys transplanted into the decedent functioned adequately. Failure may well have been associated with the effects of brain death, but an immune/inflammatory response to the xenograft could not be excluded. Subsequently, 2 further pig kidney transplants and 2 pig heart transplants have been carried out in human decedents, but again the data obtained do not add much to what is already known. In view of the profound changes that take place during and after brain death, it may prove difficult to determine whether graft failure or dysfunction results from the effects of brain death or from an immune/inflammatory response to the xenograft. A major concern is that, if the results are confusing, they may impact decisions relating to the introduction of clinical xenotransplantation.

Novel factors potentially initiating acute antibody-mediated rejection in pig kidney xenografts despite an efficient immunosuppressive regimen.

Antibody-mediated rejection (AMR) is a common cause of graft failure after pig-to-nonhuman primate organ transplantation, even when the graft is from a pig with multiple genetic modifications. The specific factors that initiate AMR are often uncertain. We report two cases of pig kidney transplantation into immunosuppressed baboons in which we identify novel factors associated with the initiation of AMR. In the first, membranous nephropathy was the initiating factor that was then associated with the apparent loss of the therapeutic anti-CD154 monoclonal antibody in the urine when severe proteinuria was present. This observation suggests that proteinuria may be associated with the loss of any therapeutic monoclonal antibody, for example, anti-CD154 or eculizumab, in the urine, resulting in xenograft rejection. In the second case, the sequence of events and histopathology tentatively suggested that pyelonephritis may have initiated acute-onset AMR. The association of a urinary infection with graft rejection has been well-documented in ABO-incompatible kidney allotransplantation based on the expression of an antigen on the invading microorganism shared with the kidney graft, generating an immune response to the graft. To our knowledge, these potential initiating factors of AMR in pig xenografts have not been highlighted previously.

Effectiveness of Heterologous Coronavirus Disease 2019 (COVID-19) Vaccine Booster Dosing in Brazilian Healthcare Workers, 2021.

BACKGROUND: Little is currently known about vaccine effectiveness (VE) for either 2 doses of Oxford-AstraZeneca (ChAdOx1) viral vector vaccine or CoronaVac (Instituto Butantan) inactivated viral vaccine followed by a third dose of mRNA vaccine (Pfizer/BioNTech) among healthcare workers (HCWs). METHODS: We conducted a retrospective cohort study among HCWs (aged ≥18 years) working in a private healthcare system in Brazil from January to December 2021. VE was defined as 1 - incidence rate ratio (IRR), with IRR determined using Poisson models with the occurrence of laboratory-confirmed coronavirus disease 2019 (COVID-19) infection as the outcome, adjusting for age, sex, and job type. We compared those receiving viral vector or inactivated viral primary series (2 doses) with those who received an mRNA booster. RESULTS: A total of 11 427 HCWs met the inclusion criteria. COVID-19 was confirmed in 31.5% of HCWs receiving 2 doses of CoronaVac vaccine versus 0.9% of HCWs receiving 2 doses of CoronaVac vaccine with mRNA booster (P < .001) and 9.8% of HCWs receiving 2 doses of ChAdOx1 vaccine versus 1% among HCWs receiving 2 doses of ChAdOx1 vaccine with mRNA booster (P < .001). In the adjusted analyses, the estimated VE was 92.0% for 2 CoronaVac vaccines plus mRNA booster and 60.2% for 2 ChAdOx1 vaccines plus mRNA booster, when compared with those with no mRNA booster. Of 246 samples screened for mutations, 191 (77.6%) were Delta variants. CONCLUSIONS: While 2 doses of ChAdOx1 or CoronaVac vaccines prevent COVID-19, the addition of a Pfizer/BioNTech booster provided significantly more protection.

Optimal dose of rituximab in ABO-incompatible kidney transplantation in patients with low anti-A/B antibody titers: A single-center retrospective cohort study.

BACKGROUND: The clinical outcomes of ABO-incompatible (ABOi) kidney transplantation have improved with the introduction of desensitization therapy with rituximab. However, rituximab prevents not only antibody-mediated rejection (AMR) but also increases the risk of adverse events, such as infection. For ABOi kidney transplantation in patients with low anti-A/B antibody titers, we previously used a rituximab-free desensitization protocol and then initiated a single dose of 100 mg rituximab in 2016. We retrospectively compared the outcomes of ABOi kidney transplantation in patients with low anti-A/B antibody titers before and after the introduction of rituximab. METHODS: ABOi kidney transplantations (n = 142) in patients with low anti-A/B antibody titers between 2007 and 2021 were included. Patients were divided into two groups (with and without rituximab) for desensitization. The primary outcomes were the incidence of acute AMR and infection. RESULTS: Sixty-six patients were desensitized without rituximab (rituximab-free group), and 76 were pretreated with 100 mg rituximab (rituximab group) before transplantation. The incidence of acute AMR was significantly lower in the rituximab group than in the rituximab-free group (.0% [0/76] vs. 7.6% [5/66], respectively; p = .047). Post-transplantation anti-A/B antibody titers were also lower in the rituximab group than in the rituximab-free group. There was no significant difference in the incidence of adverse events, including infections, between the two groups. CONCLUSION: In ABOi kidney transplantation patients with low anti-A/B antibody titers, the desensitization protocol with a single dose of 100 mg rituximab was effective in preventing acute AMR without increasing the risk of other adverse events.

Discussion and Initiation of HIV Pre-exposure Prophylaxis Were Rare Following Diagnoses of Sexually Transmitted Infections Among Veterans.

BACKGROUND: Healthcare encounters for the diagnosis and treatment of sexually transmitted infections (STIs) are common and represent an opportunity to discuss and initiate HIV pre-exposure prophylaxis (PrEP). Little is known about how frequently PrEP is discussed and initiated in association with encounters for STIs. DESIGN: Retrospective cohort and nested case-control study, matched by STI date, in national Veterans Health Administration (VHA) facilities  from January 2013 to December 2018. PARTICIPANTS: Veterans with a first STI diagnosis (i.e., early syphilis, gonorrhea, or chlamydia) based on ICD codes, excluding those with prior HIV diagnosis, prior PrEP use, or STI diagnosed on screening during a visit to initiate PrEP. MAIN MEASURES: Frequency of PrEP initiation within 90 days of healthcare encounter for STIs. In the case-control study, we performed a structured chart review from the initial STI-related clinical encounter and quantified frequency of PrEP discussions among matched patients who did and did not initiate PrEP in the following 90 days. KEY RESULTS: We identified 23,312 patients with a first STI, of whom 90 (0.4%) started PrEP within 90 days. PrEP initiation was associated with urban residence (OR = 5.0, 95% CI 1.8-13.5), White compared to Black race (OR = 1.7, 95% CI 1.0-2.7), and syphilis diagnosis (OR = 5.7, 95% CI 3.7-8.6). Chart review revealed that discussion of PrEP was rare among people with STIs who did not subsequently start PrEP (1.1%, 95% CI 0.1-4.0). PrEP initiation was associated with documentation of sexual history (80.0% of initiators vs. 51.0% of non-initiators, p < 0.01) and discussion of PrEP (52.2% vs. 1.1%, p < 0.01) during the initial STI diagnosis encounter. CONCLUSIONS: Discussion and initiation of PrEP were rare following healthcare encounters for STIs. Interventions are needed to improve low rates of sexual history-taking and discussion of PrEP during healthcare encounters for STIs.

Two-year outcomes of low-exposure extended-release tacrolimus and mycophenolate mofetil regimen in de novo kidney transplantation: A multi-center randomized controlled trial.

BACKGROUND: Once-daily extended-release tacrolimus (TACER) is commonly administered following kidney transplantation (KTx); however, its optimal dosage remains unknown. METHODS: In this multi-center, randomized controlled trial, 62 living donor KTx recipients were assigned to either standard-exposure (SE; n = 32) or low-exposure (LE; n = 30) TACER (Graceptor®, Astellas Pharm Inc.) groups. All patients received basiliximab and mycophenolate mofetil (MMF). The primary outcomes were acute rejection, graft/patient survival, and the secondary outcomes were incidence of cytomegalovirus infection, and de novo donor-specific antibodies (dnDSA) production. RESULTS: The tacrolimus trough level and estimated area under the blood concentration-time curve (eAUC) were significantly higher in SE than in LE (SE vs. LE; 1 year: 5.0 ± 0.9 ng/ml and 206.9 ± 26.8 ng h/ml vs. 3.4 ± 1.0 ng/ml and 153.9 ± 26.4 ng h/ml; 2 years: 4.8 ± 1.0 ng/ml and 204.9 ± 30.1 ng h/ml vs. 3.8 ± 0.9 ng/ml and 164.4 ± 27.0 ng h/ml). In contrast, the dosage and eAUC of MMF did not differ between groups. Two-year graft and patient survival rates were 100% in both groups, and acute rejection rates were 0% and 10% in the SE and LE, respectively (p = 0.11). The mean estimated glomerular filtration rates did not differ between the groups. Cytomegalovirus infection was slightly lower in the LE (SE: 12.5% and LE: 6.7%, p = 0.37). In the LE, four cases of dnDSA were noted within 2 years of transplantation; no case was observed in the SE (p = 0.034). CONCLUSIONS: Although the LE TACER regimen showed similar rates of acute rejection, as well as graft and patient survival compared with SE after KTx, LE was significantly more associated with dnDSA. Further investigation of its long-term effect on graft survival is warranted. (University Hospital Medical Information Network Clinical Trials Registry ID: UMIN000033089).

Pelvic and central nervous system tuberculosis complicated by a paradoxical response manifesting as a spinal tuberculoma: a case report.

BACKGROUND: The post-partum period is a risk factor for tuberculosis (TB), possibly including the period after miscarriage as illustrated here. This case demonstrates how non-specific symptoms can hide widely disseminated TB. CASE PRESENTATION: A healthy 26-year-old female with a history of recent miscarriage presented to the emergency department with non-specific symptoms of headache, abdominal pain, and sub-acute fevers. She had immigrated to the United States from the Marshall Islands 9 years prior. Two months prior to presentation she had a miscarriage at 18 weeks of pregnancy. On admission, transvaginal ultrasound revealed retained products of conception and abdominal computed tomography revealed findings consistent with tubo-ovarian abscesses and peritonitis. The obstetrics and gynecology service performed dilation and curettage (D&C) to remove retained products of conception. Acid-fast bacilli cultures from cerebrospinal fluid as well as specimens from D&C and intra-abdominal abscesses subsequently all grew TB. She was diagnosed with TB meningitis, peritonitis, endometritis, and tubo-ovarian abscesses. Her treatment course was complicated by a paradoxical response resulting in a spinal tuberculoma causing lower extremity weakness. The tuberculoma was treated with surgical decompression as well as continuation of treatment with anti-tubercular chemotherapy and steroids. CONCLUSION: Disseminated and extrapulmonary TB can present with non-specific symptoms. Recognition of risk factors for TB is critical for prompt diagnostic evaluation and treatment of this deadly disease. A paradoxical reaction needs to be taken into consideration when any new neurological symptoms occur during TB treatment.

Elevated parathyroid hormone one year after kidney transplantation is an independent risk factor for graft loss even without hypercalcemia.

BACKGROUND: Hypercalcemic hyperparathyroidism has been associated with poor outcomes after kidney transplantation (KTx). However, the clinical implications of normocalcemic hyperparathyroidism after KTx are unclear. This retrospective cohort study attempted to identify these implications. METHODS: Normocalcemic recipients who underwent KTx between 2000 and 2016 without a history of parathyroidectomy were included in the study. Those who lost their graft within 1 year posttransplant were excluded. Normocalcemia was defined as total serum calcium levels of 8.5-10.5 mg/dL, while hyperparathyroidism was defined as when intact parathyroid hormone levels exceeded 80 pg/mL. The patients were divided into two groups based on the presence of hyperparathyroidism 1 year after KTx. The primary outcome was the risk of graft loss. RESULTS: Among the 892 consecutive patients, 493 did not have hyperparathyroidism (HPT-free group), and 399 had normocalcemic hyperparathyroidism (NC-HPT group). Ninety-five patients lost their grafts. Death-censored graft survival after KTx was significantly lower in the NC-HPT group than in the HPT-free group (96.7% vs. 99.6% after 5 years, respectively, P < 0.001). Cox hazard analysis revealed that normocalcemic hyperparathyroidism was an independent risk factor for graft loss (P = 0.002; hazard ratio, 1.94; 95% confidence interval, 1.27-2.98). CONCLUSIONS: Normocalcemic hyperparathyroidism 1 year after KTx was an independent risk factor for death-censored graft loss. Early intervention of elevated parathyroid hormone levels may lead to better graft outcomes, even without overt hypercalcemia.

Coronavirus Disease 2019 Serial Testing Among Hospitalized Patients in a Midwest Tertiary Medical Center, July-September 2020.

We implemented serial coronavirus disease 2019 testing for inpatients with a negative test on admission. The conversion rate (negative to positive) on repeat testing was 1%. We identified patients during their incubation period and hospital-onset cases, rapidly isolated them, and potentially reduced exposures. Serial testing and infectiousness determination were resource intensive.

An autopsy case study of lymphocytic hypophysitis induced by nivolumab treatment for esophageal malignant melanoma.

Immune checkpoint inhibitors such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed death-1 antibodies are effective against malignant tumors. However, they induce unique adverse events known as immune-related adverse events. Hypophysitis is one of the most frequent immune-related adverse events of anti-cytotoxic T-lymphocyte antigen-4 therapies. However, there have been few reports describing the pathological findings of hypophysitis induced by anti-programmed death-1 antibodies. The present case is the first autopsy case of hypophysitis induced by nivolumab monotherapy, an anti-programmed death-1 antibody. Pathologically, lymphocytes infiltrated the anterior lobe of the pituitary gland, and the number of pituitary cells, especially adrenocorticotropic hormone-positive cells, decreased. However, necrosis and remarkable fibrosis were not observed. Immunohistologically, some pituitary cells expressed programmed death-ligand 1. Lymphocytes were predominantly CD8-positive T cells, and CD68-positive macrophages and CD20-positive B-cells were also observed. IgG and C4d were deposited on pituitary cells, but IgG4 (a subclass of nivolumab) was not detected. These findings indicate that type IVc and type II hypersensitivity mechanisms may occur in hypophysitis induced by anti-programmed death-1 antibodies and that the inflammatory mechanisms underlying hypophysitis induced by anti-programmed death-1 and anti-cytotoxic T-lymphocyte antigen-4 antibodies are different.

Palliative care consultation in patients with Staphylococcus aureus bacteremia.

BACKGROUND: Palliative care consultation has shown benefits across a wide spectrum of diseases, but the utility in patients with Staphylococcus aureus bacteremia remains unclear despite its high mortality. AIM: To examine the frequency of palliative care consultation and factors associated with palliative care consult in Staphylococcus aureus bacteremia patients in the United States. DESIGN: A population-based retrospective analysis using the Nationwide Inpatient Sample database in 2014, compiled by the Healthcare Costs and Utilization Project of the Agency for Healthcare Research and Quality. SETTING/SUBJECTS: All inpatients with a discharge diagnosis of Staphylococcus aureus bacteremia (ICD-9-CM codes; 038.11 and 038.12). MEASUREMENTS: Palliative care consultation was identified using ICD-9-CM code V66.7. Patients' baseline characteristics and outcomes were compared between those with and without palliative care consult. RESULTS: A total of 111,320 Staphylococcus aureus bacteremia admissions were identified in 2014. Palliative care consult was observed in 8140 admissions (7.3%). Palliative care consultation was associated with advanced age, white race, comorbidities, higher income, teaching/urban hospitals, Midwest region, Methicillin-resistant Staphylococcus aureus bacteremia and the lack of echocardiogram. Palliative care consult was also associated with shorter but more expensive hospitalizations. Crude mortality was 53% (4314/8140) among admissions with palliative care consult and 8% (8357/10,3180) among those without palliative care consult (p < 0.001). CONCLUSIONS: Palliative care consultation was infrequent during the management of Staphylococcus aureus bacteremia, and a substantial number of patients died during their hospitalizations without palliative care consult. Given the reported benefit in other medical conditions, palliative care consultation may have a role in Staphylococcus aureus bacteremia. Selecting patients who may benefit the most should be explored.

First-in-human phase I study of JPH203, an L-type amino acid transporter 1 inhibitor, in patients with advanced solid tumors.

This open-label first-in-human study evaluated JPH203, which is a novel selective L-type amino acid transporter 1 inhibitor. We also evaluated the association between the N-acetyltransferase 2 phenotype and outcomes. Japanese patients with advanced solid tumors received daily intravenous JPH203 treatment for 7 days, followed by a 21-day rest period, at escalating doses of 12-85 mg/m2. Dose-limiting toxicities were evaluated during the first cycle using a 3 + 3 design. The study enrolled 17 patients, although grade 3 liver dysfunction was detected in one of six patients receiving 60 mg/m2 and in the first patient to receive 85 mg/m2. Further enrollment was terminated and the maximum tolerated dose was defined as 60 mg/m2. The AUC∞ increased between 12 mg/m2 and 25 mg/m2, although no differences were observed at 25-40 mg/m2. Partial response was observed for one patient with biliary tract cancer (BTC) at the 12 mg/m2 dose, and disease control was achieved by 3 of 6 patients at the 12 mg/m2 and 25 mg/m2 dose levels. Based on these results, we recommend a phase II dose of 25 mg/m2. The disease control rate for BTC was 60%. Two patients with grade 3 liver dysfunction had the rapid N-acetyltransferase 2 phenotype, and disease control was more common for the non-rapid phenotype (50% vs. 12.5%). It appears that JPH203 was well-tolerated and provided promising activity against BTC. The N-acetyltransferase 2 phenotype might help predict the safety and efficacy of JPH203. Clinical trial registration: UMIN000016546.

Conformational Restriction of Histamine with a Rigid Bicyclo[3.1.0]hexane Scaffold Provided Selective H3 Receptor Ligands.

We designed and synthesized conformationally rigid histamine analogues with a bicyclo[3.1.0]hexane scaffold. All the compounds were selectively bound to the H3 receptor subtype over the H4 receptor subtype. Notably, compound 7 showed potent binding affinity and over 100-fold selectivity for the H3 receptors (Ki = 5.6 nM for H3 and 602 nM for H4). These results suggest that the conformationally rigid bicyclo[3.1.0]hexane structure can be a useful scaffold for developing potent ligands selective for the target biomolecules.

Increased CD40L+PD-1+ follicular helper T cells (Tfh) as a biomarker for predicting calcineurin inhibitor sensitivity against Tfh-mediated B-cell activation/antibody production after kidney transplantation.

It is unclear to what extent the development of follicular helper T cells (Tfh) and de novo donor-specific human leukocyte antigen antibody (DSA) production could be influenced by immunosuppressive agents, particularly calcineurin inhibitor (CNI; cyclosporine or tacrolimus), after kidney transplantation. Here, the effects of immunosuppressive agents on Tfh-mediated B-cell activation and antibody production were investigated. In vitro circulating Tfh (cTfh; memory CD4+CXCR5+)/B-cell (CD19+) co-culture assays revealed that CNI considerably inhibited cTfh-mediated B-cell activation and IgG antibody secretion through the suppression of IL-21 and IL-2. Both IL-21 and CD40L up-regulated IL-2 receptors (CD25) on B cells, and anti-CD25 antibody induced apoptosis of activated B cells, resulting in the inhibition of IgG production. The frequency of cTfh-expressed CD40L and PD-1 was elevated in patients with de novo DSA 1 year after transplantation. The degree of inhibition by CNI was dependent on Staphylococcal enterotoxin B-induced CD40L+PD-1+ cTfh up-regulation level. Our data demonstrate that CD40L+PD-1+cTfh could be a marker to implicate individual difference in CNI sensitivity for Tfh-mediated B-cell activation in kidney transplantation.

Anal Cancer Precursor Lesions in HIV-Infected Persons: Tissue Human Papillomavirus Type Distribution and Impact on Treatment Response.

BACKGROUND: Data on tissue distribution of human papillomavirus types in anal high-grade squamous intraepithelial lesions are limited and the impact on treatment outcomes poorly understood. OBJECTIVE: We aimed to investigate potential predictors of treatment failure after electrocautery ablation, including human papillomavirus type(s) isolated from index lesions. DESIGN: This was a retrospective cohort study. SETTINGS: The study was conducted at a tertiary academic referral center in New York City. PATIENTS: Seventy-nine HIV-infected patients with a diagnosis of anal high-grade squamous intraepithelial lesions between January 2009 and December 2012 were included, and genomic DNA was extracted from biopsy tissue. MAIN OUTCOME MEASURES: The prevalence of human papillomavirus types in index lesions and surveillance biopsies after electrocautery ablation were analyzed to evaluate treatment response. RESULTS: Of 79 anal high-grade squamous intraepithelial lesions, 71 (90%) tested positive for ≥1 human papillomavirus type; 8 (10%) had no human papillomavirus detected. The most common type was 16 (39%), followed by 33 (15%). Human papillomavirus type 18 was seen in 3%. Sixty-one patients (77%) underwent electrocautery ablation and had subsequent surveillance biopsies. Surveillance biopsies yielded benign findings or low-grade squamous intraepithelial lesions in 31 (51%) of 61 and recurrent high-grade squamous intraepithelial lesions in 30 (49%) of 61 patients (mean follow-up: 35 mo). Ablation response did not differ significantly based on baseline demographics, smoking history, history of anogenital warts, mean CD4 T-cell count, antiretroviral-therapy use, and HIV viral load (<50 copies/mL). The recurrence of high-grade lesions was not significantly associated with high-risk human papillomavirus types detected in index lesions. LIMITATIONS: Human papillomavirus genotyping in surveillance biopsies was not performed. CONCLUSIONS: Anal high-grade squamous intraepithelial lesions in HIV-infected patients contain a wide range of human papillomavirus types, and individual lesions commonly harbor multiple types concomitantly. Recurrence of anal high-grade squamous intraepithelial lesions after electrocautery ablation occurs frequently and is not affected by high-risk human papillomavirus types. See Video Abstract at http://links.lww.com/DCR/A833.

Suppressive Effect of Everolimus on IL-2, IL-10, IL-21, and IFNγ Levels: Implications for the Successful Minimization of Calcineurin Inhibitor Use in Transplantation.

BACKGROUND: Success with calcineurin inhibitors (CNIs) such as cyclosporine A (CSA) and tacrolimus (TAC) in organ transplantation has demonstrated that cytokine suppression is a key factor in patient management. However, the exact effects of recently introduced immunosuppressive agents other than CNI on cytokine expression remain unknown. In this study, the action of the mTOR-inhibitor everolimus (EVR) and that of the antimetabolite mycophenolic acid (MPA) on the transcription of several cytokines was investigated. METHODS: Peripheral blood mononuclear cells obtained from healthy volunteers were stimulated with anti-CD3/28 microbeads in the presence of CSA, TAC, EVR, and/or MPA for 8 hours. The mRNA levels of each cytokine were measured using quantitative real-time polymerase chain reaction. RESULTS: MPA had no inhibitory effect on any of the cytokines tested. EVR showed moderate inhibition of IL-2, IL-10, IL-21, and IFNγ levels. These cytokines were further analyzed to investigate the additive effect of EVR in combination with CNI. The beneficial effect of EVR addition was seen at low concentrations of CSA or TAC, while no additive effect was observed at high concentrations. CONCLUSIONS: EVR might effectively inhibit the activation of recipient immune cells in combination with a low dose of CNI, maximizing clinical benefit by preventing graft rejection and alleviating CNI-induced adverse effects.

Design and synthesis of cyclopropane-based conformationally restricted GABA analogues as selective inhibitors for betaine/GABA transporter 1.

We previously designed and synthesized a series of cyclopropane-based conformationally restricted analogues of γ-aminobutyric acid (GABA). The study demonstrated that the critical conformation of the analogues that selectively active to betaine/GABA transporter 1 (BGT1) subtype is the trans-syn-form, in which the amino and carboxyl groups are in trans-configuration and the cyclopropane ring and the carboxyl group are in syn-arrangement. In this study, we designed and synthesized cyclopropane-based GABA analogues, which were conformationally restricted in the trans-syn-form by cyclopropylic strain based on the stereochemistry of the carbon adjacent to cyclopropane. Their conformation was confirmed as the syn-form by calculations and NMR studies, and their pharmacological evaluation clarified that compounds 11a and 11d had the BGT1 selectivity, although their inhibitory effects were insufficient.

Design and synthesis of histamine H3/H4 receptor ligands with a cyclopropane scaffold.

We previously designed and synthesized a series of histamine analogues with an imidazolylcyclopropane scaffold and identified potent non-selective antagonists for histamine H3 and H4 receptor subtypes. In this study, to develop H4 selective ligands, we newly designed and synthesized cyclopropane-based derivatives having an indole, benzimidazole, or piperazine structure, which are components of representative H4 selective antagonists such as JNJ7777120 and JNJ10191584. Among the synthesized derivatives, imidazolylcyclopropanes 12 and 13 conjugated with a benzimidazole showed binding affinity to the H3 and H4 receptors comparable to that of a well-known non-selective H3/H4 antagonist, thioperamide. These results suggest that the binding modes of the cyclopropane-based H3/H4 ligands in the H4 receptor can be different from those of the indole/benzimidazole-piperazine derivatives.