Maxillary surgery alone can be proposed for the surgical management of class III malocclusion, but anticipating outcomes for the labiomental muscle complex is challenging due to the mandibular autorotation phenomenon. The objective of this study was to quantify the mandibular and labiomental movements induced by maxillary osteotomy alone in the management of class III malocclusion according to different clinical and surgical variables.The post-operative changes in mandibular and labiomental shapes were studied by geometric morphometry from the pre- and post-operative lateral cephalometric radiograph of 25 patients. The explanatory variables tested were maxillary advancement, maxillary rotation, and divergence.Soft tissues repositioning are different from postoperative mandibular repositioning after maxillary osteotomy. Neuromuscular adjustments of mandible depend on divergence and the maxillary rotation. Labiomental response only depends on divergence.The surgical procedure does not have the same bone-related and musculocutaneous effects on patients with the same class III malocclusion. It is therefore essential for surgeons to understand the effects of their procedure on musculocutaneous tissues in order to best anticipate post-operative outcomes. Class III malocclusion can manifest in different clinical forms and be associated with varying degrees of sagittal and vertical, maxillary and mandibular abnormalities . MorphomIn addition to occlusal stability and operative morbidity, the surgeon must also take into account patient satisfaction with post-operative morphology. Indeed, the reason patients agree to orthodontic surgical management lie in the resulting morphological changes, and not in the occlusal or functional changes , 17. AntThe mandibular autorotation phenomenon (MAP), which must be taken into account during any maxillary surgery, is still poorly understood as demonstrated by the limited number of reports found in the literature. However, Chang et al.  indicateThe objective of our study was therefore to quantify the labial and mandibular movements induced by maxillary osteotomy alone in the management of class III malocclusion according to different clinical and surgical variables. We tested how post-operative mandibular position correlated with maxillary advancement (H1), maxillary impaction movement (H2), and/or individual divergence profiles (H3). We also investigated how post-operative changes in labiomental morphology correlated with maxillary advancement (H4), maxillary impaction movement (H5), and/or individual divergence profiles (H6).st January 2013 until 31th March 2022 (10 years and 3 months). We included all patients that had undergone an isolated LeFort I osteotomy in our Plastic and Maxillo-facial Surgery Department  to correct a class III malocclusion as defined by ANB angle (below 0°) [We carried out a retrospective, single-center, cohort study from 1elow 0°) . PatientAn official waiver of ethical approval was granted from the IRB of Toulouse University Hospital given the retrospective nature of the study as asserted by French Jardé law (study reference RnIPH 2023–07). All the procedures performed were part of routine care, and both in accordance with institutional guidelines and with the principles and regulations of the Declaration of Helsinki. Informed patient consent was obtained from all participants and all data has been anonymized for publication purposes.The intervention consisted of a LeFort I osteotomy , a standGiven the primary study objective was to determine the labial and mandibular movements induced by maxillary surgery, we studied post-operative changes in mandible position and lower lip shape determined by geometric morphometry from LCR. We considered post-operative lower labial edema to be clinically insignificant after maxillary surgery alone.Geometric morphometry (GM) is based on the acquisition, processing, and analysis of landmarks placed at key anatomical locations on objects to quantify morphological variation, while excluding biases related to position, orientation, and scale .Landmarks can be categorized into "anatomical" landmarks and semilandmarks . AnatomiWe defined a set of LMs  and SLs on curves that were placed on the lateral cephalometric radiographs of each patient from our sample . To ensuWe used four anatomical LMs : the Ar The mandibular curve was defined by 15 SLM, between the points Ar and B. The labio-mental shape was characterized by a second curve, defined by 13 SLM placed between Sto and Me’ .The mandibular and labio-mental shapes were therefore characterized by the Cartesian coordinates of these SLM.The repeatability (i.e. intra-operator error test) of the measurements was assessed using the intraclass correlation coefficient  . Five laData on three explanatory variables were collected for each patient and tested as potential predictors for post-operative changes in mandibular and labio-mental morphology: maxillary advancement, maxillary impaction, and divergence.Maxillary advancement (in mm) was characterized by the difference between the pre- and post-operative coordinates  of the ANS  point on the lateral radiographs. For maxillary impaction, we distinguished "clockwise maxillary impaction" (when posterior impaction was more significant), "anti-clockwise maxillary impaction" (when anterior impaction was more significant), and "homogenous maxillary impaction" (when both impactions were similar). The anterior and posterior impactions were characterized by the difference between the pre- and post-operative coordinates  of the ANS and PNS  points on the lateral radiographs. Finally, divergence was defined by the Frankfurt-mandibular plane angle . A patient was considered hypo-divergent if FMA was <22°, normo-divergent if FMA was 22–28°, and hyper-divergent if FMA was >28°.Since diagnostic cephalometry enables the study of skeletal malocclusion, divergence and characterization of maxillary movements were carried out using the Viewbox Cephalometric Software.The SLM coordinates defining the lower lip and mandibular shapes were then aligned by Procrustes superimposition. The resulting Procrustes  coordinates were extracted and used as input variables in all subsequent analyzes , 35. P-vThe effect of maxillary surgery on mandibular morphology changes was confirmed by an Anova with repeated measurements (n = 10000) for the Mahalanobis distances between the "pre-operative mandible" and "post-operative mandible" groups. We repeated this for the "pre-operative lip" and "post-operative lip" groups.A Two-Block Partial Least Squares regression (2b-PLS) was computed to test for covariation between pre-operative (first block) and post-operative (second block) mandibular shape. The influence of divergence and maxillary movement (H2 and H3) were assessed by examining how groups were discriminated along the PLS axis. Another 2b-PLS regression was computed to test for covariation between pre-operative (first block) and post-operative (second block) labiomental shape. The influence of divergence and maxillary movement (H5 and H6) were assessed by examining how groups were discriminated along the PLS axis. When PLS axes revealed some differences between groups, a canonical analysis of the variables was ran on the co-variance matrix of shape (pre- and post-operative) coordinates in sub-groups for the different variables . The effProcrustes superimposition and statistical analyzes were carried out using the MorphoJ software  . Surgeries were performed by three different surgeons but the majority (76%) of the procedures were performed by the same surgeon. The post-operative lateral cephalometric radiographs were carried out on average 8.5 months (±7 months) after the surgery. Data for the different variables studied are detailed in Multivariate analyzes of variance indicated that mandibular shape was significantly different after surgery (p <0.0001).The 2b-PLS regression revealed that pre- (block 1) and post-operative (block 2) mandibular shape strongly covaried  and appeared to evolve according to PLS 1 divergence (which represented 67.87% of the co-variation) .We therefore analyzed these divergence-related changes in mandibular shape by carrying out a canonical analysis of pre-operative and post-operative variables in the different sub-groups of divergence .In hypo-divergent patients, we noted a slight symphyseal advancement with no associated vertical movement . The changes were more pronounced for hyper-divergent patients. We noted a reduction in gonial angle and symphyseal ascension and advancement . There were no significant changes among normo-divergent patients .Maxillary advancement had no effect on mandibular shape  regardless of the patient divergence profile  . Clockwise maxillary impaction appeared to induce symphyseal advancement and ascension while the height of the mandibular angle remains similar. There were also active changes in mandibular position when anti-clockwise maxillary impaction was performed (p<0.0004). Anti-clockwise maxillary impaction induced symphyseal ascension without advancement and a reduction in mandibular angle. Homogenous maxillary impaction did not induce significant mandibular repositioning (p = 0.9) .The mandibular autorotation phenomenon varied according to divergence and maxillary impaction movement.There was a difference in morphology between the pre-operative and post-operative lower lip shapes. Maxillary surgery therefore affects lower lip shape .The PLS analysis enabling the study of variation in pre- (block 1) and post-operative (block 2) labio-mental shapes confirmed that these shapes were correlated  and that they appeared to evolve according to PLS 1 divergence (which represented 59.8% of the co-variation) .We therefore analyzed changes in post-operative lower lip shape according to divergence by carrying out a canonical analysis of pre-operative and post-operative variables in the different sub-groups of divergence .In hypo-divergent patients, maxillary surgery appeared to induce a push back of the soft tissue of the chin and red lip protrusion (p<0.0001). Maxillary surgery induced similar but more marked changes in hyper-divergent patients. We noted a more pronounced labio-mental fold (p = 0.0015) a reduction in labio-mental height. The soft tissue of the chin was pushed back with red lip protrusion in normo-divergent patients (p<0.0001).Maxillary advancement had no effect on changes in labio-mental shape  regardless of patient divergence profile   and post-operative (block 2) labio-mental shapes showed that surgical movement did not underlie the correlation between pre- and post-operative labio-mental shapes .In all, only divergence significantly affected post-operative lower lip shape.We carried out co-variation analysis (PLS) between pre-operative mandibular shape (block 1) and post-operative labio-mental shape (block 2); we found co-variation between them (coef 0.36 p = 0.002). Analysis of the distribution of individuals on PLS 1 (which represented 68.52% of the co-variation) showed that divergence underlies this correlation  contraryAmong the explanatory variables we studied, only divergence seemed to cause the changes in shape . MandibuThe objective of our study was to quantify the mandibular and labio-mental movements induced by maxillary osteotomy alone in the management of class III skeletal malocclusion. By testing a series of explanatory factors, we demonstrate here that changes in post-operative mandibular position were not dependent on the extent of the maxillary advancement (H1 refuted), but depended on maxillary impaction movement (H2) as well as the individual divergence profile (H3). We also demonstrate that changes in labio-mental morphology were not dependent on either the extent of the maxillary advancement or maxillary impaction movement (H4 and H5 refuted). Overall, only divergence caused changes in labio-mental shape. Our findings show that "bone-related" modifications must be distinguished from "labio-mental" modifications and that these neuromuscular adjustments depend on divergence and the surgical maxillary movement induced.Regarding our morphological analysis of the mandible, our results confirm that LeFort I osteotomy induces post-operative mandibular repositioning . This MAP is traditionally defined as being a neuromuscular response to a new occlusion after surgical upper maxillary repositioning . Indeed,The pre- and post-operative mandibular shapes were also correlated with divergence profile. Maxillary surgery induced a symphyseal advancement without associated vertical movement in hypo-divergent patients  and a symphyseal advancement and upward movement in hyper-divergent patients . There was no significant post-operative change in normo-divergent patients . It is noteworthy that maxillary surgery in a normo-divergent patient did not induce a clear change in mandibular position, but it did cause a significant labio-mental shape change. There was consequently a neuromuscular adjustment reflex with no detection of mandibular autorotation. The term "mandibular autorotation" does not therefore seem appropriate for describing this neuromuscular adjustment.Regarding our morphological analysis of labio-mental shape, our results confirm that LeFort I osteotomy induces a change in the soft labio-mental tissues . Again, only divergence significantly influenced the change observed in lower lip shape. Similar to our conclusions above, it does not seem appropriate to anticipate these labio-mental effects without analyzing divergence. Different teams have however attempted to correlate the maxillary impaction movements with the movements of cephalometric points ; no convWe describe here that advancement of the bony chin point paradoxically causes the soft tissue of the chin to be pushed back. This dissociation between mandibular movements and their cutaneous effects can be explained by the contraction of the labio-mental muscle complex. In fact, mobilization of bone structures induces movement in all the muscular-cutaneous tissues. The muscles change shape, contract or relax, and the tension inevitably impacts skin appearance. We think that advancement of the bony chin point induces a reflex contraction in the mentalis muscle, which is responsible for an upper movement in the soft tissue of the chin and an eversion in lip vermilion. The mentalis muscle acts as: (1) a levator muscle for the skin on the chin, causing wrinkling, and (2) an indirect levator muscle of the lower lip, projecting it forwards , 40. TheThe limitations of our study owe to the single center and retrospective design that ultimately limit patient inclusion. Inclusion of more patients are required to confirm the effect of clinical explanatory variables studied. In addition, since mandibular autorotation depends on neuromuscular rehabilitation, it would have been interesting to repeat the measurements at different post-operative times to analyse the stability in changes observed. Indeed, some authors have suggested performing a postoperative electromyogram to study muscle contraction secondary to bone movements after mandibular osteotomy , 43. ThiThis is the first study denoting post-operative changes in mandibular-labio-mental morphology after maxillary surgery according to different clinical and surgical variables. It is also the first time that geometric morphometric has been used to characterise and explain the neuromuscular adjustment of the chin to mandibular movement. Our data therefore strengthens the idea that mandibular-mentonal neuromuscular readjustment cannot be reduced to a simple mandibular autorotation movement. We think that understanding this mechanism requires a better characterization of the patients included (notably divergence) in the former published studies. For instance in our study, we could consider it inadequate to analyse mandibular repositioning in a cohort of patients not presenting with the same sagittal malocclusion. Given that skeletal malocclusion can be due to cranio-facial growth disorders, we can assume that a patient presenting with class II malocclusion will not have the same muscular development as a patient with class III malocclusion, and therefore potentially experience a different neuromuscular response to surgical repositioning of the maxilla. There are also many other confounding factors that can influence the muscular response which require investigation in future research, such as phenotypic sub-groups, sex, and post-operative follow-up.Maxillary advancement alone does not result in mandibular or labiomental changes and so the clinical indication of maxillary surgery alone for the correction of class III dentoskeletal dsymorphoses can be justified. Surgical maxillary rotation results in mandibular upper movement associated with varying degrees of advancement, the extent of which depends on maxillary rotation movement and the divergence of the patient. However, this mandibular movement would not have a significant impact on labio-mentonal projection, morphological criterion of patient concern.The surgical procedure therefore does not have the same bone-related and musculocutaneous effects on patients with the same class III malocclusion. It is therefore essential for surgeons to understand the effects of their procedures on musculocutaneous tissues to anticipate post-operative outcomes. Overall, we can conclude that the term "mandibular autorotation" is not appropriate for describing these complex neuromuscular adjustments and further studies are needed to understand this phenomenon.S1 Text(TXT)Click here for additional data file.S2 Text(TXT)Click here for additional data file.S3 Text(TXT)Click here for additional data file.


Organic semiconductors are being explored as retinal prosthetics with the prime attributes of bio-compatibility and conformability for seamless integration with the retina. These polymer-based artificial photoreceptor films are self-powered with light-induced signal strength sufficient to elicit neuronal firing events. The molecular aspect of these semiconductors provides wide spectral tunability. Here, we present results from a bulk heterostructure semiconductor blend with a wide spectral response range. This combination elicits clear spiking activity from a developing blind-chick embryonic retina in the subretinal configuration in response to white light. The response is largely triggered by the blue–green spectral regime rather than the red-NIR regime for the present polymer semiconductor layer attributes. I.The possibility of eliciting firing activities from retinal ganglion neurons (RGCs) using artificial photoreceptors has opened up a range of options to restore and augment vision.Techniques such as optogenetics have been used where bipolar or RGCs are delivered a light-sensitive protein such as channelrhodopsin (ChR) that causes these cells to fire in response to light. Implanting of electrodes like platinumThe initial choice of the polymer semiconductor for the research groups active in this area was the well-studied poly (P3HT).Two configurations are commonly used for interfacing the artificial photoreceptor layer with the retina. In the epiretinal configuration, the prosthetic is introduced adjacent to the retinal ganglion cell (RGC) layer. Such a configuration aims to stimulate RGCs directly without using the multilayered network architecture of the retina.The developing chick embryo provides an elegant, accessible model for demonstrating the use of organic BHJs as an artificial polymer photoreceptor (APPR) layer.Experiments with plain P3HT and P3HT: N2200 in the epiretinal and subretinal positions have been done before in the field. These materials have been shown to stimulate activity from the developing blind chick retina for a broad set of visible wavelengths (450–580 nm). However, they were unable to elicit activity from the retina when illuminated with Red/NIR light. This was attributed to the absorption peak of P3HT being at a wavelength of In this pursuit, we explore the viability of the donor–acceptor of DPP-IT4F (1:1) for this purpose. Polythiophene)] (DPP-DTT) is a high-mobility p-type polymer. It is a low bandgap polymer with a peak absorption in the We present results from our experiments using the DPP-DTT: IT4F polymer BHJ films interfaced to a developing blind chick retina (E12–E15) in the subretinal configuration. The response of RGCs to flashes of blue, green, red, infrared (IR), and white light stimuli was recorded using a multi-electrode array (MEA).II.The BHJ film of DPP-DTT: IT4F in contact with the electrolyte media was studied for its spectral and transient response. The device configuration consisted of a All MEA recordings were done on developing chick retina (E12–E15) interfaced with the BHJ in the subretinal configuration. RGC firing was recorded using an The BHJ-coupled (APPR) retina showed clear light-elicited firing of RGCs on multiple electrodes in response to the white-light stimulus in the background of spontaneous activity and retinal waves. The white light LED source is essentially a convolution of a narrow-blue emitter  has been shown in this work to elicit light-induced spiking activity when interfaced in the subretinal configuration with a developing blind chick retina. The spiking activity is markedly different from the spontaneous activity at these developmental stages. The latency of the response and the proximity of the polymer to the developing photoreceptor/bipolar side of the retina points to a network-mediated activation of the RGCs instead of direct activation. This activation mechanism will help elicit physiologically relevant spiking from the population of RGCs and would be effective as a visual prosthetic compared to direct activation. Even though the polymer BHJ responds to the incident light in the IV.A.Gallus gallus domesticus) embryos (E12–E15) were obtained after cracking the egg, sacrificing the animal, and enucleation of the eye. The retina was then placed in ice-cold aCSF  are plotted as tick marks after alignment of the spike times with the stimulus time. Spikes until the next stimulus trial (


Malaria in pregnancy remains a major public health problem in endemic areas of the sub-Saharan African (SSA) region. However, there is limited understanding of the association between women’s empowerment and the uptake of sulfadoxine–pyrimethamine for intermittent preventive treatment of malaria during pregnancy (IPTp-SP) in Kenya. This study examines the association between women’s empowerment indicators  and the uptake of three or more doses of IPTp-SP in the Lake endemic region of Kenya.The analysis utilized a dataset from a cross-sectional baseline survey of 3129 women aged 15–49 years in Kisumu and Migori Counties who had a live birth within the last 2 years preceding the study. Data were collected between June to August 2021. A descriptive analysis was conducted to show the distribution of respondents by key background characteristics, and bivariate and multivariate logistic regression to examine statistically significant associations between women’s empowerment measures and the uptake of 3+ doses of IPTp-SP.Among the 3129 women surveyed, 1978 (65.7%) received 3+ doses of IPTp-SP during their most recent pregnancy. Controlling for individual characteristics and the number of ANC visits, the odds of taking 3+ doses of IPTp-SP increased among women who had high decision-making autonomy ; and tertiary level of educational attainment . However, the association between control of assets and uptake of IPTp-SP was positive but not statistically significant.Women’s decision-making autonomy and educational attainment were positively associated with the uptake of IPTp-SP. As a result, maternal health interventions should focus on less empowered women, specifically those with less decision-making autonomy and no/low formal education, as they are less likely to achieve optimal uptake of IPTp-SP during pregnancy. In 2021, there were approximately 247 million malaria cases globally, with the sub-Saharan Africa (SSA) region bearing the heaviest burden, accounting for about 95% of cases and 96% of malaria-related deaths . MalariaThe World Health Organization (WHO) recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine–pyrimethamine (SP) as a malaria preventive chemotherapy . IPTp-SPA vast amount of literature addresses the factors associated with the uptake of 3+ doses of IPTp-SP in SSA. Major strands of evidence indicate that the uptake of 3+ doses of IPTp-SP is associated with the mother’s level of education , socio-eThe concept of women’s empowerment is multifaceted . It encoThis study examines the association between various indicators of women’s empowerment , and the uptake of 3+ doses of IPTp-SP among women aged 15–49 years who had a live birth within the 2 years prior to the survey. The study hypothesis is that women’s empowerment is positively associated with the uptake of 3+ doses of IPTp-SP during their most recent pregnancy. Exploring the association between women’s empowerment and the uptake of 3+ doses of IPTp-SP can provide valuable insights for malaria prevention programmes and inform their strategies effectively.Revive IPTp-SP project. This project aims to revitalize and support the effective delivery and uptake of IPTp-SP in Kenya.The data for this paper are derived from a cross-sectional baseline survey conducted for the The study was conducted in two malaria-endemic counties, namely Migori and Kisumu, situated in the Lake region of Kenya . Both coKenya’s IPTp strategy recommends provision of IPTp-SP at each routine ANC visit under directly observed therapy (DOT), starting as early as possible in the second trimester. However, HIV-positive pregnant women on daily cotrimoxazole chemoprophylaxis are not recommended to receive IPTp-SP for the prevention of MiP . AccordiThe target population comprised women aged 15–49 years, who had a pregnancy and gave birth to a live baby within the 2 years preceding the survey and were residents of Kisumu and Migori counties.A sample size of 4080 women (2470 in Migori and 1610 in Kisumu) aged 15–49 years, who had a pregnancy and gave birth to a live baby within the last 2 years preceding the survey were targeted for inclusion in the study. The sample size was determined to detect a minimum 5-percentage point increase in the proportion of women taking three or more doses of IPTp-SP at follow-up, with at 95% confidence level and 80% power, while accounting for homogeneity among participants from the same clusters and a 25% non-response rate ; (b) marital status categorized into two ; and (c) gravidity categorized into four ; and (2) knowledge of MiP prevention—a composite variable based on five questions that asked respondents their knowledge of approaches used for preventing MiP , gestational age one should start taking IPTp-SP , and the recommended number of doses of SP that a pregnant woman is expected to take during entire pregnancy period . Each item was dichotomised into 1 (yes) and 0 (otherwise). Finally, a three-category variable was created out of the five binary variables with values 0–1 (no/low knowledge), 2–3 (moderate knowledge), and 4–5 (high knowledge).The analysis adjusted for the number of ANC visits as the entry step for women in this study to receive the WHO-recommended intervention package. Women who completed at least four ANC visits were coded 1 and 0 otherwise. The rationale is that women who completed at least four ANC visits should have received at least three doses of IPTp-SP according to the national guidelines for diagnosing, treating, and preventing malaria in Kenya , 23.The analysis involved: (1) descriptive statistics (frequencies) to show the distribution of respondents by key background characteristics and uptake of 3+ doses of IPTp-SP; and (2) bivariate (model I) and multivariate (models II and III) logistic regression to determine the association between women’s empowerment  and the uptake of 3+ doses of IPTp-SP. Model II adjusted for individual characteristics  to examine the degree to which the association between women’s empowerment and the uptake of 3+ IPTp-SP doses is affected by current individual attributes. Model III adjusted for the effects of ANC visits to test the robustness of the result to exclusion or inclusion of this variable that acts as the entry point for receiving IPTp-SP via DOT. Comparing models II and III helps avoid making “The Table 2 Fallacy” .OR) and adjusted odds ratios (aOR) were reported with 95% confidence intervals (CI), and all predictors with p < 0.05 were considered to be independently associated with the uptake of 3+ doses of IPTp-SP. A weighted analysis was performed to account for the complex survey structure and derive representative estimates using the svy command in Stata. Correlation and Variance Inflation Factor (VIF) analyses were performed to check for multicollinearity and tolerance values of all variables. No major multicollinearity problems were found (mean VIF 1.18). Figure Crude odds ratios  and the AMREF Ethics and Scientific Review Committee (AMREF-ESRC P886/2020). In addition, the Kenya National Commission for Science, Technology, and Innovation (NACOSTI/P/21/8778) granted research clearance. Written informed consent was obtained from participants aged 18 years and above and emancipated minors before conducting the interviews.Table Table In Model II, after adjusting for individual factors , decision-making power and educational attainment remained significantly associated with the uptake of 3+ doses of IPTp-SP (p < 0.05). However, control over assets and employment became less important.In Model III, which adjusted for the number of ANC visits . Similarly, women with moderate decision-making power were more than twice as likely to take 3+ doses of IPTp-SP during their last pregnancy compared to those without decision-making power . Furthermore, after adjusting for individual characteristics and ANC visits, who had attained tertiary education had 50% higher odds of taking 3+ doses of IPTp-SP than those with no schooling or some primary education.This study examined the association between women’s empowerment and the uptake of 3+ doses of IPTp-SP in two malaria-endemic counties in Kenya. Specifically, this paper explored the association between different dimensions of women’s empowerment  with optimal uptake of IPTp-SP.Overall, the study reveals that 75% (751/1151) of women who received less than 3 doses of IPTp-SP despite having attended more than 4 ANC visits for their most recent births. The gap between ANC visits and uptake of 3+ doses of IPTp-SP in the study settings may be attributed to health system-related barriers, such as stock-outs of SP, inadequate capacity of health providers due to lack of training, and non-adherence to national policy guidelines due to competing checklist of ANC elements to be covered , 28. WhiLow uptake of 3+ doses of IPTp-SP may also be due to individual-related factors. For instance, women’s late presentation for ANC delays the start of malaria prevention and treatment in pregnancy and subsequently the number of IPTp doses a woman will receive , 14, 30.The analysis of the association between women’s empowerment and IPTp-SP uptake suggests that women’s decision-making power  is an important factor associated with the uptake of 3+ doses of IPTp-SP. The finding is consistent with previous studies on the relationships between women’s decision-making autonomy and the utilization of maternal health services  –18. One Similarly, women who attained tertiary education were more likely to have completed 3+ doses of IPTp-SP compared with their counterparts with no/incomplete primary level of educational attainment. The literature suggests that more educated women may have a greater awareness of the benefits of accessing maternal health services than their less educated counterparts . AdditioIncluding the number of ANC visits in model III had a negligible effect on the association between decision-making power or educational attainment and the uptake of 3+ doses of IPTp-SP. Similar to studies elsewhere , 35–37, The association between control of assets and the uptake of 3+ doses of IPTp-SP was positive but not statistically significant after adjusting for individual characteristics and ANC visits. The study did not also find a statistically significant association between employment (a proxy of economic empowerment) and optimal uptake of IPTp-SP in the adjusted models. However, research shows that women with economic empowerment or cash income have improved access to health services during pregnancy and delivery –40. One The main strength of this study is the use of multidimensional measures of women’s empowerment to examine its association with optimal uptake of IPTp-SP. Women were randomly sampled to participate in the community survey; hence the result can be generalised in similar settings. However, the study has some limitations. The study used cross-sectional data, which does not permit cause-effect relationship analysis. In addition, there is the likelihood of reporting bias/discordance regarding decision-making autonomy within the family due to the subjective nature of this phenomenon. Recall bias on self-reported IPTp-SP use, especially among women who did not have an ANC booklet for verification, may also affect the findings. In addition, the study did not account for unpartnered women when computing decision-making indicators to enable comparison with the partnered ones. Despite these limitations, the findings highlight the association between women’s empowerment and optimal uptake of IPTp-SP in endemic areas in Kenya.Women’s decision-making autonomy and educational attainment were positively associated with the uptake of 3+ doses of IPTp-SP. As a result, maternal health interventions should focus on less empowered women, specifically those with less decision-making autonomy and no/low formal education, as they are less likely to achieve optimal uptake of IPTp-SP during pregnancy.


More than 50% of pre-clinical studies fail despite a long and expensive journey of drug discovery using animal models . CurrentB2M) and the Class II Major Histocompatibility Complex Transactivator (CIITA) genes  that is enriched in LRs [Chung Ming Tse et al. describe colonoid cultures derived from Caco-2/BBe cells as a three-dimensional model (3D) of the human intestinal epithelium. This culture was utilized to study two unsolved issues of lipid rafts (LRs): the membrane aggregates enriched in ceramides that are called ceramide-rich platforms (CRPs) and the intestinal Cld in LRs . The stud in LRs .BMP2 polyplexes and included in chitosan hydrogel or PRP-based fibrin 3D hydrogel. When implanted into critical-size calvarial defects in rats, all matrices with BMP2 polyplexes led to new bone formation. The most significant effect on osteoinduction was observed for the PLA/PRP matrices, suggesting that PLA granules and PRP-based fibrin hydrogel containing BMP2 polyplexes are the most promising for future applications in bone regeneration [Wei-Han Lin et al. generated a centimeter-scale human cardiac disk and coupled it to a hydrogel-based soft-pressure sensor based on their recently established method of 3D bioprint human pluripotent stem cells in an extracellular matrix-based bioink that allows for in situ cell expansion prior to cardiac differentiation. This, bionic-engineered testbeds can be indicators of tissue health and function and provide a unique insight into human cell responses to ablative interventions . Irina Nneration .The review of Alexandra Dobranici et al. addresses magnetic fields and nanoparticles (MNPs) that may trigger focal adhesion changes, which are further translated into the reorganization of the cytoskeleton architecture and have an impact on nuclear morphology and positioning through the activation of mechanotransduction pathways. Their review presents an updated and integrated perspective on the molecular mechanisms that govern the cellular response to magnetic cues, with a special focus on neurogenic differentiation and the possible utility of nervous TE, as well as the limitations of using magnetism for these applications . Agniesz


Teaching point: A hypoechogenic mass within the fibrous capsule of a breast implant could correspond with a silicone-induced granuloma. A 61-year-old asymptomatic woman presented at the mammography unit for a routine breast cancer screening. She underwent a breast augmentation with silicone breast implants and free silicone breast injections in 1997. Mammography showed prepectoral breast implants and bilateral several extremely dense lobulated masses with rim calcification, consistent with free silicone deposits. On ultrasound, a circumscribed hypoechogenic mass of 2.5 cm with internal vascularisation was observed between the fibrous capsule and breast implant in the upper outer quadrant (UOQ) of the right breast . The masBMRI showed a mass with a heterogeneous T2 hyperintense centre and T2 hypointense peripheral rim extending from the fibrous capsule and protruding in the implant on the T2-weighted and silicone-only sequences –b. The mBreast implant-associated complications have been increasingly reported, including BIA-ALCL and silicone-induced granulomas of breast implant capsule (SIGBIC). SIGBIC typically presents as a mass within the capsule surrounding the breast implant. It is triggered by silicone bleeding, which causes the accumulation of silicone particles in the capsule and a granulomatous inflammation as part of a chronic inflammatory foreign body-like reaction.On BMRI, SIGBIC can present as a well-defined, heterogeneous T2 hyperintense mass within the fibrous capsule of the breast implant and external compression on the implant. On the dynamic imaging sequence, a black-drop sign can be present as a marked low signal focus at the interface between the mass and the implant, which corresponds to silicone granules within the implant fibrous capsule. They typically show progressive contrast enhancement, and early contrast enhancement of the mass can be seen in extracapsular extension . SIGBIC


These analyses do not support the authors’ strong conclusions in favor of larotrectinib and, therefore, could mislead health care providers.We read with intrigue the recent publication in this journal by Roth et al. (2020) “The Potential Long-Term Comparative Effectiveness of Larotrectinib and Entrectinib for Second-Line Treatment of TRK Fusion-Positive Metastatic Lung Cancer.”1.3 respectively. The data were derived after only 13 months of follow-up in both trials and extrapolated to generate lifetime survival curves. While the authors had complete information for larotrectinib, progression-free and overall survival curves for entrectinib in this subpopulation have not been published, so the authors made assumptions about these distributions. These limitations impart a high level of uncertainty to all estimates.The comparison used in the study is based on a subset of 12 and 10 patients with TRK fusion-positive metastatic non-small-cell lung cancer (NSCLC) from the larotrectinib and entrectinib trials,2.4 In some cases, comparisons between therapies across single-arm studies may be considered using newer methods, such as simulated treatment comparison and matching-adjusted indirect comparison. While they may allow adjustment for differences in patient characteristics to some extent, even these techniques have limitations when the sample sizes are small and there is high heterogeneity in patient characteristics between the 2 trials. Chu et al. (2020), in their systematic review of the efficacy of TRK inhibitors, state that “a robust quantitative synthesis of results comparing the relative efficacy of the different NTRK mutation-specific agents versus the current standards of care is challenging.”5When head-to-head trials of 2 therapies are not available, network meta-analyses/indirect treatment comparison methods may be used to inform decisions, if the analyses can be anchored to a common control arm. The ISPOR Good Practice Task Force guidance for network meta-analyses/indirect treatment comparisons considers naive comparisons between 2 trials to be a “fatal flaw” in the analysis.2) cited by the authors does not present data for the subset of patients with NSCLC. Data for the subset of patients with NSCLC in the larotrectinib trials are presented in the publication by Farago et al. (2019),6 which we cite here.Despite evidence of substantial differences between the larotrectinib and entrectinib single-arm trials, the authors conducted a naive comparative effectiveness analysis, with no statistical adjustment to account for these differences. The source used by the authors for baseline characteristics of patients with NSCLC in larotrectinib trials is unclear, since the reference  metastases and poorer Eastern Cooperative Oncology Group performance status (ECOG PS) than that of the larotrectinib trial population:Age: Patients in the larotrectinib trial 6 were much younger than patients in the entrectinib trial .3 In fact, the youngest patient in the larotrectinib trial was 21 years younger than the youngest patient in the entrectinib trial.CNS metastases at baseline: A higher proportion of patients in the entrectinib trial (60%) had brain metastases at baseline compared with the larotrectinib trial (50%).6ECOG PS: While Farago et al. did not provide ECOG PS data for larotrectinib, these data were given in the Drilon et al. (2019). presentation, which included 11 of the 12 patients with NSCLC.7 A greater proportion of patients in the entrectinib trial had an ECOG PS of 2 (20%) compared with larotrectinib (9%).73.Based on the wholesale acquisition cost , the monthly cost for larotrectinib  is almost twice that for entrectinib .While the Roth et al. analysis evaluates quality-adjusted life-years regardless of the limitations, the authors chose not to consider the relative costs of the 2 therapies despite the substantial difference, which is surprising given the authors’ health economics expertise.Given the heterogeneity resulting from the very different, small patient subpopulations and lack of statistical adjustment, the analyses presented by Roth et al. should be interpreted with caution. We appreciate that the authors conducted sensitivity analyses using worst- and best-case scenarios; however, these do not overcome the inherent limitations of single-arm studies with vastly different patient characteristics. The authors’ conclusion that “larotrectinib provided improved life-year and quality-adjusted life-years outcomes compared to entrectinib” is an inappropriate extrapolation using a limited dataset and does not provide robust information to the readers.


Seasonal malaria chemoprevention (SMC) has proven highly efficacious in reducing malaria incidence. However, the continued success of SMC is threatened by the spread of resistance against one of its main preventive ingredients, Sulfadoxine-Pyrimethamine (SP), operational challenges in delivery, and incomplete adherence to the regimens. Via a simulation study with an individual-based model of malaria dynamics, we provide quantitative evidence to assess long-acting injectables (LAIs) as potential alternatives to SMC. We explored the predicted impact of a range of novel preventive LAIs as a seasonal prevention tool in children aged three months to five years old during late-stage clinical trials and at implementation. LAIs were co-administered with a blood-stage clearing drug once at the beginning of the transmission season. We found the establishment of non-inferiority of LAIs to standard 3 or 4 rounds of SMC with SP-amodiaquine was challenging in clinical trial stages due to high intervention deployment coverage. However, our analysis of implementation settings where the achievable SMC coverage was much lower, show LAIs with fewer visits per season are potential suitable replacements to SMC. Suitability as a replacement with higher impact is possible if the duration of protection of LAIs covered the duration of the transmission season. Furthermore, optimising LAIs coverage and protective efficacy half-life via simulation analysis in settings with an SMC coverage of 60% revealed important trade-offs between protective efficacy decay and deployment coverage. Our analysis additionally highlights that for seasonal deployment for LAIs, it will be necessary to investigate the protective efficacy decay as early as possible during clinical development to ensure a well-informed candidate selection process. Children carry the majority of the global malaria burden, with an estimated 67% of all malaria-related deaths (272 000 in 2019) occurring in those under 5 years of age . SP+AQ pDespite its potential, poor adherence limits the effectiveness of SMC and the spread of drug resistance has potential to limit the effectiveness of SMC. Additionally, the monthly delivery of SMC-SP+AQ (one day of SP and three days of AQ) throughout the transmission season is relatively expensive, due to human resources and especially due to operational constraints during the rainy season . ConsequThe need for alternative prevention tools that simplify deployment and possess a reduced risk of resistance is pressing. In the absence of an effective vaccine being deployed, long-acting injectables (LAIs) with an anti-infective effect could provide potential alternative seasonal prevention tools by simplifying the deployment and reducing the risk of resistance through decreased selection pressure for SP resistance . LAIs arIn silico modelling and simulation approaches of malaria transmission and control, allow the quantification of the impact of varying tool specifications in relation to varying operational and setting constraints which would not be feasible in real life clinical trials. They thus allow for the exploration of the potential to meet non-inferiority criteria. In the absence of non-inferiority evidence at the early stages of development, modelling and simulation approaches therefore provide a quantitative basis to further inform decision making. They guide tool development from the early stages by predicting potential public health impact  in public-health impact (incidence reduction) to a continued implementation of SMC-SP+AQ  while mresponse .OpenMalaria, we simulated a range of transmission settings  was set to 10% in low access to healthcare settings and 50% in high access to healthcare settings , protective efficacy half-life of decay L and shape parameter k , malaria vaccine-like decay, namely biphasic-like decay [biphasic LAIs) and sigmoidal-like decay . The protective efficacy decay over time E(t) for exponential and biphasic LAIs was modelled as either Weibull-like decay:k = 1 yields exponential LAIs and k = 0.69 yields biphasic LAIs. Sigmoidal LAIs were defined by the following Hill equation with k = 8.As the decay of efficacy of LAIs is not yet known, we explored a range of possible scenarios. In both the clinical and implementation analysis, the prevention of infection by LAI was modelled as pre-erythrocytic protection from infection Fig C in . The decke decay ,43 (refe50). Because SP has a long clearance half-life [The individual protection profile over time after one administration of SMC-SP+AQ, was parameterized using published clinical trial results . The proalf-life , we assucpp0.25-5y, int) over the clinical trial length  or in the last implementation year only as cases per person per year (cpppy)  .The health targets analysed in this study were based on incidence reduction by LAIs, clinical cases averted by LAIs compared with SMC, and non-inferiority with regard to clinical burden in the modelled clinical trials. Clinical cases per person (cpp) in the intervention age group   were calincred was calculated via the cumulative incidence in the year before trial implementation cppcont and the cumulative incidence during the clinical trial cppintThe incidence reduction percentage cppint was performed to analyse the establishment of non-inferiority of LAIs to SMC-SP+AQ as described in [Survival analysis on the number of clinical cases per person ribed in . The impcpp0.25-5y, SMC and LAIs cpp0.25-5y, LAI was compared using the relative difference diffcpp as an indicator for the malaria burden.Additionally, the intervention impact defined as clinical incidence difference between SMC-SP+AQ clinical cases per person per year OpenMalaria simulations to train heteroskedastic GPs for each LAI efficacy decay type in each seasonal and transmission intensity setting  [clinical trial stage consisted of the tool properties including initial protective efficacy and protective efficacy half-life. In the implementation stage, the input parameters additionally included the respective SMC-SP+AQ and LAI deployment coverage. To define the covariance structure of the Gaussian process models, we used a Matérn kernel with smoothness parameter 5/2 accounting for the high variability in the parameter space [To perform a fast and efficient search of the parameter space of LAI properties, we used a database of  1.1.2.) . The inper space  The traier space  (Table Bsoboljansen in the R-packages sensitivity (version 1.16.2) with 500 000 sampled points and 1000 bootstrap replicates.We identified the main drivers of intervention impact via a global sensitivity analysis, performed using decomposition of variance via Sobol analysis on the emulator output predictions. We conducted an EIR-stratified sensitivity analysis to assess the potential change in drivers of impact over the whole transmission range. Within the pre-defined parameter space, the total effect indices quantify the interactions between individual parameter contributions to the emulator output variance . The totclinical trial stage, we discretized the space of the initial protective efficacy and protective efficacy half-life of LAIs within the range of plausible values  with a minimum of 3 starting values and 200 simulations. To determine the benefits of reallocation of resources from reduced visits within a season towards increasing deployment coverage, we compared the number of cases per person per year in a simulation with SMC implemented at a given coverage to the number of cases per person per year with LAI at a coverage that was 20% higher than the optimal coverage.In the clinical trial stage at high deployment coverage (100%) and found that the decay shape of LAI protective efficacy and protection half-life play an important role in achieving a targeted incidence reduction .ectively  to reachclinical trial stages, we found a predicted mean achievable incidence reduction of 71% to 90% in Mali and Senegal-like seasonal settings  and 88 days in Mali-like (long season) seasonal transmission patterns (0.25-5y), the parameter space where non-inferiority could be established varied more than in higher initial incidence settings. If resistance against SP was prevalent, which we modelled as a shorter duration of protection through a decrease in protective efficacy half-life to 20 days (from 32 days), sigmoidal LAIs were predicted to be non-inferior in a wider range of tool property combinations  by 20% (from 100 to 80%) in a setting with an initial clinical incidence of 1.4 cases per person per year0.25-5y. Furthermore, in settings with relatively high levels of initial clinical malaria incidence and corresponding high transmission intensity, namely cases per person per year0.25-5y>2.4 and EIR>150, a change in dynamics to establish non-inferiority was observed. In these settings, we predicted LAIs will likely fail to sufficiently protect the targeted population from clinical malaria even at very high deployment coverage  and cost of goods [implementation stage  are not available as of now, we were unable to include detailed economic analysis in the assessment of LAIs in of goods ,52, withsigmoidal LAIs in long seasonal transmission settings . Deploying a sigmoidal LAI at 46% coverage with a half-life of 150 days and initial efficacy of 100% is sufficient to establish non-inferiority over SMC-SP+AQ at 60% coverage . Over the analyzed transmission settings and parameter space, the estimated minimum essential (80%) and ideal (95%) incidence reduction targets for LAIs as defined by Macintyre et al. (2018)  are hardOpenMalaria can provide more informed first insights into the potential public health impact of new LAIs.We investigated three very different decay profiles of potential LAI protection because this information is currently unknown. While the pharmacokinetic profile of potential LAIs can be evaluated in pharmacokinetic studies, their protective efficacy profile and decay shape are harder to derive. Currently, murine  or humanIn summary, our findings suggest that when defining key efficacy characteristics for TPPs for LAIs, there are two important processes that should be carried out: (1) evaluate the feasibility of existing or newly specified efficacy and duration requirements for LAIs  by estimclinical trial stages is challenging due to not only the high protective ability of SMC-SP+AQ but also clinical trial designs. This motivates an important discussion on the clinical development of LAIs under the use-case of SMC replacement: the necessity and extent of clinical trial testing or non-inferiority criteria should be assessed. We estimated SMC-SP+AQ in a clinical study results in incidence reductions of 71% to 90% in children under five, aligning to a efficacy of 86% (95% CI 78–91%) in a clinical trial in Senegal [Our non-inferiority analysis  highligh Senegal . Monthly Senegal , thus hiReplacing SMC-SP+AQ with LAIs will likely prove beneficial in reducing deployment costs due to fewer deployment rounds. In the absence of information on costs of LAIs (costs of goods and supply chain), we are unable to adequately assess economic considerations and thus our results assume that coverage is the main driver of implementation cost. If LAIs are assumed to have a longer clearance half-life and therefore higher protective efficacy for longer than SP+AQ, resources are freed up through decreased deployment rounds within a season. These resources could be reallocated to increase the overall coverage in a single round of LAI in the target population, including populations in remote places. Additionally, the overall adherence to the blood-stage clearing co-administration of antimalarials could be increased, thereby reducing the probability of emergence of resistance. However, if transmission intensity is very high, we found that the optimisation of protective efficacy half-life and deployment coverage is insufficient to adequately protect the targeted population. Instead, it might be necessary to expand the deployment of LAIs to multiple administration rounds within a transmission season.The optimisation of deployment coverage of LAIs to reach non-inferiority to SMC-SP+AQ where optimal coverage cannot be met exposes an additional use case for LAIs. If external circumstances, such as the current COVID-19 pandemic, prevent the regular implementation of SMC and bed-nets campaigns, millions of children will experience an increased risk of malaria , LAIs maOur modelling and simulation analysis provides important insights into the likely impact of new malaria tools that are currently under clinical development. Our modelling framework divides the unknown parameter space of realistic properties of new tools into setting-specific attainable incidence reduction by translating the decay of individual protection against infection of a new tool into estimates of population impact on clinical incidence. While in clinical trials often only one (high) deployment coverage and a limited number of trial-arms can be investigated, a simulation-based approach can explore the trade-off between operational constraints and tool properties to narrow down beneficial implementation settings and use cases without the need for expensive field studies. Not only does this approach offer the opportunity to assess the potential population impact of new tools currently under development, but it also provides a methodology to assess the potential clinical trial outcomes. It assists the evaluation of clinical trial scenarios that might be considered over several different malaria transmission and health-system settings to supporting thinking on appropriate population impact endpoints that are suitable to inform decision making. This is particularly true for existing interventions with high efficacy for which the establishment of non-inferiority in clinical non -inferiority trials is problematic, due to the required large sample sizes . Here, oFurthermore, beyond the current scope of our study, as more information on likely costs of LAIs become available and further certainty in implementation and cold-chain needed, this work can serve as a basis for cost-effectiveness or economic analysis.As with all modelling studies there are limitations to our analysis. In this study, despite exploring a large range of characteristics on tool properties, deployment, and transmission settings, our results are constrained by the investigated parameter-space. First, we only investigated the impact of one administration round of LAIs with an antimalarial treatment and assumed that the time-point of administration would coincide with the first SMC application round. However, depending on the LAI profile, the time of deployment may need to be optimised. Second, the implementation of protective efficacy of LAIs is solely assumption-driven, as clinical data is not yet available. With additional information on likely achievable protective efficacy half-life, initial protective efficacy, and efficacy decay shapes, the preliminary LAI profiles can be further defined and re-evaluated as LAIs are developed. The re-definition of plausible parameter ranges will also impact the results of the sensitivity analysis and trade-offs, and potentially shift the recommended focus of development efforts. Additionally, target mediated drug disposition might change the pharmacokinetic profile of mAbs dependent on the transmission intensity and parasite growth within the human host and therefore also its efficacy profile . Third, in vitro and/or in vivo murine malaria infection experiments [Potential candidate LAIs include mABs and small-molecule drugs, and to date most known mAbs for use in malaria (largely by-products from research into whole sporozoite vaccines ) have beeriments ,21. As teriments , strategeriments  and 80 teriments  in healteriments  and P218eriments . Althougeriments  are agaiHere, we provided the first quantitative evaluation of the TPPs of future LAIs for malaria as a seasonal prevention tool in children. Simulation analysis of LAIs in real-life implementation settings revealed that the ability of LAIs to prevent clinical cases in children is strongly dependent on the length of the malaria transmission season and transmission intensity. We also found it is important to focus on improving the protective efficacy duration  of LAIs in development, as the speed of protective efficacy decay is a key driver of overall impact  or the chance to meet non-inferiority criteria compared with SMC-SP+AQ. However, if a reasonable duration is possible  then development should focus on increasing deployment coverage to optimise the LAIs chance of higher impact. This provides evidence for the potential trade-offs between tool properties and operational constraints as LAIs are developed and deployed. In general, our findings support the need for a thorough and combined investigation of tool properties and use cases in the future development of LAIs. This combined effort includes earlier modelling alongside clinical studies to provide evidence of translation of impact at population levels before late stage clinical studies and optimise the success of new malaria tools. Our research here provides an initial foundation to support dialogue between stakeholders, scientists, and clinicians at each clinical development stage of novel anti-infective LAI’s to reduce clinical malaria incidence. LAIs have the potential to be a game changer in protecting vulnerable populations from malaria. Our analysis serves as a stepping stone for the refinement of TPPs for LAIs, thereby assisting the target-oriented use-case of development and implementation of new LAIs.S1 TextFig A: Prevalence—incidence relationship in the simulated Open Malaria settings. Fig B: Modelled malaria transmission pattern and simulated prevalence defining seasonality settings. Fig C: Simulated protective efficacy decay shapes of long acting injectables (LAI) and seasonal malaria chemoprevention (SMC) over one transmission season. Fig D: Exemplary illustration of incidence and survival estimates of sigmoidal LAIs and SMC-SP+AQ in implementation stages over one implementation year. Fig E: Estimated impact of LAI properties and operational factors on the level of clinical incidence reduction. Fig F: Estimated impact of LAI properties and operational factors on the level of clinical incidence reduction. Fig G: Incidence reduction achieved through implementation of SMC-SP+AQ over varying deployment coverage. Fig H: Estimated minimal LAI coverage required during implementation stages to achieve non-inferiority in a given setting. Fig I: Estimated minimal LAI coverage required during implementation stages to achieve non-inferiority in a given setting. Fig J: Estimated minimal LAI coverage required during implementation stages to achieve non-inferiority in a given setting and predicted gains in cases averted of subsequent exponential LAI coverage increments. Fig K: True over predicted RSS of the GP. Fig L: Decay of protective efficacy of SMC-SP+AQ over time. Fig M: Cumulative hazard of malaria in children who received SMC with SP-AQ (blue) compared to controls (black). Fig N: Prevalence of malaria in children who received SMC with SP-AQ (blue) compared to controls (black) over the trial. Table A: Simulated prevalence–incidence settings. Table B: Emulator performance for the investigated outcomes. Table C: Incidence reduction achieved through implementation of SMC-SP+AQ in a clinical trial setting. Table D: Inputs into OpenMalaria (OM) to check adequate parameterization of SMC-SP-AQ. Table E: Results of the GP optimization. Table F: Comparison of trial results of Zongo et al., 2015 3 and model outputs using the model specification in Table D with the best parameter set.(PDF)Click here for additional data file.


The need for airway imaging is defined by the limited sensitivity of common clinical tests like spirometry, lung diffusion (DLCO) and blood gas analysis to early changes of peripheral airways and to inhomogeneous regional distribution of lung function deficits. Therefore, X-ray and computed tomography (CT) are frequently used to complement the standard tests.th order (CT: eighth). Bronchiectasis can be identified by wall thickening and fluid accumulation. Smaller airways become visible, when altered by peribronchiolar inflammation or mucus retention (tree-in-bud sign).As an alternative, magnetic resonance imaging (MRI) offers radiation-free lung imaging, but at lower spatial resolution. Non-contrast enhanced MRI shows healthy airways down to the first subsegmental level/43He, 129Xe) directly shows the large airways and peripheral lung ventilation. Dynamic contrast-enhanced MRI (DCE MRI) indirectly shows airway dysfunction as perfusion deficits resulting from hypoxic vasoconstriction of the dependent lung volumes. Further promising scientific approaches such as non-contrast enhanced, ventilation-/perfusion-weighted MRI from periodic signal changes of respiration and blood flow are in development.The strength of MRI is functional imaging. Dynamic, time-resolved MRI directly visualizes expiratory airway collapse down to the lobar level . Obstruction of even smaller airways becomes visible as air trapping on the expiratory scans. MRI with hyperpolarized noble gases  as well as for clinical imaging .In summary, MRI of the lungs and airways excels with its unique combination of morphologic and functional imaging capacities for research ( Scientific research and advanced concepts for clinical monitoring of airway disease have raised the need for reliable biomarkers. These would be expected to reflect the status of the airway system at a given time point and should allow for follow-up and monitoring disease activity. In basic clinical practice, this is done with pulmonary function tests , lung diffusion tests (DLCO) and blood gas analysis.The potential role of imaging becomes evident against the background that standard global pulmonary function tests  per definition do not account for regional changes of lung function. Focal disease with regional functional impairment can be compensated by healthy or recovering portions of the lung at other locations. Therefore global tests can be insensitive to early disease in the lung periphery or dynamic disease development with changing distribution of pathology all over the airways and lungs.th generation and beyond. Therefore, any measurement of total airway resistance mainly reflects changes in the segmental and subsegmental airways. Consequently, standard pulmonary function tests are highly efficient to measure changes of the central airways related to obstruction or bronchospasms  but they hardly measure dysfunction in small airways which are <2 mm in diameter. Any disease activity in the lung periphery is therefore underrepresented in PFT unless it becomes significant.Many clinical tests such a spirometry measure global changes of airway resistance. From the trachea, airway resistance initially increases towards its maximum around the fourth-eighth airway generation . From there, it decreases again as a consequence of further branching of the airways and continuous increase of total cross-sectional area reaching a minimum at the 15 Finally, lung diffusion capacity tests (DLCO) give insight into the overall impairment of lung function. All these tests assess global airway function, but do not allow to draw conclusions on the regional distribution of lung pathology.Non-standard clinical tests to measure small airways dysfunction beyond standard spirometry/FEV1 are the multiple breath nitrogen washout test (MBNW) and the forced oscillation technique (FOT). MBNW uses the washout-kinetics of nitrogen as inert tracer gas from the lungs during tidal breathing and allows for calculation of the functional residual capacity (FRC) and the lung clearance index (LCI). FOT is based on the response of the respiratory system to small externally produced oscillatory (vibratory) forces applied with a loudspeaker from the mouth. Responses to higher frequencies correspond to the mechanical properties of the large airways, lower frequencies to the small airways, making the test particularly sensitive to small airways obstruction. Both tests allow for the detection of global ventilation heterogeneity due to small airways dysfunction. This is considered an important marker of asthma disease activity, even in the absence of abnormalities in standard spirometry. The most frequently applied imaging technique to complement clinical PFT with airway imaging is computed tomography (CT). However, CT per se is not available without radiation exposure, which limits its frequent and repeated use, in particular in children. Among all alternative technologies, MRI of the lung comprises morphological and functional aspects more than any other imaging modality. It is therefore the aim of this article to highlight and summarize the available technology and diagnostic scope of lung MRI for airway imaging.From imaging, it is expected to contribute information beyond the scope of these tests.MRI with practical “easy-to-use” protocols for common clinical indications is being increasingly appreciated as an alternative to CT. Two- and three-dimensional (2D and 3D) imaging without radiation exposure as well as superior soft-tissue contrast and exclusive morpho-functional imaging capacities beyond the scope of CT are offered. Fast imaging protocols are based on breath hold-acquisitions or triggering/gating to compensate for motion artefacts and comprise useful components for airway imaging.T2-weighted fast spin-echo sequences are typically acquired with or without fat-signal suppression and provide high contrast for fluid detection. This is useful for the assessment of bronchial wall thickening and mucus plugging. Bronchial wall imaging can be further improved with black-blood preparations using heavy T2-weighting (longer effective echo time). Black-blood preparation removes signal of pulmonary vessels, facilitating detection of bronchiectasis, mucus plugging and small nodules. Due to the long echo times, 3D-acquisitions are difficult to realize with T2-weighted images. Therefore, this part of the protocol is typically acquired in 2D-series.T1-weighted signal are obtained with gradient echo steady-state free precession (SSFP) sequences, which enhance the visibility of material with water-like characteristics, such as mucus plugs in the airways. Two-dimensional SSFP sequences are very fast and can cover the entire thorax in a single breath-hold with a good image quality or be applied for cine-imaging at a single position, e.g., for imaging respiratory dynamics and airway collapse. Due to the faster acquisition schemes, SSFP-sequences are available in 2D and 3D-mode.Images with a mixed T2/T1-weighted images are typically acquired with three-dimensional gradient echo sequences using short and ultra-short echo times (3D-GRE). These are considered the most robust acquisition format for lung MRI and particularly useful to review central airway pathology. Gradient echo sequences with low flip angles produce proton-density weighted acquisitions which are frequently used to assess airways without the use of contrast agents and to detect air-trapping in end-expiratory images. Very fast T1-weighted 3D-GRE sequences are used to assess lung parenchymal perfusion when combined with contrast administration .These morphologic MR sequences reach pixel-sizes down to 1.8 × 1.5 mm in breath-hold and 1.3 × 1 mm in triggered/gated acquisitions at slice thicknesses of 4–6 mm. Isotropic acquisitions in breath-hold may reach 2 × 2 x 2 mm. This allows for a visualization of bronchi down to the fourth generation  in healthy subjects. Ultra-short echotime or zero echotime imaging (UTE or ZTE) address the central challenges of pulmonary MRI: low proton density of the lungs and fast decay of the already low signal due to a very rapid transverse (R2*) relaxation rate. Images are typically acquired as a 3D volume over a couple of minutes, either as externally or self-navigated acquisition, which allows for retrospective reconstructions of different respiratory phases (4D-MRI). However, as with any gated approach, it remains difficult to achieve motion-free images over the whole volume, with the best results typically in the upper parts of the lung and in end-expiration. Compared to 3D-GRE imaging, UTE or ZTE imaging appears to provide a higher signal-to-noise ratio in the peripheral airways. In respect to field strength, 1.5 Tesla MRI remains superior to 3 T when using a 3D-UTE sequence offering better bronchi visualization, SNR and CNR, as well as less ringing artifacts.Further increase of spatial resolution to voxel sizes below 1 × 1 x 1 mm and therefore approaching the scale of high-resolution CT can be achieved with self-gated UTE sequences. The spatial resolution of UTE was found enough for the assessment of lobar bronchial metrics , lumen area (LA) percentage of bronchial wall area (WA%) and plain wall thickness (WT)) to differentiate severe from non-severe asthma with the smallest measured bronchus having a luminal diameter of only 2.25 mm and good correlation with CT. However, due to a lower spatial resolution compared to HRCT and the susceptibility to motion artifacts, non-contrast-enhanced MRI appears to be not yet suitable as a screening test for subtle changes of airway structure. If the detection of such would be crucial for therapeutic decision, a HRCT for the baseline examination might still be advisory, to then switch to MRI for follow-up.Being limited to visualization of airways in excess of 2–3 mm (fourth generation), MRI stays behind CT, where peripheral airways can be detected up to the eighth generation. This is still good enough to detect wall thickening of central airways using UTE MRI in asthma with comparable results to CT. Bronchiectasis can be easily identified by wall thickening and accumulation of fluid , become visible on MRI, when altered by peribronchiolar inflammation or mucus retention (tree-in-bud).of fluid .20 Based on a standardized MRI protocol, a semiquantitative scoring system for airway pathology and the validation of the concept in a multicenter setting, clinical imaging of airway disease with MRI has become state-of-the-art for imaging in cystic fibrosis  lung disease. MRI has been shown to be efficient in imaging bronchial wall thickening, bronchiectasis, mucus plugging, air-fluid levels, consolidation/infiltration, mosaic pattern air trapping and lobar or segmental destruction, with reasonable quality compared to CT.fibrosis .1,9 The sensitivity of the fast MRI protocol for key diagnostic features, e.g., of ABPA  ranged from 68 to 100% with negative predictive values of 71 to 100%, the lowest for bronchiectasis and highest for mucus retention. Specificity and positive predictive values were excellent (100%). In research, morphologic MRI of the airways has become part of large multicenter-trials, i.e. for imaging of COPD.Similarly, MRI has been successfully applied for other diseases of the bronchial system related to muco-cilial dysfunction such asallergic bronchopulmonary aspergillosis (ABPA) or Kartagener syndrome.Principally, dynamic 3D-imaging is favorable over 2D-imaging, since the complex movements of the trachea make it difficult to find a single slice position which covers the trachea completely at all time points throughout the respiratory cycle. Given a reasonably regular respiratory cycle, dynamic, gated reconstructions from free-breathing long-term acquisitions combine better spatial resolution and a high signal-to-noise ratio, such as dynamic UTE MRI, which has been successfully applied for the assessment of tracheomalacia in neonates without sedation.Inspiratory and expiratory scans can be used to detect large airway collapse in expiration . Real-ti . Since it has been shown that the sensitivity of MRI is lower compared to CT, it may be speculated, that such limited, clinically insignificant air trapping will not be seen with MRI, while any air trapping large enough to detect with MRI is probably clinically significant, which would make MRI the less sensitive, but potentially more specific test. Further research to prove this hypothesis might be useful.Beyond direct visualization of large airway collapse, expiratory MRI scans can show indirect signs of small airway dysfunction. Expiratory collapse or occlusion of smaller airways with mucus results in incomplete deflation of the dependent lung tissue in expiration and produces a mosaic pattern or air trapping on expiratory scans as indirect signs of bronchiolar involvement . Any mor Due to their small size, the direct visualization of small airway involvement is challenging for both CT and MRI. As mentioned above, mucus plugging and peri-bronchial infiltration (tree-in-bud sign) or air trapping may help, as well as the observation of air trapping on expiratory scans.Per se, local ventilation deficits or air trapping resulting from small airway dysfunction can be quantified with lung deformation mapping from MRI in inspiration and in expiration. This has been used to study local lung mechanics in early fibrosis, but would be principally suitable to study lung ventilation as well – although, dedicated studies or clinical evidence have not been published so far.The abovementioned difficulties in the assessment of small airways disease with standard pulmonary function tests becomes relevant in smoker’s COPD, for example. Current pathogenetic concepts discuss accumulation of inhaled fine airborne particles at the level of small bronchioles, where tidal gas flow decreases and diffusion becomes the main mechanism of gas exchange. Here, the persistent deposition of toxic material stimulates a chronic inflammatory immune cell infiltration. Tissue repair and remodeling start to increase airway resistance and finally narrow and reduce the terminal bronchioles leading to a relatively late decline in FEV1.3He and 129Xe. In Asthma, for example, the distribution of the inhaled gases correlates with airway inflammation and re-modelling, luminal occlusions or airway smooth muscle dysfunction  diffusivity is 0.88 cm2/s with a free displacement of 0.59 mm at a typical diffusion time of 2 ms.The diffusion of the gas is therefore restricted inside acinar ducts and acini with diameters around 0.7 mm and 0.3 mm, respectively. This effect can be assessed with appropriate MR sequences and quantified as a reduction of the apparent diffusion coefficient (ADC), compared to 3He outside the lung. Consequently, any expansion of the alveoli and tissue destruction associated with emphysema result in a higher ADC which correlates to the average terminal airway diameters. In COPD for instance, increased ADC in enlarged, emphysematous spaces allows for the calculation of the emphysema index. In idiopathic pulmonary fibrosis, the fibrotic changes lead to a loss of alveolar surface area, the formation of honeycomb cysts, and dilation of terminal bronchi. These conditions result in higher 3He diffusion and an elevation of the calculated ADC. Accordingly, a higher ADC is found in areas of air trapping and local hyperinflation of asthmatic patients’ lung. Thus, at the very last stretch of the airway tree, MRI with hyperpolarized gases even allows for quantitative assessment of terminal airways and the alveolar space dimensions.Beyond visualization of the ventilated air spaces and ventilation defects from small airway dysfunction, hyperpolarized 129Xe also allows to assess the gas transfer into the alveolar–capillary tissue space and from the tissue barrier into red blood cells in the pulmonary microvasculature. However, the limited availability and high cost of the gases and the need of dedicated hardware and complex image analysishave so far limited MRI with hyperpolarized gases to research purposes and a broad clinical implementation is not expected in the near future.Finally, hyperpolarized 19F  and the feasibility of this approach has been shown. The scientific value of inert 19F imaging has been demonstrated with a study on lung ventilation deficits in COPD patients. However, this approach does not need preparation of the gases with hyperpolarization, but it still requires appropriate MR hardware tuned to the resonance frequency of the gas. The achievable signal intensity is low due to the limited density of fluorine in the gas and the necessary robustness and evidence to adopt this promising technique for clinical imaging still need to be proven.A less complex approach uses direct imaging of the non-hyperpolarized gases with MR at the resonant frequency. The most promising element is  Significant improvements are expected from recent work at lower field strength with potentially higher signal intensities in the lung tissue, which might draw more attention on this very useful approach.Alternatively, the T1-shortening effect of oxygen can be used to assess lung ventilation. Basically, this needs only a state-of-the-art MR scanner and medical oxygen, which should be easily available in any hospital. For the assessment of lung ventilation, two series of multiple images while breathing room air or oxygenated air are acquired, respectively. The signal intensity on the resulting subtracted images correlates with the elevated oxygen concentration inside the ventilated alveolar space. Oxygen-enhanced MRI has already been used to assess lung ventilation in adults and children, but poorer SNR and the long acquisition time of this technique have so far hampered its broader use in the clinic. These approaches are highly experimental and based not only on the measurement of T1 itself but also on effects such as T1-dependence on the applied echo time TE. An adoption for clinical imaging in the near future is not expected.Finally, it has been hypothesized that even plain, non-contrast-enhanced MRI might be suitable to quantify blood content and aeration separately, since both contribute to the MR signal characteristics of the lung parenchyma. In fact, T1* measurements in patients in COPD and asthma have shown encouraging results. To eliminate respiratory motion, the images are registered to the inspiratory or expiratory frame or at any favorable position in between. Then, signal intensity changes of the lung parenchyma related to the cardiac and respiratory cycle are decomposed using a Fourier transform to obtain perfusion- and ventilation-weighted images. Besides Fourier MRI, other approaches with comparable diagnostic scope have been developed . Such completely non-invasive techniques are particularly useful for scientific work with healthy subjects, for example to assess small airways disease in smokers after exposure to tobacco fume or vaping electronic cigarettes without application of intravenous orgaseous contrast agents  obtained in free breathing without cardiac or respiratory gating.t agents .55 Fou This means that any kind of airway obstruction produces a corresponding perfusion deficit in the dependent lung. Therefore, any technique for the assessment of lung perfusion can be used to indirectly assess airway dysfunction by the detection of the resulting perfusion deficits.Indirect imaging of airway dysfunction is based on the physiological process of hypoxic vasoconstriction in the human lung. This mechanism triggers constriction of intrapulmonary arteries in response to alveolar hypoxia, diverting blood to better-oxygenated lung segments, thereby optimizing ventilation/perfusion matching and systemic oxygen delivery. Reasonably short acquisition times of 1.5 s or less per full lung volume are achieved by combining parallel imaging and data sharing. The resulting images can be evaluated with a dynamic display. For quick review, subtraction of the baseline images from the contrast-enhanced series facilitates the detection of perfusion deficits. Airway dysfunction is indicated by perfusion deficits related to hypoxemic vasoconstriction in areas of reduced or missing pulmonary ventilation. However, the images need careful interpretation, since before assuming perfusion deficits from hypo-ventilation, lung parenchyma defects , or vessel occlusion from pulmonary embolism need to be excluded. Acquisition of morphologic and angiographic image series in the same study and review together with the DCE series are therefore mandatory. This is, for example, needed in COPD patients, where perfusion deficits from emphysema and small airways disease overlap.Compared to other techniques, dynamic first-pass perfusion MRI (DCE MRI) is easy to implement and provides a reasonably robust image quality for this purpose. It produces a time-resolved image series of pulmonary contrast transit using an intravenously injected contrast material bolus and multiple acquisitions of lung volumes with a very fast 3D gradient echo sequence. On the other hand, the intravenous application of gadolinium-based MR contrast material is controversial and alternative techniques would be appreciated. DCE MRI has been implemented, for example, to monitor lung ventilation and perfusion deficits after physiotherapy and antibiotic medication of children with cystic fibrosis  is in development, but not yet commercially available. In the meantime, semi-quantitative visual scoring systems have already found broad clinical use.The fact that DCE MRI provides information on both, perfusion and ventilation deficits of the lung, that have made is the so far most widespread functional imaging approach and a common component of clinical lung MRI protocols.osis CF, .21 Ful This has been successfully applied for physiologic studies in healthy subjects, for example to assess the effects of hypoxia and to investigate the effects of hypoxic vasoconstriction on pulmonary blood flow heterogeneity. A broad clinical use of ASL in the lungs has so far not been reported.However, any technique for the assessment of lung perfusion can be used for the indirect approach. For instance, arterial spin labeling (ASL) is based on the signal from tagged blood inflow into a pre-saturated, signal-inverted volume and produces perfusion maps that indirectly reflect the effects of hypoxic vasoconstriction. and pediatric patients. Briefly, common standard protocol suggestions include T2-weighted fast spin echo (FSE) sequences, steady-state free precession (SSFP) sequences for respiratory motion and T1-weighted 3D gradient echo (3D-GRE) sequences in breath-hold. Adjusted to the size of the patient, the fields of view (FOVs) are typically 450–500 mm in coronal and approximately 400 mm in transverse acquisitions with matrices of 256–384 pixels (for triggered FSE up to 512) and pixel sizes smaller than 1.8 × 1.8 mm. Suitable slice thicknesses are 4 to 6 mm for the 2D acquisitions, 4 mm or less for 3D acquisitions in transverse and 2 mm or less in coronal orientation (as would be applied for pulmonary angiography). This provides a sufficient spatial resolution for the assessment of the tracheobronchial morphology, as introduced above. Acquisition in inspiratory and expiratory breath-hold facilitates the detection of airway collapse and air trapping.The currently available MRI protocols from standard clinical equipment already cover many aspects of airway imaging. Detailed protocol descriptions can be found in the literature with adaptions for use in adult The dynamic study produces a comprehensive lung perfusion study with excellent temporal resolution and at the same time serves for the determination of optimum contrast bolus timing for the acquisition of the high-resolution angiogram.Another standard component is the aforementioned DCE MRI with fast, time-resolved 3D gradient echo (3D-GRE) acquisitions. Standard protocol suggestions recommend to use a combination of the time-resolved, low spatial resolution acquisition for first pass perfusion imaging with a high spatial resolution acquisition for a breath-hold angiogram.indirect visualization of ventilation disorders appearing as lung perfusion deficits from hypoxic vasoconstriction. As discussed, this requires exclusion of lung parenchyma defects and pulmonary embolism. Therefore, it is recommended to acquire and interpret DCE MRI only in combination with morphologic sequences and a standard MR angiography, as described above.This is used for the e.g., imaging with hyperpolarized gases) will become step by step available for clinical use as well.These protocols are either already pre-installed on the systems or can be quickly assembled from standard sequence packages for abdominal and cardiac MRI. For the near future, it can be expected that the more complex procedures outlined in this article  or directly with hyperpolarized noble gases, inert fluorine or oxygen-enhanced imaging. Non-contrast enhanced ventilation-perfusion imaging techniques complete the bunch of promising approaches, each of them with different levels of development and clinical feasibility. At the very last stretch of the airway tree, for research purposes, MRI with hyperpolarized gases even allows for measurements of terminal airways and the alveolar space.This makes MRI the most comprehensive imaging modality covering all aspects of airway morphology and function and allows to use it for scientific purposes and an increasing number of clinical indications as well- with semi-quantitative visual scores or automated quantitative evaluation producing useful biomarkers for clinical decisions.


This is a peer-review report submitted for the paper “The Influence of SARS-CoV-2 Variants on National Case-Fatality Rates: Correlation and Validation Study.”I would like to appreciate the author for this study  addressiIn conclusion, the subject addressed in this manuscript is worth investigation, and the manuscript is recommended for possible consideration after addressing the above minor concerns.