Time-resolved fate mapping identifies the intestinal upper crypt zone as an origin of Lgr5+ crypt base columnar cells.

In the prevailing model, Lgr5+ cells are the only intestinal stem cells (ISCs) that sustain homeostatic epithelial regeneration by upward migration of progeny through elusive upper crypt transit-amplifying (TA) intermediates. Here, we identify a proliferative upper crypt population marked by Fgfbp1, in the location of putative TA cells, that is transcriptionally distinct from Lgr5+ cells. Using a kinetic reporter for time-resolved fate mapping and Fgfbp1-CreERT2 lineage tracing, we establish that Fgfbp1+ cells are multi-potent and give rise to Lgr5+ cells, consistent with their ISC function. Fgfbp1+ cells also sustain epithelial regeneration following Lgr5+ cell depletion. We demonstrate that FGFBP1, produced by the upper crypt cells, is an essential factor for crypt proliferation and epithelial homeostasis. Our findings support a model in which tissue regeneration originates from upper crypt Fgfbp1+ cells that generate progeny propagating bi-directionally along the crypt-villus axis and serve as a source of Lgr5+ cells in the crypt base.

Estimating the benefits of stream water quality improvements in urbanizing watersheds: An ecological production function approach.

Streams in urbanizing watersheds are threatened by economic development that can lead to excessive sediment erosion and surface runoff. These anthropogenic stressors diminish valuable ecosystem services and result in pervasive degradation commonly referred to as "urban stream syndrome." Understanding how the public perceives and values improvements in stream conditions is necessary to support efforts to quantify the economic benefits of water quality improvements. We develop an ecological production framework that translates measurable indicators of stream water quality into ecological endpoints. Our interdisciplinary approach integrates a predictive hierarchical water quality model that is well suited for sparse data environments, an expert elicitation that translates measurable water quality indicators into ecological endpoints that focus group participants identified as most relevant, and a stated preference survey that elicits the public's willingness to pay for changes in these endpoints. To illustrate our methods, we develop an application to the Upper Neuse River Watershed located in the rapidly developing Triangle region of North Carolina (the United States). Our results suggest, for example, that residents are willing to pay roughly $127 per household and $54 million per year in aggregate (2021 US$) for water quality improvements resulting from a stylized intervention that increases stream bank canopy cover by 25% and decreases runoff from impervious surfaces, leading to improvements in water quality and ecological endpoints for local streams. Although the three components of our analysis are conducted with data from North Carolina, we discuss how our findings are generalizable to urban and urbanizing areas across the larger Piedmont ecoregion of the Eastern United States.

Adjusting for race in metrics of organ procurement organization performance.

The Scientific Registry of Transplant Recipients has previously reported the effects of adjusting for demographic variables, including race, in the Centers for Medicare & Medicaid Services (CMS) organ procurement organization (OPO) performance metrics: donation rate and transplant rate. CMS chose not to adjust for most demographic variables other than age (for the transplant rate), arguing that there is no biological reason that these variables would affect the organ donation/utilization decision. However, organ donation is a process based on altruism and trust, not a simple biological phenomenon. Focusing only on biological impacts on health ignores other pathways through which demographic factors can influence OPO outcomes. In this study, we update analyses of demographic adjustment on the OPO metrics for 2020 with a specific focus on adjusting for race. We find that adjusting for race would lead to 8 OPOs changing their CMS tier rankings, including 2 OPOs that actually overperform the national rate among non-White donors improving from a tier 3 ranking (facing decertification without possibility of recompeting) to a tier 2 ranking (allowing the possibility of recompeting). Incorporation of stratified and risk-adjusted metrics in public reporting of OPO performance could help OPOs identify areas for improvement within specific demographic categories.

OPTN/SRTR 2022 Annual Data Report: Pancreas.

The postpandemic recovery did not occur in pancreas transplantation as in other organs. The number of pancreas transplants in the United States decreased to 918 in 2022 from 963 in 2021. The number of simultaneous pancreas-kidney transplants decreased to 810 in 2022 from 820 in 2021, but the largest decrease was in pancreas transplant alone: 62 in 2022 compared with 92 in 2021. Pancreas-after-kidney transplants decreased to 46 in 2022 from 51 in 2021. The trend of increasing proportions of pancreas transplants in patients with type 2 diabetes seen over the past few years ended in 2022; there were 22.4% of such transplants in 2022 compared with 25.8% in 2021. The proportion of recipients older than 45 years decreased in 2022 as well. However, the proportions of candidates with type 2 diabetes and older candidates on the waiting list did not decrease. The number of pancreas donors decreased and the pancreas nonuse rate increased in 2022. Outcomes after pancreas transplant continued to improve, with an impressive 8.1% pancreas and 4.3% kidney graft failure rate for simultaneous pancreas-kidney transplant at 1 year in 2022. The proportion of pancreas transplants performed by medium-volume centers (11-24 transplants/year) returned to 37.2% in 2022 from a high of 48.3% in 2021, whereas the proportion of those done by large-volume centers (25 or more transplants/year) returned to 25.3% in 2022 from a low of 15.9% in 2021.

OPTN/SRTR 2022 Annual Data Report: Deceased Organ Donation.

The Scientific Registry of Transplant Recipients uses data collected by the Organ Procurement and Transplantation Network to calculate metrics such as organs recovered per donor, organs transplanted per donor, and organs recovered for transplant but not transplanted (ie, nonuse). In 2022, there were 14,905 deceased donors, a 7.5% increase from 13,863 in 2021, and this number has been increasing since 2010. The number of deceased donor organs used for transplant increased to 37,334 in 2022, a 4.6% increase from 35,687 in 2021; this number has been increasing since 2012. The increase may be due in part to the rising number of deaths of young people amid the ongoing opioid epidemic. The number of organs transplanted included 10,130 left kidneys, 10,039 right kidneys, 298 en bloc kidneys, 922 pancreata, 8,847 livers, 83 intestines, 4,169 hearts, and 2,633 lungs. Compared with 2021, transplants of all organs except pancreata and intestines increased in 2022. In 2022, 3,563 left kidneys, 3,673 right kidneys, 156 en bloc kidneys, 366 pancreata, 965 livers, 4 intestines, 54 hearts, and 219 lungs were not used. These data suggest an opportunity to increase the number of transplants by reducing the number of unused organs. Despite the COVID-19 pandemic, there was no dramatic increase in the number of unused organs and there was an increase in the total numbers of donors and transplants.

OPTN/SRTR 2022 Annual Data Report: Vascularized Composite Allograft.

This year's chapter on vascularized composite allograft (VCA) encompasses reviews of data collected from 2014 (when VCA was included in the Final Rule) through 2022. The present Annual Data Report shows that the number of VCA recipients in the United States continues to be small and has remained consistent from the prior report. The data continue to be limited by sample size, with trends persistently demonstrating a predominance of White males in the young/middle-aged population as both donors and recipients for nonuterus VCA transplants, and White women younger than 35 years as the predominant recipients of uterus transplant. Similar to the 2021 report, there were only eight failed uterus grafts and one failed nonuterus VCA graft reported from 2014 through 2022. Standardization of definitions of success and failure as well as outcome measures for the different VCA types remain unmet needs in VCA transplantation.

Augmenting the Unites States transplant registry with external mortality data: A moving target ripe for further improvement.

The Organ Procurement and Transplantation Network conducts a robust death verification process when augmenting the United States transplant registry with external sources of data. Process enhancements added over 35,000 externally verified deaths across waitlist candidates and transplant recipients for all organs beginning in April 2022. Ninety-four percent of added posttransplant deaths occurred beyond 5 years posttransplant, and over 74% occurred beyond 10 years. Deceased donor solid organ recipients transplanted from January 1, 2010, through October 31, 2020, were analyzed from January and July 2022 Organ Procurement and Transplantation Network Standard Transplant Analysis and Research and the Scientific Registry of Transplant Recipients Standard Analysis Files to quantify the impact of including vs excluding unverified deaths (not releasable to researchers) on posttransplant patient survival estimates. Across all organs, 1- and 5-year posttransplant survival rates were not substantially impacted; meaningful differences were observed in 10-year survival among kidney recipients. These findings bear important implications for anyone who utilized transplant registry data to examine long-term outcomes prior to the updated verification process. Users of transplant surveillance data should interpret results of long-term outcomes cautiously, particularly differences across subpopulations, and the transplant community should identify ways to improve data quality and minimize the reporting burden on transplant institutions.

OPTN/SRTR 2022 Annual Data Report: Kidney.

The year 2022 had continued successes and challenges for the field of kidney transplantation, as the community adapted to ongoing surges of the COVID-19 pandemic and broader geographic organ distribution. The total number of kidney transplants in the United States reached a record count of 26,309, driven by continued growth in deceased donor kidney transplants (DDKTs). The total number of candidates listed for DDKT rose slightly in 2022 but remained below 2019 listing levels, with 12.4% of candidates having been waiting 5 years or longer. Following the height of the COVID-19 pandemic, pretransplant mortality in 2022 declined across age, race and ethnicity, sex, and blood type groups. Pretransplant mortality continued to vary substantially by donation service area. The proportion of deceased donor kidneys recovered but not used for transplant (nonuse rate) rose to a high of 26.7% overall, with greater nonuse of biopsied kidneys (39.8%), kidneys from donors aged 55 years or older (54.7%), and kidneys with a kidney donor profile index (KDPI) of 85% or greater (71.3%). Nonuse of kidneys from donors who are hepatitis C virus (HCV) antibody positive rose to 30.2% but only slightly exceeded that of HCV antibody-negative donors. Disparities in access to living donor kidney transplant (LDKT) persist, especially for non-White and publicly insured patients. Delayed graft function continues an upward trend and occurred in 26.3% of adult kidney transplants in 2022. Five-year graft survival after LDKT compared with DDKT was 90.0% versus 81.4% for recipients aged 18-34 years and 80.8% versus 67.8% for recipients aged 65 years or older, respectively. The total number of pediatric kidney transplants performed in 2022 decreased to 705, its lowest point in the past decade; 502 (71.2%) were DDKTs and 203 (28.8%) were LDKTs. Among pediatric recipients, LDKT remains low, with continued racial disparities. The rate of DDKT among pediatric candidates has decreased by almost 25% since 2011. Congenital anomalies of the kidney and urinary tract remain the leading primary kidney disease diagnosis among pediatric candidates with a reported diagnosis. Most pediatric deceased donor recipients received a kidney from a donor with a KDPI of less than 35%. The rate of delayed graft function was 5.8% in 2022 and has been stable over the past decade. Long-term graft survival continues to improve, with superior outcomes for living donor transplant recipients.

OPTN/SRTR 2022 Annual Data Report: COVID-19.

This chapter updates the COVID-19 chapter from the 2021 Annual Data Report with trends through November 12, 2022, and introduces trends in recovery and use of organs from donors with a positive COVID-19 test. Posttransplant mortality and graft failure, which remained a concern in all organs at the last report due to the Omicron variant wave, have returned to lower levels in the most recent available data through November 2022. Use of organs from donors with a positive COVID-19 test has grown, particularly after the first year of the pandemic. Mortality due to COVID-19 should continue to be monitored, but most other measures have sustained their recovery and may now be responding more to changes in policy than to ongoing concerns with COVID-19.

A Summer of Fevers and Fussiness: Eighteen Infants Admitted With Parechovirus Meningitis.

OBJECTIVE: To define the presentation, spectrum of illness, and outcomes in infants with parechovirus (PeV) meningitis admitted to our inpatient general pediatrics service during a spike in incidence of admissions in summer 2022. PATIENTS AND METHODS: This study is a retrospective case series of all patients aged 3 months and younger discharged from our institution with a CSF BioFire (BioFire Diagnostics, Salt Lake City, UT) FilmArray Polymerase Chain Reaction Meningitis/Encephalitis Panel result positive for PeV between January 1 and September 19, 2022. We collected and analyzed clinical and demographic data. RESULTS: Eighteen infants with PeV meningitis were admitted within our time frame, with 8 (44%) of the admissions occurring in July. Patients' mean age was 28.7 days and mean length of stay was 50.5 hours. Although all had a history of fever, only 72% were febrile on presentation. Laboratory findings showed a procalcitonin of less than 0.5 ng/mL in 86% of the 14 patients who had it drawn and no cerebrospinal fluid (CSF) pleocytosis in 83% of the patients who had CSF cell counts sent. Neutropenia was present in 17%. Although 89% of infants were given initial antibiotics, antibiotics were discontinued in 63% once their CSF panel returned positive for PeV, and in all by 48 hours. CONCLUSIONS: Infants hospitalized with PeV meningitis were febrile and fussy, but experienced uncomplicated hospital stays without neurological deficits. Parechovirus meningitis must be considered as a common cause of acute viral meningitis in young infants even without CSF pleocytosis. This study, although limited in scope and follow-up, can potentially assist in the diagnosis and treatment of PeV meningitis at other institutions.

Analysis of 20 Years of Ethics Consultations at a U.S. Children's Hospital.

AbstractEmpirical studies of pediatric clinical ethics cases are scant in the biomedical and bioethics literature. In this study, more than 100 detailed records of clinical ethics consultations spanning from 2000 to 2020 at a moderately sized U.S. Mid-Atlantic children's hospital were abstracted and analyzed. Findings of the analysis were generally consistent with other studies in pediatric clinical ethics, with additional insight into aspects of moral distress associated with cases, family engagement with consultations, and other characteristics of interest also documented. Over the 20-year time frame, ethics consults were completed on average twice a year, with a detectable upward trend. Consultations were requested across the spectrum of services and units within the hospital, with critical care environments represented most frequently and genetic and neurological conditions being the most common primary diagnoses. Ethical analysis most commonly related to questions around the principles of autonomy and beneficence.

Impact of donor kidney biopsy on kidney yield and posttransplant outcomes.

Procurement biopsy is performed to determine kidney quality, but evidence supporting such association is poor. We investigated the impact of glomerulosclerosis percentage (GS%) on kidney yield and patient outcomes. Information on deceased kidney donors from July 1, 2017, to June 30, 2019, was collected. Association between GS% and kidney yield (number of kidneys procured per donor) and posttransplant graft and patient outcomes were studied. Maximal GS% and minimal GS% were calculated to determine the relationship between GS% and kidney yield; minimal GS% only for correlation with posttransplant outcomes. Multinomial logistic regression and Cox models with least absolute shrinkage and selection operator were used to analyze the association of GS% with kidney yield and posttransplant outcomes, respectively. The kidney yield was 1.63 when maximal GS% and minimal GS% were <5%, but was 0.88 when both GS% were >20%. The hazard ratio for graft failure 1 year after transplant was 1.05 when minimal GS% was 16% to 20%, but was 1.3 for GS% of >20%. The hazard ratio for mortality increased from 1 to 1.2 when minimal GS% reached >20%. In summary, higher GS% was associated with lower kidney yield and inferior posttransplant outcomes. Incorporation of GS% into Scientific Registry of Transplant Recipients models may reassure organ procurement organizations and transplant centers pursuing kidneys with relatively high GS% levels, thereby reducing kidney discard rates.

Impacts of removing race from the calculation of the kidney donor profile index.

The kidney donor risk index (KDRI), standardized as the kidney donor profile index (KDPI), estimates graft failure risk for organ allocation and includes a coefficient for the Black donor race that could create disparities. This study used the Scientific Registry of Transplant Recipients data to recalculate KDRI coefficients with and without the Black race variable for deceased donor kidney transplants from 1995 to 2005 (n = 69 244). The recalculated coefficients were applied to deceased kidney donors from 2015 to 2021 (n = 72 926) to calculate KDPI. Removing the Black race variable had a negligible impact on the model's predictive ability. When the Black race variable was removed, the proportion of Black donors above KDPI 85%, a category with a higher risk of organ nonuse, declined from 31.09% to 17.75%, closer to the 15.68% above KDPI 85% among non-Black donors. KDPI represents percentiles relative to all other donors, so the number of Black donors moving below KDPI 86% was roughly equal to the number of non-Black donors moving above KDPI 85%. Removing the Black donor indicator from KDRI/KDPI may improve equity without substantial overall impact on the transplantation system, though further improvement may require the use of absolute measures of donor risk KDRI rather than relative measures of risk KDPI.

OPTN/SRTR 2021 Annual Data Report: COVID-19.

This chapter updates the COVID-19 chapter from the 2020 Annual Data Report with trends through February 12, 2022, and introduces trends in COVID-19-specific cause of death on the waiting list and posttransplant. Transplant rates remain at or above prepandemic levels for all organs, indicating a sustained transplantation system recovery following the initial 3-month disruption due to the onset of the pandemic. Posttransplant mortality and graft failure remain a concern in all organs, with rates surging corresponding to waves of the pandemic. Waitlist mortality due to COVID-19 is also a concern, particularly among kidney candidates. While the recovery of the transplantation system has been sustained in the second year of the pandemic, ongoing efforts should focus on reducing posttransplant and waitlist mortality due to COVID-19, and graft failure.

OPTN/SRTR 2021 Annual Data Report: Deceased Organ Donation.

The Scientific Registry of Transplant Recipients uses data collected by the Organ Procurement and Transplantation Network to calculate metrics such as donation rate, organ yield, and rate of organs recovered for transplant but not transplanted (ie, nonuse). In 2021, there were 13,862 deceased donors, a 10.1% increase from 12,588 in 2020, and an increase from 11,870 in 2019; this number has been increasing since 2010. The number of deceased donor transplants increased to 41,346 transplants in 2021, a 5.9% increase from 39,028 in 2020; this number has been increasing since 2012. The increase may be due in part to the rising number of deaths of young people amid the ongoing opioid epidemic. The number of organs transplanted included 9,702 left kidneys, 9,509 right kidneys, 551 en bloc kidneys, 964 pancreata, 8,595 livers, 96 intestines, 3,861 hearts, and 2,443 lungs. Compared with 2019, transplants of all organs except lungs increased in 2021, which is remarkable as this occurred despite the COVID-19 pandemic. In 2021, 2,951 left kidneys, 3,149 right kidneys, 184 en bloc kidneys, 343 pancreata, 945 liver, 1 intestine, 39 hearts, and 188 lungs were not used. These numbers suggest an opportunity to increase numbers of transplants by reducing nonused organs. Despite the pandemic, there was no dramatic increase in number of nonused organs and there was an increase in total numbers of donors and transplants. The new Centers for Medicare & Medicaid Services metrics for donation rate and transplant rate have also been described and vary across organ procurement organizations; the donation rate metric varied from 5.82 to 19.14 and the transplant rate metric varied from 18.7 to 60.0.

OPTN/SRTR 2021 Annual Data Report: Pancreas.

The number of pancreas transplants in the United States was largely unchanged in 2021 at 963 transplants compared with 962 in 2020, showing that recovery from the COVID-19 pandemic was not as pronounced in pancreas transplantation as in other organs. The number of simultaneous pancreas-kidney transplants (SPKs) decreased from 827 to 820, whereas the number of pancreas-after-kidney transplants and pancreas transplants alone increased marginally to compensate. The proportion of patients with type 2 diabetes on the waiting list increased to 22.9% in 2021, compared with 20.1% in 2020. Consequently, the proportion of transplants in patients with type 2 diabetes increased from 21.3% in 2020 to 25.9% in 2021. The proportion of transplants in older recipients (aged 55 years or older) also increased to 13.5% in 2021 from 11.7% in 2020. Outcomes after SPK continue to be the best of the three categories of pancreas transplants: 1-year graft failure for kidney at 5.7% and pancreas at 10.5% for transplants performed in 2020. The proportion of pancreas transplants performed by medium-volume centers (11-24 transplants per year) increased sharply to 48.3% in 2021 from 35.1% in 2020, with a corresponding decrease in transplants in large-volume centers (25 or more transplants per year) to 15.9% in 2021 from 25.7% in 2020.

OPTN/SRTR 2021 Annual Data Report: Vascularized Composite Allograft.

Year 2020 marked the first OPTN/SRTR Annual Data Report that included a chapter on vascularized composite allograft (VCA), which encompassed reviews of data collected between 2014 (when VCA was included in the Final Rule) and 2020. The present Annual Data Report shows that the number of VCA recipients in the United States continues to be small and trended downward in 2021. While data continue to be limited by sample size, trends continue to show a predominance in White, young/middle-aged, male recipients. Similar to the 2020 report, eight uterus and one non-uterus VCA graft failures were reported from 2014 through 2021. Critical to advancement of VCA transplantation will be the standardization of definitions, protocols, and outcome measures for the different VCA types. Like intestinal transplants, it is likely that VCA transplants will be concentrated and performed at referral transplant centers.

OPTN/SRTR 2021 Annual Data Report: Kidney.

The year 2021 marked both successes and challenges for the field of kidney transplantation, in the context of the ongoing COVID-19 pandemic and broader geographic organ distribution. The total number of kidney transplants in the United States reached a record count of 25,487, driven by growth in deceased donor kidney transplants. The total number of candidates listed for deceased donor kidney transplant rose slightly in 2021 but remained below 2019 listing levels, with nearly 10% of candidates having been waiting 5 years or longer. Pretransplant mortality declined slightly among candidates of Black, Hispanic, and other races, in parallel with increasing numbers of Black and Hispanic transplant recipients. In the context of broader organ sharing, there is growing disparity in pretransplant mortality among non-metropolitan compared with metropolitan residents. The proportion of deceased donor kidneys recovered but not used for transplant (nonuse rate) rose to a high of 24.6% overall, with greater nonuse among biopsied kidneys (35.9%), kidneys from donors aged 55 years or older (51.1%), and kidneys with kidney donor profile index (KDPI) of 85% or greater (66.6%). Nonuse of kidneys from donors who are hepatitis C virus (HCV) antibody positive only slightly exceeded that of HCV antibody-negative donors. Disparities in access to living donor kidney transplant persists, especially for non-White and publicly insured patients. Delayed graft function continues an upward trend and occurred in 24% of adult kidney transplants in 2021. Five-year graft survival after living compared with deceased donor transplant was 88.6% versus 80.7% for recipients aged 18-34 years, and 82.1% versus 68.0% for recipients aged 65 years or older. The total number of pediatric kidney transplants performed increased to 820 in 2021, the highest number since 2010. Despite numerous efforts, living donor kidney transplant remains low among pediatric recipients, with continued racial disparities. The rate of deceased donor transplants among pediatric candidates recovered in 2021 from a low in 2020. Congenital anomalies of the kidney and urinary tract remain the leading primary kidney disease diagnosis among pediatric candidates. Most pediatric deceased donor recipients receive a kidney from a donor with KDPI less than 35%. Graft survival continues to improve, with superior outcomes for living donor transplant recipients.

Spectrum of motor responses elicited by electrical stimulation of primary motor cortex: A polygraphic study in patients with epilepsy.

OBJECTIVE: To study the neurophysiology of motor responses elicited by electrical stimulation of the primary motor cortex. METHODS: We studied motor responses in four patients undergoing invasive epilepsy monitoring and functional cortical mapping via electrical cortical stimulation using surface EMG electrodes. In addition, polygraphic analysis of intracranial EEG and EMG during bilateral tonic-clonic seizures, induced by cortical stimulation, was performed in two patients. RESULTS: (a) Electrical cortical stimulation: The motor responses were classified as clonic, jittery, and tonic. The clonic responses were characterized by synchronous EMG bursts of agonist and antagonistic muscles, alternating with silent periods. At stimulation frequencies of <20 Hz, EMG bursts were of ≤50 ms duration (Type I clonic). At stimulation frequencies of 20-50 Hz, EMG bursts were of >50 ms duration and had a complex morphology (Type II clonic). Increasing the current intensity at a constant frequency converted clonic responses into jittery and tonic contractions. (b) Bilateral tonic-clonic seizures: The intracranial EEG showed continuous fast spiking activity during the tonic phase along with interference pattern on surface EMG. The clonic phase was characterized by a polyspike-and-slow wave pattern. The polyspikes were time-locked with the synchronous EMG bursts of agonists and antagonists and the slow waves were time-locked with silent periods. INTERPRETATION: These results suggest that epileptic activity involving the primary motor cortex can produce a continuum of motor responses ranging from type I clonic, type II clonic, and tonic responses to bilateral tonic-clonic seizures. This continuum is related to the frequency and intensity of the epileptiform discharges with tonic seizures representing the highest end of the spectrum.

Development of a long-acting direct-acting antiviral system for hepatitis C virus treatment in swine.

Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis worldwide and kills more Americans than 59 other infections, including HIV and tuberculosis, combined. While direct-acting antiviral (DAA) treatments are effective, limited uptake of therapy, particularly in high-risk groups, remains a substantial barrier to eliminating HCV. We developed a long-acting DAA system (LA-DAAS) capable of prolonged dosing and explored its cost-effectiveness. We designed a retrievable coil-shaped LA-DAAS compatible with nasogastric tube administration and the capacity to encapsulate and release gram levels of drugs while resident in the stomach. We formulated DAAs in drug-polymer pills and studied the release kinetics for 1 mo in vitro and in vivo in a swine model. The LA-DAAS was equipped with ethanol and temperature sensors linked via Bluetooth to a phone application to provide patient engagement. We then performed a cost-effectiveness analysis comparing LA-DAAS to DAA alone in various patient groups, including people who inject drugs. Tunable release kinetics of DAAs was enabled for 1 mo with drug-polymer pills in vitro, and the LA-DAAS safely and successfully provided at least month-long release of sofosbuvir in vivo. Temperature and alcohol sensors could interface with external sources for at least 1 mo. The LA-DAAS was cost-effective compared to DAA therapy alone in all groups considered (base case incremental cost-effectiveness ratio $39,800). We believe that the LA-DAA system can provide a cost-effective and patient-centric method for HCV treatment, including in high-risk populations who are currently undertreated.