The Anopheles coluzzii range extends into Kenya: detection, insecticide resistance profiles and population genetic structure in relation to conspecific populations in West and Central Africa.

BACKGROUND: Anopheles coluzzii is a primary vector of malaria found in West and Central Africa, but its presence has hitherto never been documented in Kenya. A thorough understanding of vector bionomics is important as it enables the implementation of targeted and effective vector control interventions. Malaria vector surveillance efforts in the country have tended to focus on historically known primary vectors. The current study sought to determine the taxonomic status of samples collected from five different malaria epidemiological zones in Kenya as well as describe the population genetic structure and insecticide resistance profiles in relation to other An. coluzzii populations. METHODS: Mosquitoes were sampled as larvae from Busia, Kwale, Turkana, Kirinyaga and Kiambu counties, representing the range of malaria endemicities in Kenya, in 2019 and 2021 and emergent adults analysed using Whole Genome Sequencing (WGS) data processed in accordance with the Anopheles gambiae 1000 Genomes Project phase 3. Where available, historical samples from the same sites were included for WGS. Comparisons were made with An. coluzzii cohorts from West and Central Africa. RESULTS: This study reports the detection of An. coluzzii for the first time in Kenya. The species was detected in Turkana County across all three time points from which samples were analyzed and its presence confirmed through taxonomic analysis. Additionally, there was a lack of strong population genetic differentiation between An. coluzzii from Kenya and those from the more northerly regions of West and Central Africa, suggesting they represent a connected extension to the known species range. Mutations associated with target-site resistance to DDT and pyrethroids and metabolic resistance to DDT were found at high frequencies up to 64%. The profile and frequencies of the variants observed were similar to An. coluzzii from West and Central Africa but the ace-1 mutation linked to organophosphate and carbamate resistance present in An. coluzzii from coastal West Africa was absent in Kenya. CONCLUSIONS: These findings emphasize the need for the incorporation of genomics in comprehensive and routine vector surveillance to inform on the range of malaria vector species, and their insecticide resistance status to inform the choice of effective vector control approaches.

Novel premature termination codon in the FOXP3 gene as the cause of familial hydrops fetalis in males.

A 19-year-old, G1P0, pregnant person was referred at 20w2d gestation for evaluation due to non-immune hydrops fetalis (NIHF), which was confirmed at the time of evaluation. Amniocentesis was performed at 20 w4d, and FISH, karyotype, chromosomal microarray, and exome sequencing (ES) were ordered. Trio ES identified a novel hemizygous c.142 C > T (p.Arg48*; maternally inherited) variant in the FOXP3 gene, resulting in a premature termination codon and establishing the diagnosis of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Intrauterine fetal demise (IUFD) was diagnosed at 21w3d. CVS was performed at 12w1d in a subsequent pregnancy (male fetus) and the known familial variant was identified. NIHF was identified at 18w1d. Ultrasound at 19w2d revealed IUFD. This is the first report of this variant in a diagnosis of IPEX syndrome, presenting with NIHF and male fetal demise. Genotype-phenotype correlations are not available in many cases of IPEX syndrome, as the same genotype can be present with variable severity in different individuals. Given the near identical presentations in this family, we anticipate a more severe phenotype with this variant. We propose a novel variant resulting in an early premature termination codon as an explanation for the severe presentation of IPEX syndrome in two successive fetuses in this family.

The Anopheles coluzzii range extends into Kenya: Detection, insecticide resistance profiles and population genetic structure in relation to conspecific populations in West and Central Africa.

Background: Anopheles coluzzii is a primary vector of malaria found in West and Central Africa, but its presence has hitherto never been documented in Kenya. A thorough understanding of vector bionomics is important as it enables the implementation of targeted and effective vector control interventions. Malaria vector surveillance efforts in the country have tended to focus on historically known primary vectors. In the current study, we sought to determine the taxonomic status of samples collected from five different malaria epidemiological zones in Kenya as well asdescribe the population genetic structure and insecticide resistance profiles in relation to other An. coluzzi populations. Methods: Mosquitoes were sampled as larvae from Busia, Kwale, Turkana, Kirinyaga and Kiambu counties, representing the range of malaria endemicities in Kenya, in 2019 and 2021 and emergent adults analysed using Whole Genome Sequencing data processed in accordance with the Anopheles gambiae 1000 Genomes Project phase 3. Where available, historical samples from the same sites were included for WGS. Results: This study reports the detection of Anopheles coluzzii for the first time in Kenya. The species was detected in Turkana County across all three time points sampled and its presence confirmed through taxonomic analysis. Additionally, we found a lack of strong population genetic differentiation between An. coluzzii from Kenya and those from the more northerly regions of West and Central Africa, suggesting they represent a connected extension to the known species range. Mutations associated with target-site resistance to DDT and pyrethroids and metabolic resistance to DDT were found at high frequencies of ~60%. The profile and frequencies of the variants observed were similar to An. coluzzii from West and Central Africa but the ace-1 mutation linked to organophosphate and carbamate resistance present in An. coluzzii from coastal West Africa was absent in Kenya. Conclusions: These findings emphasise the need for the incorporation of genomics in comprehensive and routine vector surveillance to inform on the range of malaria vector species, and their insecticide resistance status to inform the choice of effective vector control approaches.

Delivery outcomes in the subsequent pregnancy following the conservative management of placenta accreta spectrum disorder: a systematic review and meta-analysis.

OBJECTIVE: Cesarean hysterectomy is generally presumed to decrease maternal morbidity and mortality secondary to placenta accreta spectrum disorder. Recently, uterine-sparing techniques have been introduced in conservative management of placenta accreta spectrum disorder to preserve fertility and potentially reduce surgical complications. However, despite patients often expressing the intention for future conception, few data are available regarding the subsequent pregnancy outcomes after conservative management of placenta accreta spectrum disorder. Thus, we aimed to perform a systematic review and meta-analysis to assess these outcomes. DATA SOURCES: PubMed, Scopus, and Web of Science databases were searched from inception to September 2022. STUDY ELIGIBILITY CRITERIA: We included all studies, with the exception of case studies, that reported the first subsequent pregnancy outcomes in individuals with a history of placenta accreta spectrum disorder who underwent any type of conservative management. METHODS: The R programming language with the "meta" package was used. The random-effects model and inverse variance method were used to pool the proportion of pregnancy outcomes. RESULTS: We identified 5 studies involving 1458 participants that were eligible for quantitative synthesis. The type of conservative management included placenta left in situ (n=1) and resection surgery (n=1), and was not reported in 3 studies. The rate of placenta accreta spectrum disorder recurrence in the subsequent pregnancy was 11.8% (95% confidence interval, 1.1-60.3; I2=86.4%), and 1.9% (95% confidence interval, 0.0-34.1; I2=82.4%) of participants underwent cesarean hysterectomy. Postpartum hemorrhage occurred in 10.3% (95% confidence interval, 0.3-81.4; I2=96.7%). A composite adverse maternal outcome was reported in 22.7% of participants (95% confidence interval, 0.0-99.4; I2=56.3%). CONCLUSION: Favorable pregnancy outcome is possible following successful conservation of the uterus in a placenta accreta spectrum disorder pregnancy. Approximately 1 out of 4 subsequent pregnancies following conservative management of placenta accreta spectrum disorder had considerable adverse maternal outcomes. Given such high incidence of adverse outcomes and morbidity, patient and provider preparation is vital when managing this population.

Surgical Techniques for the Management of Placenta Accreta Spectrum.

The surgical management of placenta accreta spectrum (PAS) is often challenging. There are a variety of techniques and management options described in the literature ranging from uterine sparing to cesarean hysterectomy. Following the inaugural meeting of the Pan-American Society for Placenta Accreta Spectrum a multidisciplinary group collaborated to describe collective recommendations for the surgical management of PAS. In this manuscript, we outline individual components of the procedure and provide suggested direction at key points of a cesarean hysterectomy in the setting of PAS. KEY POINTS: · The surgical management of PAS requires careful planning and expertise.. · Multidisciplinary team care for pregnancies complicated by PAS can decrease morbidity and mortality.. · Careful surgical techniques can minimize risk of significant hemorrhage by avoiding pitfalls..

Unraveling the genomic complexity of sylvatic mosquitoes in changing Neotropical environments.

Sylvatic New World mosquitoes (e.g. Old-growth Forest species) can transmit viruses among non-human primates. This could be a continuous source of viral cycling and spillover events from animals to humans, particularly in changing environments. However, most species of Neotropical sylvatic mosquitoes (genera Aedes, Haemagogus, and Sabethes), which include vector and non-vector species, currently lack genomic resources because there is no reliable and accurate approach for creating de novo reference genomes for these insects. This is a major knowledge gap in the biology of these mosquitoes, restricting our ability to predict and mitigate the emergence and spread of novel arboviruses in Neotropical regions. We discuss recent advances and potential solutions for generating hybrid de novo assemblies from vector and non-vector species using pools of consanguineous offspring. We also discussed research opportunities likely to emerge from these genomic resources.

Intrauterine closure of myelomeningocele defects with primary linear repair versus bipedicle fasciocutaneous flaps: a post-MOMS cohort study with long-term follow-up.

OBJECTIVE: The objective of this study was to determine the effects of in utero bipedicle flaps on maternal-fetal morbidity/mortality, the need for CSF diversion, and long-term functional outcomes. METHODS: Eighty-six patients who underwent fetal myelomeningocele repair from 2011 to 2021 at a single institution were reviewed. Primary outcomes included intrauterine fetal demise, postnatal death, postnatal myelomeningocele repair dehiscence, and CSF diversion by final follow-up. RESULTS: The cohorts were no different with regard to race, ethnicity, maternal age at fetal surgery, body mass index, gravidity, parity, gestational age at fetal surgery, estimated fetal weight at fetal surgery, or fetal lesion level. Of the 86 patients, 64 underwent primary linear repair and 22 underwent bipedicle flap repair. There were no significant differences in rates of intrauterine fetal demise, postnatal mortality, midline repair site dehiscence, or the need for CSF diversion by final follow-up. Operative times were longer (32.5 vs 18.7 minutes, p < 0.001) and gestational age at delivery was lower (232 vs 241 days, p = 0.01) in the bipedicle flap cohort, but long-term functional outcomes were not different. CONCLUSIONS: Analysis of the total cohort affirms the long-term benefits of fetal myelomeningocele repair. In utero bipedicle flaps are safe and can be used for high-tension lesions without increasing perioperative risks to the mother or fetus. In utero flaps preserve the long-term benefits seen with primary linear repair and may expand inclusion criteria for fetal repair, providing life-changing care for more patients.

A comparison of MRI appearance and surgical detethering rates between intrauterine and postnatal myelomeningocele closures: a single-center pilot matched cohort study.

INTRODUCTION: Intrauterine myelomeningocele repair (IUMR) and postnatal myelomeningocele repair (PNMR) differ in terms of both setting and surgical technique. A simplified technique in IUMR, in which a dural onlay is used followed by skin closure, has been adopted at our institution. The goal of this study was to compare the rates of clinical tethering in IUMR and PNMR patients, as well as to evaluate the appearance on MRI. METHODS: We conducted a retrospective review of 36 patients with MMC repaired at our institution, with 2:1 PNMR to IUMR matching based on lesion level. A pediatric neuroradiologist blinded to the clinical details reviewed the patients' lumbar spine MRIs for the distance from neural tissue to skin and the presence or absence of a syrinx. An EMR review was then done to evaluate for detethering procedures and need for CSF diversion. RESULTS: Mean age at MRI was 4.0 years and mean age at last follow-up was 6.1 years, with no significant difference between the PNMR and IUMR groups. There was no significant difference between groups in the distance from neural tissue to skin (PNMR 13.5 mm vs IUMR 17.6 mm; p = 0.5). There was no difference in need for detethering operations between groups (PNMR 12.5% vs IUMR 16.7%; RR 0.75; CI 0.1-5.1). CONCLUSIONS: There was no significant difference between postnatal- and intrauterine-repaired myelomeningocele on MRI or in need for detethering operations. These results imply that a more straightforward and time-efficient IUMR closure technique does not lead to an increased rate of tethering when compared to the multilayered PNMR.

Notes From the Field: Dispensing of Oral Antiviral Drugs for Treatment of COVID-19 by Zip Code-Level Social Vulnerability - United States, December 23, 2021-August 28, 2022.

Equitable access to COVID-19 therapeutics is a critical aspect of the distribution program led by the U.S. Department of Health and Human Services (HHS).* Two oral antiviral products, nirmatrelvir/ritonavir (Paxlovid)† and molnupiravir (Lagevrio),§ received emergency use authorization (EUA) from the Food and Drug Administration (FDA) in December 2021, to reduce the risk for COVID-19-associated hospitalization and death for those patients with mild to moderate COVID-19 who are at higher risk for severe illness (1,2). HHS has been distributing these medications at no cost to recipients since their authorization. Data collected from provider sites during December 23, 2021-May 21, 2022, indicated substantial disparities in the population-adjusted dispensing rates in high social vulnerability (high-vulnerability) zip codes compared with those in medium- and low-vulnerability zip codes (3). Specifically, dispensing rates for the 4-week period during April 24-May 21, 2022, were 122 per 100,000 residents (19% of overall population-adjusted dispensing rates) in high-vulnerability zip codes compared with 247 (42%) in medium-vulnerability and 274 (39%) in low-vulnerability zip codes. This report provides an updated analysis of dispensing rates by zip code-level social vulnerability and highlights important intervention strategies.

Dispensing of Oral Antiviral Drugs for Treatment of COVID-19 by Zip Code-Level Social Vulnerability - United States, December 23, 2021-May 21, 2022.

The COVID-19 pandemic has highlighted and exacerbated long-standing inequities in the social determinants of health (1-3). Ensuring equitable access to effective COVID-19 therapies is essential to reducing health disparities. Molnupiravir (Lagevrio) and nirmatrelvir/ritonavir (Paxlovid) are oral antiviral agents effective at preventing hospitalization and death in patients with mild to moderate COVID-19 who are at high risk* for progression to severe COVID-19 when initiated within 5 days of symptom onset. These medications received Emergency Use Authorization from the Food and Drug Administration (FDA) in December 2021† and were made available at no cost to recipients through the U.S. Department of Health and Human Services (HHS) on December 23, 2021. Beginning March 7, 2022, a series of strategies was implemented to expand COVID-19 oral antiviral access, including the launch of the Test to Treat initiative.§ Data from December 23, 2021-May 21, 2022, were analyzed to describe oral antiviral prescription dispensing overall and by week, stratified by zip code social vulnerability. Zip codes represented areas classified as low, medium, or high social vulnerability; approximately 20% of U.S. residents live in low-, 31% in medium-, and 49% in high-social vulnerability zip codes.¶ During December 23, 2021-May 21, 2022, a total of 1,076,762 oral antiviral prescriptions were dispensed (Lagevrio = 248,838; Paxlovid = 827,924). Most (70.3%) oral antivirals were dispensed during March 7-May 21, 2022. During March 6, 2022-May 21, 2022, the number of oral antivirals dispensed per 100,000 population increased from 3.3 to 77.4 in low-, from 4.5 to 70.0 in medium-, and from 7.8 to 35.7 in high-vulnerability zip codes. The number of oral antivirals dispensed rose substantially during the overall study period, coincident with the onset of initiatives to increase access. However, by the end of the study period, dispensing rates in high-vulnerability zip codes were approximately one half the rates in medium- and low-vulnerability zip codes. Additional public health, regulatory, and policy efforts might help decrease barriers to oral antiviral access, particularly in communities with high social vulnerability.

Cost savings analysis of prescription assistance programs at a student-run free clinic.

The Free Clinic at Lubbock Impact (TFC) is a student-run, volunteer free clinic affiliated with Texas Tech University Health Sciences Center in Lubbock, Texas, that provides free weekly health services to the local uninsured patient population. The clinic also helps patients enroll in prescription assistance programs (PAPs) from pharmaceutical companies, which supply eligible patients with certain medications at little or no cost. This study presents a cost savings analysis of TFC patients enrolled in PAPs from February 2019 through February 2020. Cost savings were calculated by matching medication doses and units with the cost per unit for each brand-name medication listed on GoodRx.com at Walgreens pharmacies located in TFC's zip code, 79410. Sixty-one patients received 23 different medications with a total cost savings value of $222,563. Medications were sorted into diabetic, respiratory, and miscellaneous disease categories, for which cost savings totaled $114,110, $60,219, and $48,234, respectively. This study highlights the value of utilizing PAPs at a free clinic to address the barrier of medication cost for uninsured patients in Lubbock, Texas, and surrounding areas.

Report of the First International Symposium on NUT Carcinoma.

NUT carcinoma is a rare, aggressive cancer defined by rearrangements of the NUTM1 gene. No routinely effective treatments of NUT carcinoma exist, despite harboring a targetable oncoprotein, most commonly BRD4-NUT. The vast majority of cases are fatal. Poor awareness of the disease is a major obstacle to progress in the treatment of NUT carcinoma. While the incidence likely exceeds that of Ewing sarcoma, and BRD4-NUT heralded the bromodomain and extra-terminal domain (BET) inhibitor class of selective epigenetic modulators, NUT carcinoma is incorrectly perceived as "impossibly rare," and therefore receives comparatively little private or governmental funding or prioritization by pharma. To raise awareness, propagate scientific knowledge, and initiate a consensus on standard and targeted treatment of NUT carcinoma, we held the First International Symposium on NUT Carcinoma on March 3, 2021. This virtual event had more than eighty attendees from the Americas, Europe, Asia, and Australia. Patients with NUT carcinoma and family members were represented and shared perspectives. Broadly, the four areas discussed by experts in the field included (1) the biology of NUT carcinoma; (2) standard approaches to the treatment of NUT carcinoma; (3) results of clinical trials using BET inhibitors; and (4) future directions, including novel BET bromodomain inhibitors, combinatorial approaches, and immunotherapy. It was concluded that standard chemotherapeutic approaches and first-generation BET bromodomain inhibitors, the latter complicated by a narrow therapeutic window, are only modestly effective in a minority of cases. Nonetheless, emerging second-generation targeted inhibitors, novel rational synergistic combinations, and the incorporation of immuno-oncology approaches hold promise to improve the prognosis of this disease.

In vivo Raman spectroscopy monitors cervical change during labor.

BACKGROUND: Biochemical cervical change during labor is not well understood, in part, because of a dearth of technologies capable of safely probing the pregnant cervix in vivo. The need for such a technology is 2-fold: (1) to gain a mechanistic understanding of the cervical ripening and dilation process and (2) to provide an objective method for evaluating the cervical state to guide clinical decision-making. Raman spectroscopy demonstrates the potential to meet this need, as it is a noninvasive optical technique that can sensitively detect alterations in tissue components, such as extracellular matrix proteins, lipids, nucleic acids, and blood, which have been previously established to change during the cervical remodeling process. OBJECTIVE: We sought to demonstrate that Raman spectroscopy can longitudinally monitor biochemical changes in the laboring cervix to identify spectral markers of impending parturition. STUDY DESIGN: Overall, 30 pregnant participants undergoing either spontaneous or induced labor were recruited. The Raman spectra were acquired in vivo at 4-hour intervals throughout labor until rupture of membranes using a Raman system with a fiber-optic probe. Linear mixed-effects models were used to determine significant (P<.05) changes in peak intensities or peak ratios as a function of time to delivery in the study population. A nonnegative least-squares biochemical model was used to extract the changing contributions of specific molecule classes over time. RESULTS: We detected multiple biochemical changes during labor, including (1) significant decreases in Raman spectral features associated with collagen and other extracellular matrix proteins (P=.0054) attributed to collagen dispersion, (2) an increase in spectral features associated with blood (P=.0372), and (3) an increase in features indicative of lipid-based molecules (P=.0273). The nonnegative least-squares model revealed a decrease in collagen contribution with time to delivery, an increase in blood contribution, and a change in lipid contribution. CONCLUSION: Our findings have demonstrated that in vivo Raman spectroscopy is sensitive to multiple biochemical remodeling changes in the cervix during labor. Furthermore, in vivo Raman spectroscopy may be a valuable noninvasive tool for objectively evaluating the cervix to potentially guide clinical management of labor.

Placental Location in Maternal-Fetal Surgery for Myelomeningocele.

INTRODUCTION: Uterine incision based on the placental location in open maternal-fetal surgery (OMFS) has never been evaluated in regard to maternal or fetal outcomes. OBJECTIVE: The aim of this study was to investigate whether an anterior placenta was associated with increased rates of intraoperative, perioperative, antepartum, obstetric, or neonatal complications in mothers and babies who underwent OMFS for fetal myelomeningocele (fMMC) closure. METHODS: Data from the international multicenter prospective registry of patients who underwent OMFS for fMMC closure (fMMC Consortium Registry, December 15, 2010-June 31, 2019) was used to compare fetal and maternal outcomes between anterior and posterior placental locations. RESULTS: The placental location for 623 patients was evenly distributed between anterior (51%) and posterior (49%) locations. Intraoperative fetal bradycardia (8.3% vs. 3.0%, p = 0.005) and performance of fetal resuscitation (3.6% vs. 1.0%, p = 0.034) occurred more frequently in cases with an anterior placenta when compared to those with a posterior placenta. Obstetric outcomes including membrane separation, placental abruption, and spontaneous rupture of membranes were not different among the 2 groups. However, thinning of the hysterotomy site (27.7% vs. 17.7%, p = 0.008) occurred more frequently in cases of an anterior placenta. Gestational age (GA) at delivery (p = 0.583) and length of stay in the neonatal intensive care unit (p = 0.655) were similar between the 2 groups. Fetal incision dehiscence and wound revision were not significantly different between groups. Critical clinical outcomes including fetal demise, perinatal death, and neonatal death were all infrequent occurrences and not associated with the placental location. CONCLUSIONS: An anterior placental location is associated with increased risk of intraoperative fetal resuscitation and increased thinning at the hysterotomy closure site. Individual institutional experiences may have varied, but the aggregate data from the fMMC Consortium did not show a significant impact on the GA at delivery or maternal or fetal clinical outcomes.

The role of heterogenous environmental conditions in shaping the spatiotemporal distribution of competing Aedes mosquitoes in Panama: implications for the landscape of arboviral disease transmission.

Monitoring the invasion process of the Asian tiger mosquito Aedes albopictus and its interaction with the contender Aedes aegypti, is critical to prevent and control the arthropod-borne viruses (i.e., Arboviruses) they transmit to humans. Generally, the superior ecological competitor Ae. albopictus displaces Ae. aegypti from most geographic areas, with the combining factors of biology and environment influencing the competitive outcome. Nonetheless, detailed studies asserting displacement come largely from sub-tropical areas, with relatively less effort being made in tropical environments, including no comprehensive research about Aedes biological interactions in Mesoamerica. Here, we examine contemporary and historical mosquito surveillance data to assess the role of shifting abiotic conditions in shaping the spatiotemporal distribution of competing Aedes species in the Republic of Panama. In accordance with prior studies, we show that Ae. albopictus has displaced Ae. aegypti under suboptimal wet tropical climate conditions and more vegetated environments within the southwestern Azuero Peninsula. Conversely, in the eastern Azuero Peninsula, Ae. aegypti persists with Ae. albopictus under optimal niche conditions in a dry and more seasonal tropical climate. While species displacement was stable over the course of two years, the presence of both species generally appears to fluctuate in tandem in areas of coexistence. Aedes albopictus was always more frequently found and abundant regardless of location and climatic season. The heterogenous environmental conditions of Panama shape the competitive outcome and micro-geographic distribution of Aedes mosquitoes, with potential consequences for the transmission dynamics of urban and sylvatic zoonotic diseases. SUPPLEMENTARY INFORMATION: The online version of this article (10.1007/s10530-021-02482-y).

Dermatologic Care for the Uninsured West Texas Population at a Student-run Free Clinic.

We highlight the operations of The Free Clinic at Lubbock Impact, describing its services and the patient population it serves. Dermatology Nights have been an integral part to the clinic, addressing skin conditions that the uninsured and homeless population experience.

The genomic signal of local environmental adaptation in Aedes aegypti mosquitoes.

Local adaptation is important when predicting arthropod-borne disease risk because of its impacts on vector population fitness and persistence. However, the extent that vector populations are adapted to the environment generally remains unknown. Despite low population structure and high gene flow in Aedes aegypti mosquitoes across Panama, excepting the province of Bocas del Toro, we identified 128 candidate SNPs, clustered within 17 genes, which show a strong genomic signal of local environmental adaptation. This putatively adaptive variation occurred across fine geographical scales with the composition and frequency of candidate adaptive loci differing between populations in wet tropical environments along the Caribbean coast and dry tropical conditions typical of the Pacific coast. Temperature and vegetation were important predictors of adaptive genomic variation in Ae. aegypti with several potential areas of local adaptation identified. Our study lays the foundations of future work to understand whether environmental adaptation in Ae. aegypti impacts the arboviral disease landscape and whether this could either aid or hinder efforts of population control.

Bromodomain and extra-terminal inhibitors-A consensus prioritisation after the Paediatric Strategy Forum for medicinal product development of epigenetic modifiers in children-ACCELERATE.

Based on biology and pre-clinical data, bromodomain and extra-terminal (BET) inhibitors have at least three potential roles in paediatric malignancies: NUT (nuclear protein in testis) carcinomas, MYC/MYCN-driven cancers and fusion-driven malignancies. However, there are now at least 10 BET inhibitors in development, with a limited relevant paediatric population in which to evaluate these medicinal products. Therefore, a meeting was convened with the specific aim to develop a consensus among relevant biopharmaceutical companies, academic researchers, as well as patient and family advocates, about the development of BET inhibitors, including prioritisation and their specific roles in children. Although BET inhibitors have been in clinical trials in adults since 2012, the first-in-child study (BMS-986158) only opened in 2019. In the future, when there is strong mechanistic rationale or pre-clinical activity of a class of medicinal product in paediatrics, early clinical evaluation with embedded correlative studies of a member of the class should be prioritised and rapidly executed in paediatric populations. There is a strong mechanistic and biological rationale to evaluate BET inhibitors in paediatrics, underpinned by substantial, but not universal, pre-clinical data. However, most pan-BET inhibitors have been challenging to administer in adults, since monotherapy results in only modest anti-tumour activity and provides a narrow therapeutic index due to thrombocytopenia. It was concluded that it is neither scientifically justified nor feasible to undertake simultaneously early clinical trials in paediatrics of all pan-BET inhibitors. However, there is a clinical need for global access to BET inhibitors for patients with NUT carcinoma, a very rare malignancy driven by bromodomain fusions, with proof of concept of clinical benefit in a subset of patients treated with BET inhibitors. Development and regulatory pathway in this indication should include children and adolescents as well as adults. Beyond NUT carcinoma, it was proposed that further clinical development of other pan-BET inhibitors in children should await the results of the first paediatric clinical trial of BMS-986158, unless there is compelling rationale based on the specific agent of interest. BDII-selective inhibitors, central nervous system-penetrant BET inhibitors (e.g. CC-90010), and those dual-targeting BET/p300 bromodomain are of particular interest and warrant further pre-clinical investigation. This meeting emphasised the value of a coordinated and integrated strategy to drug development in paediatric oncology. A multi-stakeholder approach with multiple companies developing a consensus with academic investigators early in the development of a class of compounds, and then engaging regulatory agencies would improve efficiency, productivity, conserve resources and maximise potential benefit for children with cancer.

Proteomic fingerprinting of Neotropical hard tick species (Acari: Ixodidae) using a self-curated mass spectra reference library.

Matrix-assisted laser desorption/ionization (MALDI) time-of-flight mass spectrometry is an analytical method that detects macromolecules that can be used for proteomic fingerprinting and taxonomic identification in arthropods. The conventional MALDI approach uses fresh laboratory-reared arthropod specimens to build a reference mass spectra library with high-quality standards required to achieve reliable identification. However, this may not be possible to accomplish in some arthropod groups that are difficult to rear under laboratory conditions, or for which only alcohol preserved samples are available. Here, we generated MALDI mass spectra of highly abundant proteins from the legs of 18 Neotropical species of adult field-collected hard ticks, several of which had not been analyzed by mass spectrometry before. We then used their mass spectra as fingerprints to identify each tick species by applying machine learning and pattern recognition algorithms that combined unsupervised and supervised clustering approaches. Both Principal Component Analysis (PCA) and Linear Discriminant Analysis (LDA) classification algorithms were able to identify spectra from different tick species, with LDA achieving the best performance when applied to field-collected specimens that did have an existing entry in a reference library of arthropod protein spectra. These findings contribute to the growing literature that ascertains mass spectrometry as a rapid and effective method to complement other well-established techniques for taxonomic identification of disease vectors, which is the first step to predict and manage arthropod-borne pathogens.