Onvansertib in Combination with FOLFIRI and Bevacizumab in Second-Line Treatment of KRAS-Mutant Metastatic Colorectal Cancer: A Phase Ib Clinical Study.

PURPOSE: Onvansertib is a highly specific inhibitor of polo-like kinase 1 (PLK1), with demonstrated safety in solid tumors. We evaluated, preclinically and clinically, the potential of onvansertib in combination with chemotherapy as a therapeutic option for KRAS-mutant colorectal cancer. PATIENTS AND METHODS: Preclinical activity of onvansertib was assessed (i) in vitro in KRAS wild-type and -mutant isogenic colorectal cancer cells and (ii) in vivo, in combination with irinotecan, in a KRAS-mutant xenograft model. Clinically, a phase Ib trial was conducted to investigate onvansertib at doses 12, 15, and 18 mg/m2 (days 1-5 and 14-19 of a 28-day cycle) in combination with FOLFIRI/bevacizumab (days 1 and 15) in patients with KRAS-mutant metastatic colorectal cancer who had prior oxaliplatin exposure. Safety, efficacy, and changes in circulating tumor DNA (ctDNA) were assessed. RESULTS: In preclinical models, onvansertib displayed superior activity in KRAS-mutant than wild-type isogenic colorectal cancer cells and demonstrated potent antitumor activity in combination with irinotecan in vivo. Eighteen patients enrolled in the phase Ib study. Onvansertib recommended phase II dose was established at 15 mg/m2. Grade 3 and 4 adverse events (AE) represented 15% of all treatment-related AEs, with neutropenia being the most common. Partial responses were observed in 44% of patients, with a median duration of response of 9.5 months. Early ctDNA dynamics were predictive of treatment efficacy. CONCLUSIONS: Onvansertib combined with FOLIFRI/bevacizumab exhibited manageable safety and promising efficacy in second-line treatment of patients with KRAS-mutant metastatic colorectal cancer. Further exploration of this combination therapy is ongoing. See related commentary by Stebbing and Bullock, p. 2005.

Guselkumab, an inhibitor of the IL-23p19 subunit, provides sustained improvement in signs and symptoms of active psoriatic arthritis: 1 year results of a phase III randomised study of patients who were biologic-naïve or TNFα inhibitor-experienced.

OBJECTIVE: Evaluation of the efficacy and safety of guselkumab, a human monoclonal antibody targeting the interleukin-23p19 subunit, in patients with psoriatic arthritis (PsA) through 1 year. METHODS: Adults who met ClASsification criteria for Psoriatic ARthritis, with active disease (≥3 swollen and ≥3 tender joints; C reactive protein ≥0.3 mg/dL) despite standard treatment (31% previously received ≤2 tumour necrosis factor inhibitors (TNFi)), were randomised (1:1:1) to guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at Week0, Week4, then Q8W; or placebo with cross-over to guselkumab 100 mg Q4W at Week24 (PBO→Q4W) through Week48. Clinical efficacy through Week52 (employing non-responder imputation) and adverse events (AEs) through Week60 were evaluated. RESULTS: Of 381 treated patients, 90% completed the study. Numerical increases in the proportions of patients achieving ≥20% improvement in ACR criteria (ACR20) were observed post-Week24, reaching 73% (94/128) and 60% (76/127) for Q4W-randomised and Q8W-randomised patients, respectively, by Week52. Proportions of patients achieving ACR50/ACR70/skin responses and minimal/very low disease activity were maintained, as were improvements in physical function and health-related quality of life, through Week52 in guselkumab-randomised patients. Response to guselkumab was maintained in both TNFi-naïve and TNFi-experienced patients. Serious AEs and serious infections occurred in similar proportions of guselkumab Q4W-randomised (3% and 0%) and Q8W-randomised (6% and 2%) patients through Week60, with no new safety concerns versus observations through Week24. No guselkumab-treated patient and two patients receiving placebo died; no study participant developed opportunistic infection or inflammatory bowel disease. CONCLUSION: Guselkumab provided sustained improvement across multiple clinical manifestations of PsA, maintaining a favourable benefit-risk profile, through 1 year regardless of prior TNFi exposure.

Efficacy and Safety of Guselkumab, an Interleukin-23p19-Specific Monoclonal Antibody, Through One Year in Biologic-Naive Patients With Psoriatic Arthritis.

OBJECTIVE: Guselkumab, a human monoclonal antibody specific to interleukin-23p19, demonstrated efficacy and safety versus placebo through week 24 of the phase III DISCOVER-2 trial in biologic-naive patients with psoriatic arthritis (PsA). Here we report 1-year DISCOVER-2 findings. METHODS: Adults with active PsA (≥5 swollen and ≥5 tender joints; C-reactive protein level ≥0.6 mg/dl) despite standard nonbiologic treatment were randomized to receive subcutaneous injections of guselkumab 100 mg every 4 weeks, guselkumab 100 mg at week 0, week 4 and every 8 weeks thereafter, or placebo with crossover to guselkumab 100 mg every 4 weeks at week 24. We primarily evaluated clinical efficacy through week 52 by imputing missing data (nonresponse for categorical end points; no change/using multiple imputation for continuous end points). Observed radiographic scores and adverse events (AEs) were summarized. RESULTS: Of 739 randomized, treated patients, 93% completed week 52. The proportions of patients in whom a ≥20% improvement from baseline in American College of Rheumatology criteria (ACR20) was achieved were maintained after week 24, reaching 71% (173 of 245) and 75% (185 of 248) for patients randomized to receive treatment every 4 weeks or every 8 weeks, respectively, by week 52. The proportions of patients in whom ACR50/ACR70 and skin responses, minimal or very low disease activity, and dactylitis or enthesitis resolution were achieved at week 24 were also maintained through week 52. Further, low levels of radiographic progression, along with improvements in physical function and health-related quality of life, were sustained through week 52 with continued guselkumab treatment. Few patients experienced serious infections through week 52, with no evidence of a dosing regimen response or increase from weeks 0-24 (4 of 493 [0.8%]) to weeks 24-52 (3 of 493 [0.6%]) among guselkumab-randomized patients. No patient developed an opportunistic infection or died. CONCLUSION: In biologic-naive PsA patients, guselkumab provided sustained improvements across diverse manifestations and maintained a favorable risk-benefit profile through week 52.

Guselkumab in patients with active psoriatic arthritis who were biologic-naive or had previously received TNFα inhibitor treatment (DISCOVER-1): a double-blind, randomised, placebo-controlled phase 3 trial.

BACKGROUND: Many patients with psoriatic arthritis have an inadequate response to tumor necrosis factor (TNF) inhibitors. Guselkumab, a specific inhibitor of interleukin-23 (IL-23) via IL-23 p19 subunit binding, significantly improved psoriatic arthritis signs and symptoms with an acceptable safety profile in a phase 2 trial. METHODS: This multicentre, double-blind, randomised, placebo-controlled, phase 3 trial was done at 86 sites in 13 countries across Asia, Australasia, Europe, and North America and enrolled adults with active psoriatic arthritis (at least three swollen and three tender joints; and C-reactive protein ≥0·3 mg/dL) despite standard therapies. Eligibility criteria included inadequate response to or intolerance of standard treatment, including at least 4 months of apremilast, at least 3 months of non-biologic disease-modifying antirheumatic drugs (DMARDs), or at least 4 weeks of non-steroidal anti-inflammatory drugs for psoriatic arthritis. About 30% of study participants could have previously received one or two TNF inhibitors. Patients were randomly assigned (1:1:1, computer-generated permuted blocks; stratified by baseline DMARD and previous TNF inhibitor use) to subcutaneous guselkumab 100 mg every 4 weeks; guselkumab 100 mg at weeks 0, 4, then every 8 weeks; or matching placebo. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) at week 24 in all patients per assigned treatment group using non-responder imputation. Safety was assessed in all patients per treatment received. This trial is registered at ClinicalTrials.gov, NCT03162796 (active, not recruiting). FINDINGS: From Aug 28, 2017, to Aug 17, 2018, we screened 624 patients, of whom 381 were randomly assigned and treated with guselkumab every 4 weeks (n=128), guselkumab every 8 weeks (n=127), or placebo (n=126). 362 patients continued study treatment up to week 24. The primary endpoint was met: ACR20 at week 24 was achieved by significantly greater proportions of patients in the guselkumab every 4 weeks group (76 [59%] of 128 [95% CI 50-68]) and every 8 weeks group (66 [52%] of 127 [43-61]) than in the placebo group (28 [22%] of 126 [15-30]), with percentage differences versus placebo of 37% (95% CI 26-48) for the every 4 weeks group and 30% (19-41) for the every 8 weeks group (both p<0·0001). Serious adverse events up to week 24 occurred in no patients receiving guselkumab every 4 weeks, four (3%) patients receiving guselkumab every 8 weeks, and five (4%) patients receiving placebo. Up to week 24, one patient in the placebo group died from cardiac failure and two had serious infections; no guselkumab-treated patient died or had serious infections. INTERPRETATION: Guselkumab demonstrated a favourable benefit-risk profile and might be an effective treatment option for patients with active psoriatic arthritis. FUNDING: Janssen Research and Development.

Influenza A 2009 (H1N1) virus in admitted and critically ill patients.

INTRODUCTION: The influenza A 2009 (H1N1) virus is a pandemic respiratory infection commanding international attention. More information is needed on patient demographics, illness severity, and risk indicators. METHODS: A total of 43 patients with H1N1 influenza A 2009 presenting to 2 urban academic medical centers during the first wave were assessed for demographics, triage vital signs, hemograms, and serum chemistries including lactate. Chest X-rays were assessed for infiltrate or effusion. Illness severity markers were recorded including anion gap (AG), strong ion gap (SIG), systemic inflammatory response syndrome score, shock index, confusion, uremia, respiratory rate, blood pressure, and age >= 65 years (CURB-65) score, and pneumonia severity index. Subgroup analysis was performed on asthmatic, pregnant, and intensive care unit (ICU) versus non-ICU patients. RESULTS: Eighty-one percent of patients were women. Pregnancy (34.8%), asthma (39.5%), diabetes mellitus (18.6%), and sickle cell (6.98%) were the most frequent comorbidities. In all, 91% had positive influenza nasopharyngeal direct antigen test, while 9% tested positive only by viral culture or real-time reverse transcriptase polymerase chain reaction (rRT-PCR); 14% required ICU admission; and 20.8% had infiltrate on chest X-ray. A trend toward greater incidence of ICU admission existed among patients with elevated SIG (P = .08), however contrary to our prior studies in noninfluenza patients, an elevated SIG in the presence of normal AG and lactate measurements did not correlate with ICU admission. CONCLUSION: A high percentage of patients with H1N1 presented with underlying comorbid conditions including asthma and pregnancy. Traditional markers of pneumonia severity including CURB-65 score, Pneumonia Severity Index (PSI), serum lactate, and AG did not correlate with ICU admission in patients with H1N1. Strong ion gap effectively identified significant acid-base disturbances not identified by lactate or AG, however the trend of greater ICU admission rates among patients with elevated SIG did not reach statistical significance. Further study is needed to identify clinical tools to aid in risk-stratifying H1N1 patients.

The utility of shock index in differentiating major from minor injury.

OBJECTIVE: The importance of early recognition of hemorrhagic shock and its effects on outcome have long been recognized. Traditional vital signs are relatively insensitive as early diagnostic markers of hemorrhage. The shock index (SI); heart rate (HR) divided by systolic blood pressure (SBP), has been suggested as such a marker. We tested the diagnostic utility of the SI in differentiating major from minor injury in trauma patients. METHODS: Retrospective study of a prospectively collected observational cohort at a level I trauma center. Demographics, injury mechanism, HR, SBP, base deficit and lactate were recorded and Injury Severity Score were calculated. Major injury was defined as either a change in hematocrit greater than 10 or blood transfusion requirement during initial 24 h, or Injury Severity Score greater than 15. RESULTS: One thousand four hundred and thirty-five trauma patients were enrolled, average age 35.2±16.9 years. Two hundred and forty-two were classified as major injury. The area under the receiver operator characteristic curves for SI [0.63 95% confidence interval (CI) 0.59-0.67] was significantly less than that for base deficit (0.72, 95% CI: 0.69-0.76) or lactate (0.69, 95% CI: 0.65-0.73). The diagnostic performance of SI was slightly better than HR (0.58) but not SBP (0.61). To reach sensitivity of 90%, the SI must be 0.5, well in the range of a normal SBP and HR. CONCLUSION: The SI can be a valuable tool, raising suspicion when it is abnormal even when other parameters are not, but is far too insensitive for use as a screening device to rule out disease. A normal SI should not lower the suspicion of major injury.

Patients with detectable cocaethylene are more likely to require intensive care unit admission after trauma.

Cocaethylene (CE) is a toxic metabolite that is formed after simultaneous consumption of cocaine and ethanol. This potent stimulant is more toxic than cocaine and has a longer half-life. The deleterious hemodynamic and cardiovascular effects of CE have been proven in animal models. The aim of this study is to assess the impact of CE on clinical outcomes after trauma. We prospectively enrolled adult (≥13 years) trauma patients requiring admission. Predictor variables were age, sex, mechanism of injury, Injury Severity Score, base deficit, and toxicology groups (ethanol alone, cocaine alone, CE, and none). The outcomes examined were mortality, intensive care unit (ICU) admission, and length of hospital stay (LOS). We used nonparametric tests to compare continuous variables and χ² test to compare categorical data. We constructed a logistic regression to identify variables that could predict mortality and ICU admission. We enrolled 417 patients (74% male; 70% blunt injury; median age, 40 [range, 13-95]; overall mortality, 2.2%). Urine toxicology and serum ethanol level screens classified patients into the following groups: 13.4% ethanol only, 4.1% cocaine only, 8.9% CE, and 46% none. Mortality and LOS were not statistically different among the groups. In logistic regression analysis, none of the variables were statistically significant in predicting mortality. However, the presence of CE significantly increased the likelihood of ICU admission (odds ratio, 5.9; 95% confidence interval, 1.6-22). The presence of detectable CE in the urine does not increase the mortality or LOS in trauma patients requiring admission but does increase the likelihood of ICU admission.

Triage hyperglycemia as a prognostic indicator of major trauma.

BACKGROUND: To test the diagnostic utility of the triage serum glucose in differentiating major from minor injuries. METHODS: Prospective database at Kings County Hospital, a Level I trauma center, from August 2005 to August 2008. INCLUSION CRITERIA: trauma patients 13+ years. EXCLUSION CRITERIA: diabetes or obvious life-threatening injuries requiring immediate surgery, isolated head trauma, or transferred or dead on arrival. We recorded age, sex, injury mechanism, base deficit (BD), lactate (LAC), and serum glucose and calculated Injury Severity Scores. Major injury: a change in hematocrit >10, blood transfused within 24 hours, or Injury Severity Score >15. Data were reported as mean differences (95% confidence interval [CI]). Groups were compared by Student's t test; receiver operator characteristic curves were compared by Wilcoxon test (two-tailed, [alpha] = 0.05). RESULTS: One thousand six hundred forty-nine patients with an average age of 35.5 years (13-95 years), 79.5% male, and 50% blunt trauma were studied. Patients with major (n = 278) compared with minor injury (n = 1371) had significantly (p < 0.0001) lower BD and higher LACs (p < 0.0001). Major injury patients had significantly (p < 0.0001) higher serum glucose levels (8.33 mMol/L, 95% CI: 7.94-8.69 mMol/L) compared with patients with minor injuries (6.49 mMol/L, 95% CI: 6.39-6.66 mMol/L). Areas under the curve for glucose (0.73, 95% CI: 0.70-0.76) are similar to BD (0.72, 95% CI: 0.68-0.76) and LAC (0.71, 95% CI: 0.67-0.75). CONCLUSIONS: Serum glucose was as discriminating as BD or LAC in differentiating minor from major injury. An initial glucose >/=11.1 mMol/L had a low sensitivity (15%) but a high specificity (94%) for major injury.

Novel influenza A(H1N1) virus among gravid admissions.

BACKGROUND: Pandemic novel influenza A(H1N1) is a substantial threat and cause of morbidity and mortality in the pregnant population. METHODS: We conducted an observational analysis of 18 gravid patients with H1N1 in 2 academic medical centers. Cases were identified based on direct antigen testing (DAT) of nasopharyngeal swabs followed by real-time reverse-transcriptase polymerase chain reaction analysis (rRT-PCR) or viral culture. Patient demographics, symptoms, hospital course, laboratory and radiographic results, pregnancy outcome, and placental pathologic information were recorded. Results were then compared with published reports of the H1N1 outbreak and reports of flu pandemics of 1918 and 1957. RESULTS: Eighteen pregnant patients were admitted with H1N1 during the study period. All patients were treated with oseltamivir phosphate beginning on the day of admission. Mean (SD) age was 27 (6.6) years (age range, 18-40 years); median length of hospital stay was 4 days. Intensive care unit admission rate was 17% (n = 3). Demographically, 2 patients were health care workers (11%); 15 were black (83%); 2, Hispanic (11%); and 1, white (6%). None reported recent travel. Half of the patients presented with gastrointestinal or abdominal complaints; 13 patients met sepsis criteria (72%). The most common comorbidities were asthma, sickle cell disease, and diabetes. Fourteen patients tested positive for H1N1 on DAT (initial or repeated) (78%); in the other 4 cases, H1N1 was identified by viral culture or rRT-PCR (22%). Seven patients delivered during hospitalization (39%), 6 prematurely and 4 via emergency cesarean delivery. There were 2 fetal deaths (11%). No maternal mortality was recorded. CONCLUSIONS: Admitted pregnant patients with H1N1 are at risk for obstetrical complications including fetal distress, premature delivery, emergency cesarean delivery, and fetal death. A high number of patients presented with gastrointestinal and abdominal complaints. Early antiviral treatment may improve maternal outcomes.

Leukocytosis as prognostic indicator of major injury.

OBJECTIVE: To test the diagnostic use of the triage white blood cell (WBC) count in differentiating major from minor injuries. METHODS: We conducted a retrospective study of a prospectively collected database of trauma patients 13 years of age or older at a Level I trauma center from January 2005 through December 2008. We excluded all patients with obvious life-threatening injuries requiring immediate surgery, isolated head trauma, transferred from another institution or dead on arrival. We recorded age, sex, injury mechanism, vital signs, WBC, base deficit (BD), lactate (LAC) and calculated injury severity scores (ISS). Major injury was defined as either a change in hematocrit >10 points or blood transfused within 24 hours, or ISS >15. RESULTS: 805 patients were included in the study with an average age of 38.6 years (Range 13-95 yrs) years. 75.3% of patients were male, 45.6% had blunt and 34.4% had penetrating trauma. For vital signs, blood pressure was not significantly different between major and minor injury patients. Major compared to minor injury patients had a statistically but not clinically significant higher heart rate. Major injury patients had significantly (p < 0.0001) higher WBC count (10.53 K/µl, 95% CI: 9.7-11.3) compared to patients with minor injuries (8.92 K/µl, 95% CI: 8.7-9.2), but both were in the normal range. Patients with major compared to minor injury had significantly (p < 0.0001) higher BD (-3.1 versus -0.027 mmol/L) and higher LAC (3.9 versus 2.48 mmol/L). Areas under the curve for WBC count (0.60, 95% CI: 0.54-0.66) are similar to BD (0.69, 95% CI: 0.63-0.74) and LAC (0.66, 95% CI: 0.60-0.71). CONCLUSION: WBC count is not a useful addition as a diagnostic indicator of major trauma in our study population.

Transpositionally active episomal hAT elements.

BACKGROUND: hAT elements and V(D)J recombination may have evolved from a common ancestral transposable element system. Extrachromosomal, circular forms of transposable elements (referred to here as episomal forms) have been reported yet their biological significance remains unknown. V(D)J signal joints, which resemble episomal transposable elements, have been considered non-recombinogenic products of V(D)J recombination and a safe way to dispose of excised chromosomal sequences. V(D)J signal joints can, however, participate in recombination reactions and the purpose of this study was to determine if hobo and Hermes episomal elements are also recombinogenic. RESULTS: Up to 50% of hobo/Hermes episomes contained two intact, inverted-terminal repeats and 86% of these contained from 1-1000 bp of intercalary DNA. Episomal hobo/Hermes elements were recovered from Musca domestica (a natural host of Hermes), Drosophila melanogaster (a natural host of hobo) and transgenic Drosophila melanogaster and Aedes aegypti (with autonomous Hermes elements). Episomal Hermes elements were recovered from unfertilized eggs of M. domestica and D. melanogaster demonstrating their potential for extrachromosomal, maternal transmission. Reintegration of episomal Hermes elements was observed in vitro and in vivo and the presence of Hermes episomes resulted in lower rates of canonical Hermes transposition in vivo. CONCLUSION: Episomal hobo/Hermes elements are common products of element excision and can be maternally transmitted. Episomal forms of Hermes are capable of integration and also of influencing the transposition of canonical elements suggesting biological roles for these extrachromosomal elements in element transmission and regulation.

Hermes transposon distribution and structure in Musca domestica.

Hermes are hAT transposons from Musca domestica that are very closely related to the hobo transposons from Drosophila melanogaster and are useful as gene vectors in a wide variety of organisms including insects, planaria, and yeast. hobo elements show distinct length variations in a rapidly evolving region of the transposase-coding region as a result of expansions and contractions of a simple repeat sequence encoding 3 amino acids threonine, proline, and glutamic acid (TPE). These variations in length may influence the function of the protein and the movement of hobo transposons in natural populations. Here, we determine the distribution of Hermes in populations of M. domestica as well as whether Hermes transposase has undergone similar sequence expansions and contractions during its evolution in this species. Hermes transposons were found in all M. domestica individuals sampled from 14 populations collected from 4 continents. All individuals with Hermes transposons had evidence for the presence of intact transposase open reading frames, and little sequence variation was observed among Hermes elements. A systematic analysis of the TPE-homologous region of the Hermes transposase-coding region revealed no evidence for length variation. The simple sequence repeat found in hobo elements is a feature of this transposon that evolved since the divergence of hobo and Hermes.

Topi, an IS630/Tc1/mariner-type transposable element in the African malaria mosquito, Anopheles gambiae.

IS630/Tc1/mariner elements are diverse and widespread within insects. The African malaria mosquito, Anopheles gambiae, contains over 30 families of IS630/Tc1/mariner elements although few have been studied in any detail. To examine the history of Topi elements in An. gambiae populations, Topi elements (n=73) were sampled from five distinct populations of An. gambiae from eastern and western Africa and evaluated with respect to copy number, nucleotide diversity and insertion site-occupancy frequency. Topi 1 and 2 elements were abundant (10-34 per diploid genome) and highly diverse (pi=0.051). Elements from mosquitoes collected in Nigeria were Topi 2 elements and those from mosquitoes collected in Mozambique were Topi 1 elements. Of the 49 Topi transposase open reading frames sequenced none were found to be identical. Intact elements with complete transposase open reading frames were common, although based on insertion site-occupancy frequency data it appeared that genetic drift was the major force acting on these IS630/Tc1/mariner-type elements. Topi 3 elements were not recovered from any of the populations sampled in this study and appear to be rare elements in An. gambiae, possibly due to a recent introduction.

Transposable element dynamics of the hAT element Herves in the human malaria vector Anopheles gambiae s.s.

Transposable elements are being considered as genetic drive agents for introducing phenotype-altering genes into populations of vectors of human disease. The dynamics of endogenous elements will assist in predicting the behavior of introduced elements. Transposable element display was used to estimate the site-occupancy frequency distribution of Herves in six populations of Anopheles gambiae s.s. The site-occupancy distribution data suggest that the element has been recently active within the sampled populations. All 218 individuals sampled contained at least one copy of Herves with a mean of 3.6 elements per diploid genome. No significant differences in copy number were observed among populations. Nucleotide polymorphism within the element was high (pi = 0.0079 in noncoding sequences and 0.0046 in coding sequences) relative to that observed in some of the more well-studied elements in Drosophila melanogaster. In total, 33 distinct forms of Herves were found on the basis of the sequence of the first 528 bp of the transposase open reading frame. Only two forms were found in all six study populations. Although Herves elements in An. gambiae are quite diverse, 85% of the individuals examined had evidence of complete forms of the element. Evidence was found for the lateral transfer of Herves from an unknown source into the An. gambiae lineage prior to the diversification of the An. gambiae species complex. The characteristics of Herves in An. gambiae are somewhat unlike those of P elements in D. melanogaster.

hAT element population genetics in Anopheles gambiae s.l. in Mozambique.

Herves is a functional Class II transposable element in Anopheles gambiae belonging to the hAT superfamily of elements. Class II transposable elements are used as gene vectors in this species and are also being considered as genetic drive agents for spreading desirable genes through natural populations as part of an effort to control malaria transmission. In this study, Herves was investigated in populations of Anopheles gambiae s.s., Anopheles arabiensis and Anopheles merus in Mozambique over a period of 2 years. The copy number of Herves within these three species was approximately 5 copies per diploid genome and did not differ among species or between years. Based on the insertion-site occupancy-frequency distribution and existing models of transposable element dynamics, Herves appears to be transpositionally active currently or, at least recently, in all species tested. Ninety-five percent of the individuals within the populations of the three species tested contained intact elements with complete Herves transposase genes and this is consistent with the idea that these elements are currently active.