Genomic surveillance reveals dynamic shifts in the connectivity of COVID-19 epidemics.

The maturation of genomic surveillance in the past decade has enabled tracking of the emergence and spread of epidemics at an unprecedented level. During the COVID-19 pandemic, for example, genomic data revealed that local epidemics varied considerably in the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage importation and persistence, likely due to a combination of COVID-19 restrictions and changing connectivity. Here, we show that local COVID-19 epidemics are driven by regional transmission, including across international boundaries, but can become increasingly connected to distant locations following the relaxation of public health interventions. By integrating genomic, mobility, and epidemiological data, we find abundant transmission occurring between both adjacent and distant locations, supported by dynamic mobility patterns. We find that changing connectivity significantly influences local COVID-19 incidence. Our findings demonstrate a complex meaning of "local" when investigating connected epidemics and emphasize the importance of collaborative interventions for pandemic prevention and mitigation.

The HI V O pen Call on I nformed C onsent and E thics in Research (VOICE) for Adolescents and Young Adults: A Digital Crowdsourcing Open Call in Low- and Middle-Income Countries.

BACKGROUND: Many adolescents and young adults (AYAs; 10-24 years old) are excluded from HIV research because of social, ethical, and legal challenges with informed consent, resulting in limited AYA-focused data. We use a participatory approach to identify strategies for improving AYA consent processes in HIV research in low- and middle-income countries (LMICs). METHODS: We conducted a digital crowdsourcing open call for ideas to improve AYA consent to HIV research in LMICs. Crowdsourcing involves engaging a group of people in problem-solving, then sharing emergent solutions. Submissions were evaluated by 3 independent judges using predefined criteria, with exceptional strategies receiving prizes. Demographic data were collected, and textual data were qualitatively analyzed for emergent themes in barriers and facilitators for improving AYA consent in HIV research, guided by a socioecological model. RESULTS: We received 110 strategies total; 65 were eligible for evaluation, 25 of which were identified as finalists. Fifty-eight participants from 10 LMICs submitted the 65 eligible submissions, of which 30 (52%) were 18 to 24 years old. Thematic analysis identified 10 barriers to AYA consent, including HIV stigma, limited education, and legal/regulatory barriers. Strategies for improving AYA consent processes revealed 7 potential facilitators: enhancing AYA engagement in research, involving parents/guardians, improving education/awareness, improving institutional practices/policy, making research participation more AYA-friendly, enhancing engagement of other key communities of interest, and empowering AYA. CONCLUSIONS: Diverse communities of interest in LMICs developed compelling strategies to enhance informed consent that may improve AYA inclusion in HIV research. These data will be used to develop practical guidance on improving AYA consent processes.

Notes from the Field: Increases in Imported Malaria Cases - Three Southern U.S. Border Jurisdictions, 2023.

Malaria is a severe and potentially fatal mosquitoborne disease caused by infection with Plasmodium spp. parasites. Although malaria is no longer endemic in the United States, imported infections are reported annually; the primary risk group has been U.S. residents traveling to areas where malaria is endemic (1). In 2023, sporadic locally acquired mosquito-transmitted malaria cases were reported in several U.S. states (2,3). This report describes increases in imported malaria cases in 2023 compared with 2022 in three public health jurisdictions along the U.S. southern border.

A pilot recruitment strategy to enhance ethical and equitable access to Covid-19 pediatric vaccine trials.

BACKGROUND/AIMS: The SARS-CoV-2 pandemic disproportionately impacted communities with lower access to health care in the United States, particularly before vaccines were widely available. These same communities are often underrepresented in clinical trials. Efforts to ensure equitable enrollment of participants in trials related to treatment and prevention of Covid-19 can raise concerns about exploitation if communities with lower access to health care are targeted for recruitment. METHODS: To enhance equity while avoiding exploitation, our site developed and implemented a three-part recruitment strategy for pediatric Covid-19 vaccine studies. First, we publicized a registry for potentially interested participants. Next, we applied public health community and social vulnerability indices to categorize the residence of families who had signed up for the registry into three levels to reflect the relative impact of the pandemic on their community: high, medium, and low. Finally, we preferentially offered study participation to interested families living in areas categorized by these indices as having high impact of the Covid-19 pandemic on their community. RESULTS: This approach allowed us to meet goals for study recruitment based on public health metrics related to disease burden, which contributed to a racially diverse study population that mirrored the surrounding community demographics. While this three-part recruitment strategy improved representation of minoritized groups from areas heavily impacted by the Covid-19 pandemic, important limitations were identified that would benefit from further study. CONCLUSION: Future use of this approach to enhance equitable access to research while avoiding exploitation should test different methods to build trust and communicate with underserved communities more effectively.

Virtue ethics and the unsettled ethical questions in controlled human infection studies.

Controlled human infection studies (CHIs) involve the intentional infection of human subjects for a scientific aim. Though some past challenge trials have involved serious ethical abuses, in the last few decades, CHIs have had a strong track record of safety. Despite increased attention to the ethics of CHIs during the COVID-19 pandemic, CHIs remain controversial, and there has been no in-depth treatment of CHIs through the lens of virtue ethics. In this article, we argue that virtue theory can be helpful for addressing CHIs that present a constellation of controversial, unresolved, and/or under-regulated ethical issues. We begin with some brief background on virtue ethics. We then substantiate our claim that some CHIs raise a constellation of ethical issues that are unresolved in the ethics literature and/or lack adequate regulatory guidance by demonstrating that CHIs can present indeterminate social value, risks to third parties, limitations on the right to withdraw from research, and questions about the upper limit of allowable risk. We argue that the presence of a virtuous investigator, with virtues such as prudence, compassion, and integrity, is especially important when these unresolved research ethics issues arise, which is the case for certain types of controlled human infection studies. We use the historical example of Walter Reed and the Yellow Fever Commission to illustrate this claim, and we also highlight some contemporary examples. We end by sketching some practical implications of our view, such as ensuring that investigators with experience running CHIs are involved in novel CHI models.

Possible Exposures Among Mpox Patients Without Reported Male-to-Male Sexual Contact - Six U.S. Jurisdictions, November 1-December 14, 2022.

The extent to which the 2022 mpox outbreak has affected persons without a recent history of male-to-male sexual contact (MMSC) is not well understood. During November 1-December 14, 2022, CDC partnered with six jurisdictional health departments to characterize possible exposures among mpox patients aged ≥18 years who did not report MMSC during the 3 weeks preceding symptom onset. Among 52 patients included in the analysis, 14 (27%) had a known exposure to a person with mpox, including sexual activity and other close intimate contact (eight) and household contact (six). Among 38 (73%) patients with no known exposure to a person with mpox, self-reported activities before illness onset included sexual activity and other close intimate contact (17; 45%), close face-to-face contact (14; 37%), attending large social gatherings (11; 29%), and being in occupational settings involving close skin-to-skin contact (10; 26%). These findings suggest that sexual activity remains an important route of mpox exposure among patients who do not report MMSC.

Shigellosis outbreak among persons experiencing homelessness-San Diego County, California, October-December 2021.

During October 2021, the County of San Diego Health and Human Services Agency identified five cases of shigellosis among persons experiencing homelessness (PEH). We conducted an outbreak investigation and developed interventions to respond to shigellosis outbreaks among PEH. Confirmed cases occurred among PEH with stool-cultured Shigella sonnei; probable cases were among PEH with Shigella-positive culture-independent diagnostic testing. Patients were interviewed to determine infectious sources and risk factors. Fifty-three patients were identified (47 confirmed, 6 probable); 34 (64%) were hospitalised. None died. No point source was identified. Patients reported inadequate access to clean water and sanitation facilities, including public restrooms closed because of the COVID-19 pandemic. After implementing interventions, including handwashing stations, more frequent public restroom cleaning, sanitation kit distribution, and isolation housing for ill persons, S. sonnei cases decreased to preoutbreak frequencies. Improving public sanitation access was associated with decreased cases and should be considered to prevent outbreaks among PEH.

Patient priorities for fulfilling the principle of respect in research: findings from a modified Delphi study.

BACKGROUND: Standard interpretations of the ethical principle of respect for persons have not incorporated the views and values of patients, especially patients from groups underrepresented in research. This limits the ability of research ethics scholarship, guidance, and oversight to support inclusive, patient-centered research. This study aimed to identify the practical approaches that patients in community-based settings value most for conveying respect in genomics research. METHODS: We conducted a 3-round, web-based survey using the modified Delphi technique to identify areas of agreement among English-speaking patients at primary care clinics in Washington State and Idaho who had a personal or family history of cancer. In Round 1, respondents rated the importance of 17 items, identified in prior qualitative work, for feeling respected. In Round 2, respondents re-rated each item after reviewing overall group ratings. In Round 3, respondents ranked a subset of the 8 most highly rated items. We calculated each item's mean and median rankings in Round 3 to identify which approaches were most important for feeling respected in research. RESULTS: Forty-one patients consented to the survey, 21 (51%) completed Round 1, and 18 (86% of Round 1) completed each of Rounds 2 and 3. Two sets of rankings were excluded from analysis as speed of response suggested they had not completed the Round 3 ranking task. Respondents prioritized provision of study information to support decision-making (mean ranking 2.6 out of 8; median ranking 1.5) and interactions with research staff characterized by kindness, patience, and a lack of judgment (mean ranking 2.8; median ranking 2) as the most important approaches for conveying respect. CONCLUSIONS: Informed consent and interpersonal interactions are key ways that research participants experience respect. These can be supported by other approaches to respecting participants, especially when consent and/or direct interactions are infeasible. Future work should continue to engage with patients in community-based settings to identify best practices for research without consent and examine unique perspectives across clinical and demographic groups in different types of research.

"Liver Failure in an Infant of Late-Onset Glutaric Aciduria Type II": Case Report.

Glutaric aciduria type II, also known as Multiple acyl-CoA Dehydrogenase Deficiency, results from a defect in the mitochondrial electron transport chain resulting in an inability to break down fatty-acids and amino acids. There are three phenotypes- type 1 and 2 are of neonatal onset and severe form, with and without congenital anomalies, respectively, and presents with acidosis, severe hypotonia, cardiomyopathy, hepatomegaly, and non-ketotic hypoglycemia. Type 3 or late-onset Multiple acyl-CoA Dehydrogenase Deficiency usually presents in the adolescent or adult age group with phenotype ranging from mild forms of myopathy and exercise intolerance to severe forms of acute metabolic decompensation on its chronic course. Type 3 Multiple acyl-CoA Dehydrogenase Deficiency rarely presents in infancy and in liver failure. We present a five-month-old developmentally normal female child with acute encephalopathy, hypotonia, non-ketotic hypoglycemia, metabolic acidosis, and liver failure, with a history of sibling death of suspected inborn error of metabolism. The blood acyl-carnitine levels in Tandem Mass Spectrometry and urinary organic acid analysis through Gas Chromatography-Mass Spectrometry were unremarkable. The patient initially responded to riboflavin, CoQ, and supportive management but ultimately succumbed to sepsis with shock and multi-organ dysfunction. The clinical exome sequencing reported a homozygous missense variation in exon 11 of the ETFDH gene (chr4:g.158706270C > T) that resulted in the amino acid substitution of Leucine for Proline at codon 456 (p.Pro456Leu) suggestive of Glutaric aciduria type IIc (OMIM#231,680).

A Novel Mutation in Cystic Fibrosis Presenting as Pseudo Bartter Syndrome: A Case Report.

Pseudo-Bartter's (PB) syndrome is characterized by hypokalemic metabolic alkalosis and failure to thrive which constitutes a rare but typical presentation of cystic fibrosis (CF) in children. The most common mutation of CF is F508del, due to loss of 3 base pairs, causing deletion of phenylalanine, at position 508. We present a case of CF presenting with failure to thrive, dehydration, PB syndrome associated with urosepsis and primo-colonization with Escherichia coli suggesting the role of epigenetic factors. The heterozygous state for Phe508del mutation in Exon 11 combination with Glu92Ala in Exon 4 resulted in epigenetic effect on atypical phenotype as PBS, a novel mutation identified in our case.

Fair Allocation of Scarce Therapies for Coronavirus Disease 2019 (COVID-19).

The US Food and Drug Administration (FDA) has issued emergency use authorizations (EUAs) for monoclonal antibodies (mAbs) for nonhospitalized patients with mild or moderate coronavirus disease 2019 (COVID-19) disease and for individuals exposed to COVID-19 as postexposure prophylaxis. EUAs for oral antiviral drugs have also been issued. Due to increased demand because of the Delta variant, the federal government resumed control over the supply and asked states to ration doses. As future variants (eg, the Omicron variant) emerge, further rationing may be required. We identify relevant ethical principles (ie, benefiting people and preventing harm, equal concern, and mitigating health inequities) and priority groups for access to therapies based on an integrated approach to population health and medical factors (eg, urgently scarce healthcare workers, persons in disadvantaged communities hard hit by COVID-19). Using priority categories to allocate scarce therapies effectively operationalizes important ethical values. This strategy is preferable to the current approach of categorical exclusion or inclusion rules based on vaccination, immunocompromise status, or older age, or the ad hoc consideration of clinical risk factors.

Responsible Inclusion of Pregnant Individuals in Eradicating HCV.

HCV infections have increased in recent years due to injection drug use and the opioid epidemic. Simultaneously, HCV cure has become a reality, with the advent of direct-acting antivirals (DAAs) and expansion of treatment programs. As a result, HCV screening recommendations now include all adults, including pregnant individuals; and many countries have endorsed widespread DAA access as a strategy to achieve HCV eradication. However, almost universally, pregnant individuals have been systematically excluded from HCV clinical research and treatment programs. This omission runs counter to public health strategies focused on elimination of HCV but is consistent with a historical pattern of exclusion of pregnant individuals from research. Our systematic review of publications on HCV treatment with DAAs in pregnancy revealed only one interventional study, which evaluated sofosbuvir/ledipasvir in 8 pregnant individuals. Given the paucity of research on this issue of great public health importance, we aimed to appraise the current landscape of HCV research/treatment and analyze the ethical considerations for responsibly including pregnant individuals. We propose that pregnancy may be an opportune time to offer HCV treatment given improved access, motivation, and other health care monitoring occurring in the antenatal period. Moreover, treatment of pregnant individuals may support the goal of eliminating perinatal HCV transmission and overcome the established challenges with transitioning care after delivery. The exclusion of pregnant individuals without justification denies them and their offspring access to potential health benefits, raising justice concerns considering growing data on DAA safety and global efforts to promote equitable and comprehensive HCV eradication. Finally, we propose a path forward for research and treatment programs during pregnancy to help advance the goal of HCV elimination.

Emergence of Extended-Spectrum ß-Lactamase-Producing Pathogens in Community-Acquired Urinary Tract Infections Among Infants at a Pediatric Emergency Department.

BACKGROUND: Extended-spectrum ß-lactamase (ESBL)-producing pathogens are common among adults and are associated with extended and multiple hospitalizations. They cause urinary tract infections (UTIs) among children with known risk factors such as urinary tract abnormalities and antimicrobial prophylaxis. The emergence of UTIs caused by ESBL-producing organisms among infants has not been well characterized. OBJECTIVE: We sought to describe the incidence and current clinical management of infants who were diagnosed with UTIs caused by ESBL-producing organisms at a pediatric emergency department (ED). In addition, we sought to describe risk factors associated with inpatient hospitalization for UTIs caused by ESBL-producing organisms. METHODS: We retrospectively identified infants who were treated in the ED from 2013 to 2017 and who had positive urinalyses and urine cultures positive for greater than 50,000 colony-forming unit per milliliter of a single ESBL-producing urinary pathogen. We abstracted details of clinical management and known previous risk factors, including prior neonatal intensive care unit hospitalization stay, prior UTI caused by an ESBL-producing organism, and known urologic abnormalities. RESULTS: Forty-five UTIs caused by ESBL-producing organisms occurred in 43 patients (mean age of 5.9 months and 59% female)-ESBL Escherichia coli represented the majority (42/45). The incidence of UTIs caused by ESBL-producing organisms ranged from 0.9% to 4.5% during the 5-year study period. The 13 patients (26%) admitted from the ED were significantly younger than discharged patients (1.9 vs 6.7 months, P = 0.016) and more likely to have had prior neonatal intensive care unit hospitalizations (50% vs 15.6%, P = 0.0456). Of the 33 visits (77%) resulting in initial outpatient management, 5 were followed by readmission for parenteral antibiotic treatment. Of those who were readmitted, 40% (n = 2) were afebrile at the time of admission. The remainder (28/33) completed outpatient oral antibiotic courses guided by susceptibilities. Two patients (4%) had negative repeat urine cultures despite in vitro resistance to initial antibiotic coverage. CONCLUSIONS: Extended spectrum ß-lactamase-producing organisms are an increasing cause of UTIs in infants presenting at a pediatric ED, and outpatient management may be reasonable for infants older than 2 months.

The effectiveness of a bespoke mobile application in improving adherence with removable orthodontic retention over 12 months: A randomized controlled trial.

INTRODUCTION: The primary aim was to analyze the effect of providing a mobile application (My Retainers) on adherence with removable retention. METHODS: Eighty-four participants planned for thermoplastic retainers were randomly allocated to 2 groups. The intervention group was given access to a bespoke mobile application, while the control group was not given access. Baseline data were obtained at the removal of orthodontic appliances with follow-up at 3 months, 6 months, 9 months, and 12 months. The primary outcome was objectively assessed retainer wear recorded using a TheraMon microelectronic sensor (MC Technology GmbH, Hargelsberg, Austria). Secondary outcomes were stability and periodontal implications. RESULTS: The objectively assessed wear time at 12 months was low in both groups, being marginally higher in the intervention (median, 3.09 h/d; interquartile range, 8.1) than the control group (median, 1.44 h/d; interquartile range, 9.22) with no between-group statistical difference (P = 0.30, 95% confidence interval [CI], -3.91 to 1.19). No statistically significant difference was identified between the groups in terms of stability and periodontal outcomes. Improvement in plaque scores (P <0.0001; 95% CI, -0.20 to 0.15) and bleeding on probing (P <0.0001, 95% CI, -0.23 to -0.12) was noted over time with no periodontal attachment loss detected over the study period. CONCLUSIONS: Provision of the mobile application did not lead to improved adherence with thermoplastic retainer wear. Similarly, no benefit in respect of either occlusal stability or periodontal health was observed over the 12-month study period. Further novel approaches to improve adherence with retainer wear and oral hygiene measures are required. REGISTRATION: NCT03224481. PROTOCOL: Not published. FUNDING: This work was supported by funding from the European Orthodontic Society.

The Essential Role of Data and Safety Monitoring Boards (DSMBs) in Ensuring the Ethics of Global Vaccine Trials to Address Coronavirus Disease 2019 (COVID-19O).

Coronavirus disease 2019 (COVID-19) vaccines are being developed and implemented with unprecedented speed. Accordingly, trials considered ethical at their inception may quickly become concerning. We provide recommendations for Data and Safety Monitoring Boards (DSMBs) on monitoring the ethical acceptability of COVID-19 vaccine trials, focusing on placebo-controlled trials in low- and middle-income countries.

Parental Enrollment Decision-Making for a Neonatal Clinical Trial.

OBJECTIVE: To describe the parental experience of recruitment and assess differences between parents who participated and those who declined to enroll in a neonatal clinical trial. STUDY DESIGN: This was a survey conducted at 12 US neonatal intensive care units of parents of infants who enrolled in the High-dose Erythropoietin for Asphyxia and encephaLopathy (HEAL) trial or who were eligible but declined enrollment. Questions assessed 6 factors of the parental experience of recruitment: (1) interactions with research staff; (2) the consent experience; (3) perceptions of the study; (4) decisional conflict; (5) reasons for/against participation; and (6) timing of making the enrollment decision. RESULTS: In total, 269 of 387 eligible parents, including 183 of 242 (75.6%) of those who enrolled their children in HEAL and 86 of 145 (59.3%) parents who declined to enroll their children in HEAL, were included in analysis. Parents who declined to enroll more preferred to be approached by clinical team members rather than by research team members (72.9% vs 49.2%, P = .005). Enrolled parents more frequently reported positive initial impressions (54.9% vs 10.5%, P < .001). Many parents in both groups made their decision early in the recruitment process. Considerations of reasons for/against participation differed by enrollment status. CONCLUSIONS: Understanding how parents experience recruitment, and how this differs by enrollment status, may help researchers improve recruitment processes for families and increase enrollment. The parental experience of recruitment varied by enrollment status. These findings can guide future work aiming to inform optimal recruitment strategies for neonatal clinical trials.

Ethically designing research to inform multidimensional, rapidly evolving policy decisions: Lessons learned from the PROMISE HIV Perinatal Prevention Trial.

Research in rapidly evolving policy contexts can lead to the following ethical challenges for sponsors and researchers: the study's standard of care can become different than what patients outside the study receive, there may be political or other pressure to move ahead with unproven interventions, and new findings or revised policies may decrease the relevance of ongoing studies. These ethical challenges are considerable, but not unprecedented. In this article, we review the case of a multinational, randomized, controlled perinatal HIV prevention trial, the "PROMISE" (Promoting Maternal Infant Survival Everywhere) study. PROMISE compared the relative efficacy and safety of interventions to prevent mother to child transmission of HIV. The sponsor engaged an independent international ethics panel to address controversy about the study's standard of care and relevance as national and international guidelines changed. This ethics panel concluded that continuing the PROMISE trial as designed was ethically permissible because: (1) participants in all arms received interventions that were effective, and there was insufficient evidence about whether one intervention was more effective or safer than the other, and (2) data from PROMISE could be useful for a diverse range of stakeholders. In general, trials designed to inform rapidly evolving policy issues should develop mechanisms to revisit social value while recognizing that the value of research varies for diverse stakeholders with legitimate reasons to weigh evidence differently. We conclude by providing four reasons that trials may depart from the standard of care after a change in policy, while remaining ethically justifiable, and by suggesting how to improve existing trial oversight mechanisms to address evolving social value.

Antinuclear Antibody Profiling in Patients of a Tertiary Care Centre in Central India.

The incidence of autoimmune disorders that includes the connective tissue diseases has seen a rise in India in recent times. Antinuclear antibodies, the telltale sign of systemic autoimmune response, thus can be used as a screening tool and also to support the diagnosis of systemic autoimmune disease. The present retrospective cross- sectional analysis aimed to study the antinuclear antibodies profile (patterns and specific antibody reactivity) amongst suspected cases of auto-immune disorders at a tertiary care teaching hospital. The study retrieved and reviewed reports of 644 patients sent for ANA testing by indirect immunofluorescence assay over a period of 1 year by different specialty departments. Positive samples were further processed for anti-ds-DNA antibody and antibodies to extractable nuclear antigen. Data collected was statistically analysed. ANA pattern positivity was observed in 31% of cases and a positive antibody reactivity was seen in 66% of them. Female predominance (82%) was noted in both pattern positivity and antibody reactivity. High levels of pattern positivity and antibody reactivity was found in the young adults (45.9%). Amongst the ANA patterns, the nuclear homogenous pattern was found the commonest. The common antibodies associated with this pattern were anti-dsDNA and U1 Sm/RNP antibodies. A stronger fluorescence intensity on initial screening showed a higher confirmation rate for specific antibodies on immunoassay. High occurrence of positive ANA patterns in autoimmune disorders suggests its utilization as a screening tool for them and would also play an adjuvant to the diagnosis. Early knowledge about future autoimmunity will earn better prognostic achievements through better treatment interventions.

Sickle Cell Trait Presenting as Chronic Calcific Pancreatitis with Pseudocyst- A Case Report.

Sickle cell disease is known to cause acute pancreatitis either due to gall stones obstructing the pancreatic duct or by vaso-occlusive mechanism. However chronic pancreatitis is a very rare complication in sickle cell anemia. We report a case of sickle cell trait presenting with chronic pancreatitis with pseudo cyst. USG abdomen and CT abdomen confirmed the diagnosis of chronic calcific pancreatitis with pseudocyst. Etiological work up for other causes did not reveal anything except sickle cell trait. This case represents a rare association between chronic calcific pancreatitis and sickle cell trait.

Ras and Rap1: A tale of two GTPases.

Ras oncoproteins play pivotal roles in both the development and maintenance of many tumor types. Unfortunately, these proteins are difficult to directly target using traditional pharmacological strategies, in part due to their lack of obvious binding pockets or allosteric sites. This obstacle has driven a considerable amount of research into pursuing alternative ways to effectively inhibit Ras, examples of which include inducing mislocalization to prevent Ras maturation and inactivating downstream proteins in Ras-driven signaling pathways. Ras proteins are archetypes of a superfamily of small GTPases that play specific roles in the regulation of many cellular processes, including vesicle trafficking, nuclear transport, cytoskeletal rearrangement, and cell cycle progression. Several other superfamily members have also been linked to the control of normal and cancer cell growth and survival. For example, Rap1 has high sequence similarity to Ras, has overlapping binding partners, and has been demonstrated to both oppose and mimic Ras-driven cancer phenotypes. Rap1 plays an important role in cell adhesion and integrin function in a variety of cell types. Mechanistically, Ras and Rap1 cooperate to initiate and sustain ERK signaling, which is activated in many malignancies and is the target of successful therapeutics. Here we review the role activated Rap1 in ERK signaling and other downstream pathways to promote invasion and cell migration and metastasis in various cancer types.