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Health technology assessment (HTA) is a cost-effective resource allocation tool in healthcare decision-making processes; however, its use is limited in low-income settings where countries fall short on both absorptive and technical capacity. This paper describes the journey of the introduction of HTA into decision-making processes through a case study revising the National Essential Medicines List (NEMLIT) in Tanzania. It draws lessons on establishing and strengthening transparent priority-setting processes, particularly in sub-Saharan Africa.
The concept of HTA was introduced in Tanzania through revision of the NEMLIT by identifying a process for using HTA criteria and evidence-informed decision making. Training was given on using economic evidence for decision making, which was then put into practice for medicine selection for the NEMLIT. During the revision process, capacity-building workshops were held with reinforcing messages on HTA.
Between the period 2014 and 2018, HTA was introduced in Tanzania with a formal HTA committee being established and inaugurated followed by the successful completion and adoption of HTA into the NEMLIT revision process by the end of 2017. Consequently, the country is in the process of institutionalizing HTA for decision making and priority setting.
While the introduction of HTA process is country-specific, key lessons emerge that can provide an example to stakeholders in other low- and middle-income countries (LMICs) wishing to introduce priority-setting processes into health decision making.
Public health strategies have focused largely on physical health. However, there is increasing recognition that raising mental health awareness and tackling stigma is crucial to reduce disease burden. National campaigns have had some success but tackling issues locally is particularly important.
To assess the public's awareness and perception of the monthly BBC Cornwall mental health phone-in programmes that have run for 8.5 years in Cornwall, UK (population 530 000).
A consultation, review and feedback process involving a multiagency forum of mental and public health professionals, people with lived experience and local National Health Service trust's media team was used to develop a brief questionnaire. This was offered to all attendees at two local pharmacies covering populations of 27 000 over a 2-week period.
In total, 14% (95% CI 11.9–16.5) were aware of the radio show, 11% (95% CI 9.0–13.1) have listened and the majority (76%) of those who listened did so more than once. The estimated reach is 70 000 people in the local population, of whom approximately 60 000 listen regularly. The show is highly valued among respondents with modal and median scores of 4 out of 5.
Local radio is a successful, cost-effective and impactful way to reach a significant proportion of the population and likely to raise awareness, reduce stigma and be well received. The format has been adopted in other regions thus demonstrating easy transferability. It could form an essential part of a public health strategy to improve a population's mental well-being.
Declaration of interest
W.H. received support from the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula UK. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. L.R. and D.S. were involved in delivering the programmes but had no role in their evaluation.
Cardiovascular disease is a leading cause of morbidity and mortality in childhood cancer survivors. Cardiologists must be aware of risk factors and long-term follow-up guidelines, which have historically been the purview of oncologists. Little is known about paediatric cardiologists’ knowledge regarding the cardiotoxicity of cancer treatment and how to improve this knowledge.
A total of 58 paediatric cardiologists anonymously completed a 21-question, web-based survey focused on four cardio-oncology themes: cancer treatment-related risk factors (n = 6), patient-related risk factors (n = 6), recommended surveillance (n = 3), and cardiac-specific considerations (n = 6). Following the baseline survey, a multi-disciplinary team of paediatric cardiologists and cancer survivor providers developed an in-person and web-based educational intervention. A post-intervention survey was conducted 5 months later.
The response rate was 41/58 (70.7%) pre-intervention and 30/58 (51.7%) post-intervention. On the baseline survey, the percentage of correct answers was 68.8 ± 10.3%, which improved to 79.2 ± 16.2% after the intervention (p = 0.009). The theme with the most profound knowledge deficit was surveillance; however, it also had the greatest improvement after the intervention (49.6 ± 26.7 versus 66.7 ± 27.7% correct, p = 0.025). Individual questions with the largest per cent improvement pertained to risk of cardiac dysfunction with time since treatment (52.4 versus 93.1%, p = 0.002) and the role of dexrazoxane (48.8 versus 82.8%, p = 0.020).
Specific knowledge deficits about the care of paediatric cancer survivors were identified amongst cardiologists using a web-based survey. Knowledge of surveillance was initially lowest but improved the most after an educational intervention. This highlights the need for cardio-oncology-based educational initiatives among paediatric cardiologists.
To evaluate the long-term safety and tolerability of deutetrabenazine in patients with tardive dyskinesia (TD) at 2years.
In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale scores compared with placebo, and there were low rates of overall adverse events (AEs) and discontinuations associated with deutetrabenazine.
Patients who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12mg/day, titrating up to a maximum total daily dose of 48mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration period and a long-term maintenance phase. Safety measures included incidence of AEs, serious AEs (SAEs), and AEs leading to withdrawal, dose reduction, or dose suspension. Exposure-adjusted incidence rates (EAIRs; incidence/patient-years) were used to compare AE frequencies for long-term treatment with those for short-term treatment (ARM-TD and AIM-TD). This analysis reports results up to 2 years (Week106).
343 patients were enrolled (111 patients received placebo in the parent study and 232 received deutetrabenazine). There were 331.4 patient-years of exposure in this analysis. Through Week 106, EAIRs of AEs were comparable to or lower than those observed with short-term deutetrabenazine and placebo, including AEs of interest (akathisia/restlessness [long-term EAIR: 0.02; short-term EAIR range: 0–0.25], anxiety [0.09; 0.13–0.21], depression [0.09; 0.04–0.13], diarrhea [0.06; 0.06–0.34], parkinsonism [0.01; 0–0.08], somnolence/sedation [0.09; 0.06–0.81], and suicidality [0.02; 0–0.13]). The frequency of SAEs (EAIR 0.15) was similar to those observed with short-term placebo (0.33) and deutetrabenazine (range 0.06–0.33) treatment. AEs leading to withdrawal (0.08), dose reduction (0.17), and dose suspension (0.06) were uncommon.
These results confirm the safety outcomes seen in the ARM-TD and AIM-TD parent studies, demonstrating that deutetrabenazine is well tolerated for long-term use in TD patients.
Presented at: American Academy of Neurology Annual Meeting; April 21–27, 2018, Los Angeles, California,USA
Funding Acknowledgements: Funding: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel
To evaluate long-term efficacy of deutetrabenazine in patients with tardive dyskinesia (TD) by examining response rates from baseline in Abnormal Involuntary Movement Scale (AIMS) scores. Preliminary results of the responder analysis are reported in this analysis.
In the 12-week ARM-TD and AIM-TD studies, the odds of response to deutetrabenazine treatment were higher than the odds of response to placebo at all response levels, and there were low rates of overall adverse events and discontinuations associated with deutetrabenazine.
Patients with TD who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12mg/day, titrating up to a maximum total daily dose of 48mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration and a long-term maintenance phase. The cumulative proportion of AIMS responders from baseline was assessed. Response was defined as a percent improvement from baseline for each patient from 10% to 90% in 10% increments. AlMS score was assessed by local site ratings for this analysis.
343 patients enrolled in the extension study (111 patients received placebo in the parent study and 232 patients received deutetrabenazine). At Week 54 (n=145; total daily dose [mean±standard error]: 38.1±0.9mg), 63% of patients receiving deutetrabenazine achieved ≥30% response, 48% of patients achieved ≥50% response, and 26% achieved ≥70% response. At Week 80 (n=66; total daily dose: 38.6±1.1mg), 76% of patients achieved ≥30% response, 59% of patients achieved ≥50% response, and 36% achieved ≥70% response. Treatment was generally well tolerated.
Patients who received long-term treatment with deutetrabenazine achieved response rates higher than those observed in positive short-term studies, indicating clinically meaningful long-term treatment benefit.
Presented at: American Academy of Neurology Annual Meeting; April 21–27, 2018, Los Angeles, California, USA.
Funding Acknowledgements: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel.
Tardive dyskinesia (TD) is a hyperkinetic movement disorder associated with antipsychotic treatment. RE KINECT (NCT03062033), a real-world study of outpatients prescribed antipsychotics, was designed to identify the presence of possible TD and characterize the impact of involuntary movements on functioning and quality of life. Data from RE-KINECT were used to compare the impact of possible TD in patients with schizophrenia/schizoaffective disorder [SZD] versus mood/other psychiatric disorders [Mood].
Adults with ≥3months of lifetime exposure to antipsychotics and ≥1 psychiatric disorder were recruited. The presence of possible TD was based on clinicians’ observation of involuntary movements in 4 body regions (head, trunk, upper extremities, and lower extremities). Baseline outcomes included demographics, medication history, location/severity of abnormal movements, impact of abnormal movements on daily activities, the Sheehan Disability Scale (SDS), and the EuroQoL 5-Dimensional questionnaire (EQ-5D-5L).
Of 204 patients with clinician-confirmed possible TD, 111 (54.4%) had a SZD diagnosis and 93 (45.6%) had a mood/other psychiatric diagnosis. Significant differences found between groups (Mood vs SZD) included: mean age (56.9 vs 52.7 years; P=0.0263); male sex (33.3% vs 62.2%; P<0.0001); African-American race (7.5% vs 26.1%; P=0.0005); mean lifetime exposure to antipsychotics (9.5 vs 19.5 years; P<0.0001); and percentage of patients currently taking ≥2 psychiatric medications (93.5% vs 79.3%; P=0.0093). Based on clinician observation, there were no significant differences between diagnosis groups in the number of body regions impacted by abnormal movements, maximum severity score across all 4 regions, or patient awareness of possible TD. Over 30% of patients in both groups reported that involuntary movements had “some” or “a lot” of impact on their ability to continue usual activities, be productive, and socialize. No significant differences between the diagnosis groups (Mood vs SZD) were found for mean SDS total score (12.8 vs 10.8), SDS domain scores (work/school [4.1 vs 4.2], social life [4.3 vs 3.7], family life [4.1 vs 3.5]), EQ-5D-5L utility score (0.68 vs 0.74), or EQ-5D-5L health state VAS (64.8 vs 68.5).
In this cohort of outpatients with possible TD, those with Mood disorders were more likely to be older, female, and white than patients with SZD. The ability to function and quality of life were equally impaired in both groups. Further studies on the impact of TD are needed.
Funding Acknowledgements: Neurocrine Biosciences, Inc.
We compared interventions to improve urinary catheter care and urine culturing in adult intensive care units of 2 teaching hospitals. Compared to hospital A, hospital B had lower catheter utilization, more compliance with appropriate indications and maintenance, but higher urine culture use and more positive urine cultures per 1,000 patient days.
Tardive dyskinesia (TD) is an involuntary movement disorder that is often irreversible, can affect any body region, and can be debilitating. In the ARM-TDand AIM-TD studies, deutetrabenazine treatment demonstrated statistically and clinically significant reductions in Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with placebo (primary endpoint).
To evaluate the efficacy of deutetrabenazine, as measured by the Clinical Global Impression of Change (CGIC) scale, in patients with TD from the pooled ARM-TDand AIM-TD (24 and 36 mg/day doses) data sets, as compared with the pooled placebo cohort.
ARM-TD and AIM-TD were 12-week, randomized, double-blind, placebo-controlled studies that evaluated the safety and efficacy of deutetrabenazine for thetreatment of TD. The key secondary endpoint of each study was the proportion of patients “much improved” or “very much improved” (treatment success) at Week 12 on theCGIC.
At Week 12, the odds of treatment success among patients treated with deutetrabenazine (n=152) was more than double that of patients given placebo (n=107; odds ratio: 2.12; P=0.005). In a categorical analysis of CGIC ratings, patients treated with deutetrabenazine showed greater improvement than patients given placebo (P=0.003). Patients treated with deutetrabenazine also had a significantly better treatment response than those given placebo (least-squares mean CGIC score treatment difference: –0.4; P=0.006).
Deutetrabenazine treatment led to statistically and clinically significant improvements in TD symptoms based on the CGIC result, suggesting that clinicians were able to recognize the benefit in patients treated with deutetrabenazine.
Presented at: The International Congress of Parkinson’s Disease and Movement Disorders; June 4–8, 2017; Vancouver, British Columbia, Canada.
These studies were funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.
In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with placebo, and was generally well tolerated.
To evaluate the long-term safety/tolerability and efficacy of deutetrabenazine in patients with TD. Week 54 open-labelresults are reported in this interim analysis.
Patients with TD who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12 mg/day, titrating up to a maximum total daily dose of 48 mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration period and a long-term maintenance phase. Safetymeasures included incidence of adverse events (AEs), serious AEs (SAEs), drug-related AEs, and AEs leading to withdrawal, dose reduction, or dose suspension. This analysis reports results up to Week 54.
304 patients enrolled in the extension study. There were 215 patient-years of exposure in this analysis, and exposure-adjusted incidence rates (EAIRs) of AEs (incidence/patient-years) were comparable to or lower than those observed with short-term deutetrabenazine treatment and placebo. The frequency of SAEs (EAIR 0.14) was similar to rates observed with short-termplacebo (EAIR 0.33) and deutetrabenazine (EAIR range 0.06–0.33) treatment. AEs leading to study discontinuation (EAIR 0.08), dose reduction (EAIR 0.17), and dose suspension (EAIR 0.09) were uncommon.
Long-term treatment with deutetrabenazine was generally safe and well tolerated in patients with TD, and did not result in cumulative toxicity.
Presented at: The American Psychiatric Association 2017 Annual Meeting; May 20–24, 2017; San Diego, California, USA.
This study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.
Tardive dyskinesia (TD) is associated with prolonged exposure to dopamine receptor blockers including antipsychotics. This registry describes the prevalence and impact of involuntary movements (possible TD) in a real-world population of patients taking antipsychotics.
RE-KINECT (NCT03062033) aims to enroll 1,000 patients from 70 US psychiatric practices. Adults with ≥3 months lifetime exposure to antipsychotic(s) and ≥1 psychiatric disorder are eligible for two-tier screening: informal observation, and then clinician observation of abnormal involuntary movements in general body regions (head/face, neck/trunk, upper/lower limbs) and confirmation of possible TD. Based on clinician assessment, patients are assigned to Cohort 1 or Cohort 2 (without or with abnormal involuntary movements, respectively). In both cohorts, the following baseline assessments are included: clinician’s assessment of clinical psychiatric severity, patient perceived health‐related quality of life (EuroQOL 5-Dimensions), social burden/disability questionnaire (Sheehan Disability Scale), and 12-month retrospective chart review ofmedical and treatment history. Cohort 2 also participate in 12-month longitudinal evaluation. Interim baseline data are available from four sites.
Baseline data are currently available for 116 patients—mean age, 49.6 years; female, 60.3%; schizophrenia/schizoaffective disorder, 32.8%; at least 1 mood disorder, 84.5%, and 10.4 years mean cumulative lifetime exposure to antipsychotic(s). The most concerning health condition for both cohorts is their mental health (69.0%), followed by physical activity and nutrition (33.6%). 32.8% of subjects had clinician confirmation of possible TD.
This novel registry aims to evaluate the real-world potential impact/burden of TD. Preliminary analyses suggest that TD is common in patients with schizophrenia and mood disorders taking antipsychotics. Further analyses will explore the burden of illness in this population.
This study was funded by Neurocrine Biosciences, Inc.
Tardive dyskinesia (TD) is an involuntary movement disorder resulting from exposure to dopamine-receptor antagonists. In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with placebo, and was generally well tolerated.
To evaluate the efficacy and safety of long-term deutetrabenazine therapy in patients with TD.
Patients with TD who completed the ARM-TD or AIM-TD studies were eligible to enter this open-label, single-arm, long-term safety study after they completed the 1-week washout period and final evaluation in the blinded portion of the trial. Efficacy endpoints included the change in AIMS score from baseline, and treatment success (defined as “much improved” or “very much improved”) on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC). This analysis reports results up to Week 54.
304 patients enrolled in the extension study. At Week 54, the mean (standard error) change in AIMS score was –5.1 (0.52). After 6 weeks of deutetrabenazine treatment, the proportion of patients who achieved treatment success was 58% per the CGIC and 53% per the PGIC, and by Week 54 was 72% per the CGIC and 59% per the PGIC, thus demonstrating maintenance or enhancement of benefit over time. Deutetrabenazine was well tolerated for up to 54 weeks, and compared with the ARM-TD and AIM-TD studies, no new safety signals were detected.
54 weeks of deutetrabenazine treatment was generally efficacious, safe, and well tolerated in patients with TD.
Presented at: The American Psychiatric Association 2017 Annual Meeting; May 20–24, 2017; San Diego, California, USA.
This study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.
This study examined the impact of the middle school transition on general anxiety trajectories from middle childhood to middle adolescence, as well as how youths’ individual vulnerability and exposure to contextual stressors were associated with anxiety trajectories. Participants were 631 youth (47% boys, M age = 7.96 years at Time 1), followed for 7 successive years from second to eighth grade. Teachers reported on youths’ individual vulnerability to anxiety (anxious solitude) in second grade; youth reported on their anxiety in second to eighth grade and aspects of their social contexts particularly relevant to the school transition (school hassles, peer victimization, parent–child relationship quality, and friendship quality) in sixth to eighth grade. The results revealed two subgroups that showed either strongly increasing (5%) or decreasing (14%) levels of anxiety across the transition and two subgroups with fairly stable levels of either high (11%) or low (70%) anxiety over time. Youth in the latter two subgroups could be distinguished based on their individual vulnerability to anxiety, whereas youth with increasing anxiety reported more contextual stressors and less contextual support than youth with decreasing anxiety. In sum, findings suggest that the middle school transition has the potential to alter developmental trajectories of anxiety for some youth, for better or for worse.
There is an international movement promoting youth participation models and principles to empower more young people to be active in positive social change. To counter the prevalence of domestic violence, young people are more often targets of change rather than the instigators. Primary prevention of domestic violence is being pursued through gender-based respectful relationships education with young people. Generally, these programs are delivered using conventional adult educator models. In this study, the first year of activity of an emerging youth-led program for delivering respectful relationships education (R4Respect) is evaluated through the views of the young participants, aged from sixteen to twenty-four years, and non-participant adult stakeholders. The development of the model was guided by Good Practice Principles for Youth Development (Seymour 2012). The program is assessed using the Tiffany–Eckenrode Program Participation Scale (TEPPS) (Tiffany et al. 2012). For this article, the major themes of the study were reviewed to identify those most relevant to the Good Practice Principles. The study affirms the importance of these principles to building a participatory model in which young people feel valued and supported. Increased funding, capacity, and greater clarity and fairness in roles and responsibilities among the youth participants are suggested as program improvements.
Active youth participation models that tackle major social problems can promote positive youth development and wellbeing. Implementation and evaluation of youth participation models to curtail violence in families and other intimate relationships is limited. The present study reports on a process evaluation of a new youth participation model called R4Respect that features a peer-led approach to respectful relationships education, which is aimed at preventing domestic violence. The evaluation uses qualitative methods, based on interviews with youth participants and adult external stakeholders, drawing on the Tiffany–Eckenrode Program Participation Scale. The evaluation demonstrates that R4Respect is successfully engaging young people as decision-makers and peer-educators in strategies aimed at improving the understanding young people have of what constitutes respect in relationships. The R4Respect model shows that young people can fulfil an important role in the prevention of domestic violence.
A few studies have evaluated the impact of clinical trial results on practice in paediatric cardiology. The Infant Single Ventricle (ISV) Trial results published in 2010 did not support routine use of the angiotensin-converting enzyme inhibitor enalapril in infants with single-ventricle physiology. We sought to assess the influence of these findings on clinical practice.
A web-based survey was distributed via e-mail to over 2000 paediatric cardiologists, intensivists, cardiothoracic surgeons, and cardiac advance practice nurses during three distribution periods. The results were analysed using McNemar’s test for paired data and Fisher’s exact test.
The response rate was 31.5% (69% cardiologists and 65% with >10 years of experience). Among respondents familiar with trial results, 74% reported current practice consistent with trial findings versus 48% before trial publication (p<0.001); 19% used angiotensin-converting enzyme inhibitor in this population “almost always” versus 36% in the past (p<0.001), and 72% reported a change in management or improved confidence in treatment decisions involving this therapy based on the trial results. Respondents familiar with trial results (78%) were marginally more likely to practise consistent with the trial results than those unfamiliar (74 versus 67%, p=0.16). Among all respondents, 28% reported less frequent use of angiotensin-converting enzyme inhibitor over the last 3 years.
Within 5 years of publication, the majority of respondents was familiar with the Infant Single Ventricle Trial results and reported less frequent use of angiotensin-converting enzyme inhibitor in single-ventricle infants; however, 28% reported not adjusting their clinical decisions based on the trial’s findings.
With improvements in early survival following congenital heart surgery, it has become increasingly important to understand longer-term outcomes; however, routine collection of these data is challenging and remains very limited. We describe the development and initial results of a collaborative programme incorporating standardised longitudinal follow-up into usual care at the Children’s Hospital of Philadelphia (CHOP) and University of Michigan (UM).
We included children undergoing benchmark operations of the Society of Thoracic Surgeons. Considerations regarding personnel, patient/parent engagement, funding, regulatory issues, and annual data collection are described, and initial follow-up rates are reported.
The present analysis included 1737 eligible patients undergoing surgery at CHOP from January 2007 to December 2014 and 887 UM patients from January 2010 to December 2014. Overall, follow-up data, of any type, were obtained from 90.8% of patients at CHOP (median follow-up 4.3 years, 92.2% survival) and 98.3% at UM (median follow-up 2.8 years, 92.7% survival), with similar rates across operations and institutions. Most patients lost to follow-up at CHOP had undergone surgery before 2010. Standardised questionnaires assessing burden of disease/quality of life were completed by 80.2% (CHOP) and 78.4% (UM) via phone follow-up. In subsequent pilot testing of an automated e-mail system, 53.4% of eligible patients completed the follow-up questionnaire through this system.
Standardised follow-up data can be obtained on the majority of children undergoing benchmark operations. Ongoing efforts to support automated electronic systems and integration with registry data may reduce resource needs, facilitate expansion across centres, and support multi-centre efforts to understand and improve long-term outcomes in this population.
Necrotising enterocolitis (NEC) is a common disease in premature infants characterised by intestinal ischaemia and necrosis. The only effective preventative strategy against NEC is the administration of breast milk, although the protective mechanisms remain unknown. We hypothesise that an abundant human milk oligosaccharide (HMO) in breast milk, 2′-fucosyllactose (2′FL), protects against NEC by enhancing intestinal mucosal blood flow, and we sought to determine the mechanisms underlying this protection. Administration of HMO-2′FL protected against NEC in neonatal wild-type mice, resulted in a decrease in pro-inflammatory markers and preserved the small intestinal mucosal architecture. These protective effects occurred via restoration of intestinal perfusion through up-regulation of the vasodilatory molecule endothelial nitric oxide synthase (eNOS), as administration of HMO-2′FL to eNOS-deficient mice or to mice that received eNOS inhibitors did not protect against NEC, and by 16S analysis HMO-2′FL affected the microbiota of the neonatal mouse gut, although these changes do not seem to be the primary mechanism of protection. Induction of eNOS by HMO-2′FL was also observed in cultured endothelial cells, providing a link between eNOS and HMO in the endothelium. These data demonstrate that HMO-2′FL protects against NEC in part through maintaining mesenteric perfusion via increased eNOS expression, and suggest that the 2′FL found in human milk may be mediating some of the protective benefits of breast milk in the clinical setting against NEC.