A Phase I Dose Escalation Study of the Safety,Tolerability, and Pharmacokinetics of Ipilimumab in Chinese Patients with Select Advanced Solid Tumors

Lessons Learned

• The overall safety profiles of ipilimumab 3 mg/kg and 10 mg/kg administered every 3 weeks, were consistent between Chinese patients with solid tumors in the current study and patients from previous U.S. ipilimumab monotherapy studies. No new safety signals were identified.
• The mean systemic exposures to ipilimumab (assessed by first dose area under the curve during the dosing interval and maximum serum concentration) were numerically lower in the Chinese patient population than in U.S. patients for both 3 mg/kg and 10 mg/kg doses; however, the range of serum concentrations in the Chinese and U.S. populations overlapped (3 mg/kg and 10 mg/kg), suggesting that ipilimumab pharmacokinetics was ethnically insensitive in this study.

BackgroundThis phase I, open‐label study assessed ipilimumab safety, tolerability, pharmacokinetics (PK), immunogenicity, and antitumor activity in Chinese patients with unresectable, metastatic, recurrent malignant melanoma (MM) or nasopharyngeal carcinoma (NPC).MethodsOf 39 patients enrolled, 25 received ipilimumab (11 patients received 3 mg/kg, and 14 patients received 10 mg/kg). Reasons for not receiving treatment were withdrawal of consent (3 patients), no longer meeting the criteria (10 patients), and one recorded as “other.” During the induction phase, patients received ipilimumab (3 mg/kg, i.v.), on day 1 of a 3‐week cycle, to a maximum of four doses or progressive disease (PD). During the maintenance phase at week 24, patients received ipilimumab (3 mg/kg, i.v.) on day 1 of a 12‐week cycle, to a maximum of 3 years or PD. Considering the co‐primary safety and PK endpoints, the successive dosing required nine patients with two or fewer dose‐limiting toxicities during the 42‐day observation period to proceed with a new cohort of nine patients at 10 mg/kg.ResultsIpilimumab safety and PK profiles were similar in Chinese and predominantly White populations. Ipilimumab was well tolerated. Most adverse events (AEs) were grades 1–2 and experienced by 11 patients treated with 3 mg/kg and 14 patients treated with 10 mg/kg. There were no new safety concerns. Incidence of anti‐ipilimumab antibodies was low (1 of 10 in the 3 mg/kg patients and 2 of 13 in the 10 mg/kg patients) and without safety implications. In the 3 mg/kg group, 8 of 11 patients had PD. In the 10 mg/kg group (all NPC, 0 MM patients), 11 of 14 patients had PD. Three patients had stable disease (one at 3 mg/kg and two at 10 mg/kg).ConclusionIpilimumab was well tolerated in Chinese patients, showing similar safety and PK to previous studies in predominantly White populations.     

Shifting US Patterns of COVID-19 Mortality by Race and Ethnicity From June–December 2020

ObjectivesThe COVID-19 pandemic has disproportionately affected racial and ethnic minorities in the United States and has been devastating for residents of nursing homes (NHs). However, evidence on racial and ethnic disparities in COVID-19–related mortality rates within NHs and how that has changed over time has been limited. This study examines the impact of a high proportion of minority residents in NHs on COVID-19–related mortality rates over a 30-week period.DesignLongitudinal study.Setting and ParticipantsCenters for Medicare & Medicaid Services Nursing Home COVID-19 Public Use File data from 50 states from June 1, 2020, to December 27, 2020.MethodsWe linked data from 11,718 NHs to (1) Nursing Home Compare data, (2) the Long-Term Care: Facts on Care in the U.S., and (3) US county-level data on COVID cases and deaths. Our primary independent variable was proportion of minority residents (blacks and Hispanics) in NHs and its association with mortality rate over time.ResultsDuring the first 6 weeks from June 1, 2020, NHs with a higher proportion of black residents reported more COVID-19 deaths per 1000 followed by NHs with a higher proportion of Hispanic residents. Between 7 and 12 weeks, NHs with a higher proportion of Hispanic residents reported more deaths per 1000, followed by NHs with a higher proportion of black residents. However, after 23 weeks (mid-November 2020), NHs serving a higher proportion of white residents reported more deaths per 1000 than NHs serving a high proportion of black and Hispanic residents.Conclusions and ImplicationsThe disparities in COVID-19–related mortality for nursing homes serving minority residents is evident for the first 12 weeks of our study period. Policy interventions and the equitable distribution of vaccine are required to mitigate the impact of systemic racial injustice on health outcomes of people of color residing in NHs.     

Development of a composite indicator to prioritize districts for implementation of human immunodeficiency virus programmes in Maharashtra,India

A key recommendation of the National AIDS Control Programme‐IV of India was to develop new strategies for geo‐prioritization of the human immunodeficiency virus (HIV) epidemic. We conducted this study to categorize the districts in Maharashtra (India) based on a multidimensional framework for geo‐prioritization of services. Programmatic data on trends of HIV prevalence, coverage of marginalized populations and vulnerability factors were included. A composite indicator based on these was developed, and the cumulative score was calculated for each district. HIV prevalence among general population has declined steadily from 0.60% in 2007 to 0.33% in 2017. The programme coverage was stable but inadequate for men who have sex with men (MSM). The coverage for female sex workers (FSWs) was inadequate and reduced over time. Nine districts were categorized as high priority, 13 as moderate priority and 11 were classified as low‐priority districts based on burden and vulnerability for HIV. The high‐priority districts were Pune, Solapur and Yavatmal for FSW interventions and Pune, Thane and Latur for MSM interventions. This multidimensional indicator is based on existing programmatic data, dynamic and can be made state‐specific. It is useful to categorize and prioritize districts for allocation of resources and geo‐prioritization of services in resource limited settings.     

Post-infectious irritable bowel syndrome:Mechanistic insights into chronic disturbances following enteric infection

Irritable bowel syndrome(IBS)is a commonly encountered chronic functional gastrointestinal(GI)disorder.Approximately 10%of IBS patients can trace the onset of their symptoms to a previous a bout of infectious dysentery.The appearance of new IBS symptoms following an infectious event is defined as post-infectiousIBS.Indeed,with the World Health Organization estimating between 2 and 4 billion cases annually,infectious diarrheal disease represents an incredible international healthcare burden.Additionally,compounding evidence suggests many commonly encountered enteropathogens as unique triggers behind IBS symptom generation and underlying pathophysiological features.A growing body of work provides evidence supporting a role for pathogen-mediated modifications in the resident intestinal microbiota,epithelial barrier integrity,effector cell functions,and innate and adaptive immune features,all proposed physiological manifestations that can underlie GI abnormalities in IBS.Enteric pathogens must employ a vast array of machinery to evade host protective immune mechanisms,and illicit successful infections.Consequently,the impact of infectious events on host physiology can be multidimensional in terms of anatomical location,functional scope,and duration.This review offers a unique discussion of the mechanisms employed by many commonly encountered enteric pathogens that cause acute disease,but may also lead to the establishment of chronic GI dysfunction compatible with IBS.     

Least-cost targets and avoided fossil fuel capacity in India’s pursuit of renewable energy

India has set aggressive targets to install more than 400 GW of wind and solar electricity generation by 2030, with more than two-thirds of that capacity coming from solar. This paper examines the electricity and carbon mitigation costs to reliably operate India’s grid in 2030 for a variety of wind and solar targets (200 GW to 600 GW) and the most promising options for reducing these costs. We find that systems where solar photovoltaic comprises only 25 to 50% of the total renewable target have the lowest carbon mitigation costs in most scenarios. This result invites a reexamination of India’s proposed solar-majority targets. We also find that, compared to other regions and contrary to prevailing assumptions, meeting high renewable targets will avoid building very few new fossil fuel (coal and natural gas) power plants because of India’s specific weather patterns and need to meet peak electricity demand. However, building 600 GW of renewable capacity, with the majority being wind plants, reduces how often fossil fuel power plants run, and this amount of capacity can hold India’s 2030 emissions below 2018 levels for less than the social cost of carbon. With likely wind and solar cost declines and increases in coal energy costs, balanced or wind-majority high renewable energy systems (600 GW or ≈ 45% share by energy) could result in electricity costs similar to a fossil fuel-dominated system. As an alternative strategy for meeting peak electricity demand, battery storage can avert the need for new fossil fuel capacity but is cost effective only at low capital costs (≈ USD 150 per kWh).

India emitted 3.2 billion metric tons of CO₂e in 2016, or 6% of annual global greenhouse gas emissions, placing it third only to China and the United States (1). One-third of these emissions were from coal-based electricity. At the same time, both per capita emissions and energy use remain well below global averages, suggesting a massive potential for growth of electricity generation and emissions (1). India’s primary energy demand is expected to double by 2040 compared to 2017 (2). Whether this energy comes from fossil or low-carbon sources will significantly affect the ability to limit average global temperature rise to below 2 °C.India is already pursuing significant technology-specific renewable energy targets—100 GW of solar and 60 GW of wind by 2022—and, in its Nationally Determined Contributions (NDC), committed to a 40% target for installed generation capacity from nonfossil fuel sources by 2030 (3). In 2019, in part to fulfill its NDC commitment, the Indian government proposed to install 440 GW of renewable energy capacity by 2030, with 300 GW of solar and 140 GW of wind capacity (4). Although costs of solar photovoltaic (PV) and wind technologies have declined significantly in recent years (5–7), the low cost of coal and integration costs associated with variable renewable energy (VRE) technologies like wind and solar may hinder India’s cost-effective transition to a decarbonized electricity system. This paper seeks to answer a number of questions that arise in the Indian context. What targets for wind and solar capacity have the lowest associated integration costs? Will these targets significantly offset the need to build fossil fuel generation capacity? What additional measures can we take to mitigate VRE integration costs?Merely comparing the levelized costs of VRE with the costs of conventional generation ignores additional cost drivers, which depend on the timing of VRE production and other conditions in the power system (8, 9). Quantifying these drivers requires models that choose lowest-cost generation capacity portfolios and simulate optimal system operation with detailed spatiotemporal data. Several prior studies address these system-level integration costs in a capacity expansion planning framework (10–16), often making decisions based on a limited sample of representative hours. Other studies explicitly estimate the relationship between long-run economic value (including integration costs) of VRE penetration levels (17, 18) but do not include VRE investment costs in their analysis. Few prior studies explore the impacts of high VRE penetration on India’s electricity system, and those that do either use the capacity expansion framework and do not evaluate the economic value of multiple VRE targets (4, 19, 20) or do not optimize capacity build around proposed VRE targets (21).Here we address this gap by estimating how different VRE targets affect the cost to reliably operate the Indian electricity system. To do so, we work with three interrelated models. First, using a spatially explicit model for VRE site selection, we identify the lowest levelized cost wind and solar sites to meet different VRE capacity targets, and study how the resource quality—and corresponding levelized cost—of selected sites changes with increasing VRE targets.Second, using a capacity investment model that accounts for VRE production patterns and optimal dispatch of hydropower and battery storage, we determine the capacity requirements and investment costs for coal, combined cycle gas turbines (CCGT), and combustion turbine (CT) peaker plants. Due to uncertainties in their future deployment (22), and because their current targets are relatively low (4), we did not consider new nuclear or hydro capacity in the main scenarios but include those in the sensitivity scenarios presented in SI Appendix, section 2. Third, we use a unit commitment and economic dispatch model to simulate hourly operation of the electricity system and estimate annual system operational costs. This model captures important technical constraints, including minimum operating levels, daily unit commitment for coal and natural gas plants, and energy limits on hydropower and battery storage. Rather than cooptimize VRE capacity, we compute the system-level economic value of a range of VRE targets by comparing the sum of the avoided new conventional capacity and energy generation costs to a no-VRE scenario. The net cost for a scenario is then the difference between the levelized cost of the VRE and the system-level economic value. Materials and Methods provides more detail on this process.Our results show that, despite greater levelized cost reduction forecasts for solar PV compared to wind technologies, VRE targets with greater amounts of wind have the lowest projected net carbon mitigation costs. This finding is robust to a range of scenarios, including low-cost solar and storage, and lower minimum generation levels for coal generators.We find that, although VRE production displaces energy production from conventional generators, it does very little to defer the need for capacity from those generators due to low correlation between VRE production and peak demand. Our findings suggest that VRE in India avoids far less conventional capacity than VRE in other regions in the world. These capacity requirements are slightly mitigated if India’s demand patterns evolve to more closely resemble demand in its major cities. Overall, we conclude that the importance of choosing the right VRE mix is significant when measured in terms of carbon mitigation costs: Whereas most solar-majority scenarios we examined lead to costs greater than or equal to estimates of the social cost of carbon (SCC), wind-majority mixes all cost far less than the SCC.     

Complications of total hip arthroplasty: periprosthetic fractures of the acetabulum

Periprosthetic fractures of the acetabulum are a rare but potentially disastrous complication of total hip arthroplasty. Such fractures occur either as early perioperative complications or late complications when they are associated with either significant trauma or as a result of the loss of the structural integrity of the bone supporting the prosthesis, such as aseptic osteolysis. The incidence of such fractures appears to be increasing with the increased use of uncemented acetabular components. This article explores the current literature on the epidemiology, etiology, and classification of periprosthetic acetabular fractures as well as offering potential treatment strategies.