Trial: Vitamin K Supplement Curbs Coronary Atherosclerosis

 

• A Dutch trial tested the effects of taking the vitamin K homologue menaquinone-7 (MK-7) on measures of atherosclerosis.
• The study showed a small but statistically significant slowing of coronary artery calcification progression after 1 and 2 years of daily MK-7 supplementation.
• In particular, results showed slower calcification in noncalcified plaques, though the clinical significance of this remains unknown.

Menaquinone-7 (MK-7) supplementation modestly slowed the progression of coronary artery calcification (CAC) for patients in the placebo-controlled VitaK-CAC trial.

Among people with existing chronic coronary atherosclerosis, CT-derived CAC scores rose to varying degrees between people randomized to the vitamin K homologue or matching placebo, going from 135 AU and 145 AU at baseline, respectively, to 150 AU and 173 AU after 1 year, then finally to 184 AU and 214 AU after 2 years (P=0.02).

Similarly, calcium mass favored those who got once-daily MK-7 supplements: from a baseline level of 25 mg and 26 mg, respectively, calcium mass rose to 28 mg and 33 mg after 1 year and ultimately reached 32 mg and 38 mg after 2 years (P=0.02), reported Peter de Leeuw, MD, PhD, of Maastricht University Medical Center in the Netherlands, and colleagues in JAMA Cardiology.

"The present data support our hypothesis that supplementation with MK-7 during a period of 2 years attenuates coronary artery calcification in individuals with symptomatic CAD [coronary artery disease]. However, the overall effect is modest, and given that the percentage of fast progressors did not differ between the two treatment groups, the clinical significance of our findings remains to be demonstrated," the authors wrote.

"Only the results of a well-designed outcome trial can provide an answer to the question as to whether the effect of MK-7 is beneficial," they cautioned.

The menaquinones, also known as vitamin K2, are a family of compounds synthesized by gut bacteria and thought to aid in bone health and cardiovascular health. MK-7 in particular has been shown to be a powerful inhibitor of vascular calcification, with good bioavailability and a relatively long half-life, hence its attractiveness as a supplement for heart protection.

Coupled with CT angiography data, the present results showed that the benefit of MK-7 supplementation seemed limited to reining in the calcification of early to moderately developed noncalcified plaques, whereas it had no effect on CAC progression in advanced plaque or on de novo atherogenesis.

MK-7 treatment also showed no effect on degree of stenosis or number of affected vessels.

VitaK-CAC investigators argued that the true efficacy of MK-7 may have been underestimated in the study, however, noting that study participants had about 80% adherence to their assigned treatment and a 17% dropout rate. What's more, they were not equipped to study the tiniest calcium deposits in atherosclerotic plaque.

"MK-7 has been suggested to structurally shift macrocalcifications, detectable by CT, to microcalcifications, subtle changes that are not detectable at the plaque level with routine CAC-protocol noncontrast cardiac CT," explained Michael Blaha, MD, MPH, and Sungwoo Choi, MD, MPH, both of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease in Baltimore, in an accompanying editorial.

"Given what is known about plaque-level calcium density, it is difficult to surmise what the impact on future cardiovascular events might be," they wrote.

The editorialists stressed the need for more research and cited important questions that remain unanswered regarding MK-7's effects on atherosclerosis and cardiovascular health.

"Would MK-7 reduce acute coronary syndromes by slowing early propagation of coronary calcification, reducing the mechanical instability thought to be associated with early calcifications? Would MK-7 increase risk by interfering with later plaque stabilization, reversing the favorable process we associate with statin treatment? Or would there be no effect at all since calcification is largely a byproduct along the continuum of plaque development?" Blaha and Choi posed.

VitaK-CAC was a relatively small study conducted at two centers in the Netherlands. Included were 180 symptomatic patients, with CAC scores of 50-400 AU, who were randomized to MK-7 (360 μg daily) or placebo.

Baseline characteristics were statistically similar between groups. Participants had a median age around 60 years and were 42% women. Statin use was reported in 78%, and the average LDL cholesterol level was 77 mg/dL.

Plasma levels of MK-7 rose significantly in the active treatment group (median 0.50 μg/L to 6.56 μg/L, P<0.001), but not among controls.

No significant adverse effects were associated with MK-7 supplements.

The researchers noted that dietary vitamin K consumption had not been tracked for study participants, but was presumably unchanged given the stability in vitamin K1 levels.

Disclosures

The study was supported by the Dutch Heart Foundation. Nattopharma/Gnosis by Lesaffre provided the MK-7 tablets.

De Leeuw disclosed no relevant conflicts. One co-author disclosed receiving grants from Gnosis by Lesaffre and holding shares in Coagulation Profile outside the submitted work.

Blaha reported grants from the NIH, FDA, American Heart Association, Amgen, Novo Nordisk, and Bayer and personal fees from Novo Nordisk, Bayer, Novartis, Merck, Boehringer Ingelheim, New Amsterdam, Genentech, Eli Lilly, Idorsia, and Scene Health.

Choi disclosed no relevant conflicts.

Primary Source

JAMA Cardiology

Source Reference: Vossen LM, et al "Two years of menaquinone-7 supplementation and coronary artery calcification: a randomized clinical trial" JAMA Cardiol 2026; DOI: 10.1001/jamacardio.2026.1279.

Secondary Source

JAMA Cardiology

Source Reference: Blaha MJ, Choi S "Coronary artery calcium progression -- a useful outcome in clinical trials?" JAMA Cardiol 2026; DOI: 10.1001/jamacardio.2026.1267.

https://www.medpagetoday.com/cardiology/atherosclerosis/121719

Chemo-Free Treatment Effective in Kids With Aggressive Blood Cancer

 A chemotherapy-free regimen was safe and effective in pediatric patients with newly diagnosed acute promyelocytic leukemia (APL), according to results from a prospective study.

The 2-year overall survival (OS) rate among all 114 patients in the study was 99.1%, reported Franco Locatelli, MD, PhD, of IRCCS Bambino Gesù Children's Hospital in Rome, during a session at the European Hematology Association annual congress in Stockholm.

The 2-year OS rates were 100% for standard-risk patients who received all-trans retinoic acid and arsenic trioxide and 97.4% for high-risk patients who also received gemtuzumab ozogamicin (Mylotarg).

In addition, 2-year event-free survival rates were 96.9% in the overall cohort, 98% in standard-risk patients, and 94.3% in high-risk patients.

Locatelli observed that the survival outcomes seen in this trial -- ICC-APL-02 -- were better than those reported in ICC-APL-01, which tested a risk-adapted combination of all-trans retinoic acid and chemotherapy in newly diagnosed pediatric patients with this rare, aggressive subtype of acute myeloid leukemia.

"We confirmed that ATRA/ATO [all-trans retinoic acid and arsenic trioxide] treatment is safe and effective in standard-risk patients," Locatelli noted. "More importantly, the combination of ATRA, ATO, and gemtuzumab showed an excellent safety profile and unprecedented efficacy in high-risk pediatric patients with de novo APL. Overall, we think that this study has now established the new standard of care for treating children with de novo APL."

He pointed out that the introduction of all-trans retinoic acid and arsenic trioxide has revolutionized the treatment of APL, leading to the use of chemotherapy-free protocols in standard-risk adult patients.

While several studies have evaluated all-trans retinoic acid and arsenic trioxide in pediatric patients with newly diagnosed APL, Locatelli said that none of them have been completely chemotherapy free.

Thus, this study represented the first large, multicenter, prospective pediatric trial that delivered a non-chemotherapy-based treatment for children and adolescents with newly diagnosed standard- and high-risk APL, he added.

ICC-APL-02 was conducted at 52 centers in five countries (Italy, France, Czech Republic, Netherlands, and Sweden), and included 114 patients (38 with high-risk APL and 76 with standard-risk APL). Median age was 13 years, and 53.5% were male.

During induction, arsenic trioxide was given at a dose of 0.15 mg/kg/day intravenously and all-trans retinoic acid was given at a dose of 25 mg/m²/day orally. Treatment started on day 1 and was continued until hematological complete remission was achieved. In high-risk patients only, gemtuzumab ozogamicin was administered on days 2 and 4 of induction treatment.

During consolidation, arsenic trioxide was given at the same dose employed during induction for 5 days a week, 4 weeks on and 4 weeks off, for 4 courses, while all-trans retinoic acid was administered 2 weeks on and 2 weeks off for 7 courses. In the high-risk group only, triple intrathecal therapy was administered at the beginning of the first and third consolidation courses.

Median duration of induction was 38 days (range 28-60), and one-third of patients experienced a transient treatment interruption (median duration 5 days), mainly due to differentiation syndrome (41.2%), pseudotumor cerebri (12.3%), and prolongation of the QTc interval (11.4%).

All but one patient achieved minimal residual disease (MRD) negativity by the end of the third consolidation course. That patient (who had high-risk disease) remained MRD-positive after the end of treatment, then obtained molecular remission with two additional doses of gemtuzumab ozogamicin, and eventually underwent autologous hematopoietic stem cell transplantation, and is now alive and disease-free.

A standard-risk patient had molecular relapse 1 year after completing the treatment protocol, then underwent a new treatment with all-trans retinoic acid and arsenic trioxide and is now alive with MRD negativity.

Disclosures

The study was sponsored by the Associazione Italiana Ematologia Oncologia Pediatrica.

Locatelli had no disclosures.

Primary Source

European Hematology Association

Source Reference: Strocchio L, et al "Anthracyclines-free treatment of 114 children and adolescents with newly diagnosed acute promyelocytic leukemia: Early final results of the ICC-APL-02 study" EHA 2026; Abstract S137.

https://www.medpagetoday.com/meetingcoverage/eha/121721

Private Medicare Denies Long-Term and Rehab Care at Exceedingly High Rates

 An HHS Office of Inspector General (OIG) report found that among 19 Medicare Advantage organizations, the three largest denied prior authorization requests for care in long-term care hospitals (LTCHs) and inpatient rehabilitation facilities (IRFs) at higher rates than most of their peers.

"In some cases, high denial rates were driven by contractors that denied prior authorization requests on behalf of the MA [Medicare Advantage] organizations, many of which were later overturned on appeal by the [organization]," the investigators noted. "This raises concerns about whether contractors are receiving appropriate training and oversight from MA organizations."

Overall, the 19 plans in June 2024 denied 65% of LTCH prior authorization requests and 54% of IRF requests. For the LTCH requests, denial rates varied widely, with CVS Health denying 80% of requests, Humana 72%, and UnitedHealthcare 71%, while the University of Pittsburgh Medical Center Health System denied 8% of requests. And for IRF requests, the three large insurers again led the pack, with denial rates of 51%, 54%, and 66%, respectively.

In terms of appeals, plans overturned 36% of LTCH denials on appeal, as well as 43% of IRF denials. Again, overturn rates varied widely; among LTCH appeals, for example, Elevance Health overturned 69%, while CVS Health overturned 10%. Among IRF appeals, Blue Cross Blue Shield of Michigan topped the list with an 86% overturn rate, while Humana overturned only 14%.

A second OIG report found that when prior authorization denials were challenged for patients needing a skilled nursing facility (SNF), appeals succeeded 95% of the time.

The authors called the pattern of denials and overturning of them "concerning" and recommended that CMS, which regulates nursing homes, "regularly collect request-level prior authorization data that include service type and contractor information." The report also urged CMS to act on whatever breakdowns are causing the high overturn rate.

To do the SNF review, the OIG collected data from the 19 largest Medicare Advantage parent companies regarding prior authorization requests that they or their contractors processed in June 2024. The authors also interviewed patient advocacy and industry organizations to hear their perspectives. The 19 plans in this study had 29.3 million people enrolled in their Medicare Advantage contracts in June 2024, which represented 86% of enrollment in the Medicare Advantage program at that time.

The 19 Medicare Advantage plans studied denied around 13,500 of 109,400 requests for SNF admission, for an overall denial rate of 12%. However, denial rates varied greatly by plan, with Molina Healthcare topping the list at a 23% denial rate for 591 requests, while MHH Healthcare denied only 0.4% of the 242 requests it received. Among some of the larger Medicare Advantage plans, Humana had a 13.5% denial rate (out of 26,450 requests), while UnitedHealth Group came in at 12.9% of 41,486 requests.

"Although no specific denial rate is expected or correct, the wide variation in MA organization denial rates for SNF requests is concerning because it is unclear why some [MA plans] had denial rates that were much higher than their peers," the authors wrote. "Extremely high or low denial rates may indicate differences in MA organization policies or performance, such as how they interpret or apply coverage criteria. In future work, OIG will conduct an in-depth review of a sample of case files to examine MA organizations' processes for reviewing prior authorization requests for post-acute care."

"Differences in denial rates between for-profit and nonprofit MA organization contracts suggest that financial incentives may be partially driving higher denial rates among some MA organizations," they added. Medicare Advantage plans "can operate for-profit contracts only, nonprofit contracts only, or both types of contracts. The MA organization with the highest SNF denial rate, Molina Healthcare, Inc., operated only for-profit contracts at the time of our review, as did the three largest MA organizations."

So what happened to the appeals? "Enrollees and providers appealed around one-fifth of requests for SNF admission that Medicare Advantage organizations denied in June 2024 (approximately 2,400 of 13,500 denials)," according to the report. "Among the denials of SNF admission that enrollees appealed, the 19 MA organizations in this study overturned 95% in favor of the enrollee (2,313 of 2,445 appeals)." That result was driven mostly by UnitedHealth Group, "which received 42% of the SNF appeal requests and overturned them 99.7% of the time."

Not surprisingly, insurers disputed the reports' results. "This report reflects data from 2024. Since then, health plans have voluntarily eliminated roughly 6.5 million prior authorizations across markets -- including more than 15% in Medicare Advantage," Mary Beth Donahue, president and CEO of the Better Medicare Alliance, which represents Medicare Advantage plans, said in a statement. "Prior authorization is an important tool for safe, appropriate, and affordable care. We remain committed to working with policymakers to continue improving prior authorization, so decisions are faster, easier, and more accurate for more than 35 million Medicare Advantage beneficiaries."

Chris Bond, spokesperson for America's Health Insurance Plans, which represents Medicare Advantage plans and other commercial insurers, said in a statement, "The reports ignore serious, well-documented concerns about wide variations in the cost and quality of post-acute care and skilled nursing facilities. More than 35 million Americans actively choose MA because it provides them with better, more affordable care -- including helping seniors transition to high-quality, clinically appropriate care settings to support their rehab and recovery."

The findings were not surprising to the American Health Care Association and the National Center for Assisted Living (AHCA/NCAL), which represents SNFs. "OIG's findings confirm what the skilled nursing community has been saying for years: that large, insurer-led Medicare Advantage plans too often deny and delay access to care, but especially post-acute care," Clif Porter, the organization's president and CEO, said in an email to MedPage Today. "It's unconscionable that insurers are making frail seniors and their families jump through numerous hoops at a critical time for their recovery."

"It's also disturbing that these plans are making patients wait days to ultimately overturn appeals 95% of the time," Porter said. "With only 18% of denials challenged, we encourage more skilled nursing patients and families to fight for their benefits."

https://www.medpagetoday.com/publichealthpolicy/medicare/121725

Drinking in Pregnancy on the Rise, CDC Data Show

 

• Alcohol consumption during pregnancy is linked with adverse birth outcomes, like miscarriage and stillbirth, as well as fetal alcohol spectrum disorders.
• In a national survey, 15.2% of pregnant women reported drinking in the past 30 days, while 4.9% reported binge drinking, and 2.2% reported heavy drinking.
• Some groups were significantly more likely to report drinking during pregnancy, including unmarried women and those who reported frequent mental distress.

Alcohol consumption during pregnancy has been on the rise in recent years, with some groups, like unmarried women and women in frequent distress, more likely to partake, CDC data showed.

Responding to a survey, 15.2% of pregnant women reported drinking in the past 30 days, while 4.9% reported binge drinking, and 2.2% reported heavy drinking, said Nicholas Deputy, PhD, of the CDC's National Center on Birth Defects and Developmental Disabilities, and colleagues.

Among pregnant women who reported current drinking, 33.2% also reported binge drinking and 14.7% also reported heavy drinking, they noted in the Morbidity and Mortality Weekly Report (MMWR).

"These findings reinforce the importance of integrating behavioral health screening, treatment, and other support into prenatal care," they wrote.

Alcohol consumption during pregnancy is linked with adverse birth outcomes, like miscarriage and stillbirth, as well as fetal alcohol spectrum disorders. No known level of alcohol consumption is considered safe but higher intensity and frequency are linked to higher risks of these adverse outcomes. The American College of Obstetricians and Gynecologists and the CDC recommend completely abstaining from alcohol during pregnancy.

According to a previous CDC report, 13.5% of pregnant women in the U.S. reported current drinking in 2018-2020. Other research has shown that drinking while pregnant was on the rise for most of the 2010s.

Nikki Zite, MD, MPH, an ob/gyn with the University of Tennessee Graduate School of Medicine in Knoxville, who was not involved with the research, told MedPage Today that this increase in drinking while pregnant is "concerning."

She noted that public health and provider education has shifted in recent years to combat mis- and disinformation about topics like vaccines, and it's possible that less time was spent on substance use screening and education.

"Media coverage and public health campaigns that historically focused on the dangers of alcohol use in pregnancy have shifted to recommendations related to other substances -- such as opioids or marijuana," Zite said. "Hopefully this MMWR will remind providers and public health officials that awareness, screening, and support for those that are at increased risk of or already consuming alcohol during pregnancy is still needed despite competing priorities."

Deputy and colleagues found that some groups were significantly more likely to drink during pregnancy. For instance, unmarried pregnant women had about twice the prevalence of current drinking (adjusted prevalence ratio [aPR] 1.8, 95% CI 1.4-2.2), binge drinking (aPR 2.2, 95% CI 1.3-3.7), and heavy drinking (aPR 2.0, 95% CI 1.1-3.6) compared with married women.

Pregnant women who reported frequent mental distress also had approximately twice the prevalence of current drinking (aPR 1.8, 95% CI 1.4-2.3) and binge drinking (aPR 1.8, 95% CI 1.2-2.6) and three times the prevalence of heavy drinking (aPR 3.0, 95% CI 1.7-5.0) compared with those who didn't report frequent mental distress.

There were also significant regional differences, which generally aligned with observed drinking trends in the overall U.S. population. For instance, women living in New England had a higher prevalence of current drinking while pregnant (19.9%) versus women living in regions that span the mid-South and Mountain West (10.4% to 12.4%).

"Recommended clinical interventions include routine screening for alcohol consumption and mental health conditions, brief behavioral counseling, and referral to specialized services," Deputy and team wrote. "Community-level approaches that include providing information about outcomes associated with alcohol consumption during pregnancy or address alcohol consumption among the general population might also help reduce prenatal alcohol exposure and prevent its associated adverse health outcomes."

For this report, the researchers analyzed 2021-2024 data from the national Behavioral Risk Factor Surveillance System (BRFSS), an annual state-based survey of health behaviors, in order to assess the prevalence of self-reported drinking during pregnancy. Eligible respondents were women ages 18 to 49 who self-reported as pregnant; information on trimester was not collected.

Drinking levels were classified using Dietary Guidelines for Americans and CDC definitions. Current drinking was defined as one or more alcoholic drinks in the past 30 days, binge drinking was defined as four or more drinks on at least one occasion in the past 30 days, and heavy drinking was defined as eight or more drinks in a 1-week period in the past 30 days.

The authors noted a few limitations to their study, including that some respondents may have become pregnant during the 30 days prior to the survey and thus their reported alcohol use may have been prior to pregnancy, not during it. Additionally, self-reported pregnancy status may be incorrect and self-reported drinking may be influenced by social desirability and recall biases. The analysis didn't include drinking patterns throughout pregnancy since respondents' trimester information was not known.

Disclosures

The authors reported no conflicts of interest.

Zite reported no disclosures.

Primary Source

Morbidity and Mortality Weekly Report

Source Reference: Thomas SA, et al "Alcohol consumption during pregnancy among women aged 18-49 years -- United States, 2021-2024" MMWR 2026; DOI: 10.15585/mmwr.mm7522a2.

https://www.medpagetoday.com/obgyn/pregnancy/121743

Medicare Pays for Programs That May Not Help After Serious Hospitalizations

 

• CMS reimburses for remote patient monitoring, which grew 10-fold from 2019 to 2022, in an effort to cut hospital readmissions.
• In this randomized trial of patients hospitalized for sepsis or serious respiratory infections, remote monitoring interventions failed to outperform usual care, with similar proportions of patients alive and out of the hospital at 90 days postdischarge.
• CMS should rethink the role of remote monitoring, according to the researchers.

Remote patient monitoring (RPM) programs after hospitalization for sepsis or lower respiratory infection -- an approach increasingly reimbursed for by Medicare -- didn't beat usual follow-up care when it came to increasing the number of days patients spent at home after discharge, according to a randomized trial.

At 90 days, the median number of days alive and at home post-discharge was 90 days across study arms, regardless of whether patients were assigned to one of four RPM interventions or to usual care, reported researchers led by Sachin Yende, MD, of the H. John Heinz III Veterans Affairs Medical Center in Pittsburgh.

The lack of effectiveness was consistent across secondary outcomes as well, the study in JAMA Network Open showed.

In fact, "in patients 65 years and older, remote monitoring reduced days spent at home and increased readmission rates compared with usual care," Yende and co-authors wrote. "These findings suggest that the CMS should reassess the role of remote therapeutic monitoring in reducing readmissions and underscore the value of tailoring remote monitoring in post-acute care for serious infections."

Sepsis, influenza, and COVID-19 lead to 3 million hospitalizations annually in the U.S., and more than 60% of hospital readmissions are caused by infections and heart and lung disease exacerbations. To cut readmissions, CMS reimburses for remote monitoring telehealth approaches, which grew 10-fold for Medicare beneficiaries from 2019 to 2022.

In the study, the rates for 90-day mortality and hospital readmission were similar across the four RPM arms, with varying levels of monitoring intensity, versus usual care:

• RPM-low standard response: 8.8% and 39.7%
• RPM-high standard response: 5.4% and 44.2%
• RPM-low enhanced response: 6.3% and 37.3%
• RPM-high enhanced response: 8.2% and 36.3%
• Usual care: 6.5% and 37.8%

"Our findings highlight the challenges of implementing and scaling remote monitoring across health systems and among patients recovering from serious illness who are managing complex care needs, including medications, follow-up appointments, and ongoing symptoms," the researchers wrote.

Yende's team assessed interventions that used remote therapeutic monitoring to collect health data through smartphone-application questionnaires and text messages to identify signs of clinical deterioration.

The open-label, randomized trial included 1,286 western Pennsylvania patients 21 years or older who had been hospitalized for sepsis or a lower respiratory tract infection, had a smartphone or internet-connected device, had no cognitive impairment, and were at moderate to high risk for hospital readmission based on a predictive model. Patients were insured through traditional fee-for-service Medicare or the UPMC Health Plan.

The trial tested four RPM interventions that combined low-intensity or high-intensity patient questionnaires with either standard or enhanced response teams, while usual care involved care managers or nurses calling patients in the week after discharge to assess their condition and coordinate follow-up care.

In the RPM arms, standard care utilized four remote monitoring nurses who responded to alerts and coordinated care with patients' clinicians. Enhanced care consisted of two nurses and two certified registered nurse practitioners with palliative care expertise and access to social workers who could diagnose and implement a treatment plan, order and perform diagnostic tests, and deliver other healthcare services.

Median patient age was 63 years, 52% were women, 80% were white, 16% were Black, and 1% were Hispanic. Nearly half of the patients (47%) had been hospitalized for sepsis, 29% for lower respiratory tract infection, and 24% for COVID-19. Median Charlson Comorbidity Index was 6, and 33% had been in the intensive care unit.

Within 30 days after discharge, 79% of the usual-care group had completed a primary care visit, a percentage virtually identical to the rates among the four RPM groups (77% to 81%).

"This level of timely outpatient engagement likely exceeded routine practice and addressed many issues targeted by remote monitoring, making additional benefit difficult to detect," Yende and colleagues noted.

Study limitations included that the findings were from a single health system, which may limit generalizability. Use of symptom-based monitoring rather than remote physiologic monitoring could limit understanding of patients' experiences in home-based settings. In addition, engagement with RPM was modest, with only 60% of the 887 patients in the four intervention arms enrolling in remote monitoring.

Disclosures

The Patient-Centered Outcomes Research Institute supported the study.

Yende had no disclosures. Co-authors reported relationships with the UPMC Center for High-Value Health Care and Berry Consultants.

Primary Source

JAMA Network Open

Source Reference: Yende S, et al "Remote monitoring approaches to reduce readmissions after infection and sepsis -- a randomized clinical trial" JAMA Netw Open 2026; DOI: 10.1001/jamanetworkopen.2026.16641.

https://www.medpagetoday.com/criticalcare/sepsis/121735