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Abstract Background Knockdown resistance (kdr) is one of the primary resistance mechanisms present in anopheline species. Although this mutation is largely spread across the Anopheles gambiae s.l. members, its prevalence in other species is still not well documented. Methods The present study investigated the distribution and allelic frequencies of kdr in An. gambiae s.l., An. pharoensis, and An. ziemanni samples collected in 2022 and 2023 in nine sites spread across five ecogeographical settings in Cameroon. Members of the An. gambiae complex were identified molecularly by polymerase chain reaction (PCR). kdr L1014F and L1014S alleles were screened by PCR and confirmed by sequencing. Results An. gambiae (49.9%), An. coluzzii (36.5%), and An. arabiensis (13%) were identified, and the frequency of the kdr L1014F was high in both An. gambiae and An. coluzzii in all sites. The kdr L1014F allele was detected for the first time in 8 out of 14 An. ziemanni samples examined and in 5 out of 22 An. pharoensis samples examined. The kdr L1014S allele was scarce and found only in the heterozygote “RS” state in An. arabiensis and An. gambiae in Yangah and Santchou. Conclusions The present study sheds light on the rapid expansion of the kdr L1014F allele in malaria vectors in Cameroon and stresses the need for surveillance activities also targeting secondary malaria vectors to improve the control of malaria transmission. Graphical Abstract

Impaired rennet coagulation properties in milk could lead to prolonged processing times and production losses. Heritability for milk coagulation has previously been estimated to be 0.28 to 0.45, indicating that genetic selection can be used to manipulate this trait. The CN proteins are expressed by the genes CSN1S1, CSN2, CSN1S2, and CSN3 and are located on bovine chromosome 6. To better understand the effect of genetic variation in the CN genes on milk coagulation, blood and milk samples from 30 Swedish Red Dairy Cattle (RDC) with divergent coagulation properties were investigated. DNA from the 30 cows was sequenced for the CN genes to determine the theoretical AA sequence and to look for genetic variation in the untranslated regions. The aim is to confirm the protein genetic variants previously reported, while searching for additional genetic variation in the CN genes of 30 RDC. We observed genetic variation in 116 SNPs in the known CN genes where 10% of the SNPs are exon variants and the remaining 90% are intron variants. A total of 2.5% of the SNPs are found in the 5′- or 3′-untranslated region (UTR) regions of the exons; 2% are synonymous variants and 6% are missense variants that concurred with the known protein variants for CSN1S1, CSN2, and CSN3. Furthermore, 6% of the SNPs are splice polypyrimidine tract intron variants. The 2 genetic variants in the 5′- and 3′-UTR in CSN1S1 and CSN3 are found with protein variants CSN1S1C and CSN3B. Because both UTR variants are associated with gain and loss of micro RNA and transcription factors, this could explain differences in expression of the genetic protein variants. Preliminary chi-squared analysis and comparison with previous GWAS studies showed potential connections between the identified SNPs and coagulation properties of milk. By advancing the knowledge of the connection between the DNA sequence and the functional properties of the CN proteins, we hope to learn more about the cheese coagulation properties of milk from RDC.

BackgroundHarmful alcohol consumption has been identified as a major contributor to disease, mortality, and social harm, accounting for 5.3% of worldwide deaths annually. In Denmark, an estimated 150,000 people suffer from alcohol use disorder (AUD), but a low proportion seek treatment due to person- and treatment-related barriers. Internet-based cognitive behavioral therapy (iCBT) has shown positive effects on the treatment gap, with patients reporting benefits such as increased knowledge and flexibility. However, there is a lack of research on blended cognitive behavioral therapy (bCBT), which combines face-to-face CBT (FtF CBT) and iCBT for AUD. ObjectiveThis study aims to investigate user experiences of bCBT. More specifically, it seeks to explore the advantages and disadvantages that users have experienced with bCBT for AUD, as well as their motivations for choosing this treatment format. MethodsA total of 30 patients who had participated in the Blend-A (Blending Internet Treatment into Conventional Face-to-Face Treatment for AUD) study and received the intervention were contacted and offered the opportunity to participate in semistructured individual telephone interviews. Of these, 12 patients consented to participate. Furthermore, an additional participant was approached at a municipal clinic and agreed to engage in an individual FtF interview. Thus, the final sample consisted of 13 patients. The interviews explored their background, experiences with digital technology, motivations for choosing internet-based treatment, and experiences with the program during AUD treatment. The interviews were audio-recorded and transcribed in full length and analyzed using thematic analysis. All data were anonymized and securely stored. ResultsWe found that users experienced several advantages of iCBT over a larger part of the treatment course, including increased anonymity and privacy. Most importantly, it offered flexibility, allowing patients to focus on their rehabilitation process at their own pace. Patients appreciated the availability of written text in the online program, finding it helpful for gaining knowledge and understanding of AUD and its impact on the individual with the condition. They emphasized how the assignments helped them fully engage in treatment by first acknowledging their problem with alcohol and then dedicating time to self-reflection before FtF sessions, allowing for more in-depth discussions with the therapist. They also appreciated the reminders, which motivated them to complete their assignments. ConclusionsOverall, patients perceived more benefits than disadvantages in using bCBT. Essentially, bCBT offers a form of assisted autonomy that cannot be fully achieved through iCBT or FtF CBT alone. It is only through their combination that patients can fully appreciate the benefits of the treatment, as they have time for self-reflection, with guidance from the therapist between FtF CBT sessions. Trial RegistrationClinicalTrials.gov NCT04535258; https://clinicaltrials.gov/ct2/show/NCT04535258

Summary: Respiratory syncytial virus (RSV) causes lower respiratory tract infections with significant morbidity and mortality at the extremes of age. Vaccines based on the viral fusion protein are approved for adults over 60, but infant protection relies on passive immunity via antibody transfer or maternal vaccination. An infant vaccine that rapidly elicits protective antibodies would fulfill a critical unmet need. Antibodies arising from the VH3-21/VL1-40 gene pairing can neutralize RSV without the need for affinity maturation, making them attractive to target through vaccination. Here, we develop an anti-idiotypic monoclonal antibody (ai-mAb) immunogen that is specific for unmutated VH3-21/VL1-40 B cell receptors (BCRs). The ai-mAb efficiently engages B cells with bona fide target BCRs and does not activate off-target non-neutralizing B cells, unlike recombinant pre-fusion (preF) protein used in current RSV vaccines. These results establish proof of concept for using an ai-mAb-derived vaccine to target B cells hardwired to produce RSV-neutralizing antibodies.

This study tackles the critical challenge of medication non-adherence in healthcare by pinpointing indicators related to medication adherence (IRMAs) across 39 European countries and Israel. Utilizing a structured expert survey methodology within the European Network to Advance Best Practices and Technology on Medication Adherence (ENABLE; COST Action CA19132), our research identified key country-specific IRMAs and collected data on these indicators to understand the multifaceted nature of medication adherence. The research was conducted in two phases: firstly, defining key IRMAs through a two-round expert survey, and secondly, gathering country-specific data on these IRMAs through literature reviews and additional expert surveys. The study revealed a diverse range of 26 top-ranked IRMAs, including six related to country characteristics, four to social/economic factors, three each to therapy-related and patient-related factors, one to condition-related factors, and nine to healthcare system-related factors. The availability of country-specific data on these IRMAs varied among the countries, highlighting the need for more comprehensive data collection and research. The findings from this study not only underscore the complexity of predicting medication adherence but also lay the groundwork for developing targeted, country-specific interventions to improve adherence. Moreover, this research offers valuable insights for policymakers, highlighting the importance of understanding the multifaceted nature of medication adherence and offering a valuable resource in formulating targeted health policies to enhance health outcomes and reduce the economic burden associated with medication non-adherence.

ObjectivesWe analyzed the impact of postoperative necrotizing enterocolitis (NEC) after cardiac surgery in neonatal age on neurodevelopmental (ND) outcome at 1 year of age.MethodsUsing data from the Swiss Neurodevelopmental Outcome Registry for Children with Congenital Heart Disease (ORCHID), we analyzed perioperative variables including postoperative NEC (Bell's stage ≥2) and 1-year ND outcome (Bayley III).ResultsThe included patients (n = 101) had congenital heart disease (CHD), categorized as follows: 77 underwent biventricular repair for CHD with two functional chambers, 22 underwent staged palliation until the Fontan procedure for CHD with single ventricle physiology (n = 22), or 4 underwent single ventricle palliation or biventricular repair for borderline CHD (n = 4). Neonatal cardiopulmonary bypass (CBP) surgery was performed at a median age (IQR) of 8 (6) days. NEC occurred in 16 patients. Intensive care unit (ICU) length of stay (LOS) and the total duration of the hospitalization were longer in children with NEC than those in others (14 with vs. 8 days without NEC, p

Summary: Coordinating immune responses – humoral and cellular – is vital for protection against severe Covid-19. Our study evaluates a multicytokine CD4+T cell signature’s predictive for post-vaccinal serological and CD8+T cell responses. A cytokine signature composed of four cytokines (IL-2, TNF-α, IP10, IL-9) excluding IFN-γ, and generated through machine learning, effectively predicted the CD8+T cell response following mRNA-1273 or BNT162b2 vaccine administration. Its applicability extends to murine vaccination models, encompassing diverse immunization routes (such as intranasal) and vaccine platforms (including adjuvanted proteins). Notably, we found correlation between CD4+T lymphocyte-produced IL-21 and the humoral response. Consequently, we propose a test that offers a rapid overview of integrated immune responses. This approach holds particular relevance for scenarios involving immunocompromised patients because they often have low cell counts (lymphopenia) or pandemics. This study also underscores the pivotal role of CD4+T cells during a vaccine response and highlights their value in vaccine immunomonitoring.

Water is a vital component for all living organisms, yet persistent water scarcity remains a global challenge. One potential solution lies in replicating the atmospheric water collection mechanism observed in the Stenocara beetle, characterized by a dorsal surface featuring alternating hydrophilic and hydrophobic regions. In this study, we have designed and examined two distinct biphilic patterned surface configurations, integrating various technologies, to mimic the beetle's water collection strategy. Our investigation evaluates the efficiency of these surfaces in both capturing water from fog and condensing water from dew. For fog collection two parameters were the most impactful: the roughness and the wettability contrast between hydrophilic and hydrophobic zones. In contrast, dew condensation was influenced by additional parameters notably the patterns' size and density that directly affect the water contact angle. It is worth noting, however, that the optimal surface for fog collection may not necessarily coincide with the most effective surface for dew condensation. Furthermore, our research includes a comparative analysis between the theoretically predicted volume of water droplet departure and the empirically observed results.

Animals are adapted to their natural habitats and lifestyles. Their brains perceive the external world via their sensory systems, compute information together with that of internal states and autonomous activity, and generate appropriate behavioral outputs. However, how do these processes evolve across evolution? Here, focusing on the sense of olfaction, we have studied the evolution in olfactory sensitivity, preferences, and behavioral responses to six different food-related amino acid odors in the two eco-morphs of the fish Astyanax mexicanus. To this end, we have developed a high-throughput behavioral setup and pipeline of quantitative and qualitative behavior analysis, and we have tested 489 six-week-old Astyanax larvae. The blind, dark-adapted morphs of the species showed markedly distinct basal swimming patterns and behavioral responses to odors, higher olfactory sensitivity, and a strong preference for alanine, as compared to their river-dwelling eyed conspecifics. In addition, we discovered that fish have an individual ‘swimming personality’, and that this personality influences their capability to respond efficiently to odors and find the source. Importantly, the personality traits that favored significant responses to odors were different in surface fish and cavefish. Moreover, the responses displayed by second-generation cave × surface F2 hybrids suggested that olfactory-driven behavior and olfactory sensitivity is a quantitative genetic trait. Our findings show that olfactory processing has rapidly evolved in cavefish at several levels: detection threshold, odor preference, and foraging behavior strategy. Cavefish is therefore an outstanding model to understand the genetic, molecular, and neurophysiological basis of sensory specialization in response to environmental change.

The massive deployment of IoT connected devices brings up different modern problems, such as radiofrequency spectrum saturation and energetic requirements. Organic photovoltaics are good candidates for indoor energy harvesting and data reception in a simultaneous lightwave information and power transfer scenario applied for IoT, at which the non-directive channel significantly contributes to the optical system performance. However, achieving the channel impulse response of diffuse links requires complex numerical approaches. This article presents the first ever OPV model used in a Monte-Carlo ray-tracing simulation, associated to theoretical and experimental validation. Finally, for the first time, an optical simulation with an OPV receiver is realized in a cubic environment, from which the received optical power and generated current distributions were obtained. Results show that the employed OPV is suited for indoor energy harvesting to supply low power IoT nodes, and with proper dedicated front-end, could manage to receive optical data in a SLIPT scenario.

This study aimed to develop a formation test that also serves as a diagnostic test. The purpose of this product is to determine students’ learning difficulty levels. We used a two-step multiple-choice assessment tool to develop this diagnostic test. Because two-step multiple-choice tests help teachers identify learning difficulties that arise in students. The research method used is research and development. This test was developed using the Moodle platform and takes the form of a closed multiple-choice test consisting of 20 questions. Media and materials experts validate diagnostic tests. Based on validation, this developed product can be used as a physics learning assessment tool to measure student learning outcomes and learning difficulties. The aspects of media learning expert is usability, navigation, visuals, product, effectiveness, and content. While, the aspects of material expert are compliance with curriculum, construction, and language. We tested high school students and found that 2 of the 20 questions about the concepts of momentum and impulse were mastered and the remaining 18 were at the level of instrumental understanding and misunderstanding. Therefore, teachers should look for strategies to expand students' conceptual knowledge of dynamics and momentum. Thus, the mastery of the student's concept is whole and thorough.

Abstract Background In spite of the global decreasing mortality associated with HIV, adolescents living with HIV (ADLHIV) in sub-Saharan Africa still experience about 50% mortality rate. We sought to evaluate survival rates and determinants of mortality amongst ADLHIV receiving antiretroviral therapy (ART) in urban and rural settings. Methods A multi-centered, 10-year retrospective, cohort-study including ADLHIV on ART ≥ 6 months in the urban and rural settings of the Centre Region of Cameroon. Socio-demographic, clinical, biological, and therapeutic data were collected from files of ADLHIV. The Kaplan–Meier method was used to estimate survival probability after ART initiation; the log rank test used to compare survival curves between groups of variables; and the Cox proportional hazard model was used to identify the determinants of mortality. Results A total of 403 adolescents’ records were retained; 340 (84%) were from the urban and 63 (16%) from the rural settings. The female to male ratio was 7:5; mean age (Standard deviation) was 14.1 (2.6) years; at baseline, 64.4% were at WHO clinical stages I/II, 34.9% had ≥ 500 CD4 cells/mm3, 91.1% were anemic, and the median [Inter Quartile Range] duration on ART was5.3 [0.5–16] years. The survival rate at 1, 5 and 10 years on ART was respectively 97.0%, 55.9% and 8.7%; with mean survival time of 5.8 years (95% CI 5.5–6.1). In bivariate analysis, living in the rural setting, non-disclosed HIV status, baseline CD4 count

Patients with ER-negative breast cancer have the worst prognosis of all breast cancer subtypes, often experiencing rapid recurrence or progression to metastatic disease shortly after diagnosis. Given that metastasis is the primary cause of mortality in most solid tumors, understanding metastatic biology is crucial for effective intervention. Using a mouse systems genetics approach, we previously identified 12 genes associated with metastatic susceptibility. Here, we extend those studies to identify Resf1, a poorly characterized gene, as a novel metastasis susceptibility gene in ER- breast cancer. Resf1 is a large, unstructured protein with an evolutionarily conserved intron-exon structure, but with poor amino acid conservation. CRISPR or gene trap mouse models crossed to the Polyoma Middle-T antigen genetically engineered mouse model (MMTV-PyMT) demonstrated that reduction of Resf1 resulted in a significant increase in tumor growth, a shortened overall survival time, and increased incidence and number of lung metastases, consistent with patient data. Furthermore, an analysis of matched tail and primary tissues revealed loss of the wildtype copy in tumor tissue, consistent with Resf1 being a tumor suppressor. Mechanistic analysis revealed a potential role of Resf1 in transcriptional control through association with compound G4 quadruplexes in expressed sequences, particularly those associated with ribosomal biogenesis. These results suggest that loss of Resf1 enhances tumor progression in ER- breast cancer through multiple alterations in both transcriptional and translational control.

Background Most studies have used cross‐sectional or limited follow‐up data to evaluate the relationship between social isolation (SI) and hypertension in older populations. The objective of this analysis was to examine the relationship between longitudinal SI and hypertension in a younger population. Methods and Results The present analysis used data from waves I to V of the National Longitudinal Study of Adolescent to Adult Health (1994–2018) and logistic regression models to describe the association of timing, duration, and transitional patterns of SI with hypertension in early middle adulthood. Models were adjusted for demographic variables and adolescent socioeconomic and health‐related confounders. SI was higher across life stages among individuals with hypertension (adolescence: 38% versus 35%, young adulthood: 52% versus 44%, and early middle adulthood: 61% versus 52%). Individuals who were socially isolated in young adulthood or early middle adulthood had greater odds of hypertension in early middle adulthood than those who were not (odds ratio [OR], 1.30 [95% CI, 1.07–1.56]; OR, 1.42 [95% CI, 1.15–1.76], respectively). Early middle adulthood hypertension was significantly associated with persistent SI across all life stages and for those who moved into persistent SI after adolescence (OR, 1.40 [95% CI, 1.02–1.93]; OR, 1.61 [95% CI, 1.18–2.19], respectively). Conclusions SI in young or early middle adulthood significantly increased the odds of hypertension, as did moving into SI and the accumulation of SI across life stages. Our analysis provides insights regarding timing for effective interventions to reduce hypertension earlier in the life course, which may prevent future adverse cardiovascular‐related events.

BackgroundThe use of digital technologies for health care has been the focus of social studies, which have concentrated on the digital divide between individuals who use technology and those who do not—with the latter often being considered as individuals with shortcomings. In Denmark, 91% of the population have computers and 97 out of 100 families have internet access, indicating that lack of access to technology is not the primary reason for nonuse. Although previous studies have primarily focused on participants' perspectives of using internet-based treatment for alcohol use disorder (AUD), no study has investigated individuals’ reasons to prefer face-to-face treatment over blended face-to-face and internet-based cognitive behavioral therapy (bCBT) for AUD among treatment-seeking populations. ObjectiveThe aim of this qualitative study was to investigate the nonuse of bCBT among patients with AUD. Specifically, this study aims to explore patients' reasons for choosing not to receive treatment via this format. MethodsThis study was conducted among Danish patients with AUD who were enrolled in the study “Blending internet treatment into conventional face-to-face treatment for alcohol use disorder (Blend-A)” but had not used bCBT. The participant group consisted of 11 patients with AUD: 3 women and 8 men. The age range of the participants was 29-78 years (mean 59 years). Individual semistructured interviews were conducted using cell phones to gather participants’ reasons for not choosing bCBT. The interviews were recorded, transcribed, and analyzed using thematic analysis. Five authors performed the analysis in 3 steps: (1) two authors read the transcripts and coded themes from their immediate impression of the material, (2) one author provided feedback, which was used to group overlapping themes together or create new themes that better reflected the content, and (3) the remaining two authors provided feedback on the analysis to improve its structure, readability, and relevance to the research aim. ResultsWe found that the participants had various reasons for choosing face-to-face treatment over bCBT; these reasons were more related to personal matters and lesser to digital health literacy. We identified 4 themes related to personal matters for choosing face-to-face treatment over bCBT: (1) patients’ need for attending sessions in person, (2) preference for verbal communication, (3) desire for immediate feedback, and (4) feeling more empowered and motivated with face-to-face sessions. ConclusionsThis study provides valuable insight into participants’ perspectives on blended therapy for AUD and highlights the importance of considering personal factors when designing digital health interventions. Our study indicates that most of the participants choose not to use bCBT for AUD because they perceive such treatment formats as impersonal. Instead, they prefer direct communication with the therapist, including the ability to express and comprehend facial expressions and body language. International Registered Report Identifier (IRRID)RR2-10.1186/s12888-021-03122-4

Abstract Objective: To evaluate the impact of a counselling programme to strengthen the health and nutrition behaviours of caregivers of children under 2 and the sustainability of that impact through reduced intervention intensity one year later. Design: The programme trained community- and facility-based health staff to provide nutrition counselling. We conducted an impact evaluation with a modified stepped-wedge design using difference-in-differences analysis to compare indicator changes in an intervention group to a comparison group (midterm survey) and then a full intervention group to a light intervention group (final survey). Setting: Batken and Jalal-Abad oblasts, the Kyrgyz Republic, 2020–2023. Participants: Caregivers of children under 2 provided 6253 responses in three telephone surveys. Results: We observed statistically significant differences between the intervention and comparison groups at midterm for the percentage of children consuming vitamin A-rich foods; an increase in the intervention group (58–62 %) and a decrease in the comparison group (61–57 %). We observed similar results with exclusive breastfeeding (51–55 % in the intervention group and 48–40 % in the comparison group). There were also positive differences in other health and nutrition indicators. With the final survey results, in general, we observed statistically significant differences indicating a bigger change in full intervention areas compared to light intervention areas. We observed small negative changes in many indicators in light intervention areas. Conclusions: This evaluation highlights the importance of continued support for local interventions, particularly counselling programmes, to foster optimal nutrition behaviours.

Abstract Objective: To assess changes in caregiver practices for young children after integrating the Responsive Care and Early Learning (RCEL) Addendum package into nutrition services after 10 months of implementation. Design: We measured changes in RCEL practices through a pre- and post-intervention assessment comprising a household survey and observations. To implement the intervention, we trained health service staff and community volunteers to deliver RCEL counselling to caregivers of children 0–23 months of age through existing community and facility-level platforms. Setting: Jalal-Abad and Batken regions in the Kyrgyz Republic. Participants: Caregivers of children aged 0–23 months at baseline. Results: We found statistically significant increases in RCEL practices, availability of early learning opportunities in the home, decreases in parenting stress and improvements in complementary feeding practices after the intervention implementation period. Conclusions: Findings show that delivery of RCEL counselling using the RCEL Addendum was associated with improved responsive care practices and early learning opportunities. We also found that integration of RCEL with infant and young child feeding counselling did not disrupt nutrition service delivery or negatively affect complementary feeding outcomes, but rather suggest synergistic benefits. Given the importance of providing holistic care to support optimal early childhood development, these findings provide new evidence on how to strengthen the delivery of nurturing care services in the Kyrgyz Republic.

Abstract Objective: This study assesses change in caregiver practices after integrating responsive care and early learning (RCEL) in nutrition and health services and community platforms in northern Ghana. Design: We trained health facility workers and community health volunteers to deliver RCEL counselling to caregivers of children under 2 years of age through existing health facilities and community groups. We assessed changes in caregivers’ RCEL practices before and after the intervention with a household questionnaire and caregiver–child observations. Setting: The study took place in Sagnarigu, Gushegu, Wa East and Mamprugu-Moagduri districts from April 2022 to March 2023. Study sites included seventy-nine child welfare clinics (CWC) at Ghana Health Service facilities and eighty village savings and loan association (VSLA) groups. Participants: We enrolled 211 adult caregivers in the study sites who had children 0–23 months at baseline and were enrolled in a CWC or a VSLA. Results: We observed improvements in RCEL and infant and young child feeding practices, opportunities for early learning (e.g. access to books and playthings) in the home environment and reductions in parental stress. Conclusions: This study demonstrates the effectiveness of integrating RCEL content into existing nutrition and health services. The findings can be used to develop, enhance and advocate for policies integrating RCEL into existing services and platforms in Ghana. Future research may explore the relationship between positive changes in caregiver behaviour and improvements in child development outcomes as well as strategies for enhancing paternal engagement in care practices, improving child supervision and ensuring an enabling environment.

Background: For every 100 patients with diabetes, 40 will develop diabetic kidney disease (DKD) over time. This diabetes complication may be partly due to poor adherence to their prescribed medications. In this study, we aimed to evaluate the differential impact of a 6- versus 12-month pharmacist-led interprofessional medication adherence program (IMAP) on the components of adherence (i.e., implementation and discontinuation) in patients with DKD, during and after the intervention.Methods: All included patients benefited from the IMAP, which consists in face-to-face regular motivational interviews between the patient and the pharmacist based on the adherence feedback from electronic monitors (EMs), in which the prescribed treatments were delivered. Adherence reports were available to prescribers during the intervention period. Patients were randomized 1:1 into two parallel arms: a 12-month IMAP intervention in group A versus a 6-month intervention in group B. Adherence was monitored continuously for 24 months post-inclusion during the consecutive intervention and follow-up phases. In the follow-up phase post-intervention, EM data were blinded. Blood pressure was measured by the pharmacist at each visit. The repeated measures of daily patient medication intake outcomes (1/0) to antidiabetics, antihypertensive drugs, and statins were modeled longitudinally using the generalized estimated equation in both groups and in both the intervention and the follow-up phases.Results: EM data of 72 patients were analyzed (34 in group A and 38 in group B). Patient implementation to antidiabetics and antihypertensive drugs increased during the IMAP intervention phase and decreased progressively during the follow-up period. At 12 months, implementation to antidiabetics was statistically higher in group A versus group B (93.8% versus 86.8%; Δ 7.0%, 95% CI: 5.7%; 8.3%); implementation to antihypertensive drugs was also higher in group A versus B (97.9% versus 92.1%; Δ 5.8%, 95% CI: 4.8%; 6.7%). At 24 months, implementation to antidiabetics and antihypertensive drugs remained higher in group A versus B (for antidiabetics: 88.6% versus 85.6%; Δ 3.0%, 95% CI: 1.7%; 4.4% and for antihypertensive drugs: 94.4% versus 85.9%; Δ 8.5%, 95% CI: 6.6%; 10.7%). No difference in pharmacy-based blood pressure was observed between groups. Implementation to statins was comparable at each time point between groups. Three patients discontinued at least one treatment; they were all in group B. In total, 46% (16/35) of patients in the 12-month intervention versus 37% (14/38) of patients in the 6-month intervention left the study during the intervention phase, mainly due to personal reasons.Conclusion: The IMAP improves adherence to chronic medications in patients with DKD. The longer the patients benefit from the intervention, the more the implementation increases over time, and the more the effect lasts after the end of the intervention. These data suggest that a 12-month rather than a 6-month program should be provided as a standard of care to support medication adherence in this population. The impact on clinical outcomes needs to be demonstrated.Clinical Trial Registration:Clinicaltrials.gov, identifier NCT04190251_PANDIA IRIS.

In the present study, digestion pattern of purified bovine κ-casein (κ-CN) variants A, B, E as well as desialylated variant B, using INFOGEST 2.0 in vitro gastrointestinal digestion were investigated using peptidomics. Peptide profiles of the digests were identified and quantified using ion abundancies by liquid chromatography electrospray quadropole time of flight mass spectrometry (LC-ESI/Q-TOF MS/MS). Results showed that the κ-CN variants A and E had comparable digestion patterns at most digestion time points. In the in vitro gastric and in the initial intestinal phases fewer peptides and with lower total abundances were identified for variant B compared to variants A and E, indicating a slower digestion rate for κ-CN B. By desialylation, the digestion rate of desialylated variant B in both gastric and initial intestinal phases increased compared to the natural sialylated counterpart. Bioinformatics search revealed nine potential bioactive peptides released from all three variants A, B and E by the in vitro intestinal digestion, with four additional potential bioactive peptides being released after desialylation of κ-CN B.

Abstract A primary objective in malaria vaccine design is the generation of high-quality antibody responses against the circumsporozoite protein of the malaria parasite, Plasmodium falciparum (PfCSP). To enable rational antigen design, we solved a cryo-EM structure of the highly potent anti-PfCSP antibody L9 in complex with recombinant PfCSP. We found that L9 Fab binds multivalently to the minor (NPNV) repeat domain, which is stabilized by a unique set of affinity-matured homotypic, antibody-antibody contacts. Molecular dynamics simulations revealed a critical role of the L9 light chain in integrity of the homotypic interface, which likely impacts PfCSP affinity and protective efficacy. These findings reveal the molecular mechanism of the unique NPNV selectivity of L9 and emphasize the importance of anti-homotypic affinity maturation in protective immunity against P. falciparum.

Microbial communities play an important role in the fitness of mosquito hosts. However, the factors shaping microbial communities in wild populations, with regard to interactions among microbial species, are still largely unknown. Previous research has demonstrated that two of the most studied mosquito symbionts, the bacteria Wolbachia and Asaia, seem to compete or not compete, depending on the genetic background of the reference mosquito host. The large diversity of Wolbachia–Asaia strain combinations that infect natural populations of mosquitoes may offer a relevant opportunity to select suitable phenotypes for the suppression of pathogen transmission and for the manipulation of host reproduction. We surveyed Wolbachia and Asaia in 44 mosquito populations belonging to 11 different species of the genera Anopheles, Aedes, and Culex using qualitative PCR. Through quantitative PCR, the amounts of both bacteria were assessed in different mosquito organs, and through metagenomics, we determined the microbiota compositions in some selected mosquito populations. We show that variation in microbial community structure is likely associated with the species/strain of mosquito, its geographical position, and tissue localization. Together, our results shed light on the interactions among different bacterial species in the microbial communities of mosquito vectors, and this can aid the development and/or improvement of methods for symbiotic control of insect vectors.

Les procédés de fabrication additive par fusion laser sur lit de poudre (FLLP) permettent aujourd’hui de fabriquer des composants métalliques à géométrie complexe, aux propriétés performantes. Parmi les différents paramètres impliqués dans le procédé, la température joue un rôle fondamental, car elle contrôle la fusion de la poudre, la solidification et la formation de la microstructure à partir du bain liquide. Différentes techniques existent pour mesurer la température à la surface d’une pièce, comme des mesures par pyromètres ou caméra infra-rouge. Cependant, le champ de température interne reste difficile à estimer par ces méthodes conventionnelles. L’objectif de nos travaux est d’étudier l’évolution du champ de température d’un objet en cours de construction, en proposant une technique de suivi in situ, basée sur la sensibilité des ondes élastiques à la température du milieu de propagation. Un dispositif expérimental a été développé afin de mesurer simultanément des temps de vol en impulsion-écho pendant l’élaboration d’une pièce cylindrique ainsi que températures à l’aide de thermocouples. Un modèle thermique par éléments finis a été développé afin de corréler les variations de temps de vol et de température observées au cours de la fabrication. Dans ce papier, la technique ultrasonore proposée ainsi que les mesures expérimentales réalisées sont exposées. Le modèle et la confrontation de ses résultats aux données expérimentales sont présentés.

Background: Disruption of natural light cycles, as experienced by shift workers, is linked to enhanced cancer incidence. Several mouse models of cancer develop more severe disease when exposed to irregular light/dark cycles, supporting the connection between circadian disruption and increased cancer risk. Cryptochrome 2 (CRY2), a repressive component of the molecular circadian clock, facilitates turnover of the oncoprotein c-MYC, one mechanism that may link the molecular clock to tumorigenesis. In Eμ-MYC mice, which express transgenic c-MYC in B cells and develop aggressive lymphomas and leukemia, global Cry2 deletion reduces survival and enhances tumor formation. Lighting conditions that mimic the disruption experienced by shift workers dampen Cry2 transcripts in peripheral tissues of C57BL/6J mice. Although it is milder than homozygous deletion of Cry2, we hypothesized that reduced Cry2 rhythmicity could alter MYC protein accumulation and contribute to enhanced cancer risk caused by circadian disruption. We tested this hypothesis in MYC-driven lymphoma. Methods: We housed Eμ-MYC mice in light-tight boxes set to either control (continuous cycles of 12-hours of light followed by 12-hours of dark, LD12:12) or chronic jetlag (eight-hour light phase advances every two to three days, CJL) lighting conditions and assessed the impact of disrupted light cycles on survival and tumor formation in Eμ-MYC mice. Results: Environmental disruption of circadian rhythms did not alter tumor location, tumor growth, or survival in Eμ-MYC mice. Conclusions: Dampened rhythms of Cry2 following disruption of circadian light exposures is milder than deletion of Cry2. The lack of phenotype caused by altered circadian gene expression in contrast to enhanced tumorigenesis caused by homozygous deletion of Cry2 suggests that CRY2 dosage impacts this model. Importantly, these findings indicate that increased cancer risk associated with circadian disruption arises from one or more mechanisms that are not recapitulated here, and may be different in distinct tumor types.

Background: The endosymbiotic bacterium Wolbachia infects numerous species of insects and Wolbachia transinfection of Aedes mosquito species is now being used for biocontrol programs as Wolbachia strains can both inhibit arboviruses and invade wild mosquito populations. The discovery of novel, resident Wolbachia strains in mosquito species warrants further investigation as potential candidate strains for biocontrol strategies. Methods: We obtained mosquito specimens from diverse Culicine mosquitoes from Cameroon including ecologically diverse locations in the Central and West Regions. Wolbachia prevalence rates were assessed in addition to the environmentally acquired bacterial species Asaia in major Culicine genera. PCR-based methods were also used with phylogenetic analysis to confirm identities of host mosquito species and Wolbachia strains were classified using multi-locus sequence typing (MLST). Results: We report high Wolbachia prevalence rates for Culicine species, including in a large cohort of Aedes africanus collected from west Cameroon in which 100% of mono-specific pools were infected. Furthermore, co-infections with Asaia bacteria were observed across multiple genera, demonstrating that these two bacteria can co-exist in wild mosquito populations. Wolbachia strain MLST and phylogenetic analysis provided evidence for diverse Wolbachia strains in 13 different mosquito species across seven different genera. Full or partial MLST profiles were generated from resident Wolbachia strains in six Culex species (quinquefasciatus, watti, cinerus, nigripalpus, perexiguus and rima), two Aedes species (africanus and denderensis) and in Mansonia uniformis, Catageiomyia argenteopunctata, Lutzia tigripes, Eretmapodites chrysogaster and Uranotaenia bilineata. Conclusions: Our study provides further evidence that Wolbachia is widespread within wild mosquito populations of diverse Culicine species and provides further candidate strains that could be investigated as future options for Wolbachia-based biocontrol to inhibit arbovirus transmission.

Public health voluntary licensing of intellectual property has successfully been applied to increase access to medicines in certain disease areas, producing health benefits and economic savings, particularly in low-income and middle-income countries. There is however limited understanding of the intricacies of the approach, the modalities by which it works in practice, its levers and the trade-offs made. Such knowledge may be critical in deciding what role licensing should have in pandemic preparedness and equitable access to health technologies more broadly. This paper examines the case for licensing, the considerations for balancing public health needs, the challenges of negotiations, and the processes for validating proposed agreements. No access mechanism is perfect, but evidence suggests that public-health licensing has an important role to play, although it remains underused. Understanding some of the realities, strengths, limitations and complexities of applying the model may help calibrate expectations and develop incentives to expand its applications.

Background: This study assessed the potential cost-effectiveness of high (80–100%) vs low (21–35%) fraction of inspired oxygen (FiO2) at preventing surgical site infections (SSIs) after abdominal surgery in Nigeria, India, and South Africa. Methods: Decision-analytic models were constructed using best available evidence sourced from unbundled data of an ongoing pilot trial assessing the effectiveness of high FiO2, published literature, and a cost survey in Nigeria, India, and South Africa. Effectiveness was measured as percentage of SSIs at 30 days after surgery, a healthcare perspective was adopted, and costs were reported in US dollars ($). Results: High FiO2 may be cost-effective (cheaper and effective). In Nigeria, the average cost for high FiO2 was $216 compared with $222 for low FiO2 leading to a −$6 (95% confidence interval [CI]: −$13 to −$1) difference in costs. In India, the average cost for high FiO2 was $184 compared with $195 for low FiO2 leading to a −$11 (95% CI: −$15 to −$6) difference in costs. In South Africa, the average cost for high FiO2 was $1164 compared with $1257 for low FiO2 leading to a −$93 (95% CI: −$132 to −$65) difference in costs. The high FiO2 arm had few SSIs, 7.33% compared with 8.38% for low FiO2, leading to a −1.05 (95% CI: −1.14 to −0.90) percentage point reduction in SSIs. Conclusion: High FiO2 could be cost-effective at preventing SSIs in the three countries but further data from large clinical trials are required to confirm this.

Abstract Respiratory syncytial virus (RSV), human metapneumovirus (HMPV), and human parainfluenza virus types one (HPIV1) and three (HPIV3) can cause severe disease and death in immunocompromised patients, the elderly, and those with underlying lung disease. A protective monoclonal antibody exists for RSV, but clinical use is limited to high-risk infant populations. Hence, therapeutic options for these viruses in vulnerable patient populations are currently limited. Here, we present the discovery, in vitro characterization, and in vivo efficacy testing of two cross-neutralizing monoclonal antibodies, one targeting both HPIV3 and HPIV1 and the other targeting both RSV and HMPV. The 3 × 1 antibody is capable of targeting multiple parainfluenza viruses; the MxR antibody shares features with other previously reported monoclonal antibodies that are capable of neutralizing both RSV and HMPV. We obtained structures using cryo-electron microscopy of these antibodies in complex with their antigens at 3.62 Å resolution for 3 × 1 bound to HPIV3 and at 2.24 Å for MxR bound to RSV, providing a structural basis for in vitro binding and neutralization. Together, a cocktail of 3 × 1 and MxR could have clinical utility in providing broad protection against four of the respiratory viruses that cause significant morbidity and mortality in at-risk individuals.

The lens plays a central role in the development of the optic cup. In fish, regression of the eye early in development affects the development of the craniofacial skeleton, the size of the olfactory pits, the optic nerve, and the tectum. Lens removal further affects olfaction, prey capture, and aggression. The similarity of the fish eye to other vertebrates is the basis for its use as an excellent animal model of human defects. Questions regarding the effects of eye regression are specifically well-suited to be addressed by using fish from the genus Astyanax. The species has two morphs; an eyeless cave morph and an eyed, surface morph. In the cavefish, a lens initially develops in embryos, but then degenerates by apoptosis. The cavefish retina is subsequently disorganized, degenerates, and retinal growth is arrested. The same effect is observed in surface fish when the lens is removed or exchanged for a cavefish lens. While studies can greatly benefit from a control group of surface fish with regressed eyes brought through lensectomies, few studies include them because of technical difficulties and the low survivorship of embryos that undergo this procedure. Here we describe a technique with significant modification for improvement for conducting lensectomy in one-day-old Astyanax and other fish, including zebrafish. Yields of up to 30 live embryos were obtained using this technique from a single spawn, thus enabling studies that require large sample sizes.

Abstract Background Antibiotic resistance is a global concern threatening achievements in health care since the discovery of antibiotics. In Kenya, this topic remains understudied in a context of rising demand for livestock products, intensification and the concomitant increase in antibiotic use. Our study investigates drivers and practices of antibiotic use in poultry farming. The study was conducted in Kiambu County, Kenya. Methods A qualitative research methodology was employed: fourteen key informant interviews, twenty in-depth interviews, and four focus group discussions were undertaken. The interviews were semi-structured. Themes and subthemes from the interviews were generated through inductive analysis. Findings Of the farmers interviewed, sixty eight percent were female, thirty three percent of the sampled farmers could not read, and the majority (eight five percent) of farmers had reared poultry for at least ten years. Research findings showed that farmers extensively used antibiotics. Antibiotic use was influenced by factors such as high disease burden, access to medicines and economic pressure. Common practices included prophylactic use, use of antibiotics to enhance production, self-prescription use, use of combination antibiotics (A combination antibiotic is one in which two or more antibiotics are added together for additional therapeutic effect.), and antibiotics classified as critically important in human medicine. Key information sources for the farmers were agro- veterinary dispensers, sellers of day-old chicks, and peer-learning. External factors driving the inappropriate use of antibiotics included access to the antibiotics, influence by marketers such as sellers of day-old chicks, and branding. Use of antibiotics was also driven by economic factors among the farmers, sellers of day-old chicks and agro-veterinary dispensers. Conclusions Our findings indicate widespread use of antibiotics among poultry farmers in our study site. The use of antibiotics is influenced by an interplay of issues at the farmers’ level as well as broader social, economic and structural level factors. A multifaceted One Health approach focusing on regulatory frameworks, knowledge transfer, and research is required to promote stewardship and judicious use of antibiotics.

Abstract Background Intravascular large B‐cell lymphoma (lVLBCL) is a very rare type of large B‐cell lymphoma. Methods We conducted a retrospective study on IVLBCL patients treated from 2000 to 2016 in LYSA cooperative group centers. Results Sixty‐five patients were identified in 23 centers. Median age at diagnosis was 69 years (range 23–92). Thirty‐four patients (64%) had an IPI score >3 and 40 patients (67%) had a performance status ≥2. The most frequent extra‐nodal locations were bone marrow (n = 34; 52%), central nervous system (n = 25; 39%), and skin (n = 21; 33%). Nodal involvement and endocrine system were observed in 34% (n = 22) and 18% (n = 12) of all cases, respectively. Twenty‐six patients (41%) had macrophage activation syndrome. Tumor cells were frequently CD5 positive (52%) with a non‐germinal center origin (86%). BCL2 was expressed in 87% of all samples analyzed (n = 20) and 43% of patients had a MYC/BCL2 double expression. Fifty‐six patients were treated with a regimen of chemotherapy containing rituximab, among whom 73% reached complete remission. The median progression‐free survival (PFS) and median overall survival (OS) were 29.4 months and 63.8 months, respectively. History of autoimmune disorder (Hazard ratio [HR] 3.3 [1.4–7.8]; p

Abstract Objectives In this review, we aim to synthesize the current emergency medicine literature in the Philippines in order to determine the depth of research available in the country while delineating the gaps, helping to provide focus to future research in the field. Methods A literature review was done using 4 databases to identify emergency medicine studies in the Philippines. To explore the research trends among eligible studies, data on study type, countries, and institutions involved as well as study themes were collected and described. Results A total of 845 studies were screened, and 43 were included in this review. Results show that only 25% of emergency medicine studies were published before 2015. Most studies were observational (37.2%) or descriptive (37.2%) in nature with the University of the Philippines/Philippine General Hospital being the most common contributing institution (17.4%). Metro Manila was the most common study site with more than half of studies conducted in the area. Lastly, among the variety of study disciplines, disaster medicine was the most frequent topic comprising 30.2% of studies reviewed. Conclusions Compared to the global scene, Philippine emergency medicine research still has a long way to go. This study was able to provide a landscape of the current literature and highlight the study trends. Further, the findings here emphasize the need to expand the scope of emergency medicine studies in the country as it is still a young and growing field with studies tending to cluster around just a small number of institutions and regions.

Seaweed is often recognized for its potential health benefits, attributed to its abundance of dietary fibers, protein, and polyphenols. While human observational studies have shown promise, the collective evidence from human intervention trials remains limited. This narrative review aims to comprehensively analyze the effects of seaweed intake on humans, while critically assessing the methodology, including Cochrane risk-of-bias assessment. A search was conducted in online databases, including PubMed, Scopus, and Google Scholar, covering the period from 2000 to May 2023. The focus was on randomized controlled clinical trials (RCTs) evaluating the impact of whole seaweed, either consumed as capsules, integrated into food products or as part of meals. Various health outcomes were examined, including appetite, anthropometric measures, cardiometabolic risk factors, thyroid function, markers of oxidative stress, and blood mineral concentrations. Out of the 25 RCTs reviewed, the findings revealed limited yet encouraging evidence for effects of seaweed on blood glucose metabolism, blood pressure, anthropometric measures, and, to a lesser extent, blood lipids. Notably, these favorable effects were predominantly observed in populations with type-2 diabetes and hypertension. Despite most trials selecting a seaweed dose aligning with estimated consumption levels in Japan, considerable variability was observed in the pretreatment and delivery methods of seaweed across studies. Moreover, most studies exhibited a moderate-to-high risk of bias, posing challenges in drawing definitive conclusions. Overall, this review highlights the necessity for well-designed RCTs with transparent reporting of methods and results. Furthermore, there is a need for RCTs to explore seaweed species cultivated outside of Asia, with a specific emphasis on green and red species. Such studies will provide robust evidence-based support for the growing utilization of seaweed as a dietary component in regions with negligible seaweed consumption, e.g., Europe.

Breast cancer is extremely rare in children and consequently no consensus has been reached on the optimal treatment modalities. We have reported the medical history of secretory breast carcinoma (SBC) in a 6-year-old girl. An areolar-sparing mastectomy was performed without axillary surgery, and without adjuvant therapy given her limited disease and the histological type. We have reviewed the literature and summarized relevant findings concerning the clinical and histological data, treatment approaches, and outcomes for 33 cases of SBC (15 children and 18 adolescents). International data suggests that local excision without axillary surgery may be a suitable therapeutic approach for children with SBC.

Abstract Background To contribute to the mission of the National Malaria Control Programme (NMCP) and guide future interventions in Cameroon in general, and in Makenene in particular, this study assessed the knowledge, attitudes and practices of the population of Makenene towards the fight against malaria. Methods Using a semi-structured questionnaire, a descriptive cross-sectional household community survey was carried out in randomly selected households in Makenene, a locality situated between forest and savannah ecotypes. Results Out of the 413 households surveyed, all (100%) claimed to have heard of malaria with over 94% (n = 391) associating disease transmission with mosquito bites. The main mosquito control tools used in the area were mosquito nets (92.25%). The majority of participants had good knowledge (55.93%; n = 231), good practices (71.67%, n = 296) but moderate attitudes (47.94%; n = 198) towards malaria control and fight. Good knowledge and practices were recorded mostly in educated persons including public servants and students. Good attitudes were adopted mostly by public servants and students of secondary and higher levels of education. Conclusion In Makenene, the population exhibits good knowledge and practices towards malaria and its control. However, despite high LLINs ownership and use, people still complain about malaria in the area. Control tools should be monitored, repaired or replaced when necessary to support the achievement of the NMCP mission.

Abstract Background Sexually Transmitted Infections (STIs) are of great global health concern. Currently, there are limited epidemiological data characterizing STIs in the general population in Rwanda. We assessed the national and regional epidemiology of STIs in Rwanda from 2014–2020 among patients syndromically screened for STIs in all health facilities in Rwanda. Methods This is a retrospective analysis of the trend of STIs epidemiology among screened patients at all health facilities in Rwanda using data from the Health Management Information System (HMIS) reporting. Adult patients (15 years and over) screened for STIs between July 2014 and June 2020 were included in the analysis. Outcomes of interest were the number of individuals screened for STIs and individuals diagnosed with at least one STI with a syndromic approach only or plus a test together. Results Overall, the number of individuals screened for STIs over the study period was 5.3 million (M) in 2014–2015, 6.6 M in 2015–2016, 6.3 M in 2016–2017, 6.7 M in 2017–2018, 6.2 M in 2018–2019, and 4.9 M in 2019–2020. There was a modest increase in the number of individuals diagnosed and treated for STIs from 139,357 in 2014–15 to 202,294 (45% increase) in 2019–2020. At the national level, the prevalence of STI syndromes amongst individuals screened at health facilities in Rwanda varied between 2.37% to 4.16% during the study period. Among the provinces, Kigali city had the highest prevalence for the whole 6 years ranging from 3.46% (95%CI: 3.41, 3.51) in 2014–2015 to 8.23% (95%CI: 8.15, 8.31) in 2019–2020. Conclusion From 2014 to 2020, the number of patients screened for STI syndromes in Rwanda varied between 4.9 M and 6.7 M. However, the prevalence of STIs among screened patients increased considerably over time, which could be associated with public awareness and improved data recording. The highest prevalence of all STIs was observed in urban areas and near borders, and private clinics reported more cases, suggesting the need to improve awareness in these settings and increase confidentiality and trust in public health clinics.

Abstract Background Choosing an appropriate strategy for mosquito vector control in an eco-climatic facies requires knowledge on vector ecology including population dynamics of species and productivity of the breeding sites. The aim of this study was to characterize Culex mosquitoes breeding places and to determine their population dynamics in two localities (Dschang and Santchou) separated by a forest cliff in the West Region of Cameroon. Field surveys were conducted from November 2019 to June 2020 in Dschang and Santchou. Mosquito breeding sites were georeferenced, and for each breeding site, physical parameters were measured and immature stages were collected. The collected immatures were reared in the laboratory until adult stage. Adult mosquitoes were identified using a stereomicroscope and morphological identification keys. Results A total of 44 breeding sites were identified: 24 in Dschang and 20 in Santchou. They were grouped into seven types and were mostly shallow, close to human dwellings, sunny, with organic matters and of anthropogenic nature. A total of 2706 mosquitoes belonging to four genera were identified. Culex genus was the most represented (90.4%) and was made up of Culex pipiens s.l. (61.79%), Culex duttoni (23.17%) and Culex (Culiciomyia) sp. (05.46%). High abundance of Culex species was observed in Santchou (52.71%) compared to Dschang (47.28%), while Dschang (S = 3; H = 0.87; D = 0.54) recorded the greatest diversity compared to Santchou (S = 2; H = 0.23; D = 0.11). Conclusions The proliferation and persistence of Culex mosquitoes independently of the breeding sites and localities might be attributable to the poor environmental management which favor the creation mosquito breeding sites. This study highlights the fact that prompt sanitation measures could be undertaken in these two localities to reduce mosquito abundance and the risk of vector-borne diseases.

Amelogenesis imperfecta (AI) is a heterogeneous group of genetic rare diseases disrupting enamel development (Smith et al., Front Physiol, 2017a, 8, 333). The clinical enamel phenotypes can be described as hypoplastic, hypomineralized or hypomature and serve as a basis, together with the mode of inheritance, to Witkop’s classification (Witkop, J Oral Pathol, 1988, 17, 547–553). AI can be described in isolation or associated with others symptoms in syndromes. Its occurrence was estimated to range from 1/700 to 1/14,000. More than 70 genes have currently been identified as causative.Objectives: We analyzed using next-generation sequencing (NGS) a heterogeneous cohort of AI patients in order to determine the molecular etiology of AI and to improve diagnosis and disease management.Methods: Individuals presenting with so called “isolated” or syndromic AI were enrolled and examined at the Reference Centre for Rare Oral and Dental Diseases (O-Rares) using D4/phenodent protocol (www.phenodent.org). Families gave written informed consents for both phenotyping and molecular analysis and diagnosis using a dedicated NGS panel named GenoDENT. This panel explores currently simultaneously 567 genes. The study is registered under NCT01746121 and NCT02397824 (https://clinicaltrials.gov/).Results: GenoDENT obtained a 60% diagnostic rate. We reported genetics results for 221 persons divided between 115 AI index cases and their 106 associated relatives from a total of 111 families. From this index cohort, 73% were diagnosed with non-syndromic amelogenesis imperfecta and 27% with syndromic amelogenesis imperfecta. Each individual was classified according to the AI phenotype. Type I hypoplastic AI represented 61 individuals (53%), Type II hypomature AI affected 31 individuals (27%), Type III hypomineralized AI was diagnosed in 18 individuals (16%) and Type IV hypoplastic-hypomature AI with taurodontism concerned 5 individuals (4%). We validated the genetic diagnosis, with class 4 (likely pathogenic) or class 5 (pathogenic) variants, for 81% of the cohort, and identified candidate variants (variant of uncertain significance or VUS) for 19% of index cases. Among the 151 sequenced variants, 47 are newly reported and classified as class 4 or 5. The most frequently discovered genotypes were associated with MMP20 and FAM83H for isolated AI. FAM20A and LTBP3 genes were the most frequent genes identified for syndromic AI. Patients negative to the panel were resolved with exome sequencing elucidating for example the gene involved ie ACP4 or digenic inheritance.Conclusion: NGS GenoDENT panel is a validated and cost-efficient technique offering new perspectives to understand underlying molecular mechanisms of AI. Discovering variants in genes involved in syndromic AI (CNNM4, WDR72, FAM20A … ) transformed patient overall care. Unravelling the genetic basis of AI sheds light on Witkop’s AI classification.

Summary: Background: Preoperative COVID-19 has been associated with excess postoperative morbi-mortality. Consequently, guidelines were developed that recommended the postponement of surgery for at least 7 weeks after the infection. We hypothesised that vaccination against the SARS-CoV-2 and the large predominance of the Omicron variant attenuated the effect of a preoperative COVID-19 on the occurrence of postoperative respiratory morbidity. Methods: We conducted a prospective cohort study in 41 French centres between 15 March and 30 May 2022 (ClinicalTrials NCT05336110), aimed at comparing the postoperative respiratory morbidity between patients with and without preoperative COVID-19 within 8 weeks prior to surgery. The primary outcome was a composite outcome combining the occurrence of pneumonia, acute respiratory failure, unexpected mechanical ventilation, and pulmonary embolism within the first 30 postoperative days. Secondary outcomes were 30-day mortality, hospital length-of-stay, readmissions, and non-respiratory infections. The sample size was determined to have 90% power to identify a doubling of the primary outcome rate. Adjusted analyses were performed using propensity score modelling and inverse probability weighting. Findings: Of the 4928 patients assessed for the primary outcome, of whom 92.4% were vaccinated against the SARS-CoV-2, 705 had preoperative COVID-19. The primary outcome was reported in 140 (2.8%) patients. An 8-week preoperative COVID-19 was not associated with increased postoperative respiratory morbidity (odds ratio 1.08 [95% CI 0.48–2.13]; p = 0.83). None of the secondary outcomes differed between the two groups. Sensitivity analyses concerning the timing between COVID-19 and surgery, and the clinical presentations of preoperative COVID-19 did not show any association with the primary outcome, except for COVID-19 patients with ongoing symptoms the day of surgery (OR 4.29 [1.02–15.8]; p = 0.04). Interpretation: In our Omicron-predominant, highly immunised population undergoing general surgery, a preoperative COVID-19 was not associated with increased postoperative respiratory morbidity. Funding: The study was fully funded by the French Society of Anaesthesiology and Intensive Care Medicine (SFAR).

BackgroundThe role of HbA1c in women with gestational diabetes mellitus (GDM) is still unclear, particularly in the Asian population.AimTo investigate the association between HbA1c levels and adverse outcomes considering maternal age, pre-pregnancy body mass index (BMI), and gestational weight gain (GWG) in women with GDM.MethodA retrospective study included 2048 women with GDM and singleton live births. Using logistic regression, the associations between HbA1c and adverse pregnancy outcomes were assessed.ResultCompared to women with HbA1c ≤ 5.0%, HbA1c was significantly associated with macrosomia (aOR 2.63,95%CI1.61,4.31), pregnancy-induced hypertension (PIH, aOR 2.56,95%CI1.57,4.19), preterm birth (aOR 1.64,95%CI 1.05,2.55), and primary Cesarean section (primary C-section, aOR1.49,95%CI1.09,2.03) in GDM women with HbA1c ≥5.5% while significantly associated with PIH (aOR 1.91,95%CI1.24,2.94) in women with HbA1c 5.1-5.4%. The associations between HbA1c and adverse outcomes varied with maternal age, pre-pregnancy BMI, and GWG. In women aged ≤29 years, there’s significant association between HbA1c and primary C-section when HbA1c was 5.1-5.4% and ≥5.5%. In women aged 29-34 years and HbA1c ≥5.5%, HbA1c was significantly associated with macrosomia. In women aged ≥35 years, there’s significant association between HbA1c and preterm birth when HbA1c was 5.1-5.4% and macrosomia and PIH when HbA1c ≥5.5%. In pre-pregnant normal-weight women, HbA1c was significantly associated with macrosomia, preterm birth, primary C-section, and PIH when HbA1c ≥5.5% while HbA1c was significantly associated with PIH when HbA1c was 5.1-5.4% . In pre-pregnant underweight women with HbA1c 5.1-5.4%, HbA1c was significantly associated with primary C-section. HbA1c was significantly associated with macrosomia among women with inadequate GWG or excess GWG and HbA1c≥5.5%. In women with adequate GWG, there’s significant association between HbA1c and PIH when HbA1c was 5.1-5.4% and ≥5.5% .ConclusionConclusively, HbA1c at the time of diagnosis is significantly associated with macrosomia, preterm birth, PIH, and primary C-section in Chinese women with GDM.

ABSTRACT: Milk with different κ-casein (CN) phenotypes has previously been found to influence its gastric digestion rate. Therefore, the aim of the present study is to disentangle contributions of genetic variation and its related sialylation on the in vitro digestion process of κ-CN. Accordingly, κ-CN was purified from milk representing homozygous cows with κ-CN phenotypes AA, BB, or EE and used as substrate molecules in model studies using the INFOGEST 2.0 in vitro static digestion model. Furthermore, the effect of removal of the terminal sialic acids present on the O-linked oligosaccharides of the purified κ-CN A, B, and E protein variants were studied by desialylation enzymatic assays. The κ-CN proteins were purified by reducing anion exchange chromatography with purities of variants A, B, and E of 93.0, 97.1, and 90.0%, respectively. Protein degradations of native and desialylated κ-CN isolates in gastric and intestinal phases were investigated by sodium dodecyl sulfate-PAGE, degree of hydrolysis (DH), and liquid chromatography electrospray ionization mass spectrometry. It was shown that after purification, the κ-CN molecules reassembled into multimer states, which then constituted the basis for the digestion studies. As assessed by DH, purified variants A and E were found to exhibit faster in vitro digestion rates in both gastric and intestinal phases compared with variant B. Desialylation increased both gastric and intestinal digestion rates for all variants, as measured by DH. In the gastric phase, desialylation promoted digestion of variant B at a rate comparable with native variants A and E, whereas in the intestinal phase, desialylation of variant B promoted better digestion than native A or E. Taken together, the results confirm that low glycosylation degree of purified κ-CN promotes faster in vitro digestion rates, and that desialylation of the O-linked oligosaccharides further promotes digestion. This finding could be applied to produce dairy products with enhanced digestibility.

Structural and functional characterisation of an antibody CV3-25 reveals wide neutralisation spectrum of the antibody against multiple SARS-CoV2 variants.

ABSTRACT: Variations in the phosphorylation and glycosylation patterns of the common κ-casein (CN) variants A and B have been explored, whereas studies on variant E heterogeneity are scarce. This study reports for the first time the detailed phosphorylation and glycosylation pattern of the κ-CN variant E in comparison with variants A and B. Individual cow milk samples representing κ-CN genotype EE (n = 12) were obtained from Swedish Red cows, and the natural posttranslational modifications of its κ-CN were identified and quantified by liquid chromatography-electrospray mass spectrometry. In total, 12 unique isoform masses of κ-CN variant E were identified. In comparison, AA and BB milk consisted of 14 and 17 unique isoform masses, respectively. The most abundant κ-CN E isoform detected in the EE milk was the monophosphorylated, unglycosylated [1P 0G, ∼70%; where P indicates phosphorylation from single to triple phosphorylation (1–3P), and G indicates glycosylation from single to triple glycosylation (1–3G)] form, followed by diphosphorylated, unglycosylated (2P 0G, ∼12%) form, resembling known patterns from variants A and B. However, a clear distinction was the presence of the rare triphosphorylated, nonglycosylated (3P 0G, ∼0.05%) κ-CN isoform in the EE milk. All isoforms detected in variant E were phosphorylated, giving a phosphorylation degree of 100%. This is comparable with the phosphorylation degree of variants A and B, being also almost 100%, though with very small amounts of nonphosphorylated, glycosylated isoforms detected. The glycosylation degree of variant E was found to be around 17%, a bit higher than observed for variant B (around 14%), and higher than variant A (around 7%). Among glycosylation, the glycan e was the most common type identified for all 3 variants, followed by c/d (straight and branched chain trisaccharides, respectively), and b. In contrast to κ-CN variants A and B, no glycan of type a was found in variant E. Taken together, this study shows that the posttranslational modification pattern of variant E resembles that of known variants to a large extent, but with subtle differences.

Abstract Extracting statistical regularities from the environment is a primary learning mechanism that might support language acquisition. While it has been shown that infants are sensitive to transition probabilities between syllables in speech, it is still not known what information they encode. Here we used electrophysiology to study how full-term neonates process an artificial language constructed by randomly concatenating four pseudo-words and what information they retain after a few minutes of exposure. Neural entrainment served as a marker of the regularities the brain was tracking during learning. Then in a post-learning phase, evoked-related potentials (ERP) to different triplets explored which information was retained. After two minutes of familiarization with the artificial language, neural entrainment at the word rate emerged, demonstrating rapid learning of the regularities. ERPs in the test phase significantly differed between triplets starting or not with the correct first syllables, but no difference was associated with subsequent violations in transition probabilities. Thus, our results revealed a two-step learning process: neonates segmented the stream based on its statistical regularities, but memory encoding targeted during the word recognition phase entangled the ordinal position of the syllables but was still incomplete at that age.

Fermentation has long been utilized to preserve and enhance the flavor and nutritional value of foods. Recently, fermented foods have gained popularity, reaching new consumer groups due to perceived health benefits. However, the microbial composition of many fermented foods re-mains unknown. Here, we characterized the bacterial composition, diversity, and richness of 47 fermented foods available in Sweden, including kombucha, water kefir, milk kefir, yogurt, plant-based yogurt alternatives, kimchi, sauerkraut, and fermented vegetables. Via 16S rRNA gene sequencing, we identified 2497 bacteria (amplicon sequence variants). The bacterial composition was strongly associated with the type of fermented food, and lactic acid bacteria and/or acetic acid bacteria dominated most samples. However, each fermented food had a unique composition, with kombucha and water kefir having the highest diversity across and within samples. Few bacteria were abundant in multiple foods and food groups. These were Streptococcus thermophilus in yogurts and plant-based yoghurts; Lactococcus lactis in milk kefirs and one water kefir; and Lactiplantibacillus plantarum in kimchi, sauerkraut, and fermented cucumber. The broad range of fermented foods included in this study and their diverse bacterial communities warrant further investigation into the implications of microbial compositions for product traits and potential impact on human health.

The triple crises of the COVID-19 pandemic, conflict and climate change have severely impacted food systems, leading to socio-economic consequences and undermining food and nutrition security across Africa. To address the malnutrition and poverty affecting approximately 700 million people in Africa, there is potential for the One Health approach implementation and operationalization to bring together multidisciplinary solutions for tackling food insecurity and ensuring food safety net. However, there is limited documentation on the potential of the One Health approach system thinking implementation to guide responses to triple crises-induced food insecurity. Therefore, this article aims to systematically understand the triple crises-induced food insecurity, connect existing solutions, and explore the role of the One Health approach in strengthening food and agriculture systems in Africa.Our finding showed the impact of triple crises exacerbating food system vulnerability in Africa and worldwide. Mitigating and resilient actions are urgently needed in tackling the emerging and persisting challenges, and infectious diseases menace and burden across Africa. We present a conceptual model illustrating the complex nature of triple crises-induced food insecurity, vulnerability areas within the food system, and actionable strategies for building community food resilience. Additionally, recommendations are provided to create an enabling environment that supports One Health approach implementation and addresses food insecurity challenges through innovative partnerships, local-led initiatives, and enhanced governance and artificial intelligence technology capacities in achieving sustainable and inclusive growth to reduce socio-economic inequalities.Stepping up integrated, actionable, and sustainable food systems programs and innovative long-lasting solutions requires investing in promoting new partnership and research collaboration in building conflict resolution and peace towards strengthening and reshaping local and global food security related climate change adaptations actions for most vulnerable communities’ benefits. These are ingredients in fastening preparedness, prevention and control of infectious diseases prevention and control, reducing food supply chains disruption towards accelerating equitable benefits of Universal Health Coverage and Sustainable Development Goals, 2030 across Africa.