Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection among Kidney Transplant Recipients: A Large Single-Center Experience.

Background: Kidney transplant recipients (KTRs) are a vulnerable immunocompromised population at risk of severe COVID-19 disease and mortality after SARS-CoV-2 infection. We sought to characterize the post-infection sequelae in KTRs at our center. Methods: We studied all adult KTRs (with a functioning allograft) who had their first episode of SARS-CoV-2 infection between 04/2020 and 04/2022. Outcomes of interest included risk factors for hospitalization, all-cause mortality, COVID-19-related mortality, and allograft failure. Results: Of 979 KTRs with SARS-CoV-2 infection, 381 (39%) were hospitalized. In the multivariate analysis, risk factors for hospitalization included advanced age/year (HR: 1.03, 95% CI: 1.02-1.04), male sex (HR: 1.29, 95% CI: 1.04-1.60), non-white race (HR: 1.48, 95% CI: 1.17-1.88), and diabetes as a cause of ESKD (HR: 1.77, 95% CI: 1.41-2.21). SARS-CoV-2 Vaccination was associated with decreased risk of hospitalization (HR: 0.73, 95% CI: 0.59-0.90), all-cause mortality (HR: 0.52, 95% CI: 0.37-0.74), and COVID-19-related mortality (HR: 0.47, 95% CI: 0.31-0.71) in the univariate and multivariate analyses. Risk factors for both all-cause and COVID-19-related mortality in the multivariate analyses included advanced age, hospitalization, and respiratory symptoms for hospital admission. Furthermore, additional risk factors for all-cause mortality in the multivariate analysis included being a non-white recipient and diabetes as a cause of ESKD, with being a recipient of a living donor as protective. Conclusions: Hospitalization due to COVID-19-associated symptoms is associated with increased mortality. Vaccination is a protective factor against hospitalization and mortality.

Resource Use and Financial Impact of Oral Step-Down Therapy for Resistant Cytomegalovirus in Solid Organ Transplant Recipients.

BACKGROUND: Cytomegalovirus (CMV) infections are common opportunistic infections in solid organ transplants (SOT) with increased health care resource USE and costs. Costs are further increased with ganciclovir-resistance (GR). This study aimed to evaluate the real-world impact of conversion to oral step-down therapy on duration of foscarnet and hospital length of stay (LOS) for treatment of GR-CMV infections in SOT. METHODS: This study included adult recipients of kidney or lung transplants who received foscarnet for genotypically documented GR-CMV while admitted at the University of Wisconsin Hospital from October 1, 2015, to January 31, 2022. Patients in the oral step-down group were converted from standard of care (SOC; foscarnet) to maribavir or letermovir; patients in the historical control group were treated with SOC. RESULTS: Twenty-six patients met the inclusion criteria: 5 in the intervention group and 21 in the SOC group. The median viral load at foscarnet initiation was 11,435 IU/mL. Patients who received oral step-down conversion had shorter mean foscarnet duration than those who received SOC (7 ± 4 vs 37 ± 25 days, P = .017). Mean hospital LOS in the oral step-down group (16 ± 3 days) was shorter than the SOC group (33 ± 21 days; P < .001). In the SOC group, 9 patients lost their graft, and 9 patients died; 2 deaths were attributed to CMV. There were 2 deaths in the oral step-down group, neither of which was attributed to CMV. CONCLUSION AND RELEVANCE: In this real-world case series of patients receiving treatment for GR-CMV infection, oral step-down conversion decreased foscarnet therapy duration and hospital LOS. Future studies are needed to evaluate better the effect of oral step-down in treating GR-CMV infection on treatment duration and cost-savings.

Histopathological Features and Role of Allograft Kidney Biopsy Among Recipients With Prolonged Delayed Graft Function: A Review.

Delayed graft function (DGF) is an early posttransplant complication predictive of adverse outcomes. This "acute kidney injury of transplantation" is often defined as allograft dysfunction requiring renal replacement within 7 d posttransplantation. DGF is an important area of study because it is emerging with efforts to expand the donor pool and address the supply-demand gap in kidney transplantation. DGF is often caused by severe kidney injury mechanisms because of multiple donors, recipients, and immunologic factors. The role of kidney biopsy, particularly in prolonged DGF, is an ongoing area of research and inquiry for clinicians and researchers alike to better define, manage, and predict outcomes of this early posttransplant event. This review aims to provide an in-depth, comprehensive summary of the literature to date on the histopathology of DGF and the role of kidney transplant biopsies in prolonged DGF.

Evaluating the impact of a blended interprofessional education course on students' attitudes towards interprofessional education: a pre-post study.

BACKGROUND: Since 2011, five educational and healthcare institutions have implemented a short interprofessional education (IPE) course to bring together undergraduates from five disciplines. To meet the logistical challenges of IPE implementation, more specifically, the large number of classrooms needed to gather students together and the need for human resources to guide learning activities, a face-to-face IPE course was redesigned into a blended (online and face-to-face collaborative learning activities) IPE course. In March 2023, 183 medical, 378 nursing, 46 radiologic technology, 69 physiotherapy, and 74 occupational therapy students participated in a one-day IPE blended course to learn interprofessional team functioning and dynamics, role clarification and responsibilities of other professions, and interprofessional communication skills. This study aimed to assess students' changes in attitudes towards IPE after being involved in a large-scale interprofessional blended learning course. METHODS: A before-after study was conducted using a French translation of the validated questionnaire "University of West of England Interprofessional Questionnaire" (UWE-IP questionnaire). Students' attitudes towards interprofessional (IP) relationships and IP learning were measured before and after the course. In March 2023, two hundred fifty-six students from five professions answered two subscales of the UWE-IP questionnaire before and after the course (response rate 34%). RESULTS: Students' attitudes towards IP relationships improved significantly after the course. The score on this subscale (min 8; max 24) changed from 11.18 (SD 2,67) before the course to 10,38 (SD 2,55) after the course, indicating a significant improvement in attitudes towards IP relationships (p < 0,001). More specifically, students had more positive attitudes on the item "I have a good understanding of the roles of different health and social care professionals." and the item "I feel that I am respected by people from other health and social care disciplines." after the course. A positive change in students' attitudes towards IP learning was observed, but the results were not significative. CONCLUSION: A face-to-face IPE course redesigned as a blended course helped overcome existing challenges to implementing an IPE course. The results suggest a blended IPE course improves students' attitudes towards interprofessionality.

[Written action plans for asthma control: How are they used by pulmonologists in France?] / Les plans d'action écrits pour l'asthme : quel usage en font les pneumologues en France ?

INTRODUCTION: Despite evidence of the benefits of the written asthma action plans (WAP) in asthma control, they remain poorly applied. The aim of our study was to assess the practices of French-speaking pulmonologists and paediatricians in their use of WAP for asthma control and to analyse the contents of several WAPs routinely consulted in treatment of asthma patients. METHODS: Members of three French medical societies (SPLF, G2A, SP2A) were requested to share their WAPs for asthma patients and to participate in an online survey about the possible influence of these documents on their practices. RESULTS: Most (95%) of the 41 WAPs taken into consideration were symptom-based and 34% included peak expiratory flow measurement. All of these action plans were in full compliance with current guidelines. Among the 110 survey respondents, while 65% systematically provided a WAP to their asthma patients, only 30% often or always supplemented the written document with therapeutic education sessions. In almost every case, it was the doctor who presented the WAP to the patient, generally devoting to less than 10minutes to explanation of what they were handing out. CONCLUSIONS: In France, WAPs are generally presented to the patient by the physician, which probably limits the time devoted to explanation of their contents. Furthermore, WAPs are rarely reinforced with therapeutic education. The current study suggests ways of improving the utilization of WAPs in asthma care and treatment.

Impact of pectus excavatum on pulmonary function and exercise capacity in patients treated with 3D custom-made silicone implants.

BACKGROUND: Pectus excavatum (PE) is the most common congenital chest wall deformity, whose cardiopulmonary consequences are controversial. PE surgery is in our experience usually performed for aesthetic reasons. OBJECTIVES: The aim of this study was to evaluate the impact of PE on respiratory function and exercise capacity in patients with PE before patient-specific silicone implant correction. METHODS: This monocentric prospective study conducted at Toulouse University Hospital included sixty patients scheduled for custom-made silicone implants correction. Respiratory function (pulmonary function tests (FPTs)) and exercise capacity (VO2 max) were measured before surgery. RESULTS: Before surgery, no (0/60) restrictive lung disease was detected, with a mean total lung capacity (TLC) of 98.5% of predicted value (IC 95%; 80.4-137). Median VO2 max (n=56) was normal (89% predicted), with no cardiac limitation. CONCLUSION: In this cohort, PE had no impact on respiratory function nor exercise capacity. In patients without cardiac or respiratory effects of PE, silicone implants should be considered the preferred approach as it adequately addressed patients' main complaint of low self-esteem.

Incidence and outcomes of fever of unknown origin after kidney transplant in the modern era.

BACKGROUND: While presumably less common with modern molecular diagnostic and imaging techniques, fever of unknown origin (FUO) remains a challenge in kidney transplant recipients (KTRs). Additionally, the impact of FUO on patient and graft survival is poorly described. METHODS: A cohort of adult KTRs between January 1, 1995 and December 31, 2018 was followed at the University of Wisconsin Hospital. Patients transplanted from January 1, 1995 to December 31, 2005 were included in the "early era"; patients transplanted from January 1, 2006 to December 31, 2018 were included in the "modern era". The primary objective was to describe the epidemiology and etiology of FUO diagnoses over time. Secondary outcomes included rejection, graft and patient survival. RESULTS: There were 5590 kidney transplants at our center during the study window. FUO was identified in 323 patients with an overall incidence rate of .8/100 person-years. Considering only the first 3 years after transplant, the incidence of FUO was significantly lower in the modern era than in the early era, with an Incidence Rate Ratio (IRR) per 100 person-years of .48; 95% CI: .35-.63; p < .001. A total of 102 (31.9%) of 323 patients had an etiology determined within 90 days after FUO diagnosis: 100 were infectious, and two were malignancies. In the modern era, FUO remained significantly associated with rejection (HR = 44.1; 95% CI: 16.6-102; p < .001) but not graft failure (HR = 1.21; 95% CI: .68-2.18; p = .52) total graft loss (HR = 1.17; 95% CI: .85-1.62; p = .34), or death (HR = 1.17; 95% CI: .79-1.76; p = .43. CONCLUSIONS: FUO is less common in KTRs during the modern era. Our study suggests infection remains the most common etiology. FUO remains associated with significant increases in risk of rejection, warranting further inquiry into the management of immunosuppressive medications in SOT recipients in the setting of FUO.

Temporal trends in kidney paired donation in the United States: 2006-2021 UNOS/OPTN database analysis.

Kidney paired donation (KPD) is a major innovation that is changing the landscape of kidney transplantation in the United States. We used the 2006-2021 United Network for Organ Sharing data to examine trends over time. KPD is increasing, with 1 in 5 living donor kidney transplants (LDKTs) in 2021 facilitated by KPD. The proportion of LDKT performed via KPD was comparable for non-Whites and Whites. An increasing proportion of KPD transplants are going to non-Whites. End-chain recipients are not identified in the database. To what extent these trends reflect how end-chain kidneys are allocated, as opposed to increase in living donation among minorities, remains unclear. Half the LDKT in 2021 in sensitized (panel reactive antibody ≥ 80%) and highly sensitized (panel reactive antibody ≥ 98%) groups occurred via KPD. Yet, the proportion of KPD transplants performed in sensitized recipients has declined since 2013, likely due to changes in the deceased donor allocation policies and newer KPD strategies such as compatible KPD. In 2021, 40% of the programs reported not performing any KPD transplants. Our study highlights the need for understanding barriers to pursuing and expanding KPD at the center level and the need for more detailed and accurate data collection at the national level.

Potassium-lowering effects of sodium zirconium cyclosilicate in the early post-transplant period.

PROBLEM: Hyperkalemia is a serious condition among intra-abdominal transplant recipients, and the safety and efficacy of sodium zirconium cyclosilicate (SZC) for its management during the early post-transplant period are not well-established. METHODS: Adults who received at least one 10-g dose of SZC within 14 days after an intra-abdominal transplant between January 2020 and July 2022 were included in our study. The primary outcome was the change in potassium (K+) levels following the first SZC dose. Other analyses explored adjunctive potassium-lowering therapies, potential gastrointestinal complications, and patient subgroups based on therapy and transplant type. RESULTS: Among the recipients (n = 46), 11 were kidney recipients, 26 were liver recipients, seven were simultaneous liver/kidney recipients, and two were simultaneous pancreas/kidney recipients. The mean time to first dose post-transplant was 7.6 (±4) days, and the mean change in serum K+ after the initial SZC dose was -.27 mEq (p = .001). No gastrointestinal complications were observed following the SZC dose. The mean increase in serum bicarbonate was .58 mEq (p = .41) following the first dose of SZC. Four kidney recipients required dialysis following the SZC dose. CONCLUSION: This study represents the largest investigation on the use of SZC in transplant recipients. A single 10-g dose of SZC reduced serum K+ levels in all subgroups, while the use of adjunctive K+-lowering therapies did not provide additional reduction beyond the effects of SZC. Importantly, no gastrointestinal complications were observed. These findings suggest that SZC may be a safe and promising therapeutic option for hyperkalemia management following solid organ transplantation.

Mechanistic Analysis of Bioorthogonal Double Strain-Promoted Alkyne-Nitrone Cycloadditions Involving Dibenzocyclooctadiyne.

The reactions of nitrones with cyclooctadiynes were studied to establish the relative rates of sequential reactions and to determine the limits and scope of this bioorthogonal chemistry. We have established the second-order rate constants for the consecutive additions of a variety of nitrones onto diyne and studied the structure-activity relationships via Hammett plots. Results show that the addition of the second nitrone to the monointermediate occurs significantly faster than the first, with both reactions being faster than analogous reactions with azides. Computational chemistry supports these observations. The rate of second addition increases with electron-deficient nitrones, as demonstrated by a large rho value of 2.08, suggesting that the reaction rate can be controlled by nitrone selectivity. To further investigate the kinetic parameters of the reaction, dinitrone monomers containing cyclic and diaryl-nitrones were designed for use in oligomerization applications. Oligomerization was used as a probe to test the limits of the reactivity and attempt to isolate monocycloaddition products. The oligomer formed from a cyclic nitrone reacts faster, and detailed MALDI mass spectrometry analysis shows that monoaddition products exist only transiently and are not isolatable. These studies inform on the scope and limits of this chemistry in a variety of applications. We successfully demonstrated bacterial cell wall labeling using heterogeneous dual cycloadditions involving nitrone and azide dipoles, where the nitrone was the faster reacting partner on the bacterial cell surface.

Real-World Experience With CMV inSIGHT T Cell Immunity Testing in High-Risk Kidney and Pancreas Transplant Recipients.

BACKGROUND: Cytomegalovirus (CMV)-specific cell-mediated immunity is important for control of CMV after transplant. Assays exist to measure this, but their place in therapy is unclear, particularly in CMV high-risk recipients, without pretransplant exposure. OBJECTIVE: The objective of this study was to evaluate predictive potential of a positive assay to determine freedom from DNAemia and describe subsequent 3-month CMV outcomes. METHODS: Adult CMV high-risk kidney and/or pancreas transplant recipients were included if a CMV inSIGHT T Cell Immunity Panel (TCIP, Eurofins Viracor) was ordered and resulted between 1 August, 2019 and 30 July, 2022. RESULTS: Seventy-six patients were included in our study; 49 tested during prophylaxis and 27 during treatment. Most TCIP assays obtained in the prophylaxis cohort were negative (n = 46, 93.9%). Rate of post-TCIP CMV infection was 10.2%. In those tested during treatment, 33.3% were positive and rate of post-TCIP CMV recurrence was 22.2%. The positive predictive value of the assay to successfully predict immunity was 66.7% during both prophylaxis and treatment. There were 4 cases of TCIP predictive failure with progressive CMV replication. At time of replication, 2 patients had concomitant clinical confounders thought to influence immune control of viral replication. All patients had intensification of immunosuppression prior to recurrent replication, but after TCIP was collected. CONCLUSION AND RELEVANCE: The data obtained from the TCIP are not static, immune control of CMV in latency can change and must be evaluated in clinical context. Timing of TCIP after transplant is significant, and patient-specific factors remain important to assess the likelihood of CMV in each unique patient-specific scenario. A CMV stewardship program can aid in application and interpretation of results.

Real world experience with conversion from valganciclovir to letermovir for cytomegalovirus prophylaxis: Letermovir reverses leukopenia and avoids mycophenolate dose reduction.

PURPOSE: Valganciclovir (VGC) is the gold-standard for cytomegalovirus (CMV) prophylaxis (PPX) after solid organ transplant (SOT). Letermovir (LTV) was recently approved in high-risk kidney transplant and has reduced myelosuppressive toxicity. Conversion from VGC to LTV may be pursued in the setting of leukopenia. It is unknown if this strategy is effective. METHODS: Adult patients receiving abdominal SOT were included if converted from VGC to LTV between January 1, 2018 and January 31, 2023. Primary objective was to describe the impact of LTV conversion as measured by WBC recovery, mycophenolate modification, and use of GCSF, and prophylaxis efficacy assessed by course completion and breakthrough DNAemia. Secondary objective was to evaluate rates of post-prophylaxis CMV. RESULTS: Seventy five SOT recipients met inclusion criteria. Mean change in WBC in response to LTV conversion by day 14 was +2.02 ± 2.52 k/uL. 75%(56/75) of the population did not require mycophenolate adjustment or had their dose increased after conversion. GCSF was required in 38.7%(29/75) prior to conversion; only 21.3%(16/75) of patients required GCSF after conversion. Early termination was uncommon, 14.7%(11/75) stopped due to lack of ongoing insurance approval, only one patient stopped due to adverse effects (1.3%). One patient had clinically significant breakthrough (1.3%) that was successfully managed with VGC. Incidence of post prophylaxis CMV was 40%. CONCLUSION: Withholding of VGC with LTV conversion may improve leukopenia without need for additional supportive measures. Most importantly, this strategy avoided additional mycophenolate modifications. In our study, LTV was associated with low rates of breakthrough. Post-prophylaxis CMV was similar to VGC prophylaxis.

Sodium-glucose cotransporter-2 inhibitor use in kidney transplant recipients.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are novel oral hypoglycemic agents garnering much attention for their substantial benefits. These recent data have positioned SGLT2i at the forefront of diabetic chronic kidney disease (CKD) and heart failure management. SGLT2i use post-kidney transplant is an emerging area of research. Highlights from this mini review include the following: Empagliflozin is the most prescribed SGLT2i in kidney transplant recipients (KTRs), median time from transplant to initiation was 3 years (range: 0.88-9.6 years). Median baseline estimated glomerular filtration rate (eGFR) was 66.7 mL/min/1.73 m2 (range: 50.4-75.8). Median glycohemoglobin (HgbA1c) at initiation was 7.7% (range: 6.9-9.3). SGLT2i were demonstrated to be effective short-term impacting HgbA1c, eGFR, hemoglobin/hematocrit, serum uric acid, and serum magnesium levels. They are shown to be safe in KTRs with low rates of infections, hypoglycemia, euglycemic diabetic ketoacidosis, and stable tacrolimus levels. More data is needed to demonstrate long-term outcomes. SGLT2i appear to be safe, effective medications for select KTRs. Our present literature, though limited, is founded on precedent robust research in CKD patients with diabetes. Concurrent research/utilization of SGLT2i is vital to not only identify long-term patient, graft and cardiovascular outcomes of these agents, but also to augment management in KTRs.

Evaluation of a

We report on an evaluation of an optical clock that uses the ^{2}S_{1/2}→^{2}D_{5/2} transition of a single ^{88}Sr^{+} ion as the reference. In contrast to previous work, we estimate the effective temperature of the blackbody radiation that shifts the reference transition directly during operation from the corresponding frequency shift and the well-characterized sensitivity to thermal radiation. We measure the clock output frequency against an independent ^{171}Yb^{+} ion clock, based on the ^{2}S_{1/2}(F=0)→^{2}F_{7/2}(F=3) electric octupole (E3) transition, and determine the frequency ratio with a total fractional uncertainty of 2.3×10^{-17}. Relying on a previous measurement of the ^{171}Yb^{+} (E3) clock frequency, we find the absolute frequency of the ^{88}Sr^{+} clock transition to be 444 779 044 095 485.277(59) Hz. Our result reduces the uncertainty by a factor of 3 compared with the previously most accurate measurement and may help to resolve so far inconsistent determinations of this value. We also show that for three simultaneously interrogated ^{88}Sr^{+} ions, the increased number causes the expected improvement of the short-term frequency instability of the optical clock without degrading its systematic uncertainty.

A Randomized Controlled Trial of Envarsus Versus Immediate Release Tacrolimus in Kidney Transplant Recipients With Delayed Graft Function.

BACKGROUND: The incidence of delayed graft function (DGF) among kidney transplant recipients (KTRs) in the United States continues to increase. The effect of immediate-release tacrolimus (tacrolimus) compared with extended-release tacrolimus (Envarsus) among recipients with DGF is unknown. METHODS: This was a single-center open-label randomized control trial among KTRs with DGF (ClinicalTrials. gov, NCT03864926). KTRs were randomized either to continue on tacrolimus or switch to Envarsus at a 1:1 ratio. Duration of DGF (study period), number of dialysis treatments, and need for adjustment of calcineurin inhibitor (CNI) doses during the study period were outcomes of interest. RESULTS: A total of 100 KTRs were enrolled, 50 in the Envarsus arm and 50 in the tacrolimus arm; of those, 49 in the Envarsus arm and 48 in the tacrolimus arm were included for analysis. There were no differences in the baseline characteristics, all P > .5, except donors in the Envarsus arm had higher body mass index (mean body mass index 32.9 ± 11.3 vs 29.4 ± 7.6 kg/m2 [P = .007]) compared with the tacrolimus arm. The median duration of DGF (5 days vs 4 days, P = .71) and the number of dialysis treatments (2 vs 2, P = .83) were similar between the groups. However, the median number of CNI dose adjustments during the study period in the Envarsus group was significantly lower (3 vs 4, P = .002). CONCLUSIONS: Envarsus patients had less fluctuation in the CNI level, requiring fewer CNI dose adjustments. However, there were no differences in the DGF recovery duration or number of dialysis treatments.

Somatosensory tinnitus and temporomandibular disorders: A common association.

BACKGROUND: Although the association between tinnitus and temporo-mandibular disorders (TMD) has been frequently reported, their rate of association in the literature shows a great variability. OBJECTIVE: We aimed to investigate the prevalence of TMD in patients with somatosensory tinnitus and, vice versa, the occurrence of somatosensory tinnitus in patients with TMD. METHODS: The study included patients with somatosensory tinnitus (audiological group) and patients with TMD (stomatological group), evaluated at the audiologic and stomatologic clinics of the Policlinic Hospital of Milan, Italy. Common causes of tinnitus, such as hearing and neurological disorders, were excluded. A cervicogenic somatic tinnitus was also ruled out. Different TMD symptoms, including joint noise and joint pain, were considered. The collected data were analysed using descriptive statistical methods, and the Pearson's Chi-squared test was performed to study the prevalence of the different symptoms by clinical groups. RESULTS: Audiological group included 47 patients with somatosensory tinnitus. Overall, TMD was diagnosed in 46 patients (97.8%), including TMJ noise in 37 (78.7%), clenching in 41 (87.2%) and pain in 7 (14.8%) patients. Stomatological group included 50 patients with TMD, including joint noise in 32 (64.0%), clenching in 28 (56.0%) and TMJ pain in 42 (84.0%) patients. A somatosensory tinnitus was diagnosed in 12 (24.0%) patients. CONCLUSION: Our study showed a high prevalence of TMD in patients with tinnitus, as well as a not uncommon occurrence of tinnitus in patients presenting with TMD. The distribution of TMD symptoms, such as joint noise, and joint pain was different between the two groups.

An unnatural enzyme with endonuclease activity towards small non-coding RNAs.

Endonucleases are enzymes that cleave internal phosphodiester bonds within double-stranded DNA or RNA and are essential for biological functions. Herein, we use genetic code expansion to create an unnatural endonuclease that cleaves non-coding RNAs including short interfering RNA (siRNA) and microRNAs (miRNAs), a function that does not exist in nature. We introduce a metal-chelating unnatural amino acid, (2,2'-bipyridin-5-yl)alanine (BpyAla) to impart endonuclease activity to the viral suppressor of RNA silencing protein p19. Upon binding of copper, the mutant p19-T111BpyAla displays catalytic site-specific cleavage of siRNA and human miRNAs. Catalysis is confirmed using fluorescence polarization and fluorescence turn-on. Global miRNA profiling reveals that the engineered enzyme cleaves miRNAs in a human cell line. The therapeutic potential is demonstrated by targeting miR-122, a critical host factor for the hepatitis C virus (HCV). Unnatural endonuclease function is shown to deplete miR-122 levels with similar effects to an antagomir that reduces HCV levels therapeutically.