After the data collection, participants were divided into two groups according to whether they had already tasted a fruit wine (neophiles) or had never tasted it (new entries). For each group, the individual’s responses  were analyzed through Principal Component Analysis. Different consumption styles and expectation patterns were defined in the two groups. However, in general, neophiles showed consumption patterns based on the evaluation of fruit quality, sales format, alcoholic content and the presence or not of bubbles, not giving importance to the brand. In contrast, new entries’ responses identified consumption patterns driven by the willingness to pay for a new product, the product value for money and packaging features. Differences between the two groups in expectations about the product sensory characteristics also emerged. These findings should contribute to this area of study by integrating environmental, economic and social dimensions and addressing food innovation and sustainability in the fruit and wine chains.The consumption of traditional wine has decreased in Europe during the last fifteen years. In parallel, new wine alternatives obtained by blending wines and fruit juices or by flavoring wines with artificial or natural flavors have appeared on the market. Recently, an innovative fruit wine obtained by co-fermentation of grape must and kiwi juice has been proposed and its potential of attraction for consumers should be exploited. To assess the potential consumer acceptability and expectations towards this new product, an online choice experiment has been conducted involving a consumer group of young adults (18–35 years old;  Sustainable development refers to a “development that meets the needs of the present without compromising the ability of future generations to encounter their own needs”; it faces economic, social and political activities with potential impacts on the environment . In thisThe concept of food sustainability is strongly linked to that of food waste. Waste concerns all the phases of the agri-food system  with methods and for specific causes that are different for each phase. A form of waste is represented by the surpluses, i.e., all those products that, while meeting the quality standards of food safety, are not purchased and/or used in the transformation processes for different causes . About 5The surplus of fruit production represents a production waste. In Italy, fruits with a high probability to generate waste include, among others, kiwi fruits and grapes. Regarding kiwis, Italy is the second highest producer in EU and the third in the world, with a market of 435,000 t per year, which generates a commercial surplus of EUR 343 million ,9. RegarConsidering young consumers as a target more attracted and willing to taste new products ,25,26, tThe data were collected through an online survey created with Google Forms  and disseminated by e-mail and social networks in 2020. The survey was conducted in accordance with the ethical standards set out in the Declaration of Helsinki. Participation of all respondents was voluntary and informed consent was provided by all respondents. Completion of the questionnaires was not rewarded and only 10% of all questionnaires sent were not completed. The questionnaire was structured by different sections, as described in The developed questions submitted in the surveys were open ended , closed-ended , and double check-all-that-apply (CATA) questions , the latter of which used to investigate on individual’s alcoholic beverages consumption and purchasing habits ,28. Quesn = 119) indicated they would not like to try this new product. Considering the latter consumers, the percentages of responses obtained regarding the reasons why they do not intend to approach this new product . Neophiles include respondents that have already tried fruit wines as they answered “yes” to the c1 question , whereasSignificant differences emerged when the consumption habits of alcoholic beverages between the two considered groups were compared, especially in the case of spirit and beer consumption. In particular, the new entries category was more oriented towards spirit consumption, while the neophiles cluster constituted regular beer consumers .In terms of consumption frequency of alcoholic beverages, the neophiles and new entries statistically differed considering the most frequent consumption level (every day), highlighting a higher propensity of consumption in the new entries .Finally, the two groups were also different regarding the purchase place of alcoholic beverages; the new entries showed the strongest preferences for the large-scale retails, while the neophiles were more oriented towards the producers and the specialized shops .The expectations about the sensory characteristics of fruit wine changed within the two groups . In partAmong the neophile consumers, four main components were distinguished, defined by the declared expectations on the new product . PCA expIn the case of new entries, four components of product expatiation were defined . The firThe survey carried out on the consumer perception of a novel fruit wine demonstrated that the marketplace could be attracted to and potentially ready for this innovation. The sustainability aspects that distinguish this product along with the social impact of a low alcoholic drink, however, obtained from a grape must may represent a further economic fly wheel in the alcoholic beverage market. The differences in consumer perception, considering individual previous experience, could represent a marketing tool to consider in the product communication strategies. Our findings will help the beverage industry to make a proper communication plan related to the drink characteristics in order to reach and satisfy the expectations of consumers. In particular, this last statement takes on greater importance for the case of new entries who, in this research, expressed sensory expectations for the new product that could not change in several fruit wines. In this case, therefore, this result makes it possible to adequately highlight the descriptors affecting the acceptability of the new entries. A capillary communication of product characteristics, as well as its impact of society and the environment, can be a successful strategy for its introduction to the market. This communication plan could also attract the interest of the neophiles, highlighting the strengths of fruit wine. However, we recognize some limits of the research related to the sample composition and size. This limit may be overcome by extending the research in other Italian regions and areas to compare different consumer profiles, especially considering more age groups of individuals. Nevertheless, from our results, the commercialization of fruit wine could have a promising future and they could represent an effective strategy to limit food losses and wastes, improving the sustainability of fruit and wine chains.


Talk, Instruct, Practice, Plan and Support (TIPPS) intervention for pregnant women to enhance infant birth weight in a conflict area in Low- and Middle-Income Countries (LMIC). The decision tool, A process for Decision-making after Pilot and feasibility Trials (ADePT), examines the methodological factors identified in a feasibility study, that may require modification for a full trial. Thus, this study aimed to use the ADePT decision tool to evaluate if the feasibility study had achieved its objectives and to identify the need for intervention, clinical context and trial design modification.A feasibility study was conducted to implement the A one-arm, pretest–posttest feasibility study recruited 25 pregnant women in their first trimester and clinic staff from a primary healthcare clinic located in Gaza City, Palestine. The TIPPS periodontal health intervention was delivered by antenatal care nurses to the pregnant women during their regular follow-up appointments. The ADePT framework was applied to evaluate the findings from the feasibility study. The ADePT checklist demonstrated sample size estimation, recruitment, consent, intervention adherence, intervention acceptability, costs and duration, completion and appropriateness of outcome assessments, retention, logistics, and synergy between protocol components.All recruited pregnant women  consented to participate in the study, and the adherence to the intervention was 88% (22 women). The TIPPS intervention was acceptable, but there was ambivalence over who should deliver it in the clinic. Only the cost of toothbrushing and TIPPS information materials was calculated, while the cost of nurses’ time was not included. The missing values of data were few . This intervention significantly reduced the mean percentage of plaque and bleeding scores after 3 months. The sample size for future randomised controlled trial was estimated around 400 participants. The participants stated the value of the intervention. The clinic staff voiced concerns regarding time and the cost of nurses providing the TIPPS intervention. This allowed suggestions to be made regarding the modification of trial design and context of implementation.The ADePT evaluation showed it was possible to progress to full trial with modifications in the trial design. What uncertainties existed regarding the feasibility? The outcome of this study supported the feasibility of implementing TIPPs intervention into Primary Health Care in Palestinian Ministry of Health. No uncertainty was identified from this study except the effectiveness of TIPPs intervention on improving infant birth weight.What are the key feasibility findings? Twenty-two pregnant mothers (88%) completed the second follow-up appointment. This intervention significantly reduced the mean percentage of plaque and bleeding scores and was acceptable and valued by antenatal care staff and participants. The sample size for future randomised controlled trial was estimated around 400 participants. An ADePt evaluation allowed the identification of the appropriate modifications for future trial design.What are the implications of the feasibility findings for the design of the main study? The outcome measures of this feasibility study were satisfactory. The full trial should be multicentred. In addition, the staff raised concerns about staff time, cost of nurses’ time and expertise to deliver TIPPS; therefore, it would be recommended to employ community health workers to deliver TIPPS intervention and to integrate the economic evaluation into trial design.existing] centres’ with a focus upon ‘primary and emergency healthcare services’.During acute periods of political unrest and violent conflict, people’s access to routine secondary and specialist facilities drops, with a greater reliance on alternative forms of healthcare . In respSpiegel and Checchi  appeal fCochrane Review further suggested that periodontal interventions to improve maternal gum health may enhance infant birth weight (when the intervention is delivered in the first trimester)  groups? The budget [for the programme] needs to be high for staff time and resources. . . [the] antenatal care programme is already free of charge and if you ask a mother to buy toothpaste and brush, she may not be able to afford the cost.’‘Potential risks to the successful implementation of TIPPS included the lack of engagement of some pregnant women to attend any appointments, the potential costs of toothbrushes, toothpaste, and interdental cleaning being unaffordable for the women and the costs to the clinic; the increased healthcare personnel costs were mentioned by the nurses and others. The following quotes are illustrative:after the increase in political instability this programme was stopped’. Concerns were raised with regard to the disruption of an already busy clinic, especially if the pregnant woman failed to attend or arrived late or on another day for their appointment, and the additional effect of TIPPS on an already busy clinic. The division of healthcare into definite disciplines was also voiced, ‘highly skilled midwives involved in oral health care and education to run a programme which previously had dentists responsible for this work.’Thinking to the future, the head of antenatal care stated that she felt that the TIPPS programme could experience difficulties, especially when violence had resulted in a previous dental treatment service being removed from the clinic, ‘The total costs for the provision of toothbrushes, toothpastes, and interdental cleaning aids, together with the costs of the TIPPS information materials for the training day and for the participating pregnant women were known. No economic evaluation was undertaken.At baseline there was no missing data for the primary and secondary outcome variables. Twelve percent of the secondary outcome variables was missing at Time 2, and 22% of the primary outcome variable was missing when collected from the mothers on the delivery of their babies  kg with a range of 2.5–4.0 kg. Twenty-two mothers were contacted following the birth of their babies. The mean birth weight of their new infants for women with more-than-one previous pregnancy was 3.12 (SD 0.30) kg with a range of 2.5–3.6 kg  and lower teeth  across the three time points. There were also statistically significant differences in mean rank percentage bleeding scores from baseline to Time 2, for upper teeth  and lower teeth  across the three time points.Figure Recruitment of the pregnant women and clinic staff went well due to LA’s specialist knowledge, interactions with clinic staff, and support from the head of the clinic. However, difficulties transporting dental supplies from the UK to Gaza city were experienced. The toothbrushes, toothpastes, and examination kits were only able to be released from customs Table  followinThe ADePT evaluation Table  demonstrInequality in oral healthcare is a growing global health issue that demands immediate action. In addition, the UN Sustainable Development Goals (SDGs), SDG3, SDG5, and SDG10  and universal health coverage (UHC) have emphasized on the importance to proceed to action, commencing with research to improve our understanding of what actions and policies would be appropriate. This research needs to be feasible and can be designed as a result of the evidence acquired from the feasibility study.This feasibility study was conducted to test the acceptability of incorporating an evidence-based TIPPS periodontal intervention into an ongoing maternal primary healthcare programme in a LMIC experiencing violence and conflict for pregnant women in their first trimester. This was an initial step to assess the methodological issues associated with proceeding to a full trial. In their paper, Bugge and Williams  suggesteThe feasibility study provided evidence regarding the success of the recruitment, the retention, and acceptability and adherence with the TIPPS intervention. The women, antenatal nurses, and administrative staff appreciated the importance of the intervention and the requirement to provide toothbrushes, toothpastes, and interdental brushes to the participants. Therefore, the TIPPS intervention, in itself, did not require amendment; however, the context in terms of additional localities and the personnel to conduct the trial needed careful thought.Recent research raised the importance of training midwives to identify pregnant women at risk of oral diseases, as they are the first contact many women have with healthcare . StudiesDue to the limited funds in the present study, the cost of providing periodontal and/or dental treatments has not been included. However, participating mothers and staff in the Primary Health Care in Palestine strongly recommended providing dental treatments as part of the intervention. Thus, this recommendation will be considered for the future RCT proposal.It would have been useful to assess the costs for clinical staff’s time and use of clinical facilities, including the cost of providing the TIPPS intervention and periodontal and/or dental treatments. This was not possible in the feasibility study, although total costs of providing the materials for the intervention were known. Therefore, as a part of a full trial, an economic assessment, including cost efficiency and the costs of using community health workers should be incorporated into the trial design.The suitability of the outcome measures was satisfactory and would be included and used in a full trial. An improvement in the gingival health of the pregnant women was shown, with infant birth weight being between 2.50 and 3.4 kg. Learning from this work, it would have been beneficial to collect a comparison treatment as a usual group to assess gingival health and infant birth weight as part of the feasibility study. This was not possible due to funding restrictions. Nevertheless, as a consequence of the feasibility work study, there is a need to reconsider the inclusion criteria regarding singleton/multiple births and to amend the trial design to stratify for first or previous pregnancies.Studies in Gaza Strip revealed that smoking among females ranged from 1.2 to 27.1% –27. DespIntervention to promote maternal oral health in Palestine and Middle East and North Africa regions are rare . This fe


Androgenetic alopecia is a multifactorial condition characterized by noticeable hair loss, affecting both men and women and representing a debilitating and chronic disorder that considerably affects the quality of life. Available topical treatments based on minoxidil or finasteride require repeated applications and are associated with a certain number of adverse effects. The challenges associated with current treatments pave the way for the research of new therapeutic strategies, more precise and selective, and capable of providing long-term results. In this context, the present review examines the new proposed formulation strategies to deliver 5-α-reductase inhibitors in order to obtain a targeted drug delivery, for improving drug retention at the site of action in the hair follicle, contemporaneously reducing drug systemic absorption, which is the cause of important adverse effects. In particular, the research will be focused on the several aspects that influence the performance of nanostructured drug delivery systems in creating a depot in the hair follicles, such as particle size, surface charge, excipients, and combined application with external stimuli . Androgenetic alopecia, in males also referred to as male-pattern baldness, is the classic thinning of hair occurring in middle-aged men and increasing directly with ageing. Its incidence varies by race and is more commonly seen in white men than in Asians, American Indians and Africans ,2,3; womAlthough it is known that common baldness in men has an autosomal dominant transmission while in women the phenotype is recessive, or even that baldness is genetically influenced, studies on this are still few, and the gene clearly responsible has yet to be identified, although genetics appear to be X-linked ,8.It is interesting to note that the testosterone hormone plays an important role in male androgenetic alopecia, regardless of genetic predisposition . Testosterone, in the cells of the hair follicle, is converted into dihydrotestosterone (DHT) by the enzyme 5α-reductase, which exists as two isoenzymes: type I and type II. The latter, expressed in the hair follicles and other androgen-dependent tissues , appears to be particularly important in male pattern baldness ,10,11.Androgen activity is mediated by binding to the human androgen receptor and the receptor–ligand complex regulates the expression of androgen-sensitive genes, acting as a transcription factor. The androgen receptor plays an important role in human development and is involved in the normal functioning of the reproductive system, the nervous system, and the immune system throughout the adult life. It is also involved in various diseases such as prostate cancer, androgen insensitivity syndrome and spinal and bulbar muscular dystrophy. Regarding baldness, it is the complex DHT-androgen receptor that acts as a transcription factor, regulating genes that control the hair cycle. The normal hair cycle  consistsIn the altered hair cycle typical of baldness, the phases remain the same, but the anagen phase is reduced, while the telogen resting phase lengthens with each new passage of the hair cycle, resulting in hair thinning and decreased hair length ,4. FinalFor these reasons, androgenetic alopecia can be considered a debilitating and chronic condition that considerably affects the quality of life. In this context, the present research aims at investigating the drugs available on the market and evaluating the new formulation strategies to improve topical therapy. In particular, the proposed tools to obtain drug retention at the site of action in the hair follicle will be examined, in order to reduce drug systemic absorption, which is the cause of important adverse effects.Currently, minoxidil and finasteride are employed for the treatment of androgenetic alopecia; they have different mechanisms of action and routes of administration, and they can be used both alone and in combination with each other.Minoxidil is a powerful arterial vasodilator whose mechanism of action consists in opening the ATP-dependent calcium channels of the arterial smooth muscle cells which causes relaxation of the vascular smooth muscle.The action of minoxidil in androgenetic alopecia therapy is not yet completely understood, even though the vasodilatory activity and the promotion of angiogenesis, as well as the ability to increase vascular endothelial growth factor (VEGF)  are cons®, currently available. The side effects of topical administration have so far been limited to local skin irritation, pruritus, and reversible hypertrichosis. Initially, minoxidil was born as a drug for systemic use for the treatment of hypertension, but in 1988 it was firstly authorized for use by FDA in the treatment of male androgenetic alopecia in a topical solution with the trade name RogaineFinasteride is a competitive inhibitor of the 5α-reductase type II enzyme and prevents the conversion of testosterone into DHT. It has been approved for treatment of androgenetic alopecia in a daily dosage per os of 1 mg, which can decrease the levels of circulating DHT in the serum and scalp by 60%. However, the clinical response to finasteride therapy is highly variable and systemic use can lead to the onset of adverse effects such as sexual dysfunction, depression, and gynecomastia .® (5 mg tablet for the treatment of benign prostatic hypertrophy) and Propecia® (1 mg tablet for the treatment of AGA). Finasteride has been reported to be effective at a concentration between 0.25% and 5% in topical solution [® was authorized for the treatment of androgenetic alopecia. The topical treatment possesses a less severe side effect profile if compared to systemic therapy, being mild skin irritation at the application site the most frequent effect observed [It is commercially available, as Proscarsolution . Recentlobserved . An impo® for the treatment of benign prostatic hypertrophy. Although its use for the treatment of androgenetic alopecia has not yet been approved, this drug appears to be very promising and worthy of consideration in this area [A drug currently of interest for the treatment of androgenetic alopecia is dutasteride, an inhibitor of the 5α-reductase enzyme that inhibits both isoforms of the enzyme by bocking or competing with NADPH, necessary for the enzyme to convert free testosterone into DHT. Dutasteride is three times more effective than finasteride in inhibiting isoform I and one hundred times more effective against isoform II, and this makes it significantly more powerful: a 0.5 mg dose of dutasteride leads to a reduction in circulating DHT 90%. Dutasteride is currently on the market as Avodarthis area .Most of the formulations marketed for this purpose are represented by solutions with a high percentage of propylene glycol and/or ethanol, excipients responsible in some cases of serious adverse effects following repeated applications . To reduce cutaneous adverse effects and to improve therapeutic efficacy, the interest of the research has focused on the development of not irritating formulations that could deliver the active compound to the superficial layers of the skin and inside the hair follicle, to obtain a sustained drug release .For topically administered substances, percutaneous absorption can occur via the intercellular, transcellular or through the skin appendages; the latter including the transport through the hair follicles and the ducts of the sebaceous and sweat glands .The main barrier to skin permeation is represented by the stratum corneum, the outermost layer of the skin, which consists of cornified cells surrounded by lipids; the major route for skin penetration is certainly the intercellular route, although in recent years the penetration through the skin appendages  has proved to be important in some specific cases. The shunt pathway has received renewed interest because it appears to be the main one for nanoparticles, liposomes and hydrophilic drugs and large polar steroid molecules that are not expected to pass quickly through the skin.From the moment a topically applied substance enters the hair follicle, it can follow different routes. Small drugs can penetrate deeply through the follicular epithelium and reach the bloodstream. On the other hand, substances that are too large to penetrate, i.e., particles, are trapped inside the hair follicles and can be depleted only following slow processes such as hair growth and sebum secretion .The design of formulations for drug delivery at the hair follicle level must take into account the complex anatomical structure and cyclic activity of the follicles, whose size and density vary according to the body area . The ope.In addition to anatomical characteristics, a large variety of factors influence drug deposition in the pilosebaceous unit, for example the type of formulation or the drug delivery system, humidity, temperature, characteristics of the molecule to be administered  and the penetration depth to be achieved .The infundibulum, which participates in the increase in surface area and interrupts the epidermal barrier down to the lower portion of the follicles, constituting an efficient reservoir for the permeation of substances;The sebaceous gland, which is related to the follicle through the sebaceous duct; andThe area of the hair bulb, where the stem cells of the germinative matrix are found and appear as an ideal target for the therapy of skin diseases. The cells in the hair matrix may represent potential target sites for hair growth control .Vogt et al.  defined In the case of androgenetic alopecia, a direct targeting of the area of the hair bulb is desirable, as the entire process of DHT formation from testosterone via 5-α-reductase and the subsequent binding of DHT with androgen receptors is settled in the dermal papilla cells . Many reports have evaluated the differences in follicular deposition after application of drugs in different vehicles, and in particular, nanostructured drug delivery systems are currently a subject of intense research interest, because of their tendency to be retained in the hair follicle . These sThe infundibulum, the sebaceous gland and the bulge region represent the relevant target structures within the hair follicle and can be selectively addressed in dependence of different particle sizes, as shown in Researchers have reported that the penetration of nanostructured drug delivery systems inside the follicular opening could be dependent on their diameter; therefore, nanoparticles can be retained in the hair shafts more than microparticles .Generally, hair follicle targeting seems to be more efficient if the drug is encapsulated or attached to a nanocarrier, preferably around 400–700 nm in size. In cases where the infundibular region represents the target zone, the smallest dimensions around 122 nm and the much larger ones (860 nm) seems to be the most suitable, while intermediate dimensions around 230–300 nm tend to penetrate into the region of the sebaceous glands. On the other hand, particles with a size of 470–643 nm penetrate deeply into the hair follicle, reaching the bulge region .It has been demonstrated that particles of 320 nm in size can be retained in the follicle for more than 10 days . It is iPatzelt et al.  indicateIn the case of PLGA-particles, Patzelt et al.  reportedOn the other hand, regarding silica particles, the same authors determined that the deepest penetration was achieved by particles with hydrodynamic diameter of 646 nm, while significantly lower penetration depths were shown by both smaller and larger particles . Comparison of PLGA and silica particles revealed comparable penetration depths for comparable particle sizes (300 and ≅640 nm), even though silica particles were able to penetrate more deeply than PLGA-particles of the same size.Other nanoparticles such as polymeric nanoparticles have been proposed to be retained in hair follicles that can act as a long-term reservoir . It has Several nano-sized drug delivery systems have been investigated, for example, penetration enhancer-containing vesicles able to promote drug deposition in the skin and nanoparticles (named “squarticles”) obtained from sebum-derived lipids that produced a 7-fold increase in the follicular uptake of minoxidil with respect to the control . Lademann et al.  found thRancan et al.  also sugHowever, particles of different size have also been proposed to penetrate hair follicles, for example polystyrene particles 20 nm in size and iron-based particles .Several studies have suggested that nanoparticles are able to deeply penetrate into hair follicles after topical application to human and animal skin, with some researchers suggesting that follicular delivery is more efficient with nanoparticles with diameters under 300 nm compared to larger nanoparticles ,32,33,34Wu et al.  investigThe nanoparticles were not able to cross the stratum corneum, neither via the transcellular nor the intercellular route. Since the intercorneocyte space appears to be filled with multiple lipid bilayers, it seems unlikely that a particle 50 nm in diameter could be transported in the intercellular channels (100 nm); conversely, there seems to be a probability for particles to be seized in skin furrows and around follicles .Another study showed that titanium oxide nanoparticles 20 nm in size penetrated the hair follicles up to 400 μm, but the presence of nanoparticles was not detected in vital tissues or in the sebaceous glands .On the other hand, a study carried out in mice showed that the 40- and 200-nm-sized polystyrene nanoparticles retained in the hair spread into the surrounding tissue and reached the sentinel lymph nodes .Moreover, Vogt et al.  found thAdditionally, Schäfer et al.  demonstrBased on the analyzed literature, summarized in Additionally, another dimensional range can be selected, represented by nanostructures with particle size below 100 nm, where data from the literature show more discrepancies. In this context, some attention must be paid to the delivery strategy if the perifollicular and living tissues are not the target sites, because occasionally smaller particles have been shown to permeate the follicular barrier.Anyway, the drug size, the deformability and the shape of the particles could also represent variables in follicular targeting; therefore, further intensive research on these aspects is fully encouraged.An important consideration in tuning up a drug delivery system is related to the abundance of sebum lipids in the hair follicle. The sebaceous gland with its secretion creates an environment rich in lipids. Indeed, the sebum is mainly made up of triacylglycerol, diacylglycerol, free fatty acids, squalene and cholesterol; therefore, the transport of drugs at this level is influenced by the interactions between sebum and drug and the choice of a suitable vehicle is fundamental. Dispersions of lipid nanoparticles, such as SLN or NLC, constituted of the same lipids, have also been proposed as a viable strategy for follicular targeting. Unfortunately, recent studies have highlighted some critical aspects of these nanocarriers compared to other topical formulations; in particular, non-specificity has been reported in the penetration at the level of the follicle, with simultaneous release on the skin surface of the encapsulated active ingredient The mechanism of penetration of the active compounds conveyed in a nanostructured form can be explained by the ratchet effect: the cuticular structure of the hair works as a ratchet that transports the particles deeper into the hair follicle, where they will remain for several days, forming a long-lasting reservoir of drug from which the drug is constantly released .Moreover, in the dry state and at neutral pH, the skin surface is negatively charged because of many factors, such as the carbohydrate content, the presence of protein residues on the cell membranes, and active ions pumps; consequently, cationic solutes may be adsorbed on the skin surface . Matos and colleagues  proposedAdditionally, positively charged liposomes showed enhanced localization at the level of the pilosebaceous unit, but the entrapped drug was poorly retained through the follicle length. Indeed, it is noteworthy that electrostatic interactions between the negatively charged skin surface and the positive nanocarrier can occur, increasing retention of the carrier in the upper skin layers and simultaneously reducing the permeation of actives in the deeper layers . On the other hand, the skin can also present positive charges due to the presence of superficial lipids that cover the stratum corneum. Previous studies have shown that negatively charged carriers such as nanostructured lipid carriers (NLC) or solid lipid nanoparticles (SLN) are capable of interacting with lipids in the outermost skin layers, producing an occlusive effect. The negatively charged NLC and SLN, forming a film on the skin surface, may increase drug permeation across the stratum corneum and enhance drug retention in the skin . Although drug delivery at the follicular target represents an important strategy for the topical administration of active ingredients at the cutaneous level, the development of new formulations to achieve this goal represents an important challenge. Fresta et al.  investigAnother important aspect concerns rigidity and flexibility of the nanostructure, influencing permeation through the stratum corneum. Ultra-flexible nanoparticles are able to permeate through the stratum corneum and to deliver actives, as a function of the hydration gradient of the skin without producing any damages .Studies have reported on biodegradable and nonbiodegradable nanoparticles, even though biodegradability is not so essential due to the probability that nanoparticles could be eliminated from the skin surface . Moreover, it is noteworthy that nanoparticles larger than 100 nm do not move from the follicles to living tissue .However, it is important to highlight that, although it is now proven that nanocarriers are effective for drug targeting to the hair follicle, their formulation in appropriate vehicles is an important aspect to consider for the future development of a pharmaceutical product. Vehicles can be both hydrophilic and lipophilic and can present different viscosity, polarity, and many other parameters. A recent study of Pelikh et al.  investigBased on the above considerations, the penetration of nanoparticles in the hair follicles can be described as a three-step process. In the first one, the particles must adhere loosely to the hair surface. In the second step, mainly influenced by the particle size, from the surface they must be positioned between the overlapping cells of the hair cuticle to take advantage of the ratchet mechanism. Finally, in the third step, the ratchet together with the pawl will then transport the particles into the hair follicle. In conclusion, it has been showed that the role of excipients may overlap with that of particle size. In addition, excipients can be considered to modify all three steps of the hair follicle penetration process. Therefore, in order to obtain a targeted penetration into the hair follicle, it is necessary not only to reach an optimal sizing of the nanoparticles, but also to select the appropriate excipients. Both aspects could be of interest in the development of the formulation of topical products .Recent studies have also reported on the influence of external physical stimuli on the follicular targeting potential of different nanoparticles. The physical stimuli strategy is based on the observation that skin massage acts like a “gear pump” able to drive the transport of the nanoparticles into the hair follicle, together with the scaly structure of the hair cuticle. Similarly, it was observed that an effervescence reaction after administration of a solid powder formulation containing minoxidil can favor drug penetration . The autAs reported by Patzelt and Lademann , stimuli2) in pulsed mode with or without mechanical vibration, that can lead to a reduced drug dosage and less frequently drug application with greater safety and efficacy for patients.Angelo et al.  also inv. Therefore, the choice of suitable excipients and vehicles is crucial.In the preparation of formulations based on 5-α-reductase inhibitors, such as finasteride and dutasteride, one of the main problems encountered is due to the poor solubility of these therapeutic agents, which can result in low bioavailability ,48. TherIn recent years, interest has focused on the development of nanostructured systems that have great potential as a drug carrier for the treatment of dermatological diseases . In factco-glycolic acid (PLGA) and polylactic acid (PLA) are widely used as representative of synthetic polymers. Generally, the choice of the polymer considers the chemical-physical characteristics of the drug that must be encapsulated, attached, or dissolved in the nanoparticles; PLGA (75:25), for example, is used for the preparation of nanoparticulate systems comprising hydrophilic or hydrophobic drugs soluble in polar solvents [.Polymeric nanoparticles are colloidal carriers made up of a biodegradable, biocompatible, and non-toxic polymer, which can be natural or synthetic. Among the natural polymers, the most used for the preparation of nanoparticles for topical use is chitosan, which, being of a cationic nature, establishes strong interactions with the negatively charged skin surface. Furthermore, chitosan has antioxidant, anti-inflammatory and antimicrobial properties that make it particularly convenient in the treatment of dermatological pathologies . On the solvents .The dimensions of between 10 and 1000 nm allow the accumulation of nanoparticles at the level of the hair follicle and the skin surface making them extremely advantageous in the delivery of therapeutic agents at the topical level ,56,57 Regarding 5-α-reductase inhibitors, several nanostructured drug delivery systems have been proposed in recent years, such as polymeric nanoparticles, liposomes, niosomes, ethosomes, liquid crystals and nanostructured lipid carriers ,58,59,60Polymeric nanoparticles represent an efficient system for hair follicle drug targeting, with some polymers, such as PLA or PLGA, seeming more advantageous with respect to others. For example, Roque et al.  investigLiposomes are vesicular carriers in which an aqueous core is enclosed in one or more lipid bilayers mainly consisting of cholesterol and phospholipids ; the preThe use of liposomes allows improving the pharmacokinetics of the administered substance, also increasing its specificity and efficacy, and decreasing its toxicity ,57.In the literature, numerous vesicular systems  for the delivery of drugs such as finasteride and dutasteride are described and some examples are summarized in −1 and degree of deacetylation around 85%) for the topical delivery of finasteride that were able to strongly interact with the skin, creating a drug depot in the epidermis and dermis.Even though liposomes have been demonstrated to enhance drug delivery in the hair follicle for the treatment of androgenetic alopecia, their industrial application is limited due to chemical-physical instability and microbial contamination. Therefore, alternatives have been proposed by researchers, such as polymersomes, self-assembled spherical vesicles based on amphiphilic block copolymers. Caon et al.  investigIn recent years, researchers’ interest has been aimed at investigating tools to control the drug release in response to some stimuli. Ushirobira et al.  proposedAnother proposed strategy is represented by formulating nanoemulsions decorated with biopolymers as polysaccharides and alginates . Nanoemulsions are thermodynamically stable O/W or W/O dispersions with droplets’ dimensions on the order of nanometers stabilized with a low percentage of surfactants. They have an average diameter of dispersed phase droplets between 20 and 1000 nm. They are able to solubilize lipophilic drugs with a high loading capacity and the high contact surface with the stratum corneum allows an increase in permeation and the transport of drugs in the skin depth. Furthermore, the surfactants included in the composition are able to interact with the lipid structure of the stratum corneum, temporarily modifying the barrier, thus facilitating the passage of the drug.Low-molecular-weight chitosan-decorated nanoemulsions containing finasteride showed low drug permeation and increased skin retention, even with droplet size of 800 nm, with respect to non-decorated nanoemulsions, maybe due to their positive charge and viscous nature . Moreover, a patented nanoemulsion based on dutasteride and containing tocopheryl phosphates and tocotrienol phosphates as co-surfactants has been proposed .Other formulative strategies to optimize the topical administration of drugs at the scalp level could be adopted to create a depot at the topical level and in recent years many patents have been developed.In 2011, a formulation containing chitosan, a polymer capable of forming a film after the evaporation of volatile solvents allowing intimate contact between the therapeutic agent and the skin and increasing its hydration with consequent promotion of absorption, was patented .Another formulation involves the use of lipids that form non-lamellar liquid crystals when they encounter biological fluids, obtaining a controlled drug delivery system . A similSince androgenetic alopecia is specifically restricted to pilosebaceous units, improving the outcome of alopecia therapy might be possible by increasing drug distribution at the target site within the hair follicles. Follicular drug targeting will provide advantages in terms of reduction of the drug dose, while simultaneously minimizing drug systemic absorption.Nanostructured drug delivery systems represent the most promising option for topical delivery, as they could improve drug-selective tissue distribution in the hair follicle region, minimizing side effects and reducing the required dose. Moreover, the use of nanotechnologies could improve drug solubility and contemporaneously increase the drug concentration at the target site by overcoming the skin barriers for penetration (stratum corneum and sebum). Indeed, the optimal dimension range to address the target site inside the hair follicle should be pursued in order to efficiently penetrate into the hair follicles and to reach the depth of the hair bulb. The particle size, the surface charge, and the effect of the combination of polymers and/or surfactants should be investigated in order to select the best formulation, capable also of interacting with sebum in order to facilitate drug partition in the hair shunt. Additionally external stimuli such as massage or ultrasound application could be considered as tools to improve drug retention inside the hair follicle.


More than 450 million people worldwide are suffering from diabetes and this number is expected to increase. In developing countries, such as Tanzania, the number of patients suffering from diabetes and associated diseases is increasing as well. Up to 80% of the Tanzanian people rely on traditional medicines for their health care services. The nature of Tanzanian is very rich in different plant and insect species, and this could be exploited through their implementation in preventive and/or curative approaches in the battle against diabetes. The implementation of healthy insects in the diets of people may help in the prevention of obesity, which is a risk factor in the etiology of diabetes, while the identification of small molecules in insects may help in the discovery of potential new drugs that can be used in the treatment of diabetes. In this paper, an overview on the potential implementation of insects against diabetes is presented. Diabetes mellitus is a chronic disease that is characterized by raised blood glucose levels. This is caused by an insufficient production or inefficient use of the hormone insulin, which is produced by the pancreatic beta-cells and helps glucose from the blood enter the cells where it is converted into energy. If left untreated, diabetes can cause other problems, including cardiovascular and eye diseases, as well as damage to various organs such as nerve and kidney damage, leading to disabling and life-threatening conditions . Worldwide, diabetes is a severe health problem. In 2019, 463 million people between the ages of 20 to 79 years were suffering from diabetes, and it is expected that this number will increase to 700 million in 2045. It is estimated that 4.2 million people died from diabetes in 2019. There is an increasing prevalence of diabetes by age and slightly less prevalence in women compared to men [In Tanzania, about 60% to 70% of the urban population and up to 80% of the rural population use traditional medicines for their health care services because the majority cannot afford to purchase modern medicines and the national budgets for public health services are too limited to enable availability/accessibility of medicines to all . These twww.vliruos.be, accessed on 3 December 2021) is to develop an increase in competence and experience of academic staff in Tanzania to identify and investigate useful insects and plants to prevent and cure diabetes and to develop a long-term approach towards a better health situation (preventive and/or curative) for diabetic patients in Tanzania. In this review, the focus is on the potential use of insects in the battle against diabetes and associated complicating diseases.This was the outset of the ‘NAturals to prevent and/or cure DIAbetes (NADIA)’ project, a collaboration between the laboratories of the authors of this paper. The main goal of the NADIA project  and 2 (T2DM). T1DM is an autoimmune disease; it occurs mainly in childhood and involves a complex interaction of genetic, immune, and environmental factors that destruct the function of the beta-cells. This form accounts for about 5–10% of people with diabetes . T1DM isT2DM is the most common type of diabetes and is linked to insulin resistance, i.e., the inability of the body’s cells to fully respond to insulin. T2DM is generally less severe than T1DM, occurs mainly in adulthood, and is usually caused by diet and lifestyle factors such as high carbohydrate/low fiber diets and a sedentary lifestyle. Genetic predisposition is also a contributing factor. [The etiology of T2DM is complex and involves interplays between several factors such as age, ethnicity, genetics, diet, physical activity, smoking, and awareness. Some of these factors can be influenced and reversed. Diet, in particular, is regarded as a main cause of T2DM among rich people who have consumed oil, flour, and sugar in large amounts since early in history. This is supported by the fact that, during the First and Second World Wars, mortality due to T2DM decreased in countries wherein famine existed but not in countries in which there was no shortage of food . Poor diLarge scale clinical trials have shown that modest changes in diet and physical activity can reduce the incidence of T2DM by more than 50% for people with impaired glucose regulation . In the Weight loss and physical activity are the main factors that drive the prevention of diabetes. However, the intervention programs that were used in the clinical studies were personalized to match the unique situation and cultural aspects of the participants . TranslaAs diabetes is associated with additional health problems such as CVD, interventions in diet can have a profound effect on these other conditions as well. Many studies have focused on the effects of diet on diabetes prevention and for ameliorating those suffering from T2DM and associated health problems. The data from meta-analyses suggest that nutrition therapy is powerful in the primary prevention of T2DM and associated risks , and sevNutritional strategies are also important in managing patients with T2DM. In addition, research has been carried out on using diet supplements for glycemic control and reduction in risk for diabetes-related complications . This inXylopia aethiopica, Psidium guajava) has shown their beneficial effects on T2DM and its complications [Traditional medicine  is defined as the sum of the knowledge, skills, and practices based on the theories, beliefs, and experiences indigenous to different cultures, whether explicable or not, that are used in the maintenance of health as well as in the prevention, diagnosis, improvement, or treatment of physical and mental illness . In deveications ,19.In Tanzania, about 60% of the urban population and up to 80% of the rural population use traditional medicines for their health care services. Most of the traditional medicines are botanical products, and there are about 75,000 traditional medicine practitioners . While tAlthough botanicals are mainly considered for use in traditional medicine in Tanzania, other sources such as insects and invertebrates may also be relevant. Here, we present an overview of the literature on the use of insects in entomophagy and entomotherapy.In Western society, eating insects is not compatible with current habits, and insects are far from accepted as a substitute for meat . In manyMineral and vitamin composition are also important for the nutritional value of edible insects; however, large variations (among and within species and orders) are observed in published numbers . In geneMore than 2 billion people worldwide, mostly in Africa, Asia, Latin America, and Oceania, include various species of insects in their diet ,30. In dAfrica is a very important source of edible insect biodiversity in the world . More thWhereas many studies suggest that the consumption of edible insects promotes desirable health outcomes, caution is also warranted as sensitive people may have allergic reactions in response to eating insects .Throughout history, insects and other arthropods and products thereof have been used worldwide for medical application . WhereasThe earliest records date back to the Egyptian Ebers papyrus of the 16th century BC that contains several accounts of medicines derived from insects and spiders. Extracts of silkworms have been used in Chinese traditional medicines for over three thousand years and living larvae of certain flies have been used worldwide for centuries to treat infected wounds . FurtherThasus gigas, which is commonly eaten in Mexico. However, its exact impact on diabetes has not yet been investigated in a properly designed scientific study [Aside from being a good source of protein and thus an important component of a healthy diet, the use of insects in diets has been implemented for specific health effects, including diabetes and associated health complications such as CVD. Cultures that consume insects also associate them with several health benefits beyond nutrition , such asic study .Due to sheer numbers, it is impossible to describe in detail the different insect species and the ways in which insects are used in traditional medicine worldwide. However, the reviews of Costa-Neto (2005)  and MeyeAbout 29 insect orders exist, but 80% of all insects belong to one of the following orders: Coleoptera, Diptera, Hymenoptera, and Lepidoptera . In TablOne of the most well-known and well-studied medical applications is the use of maggots for wound healing. Living fly larvae are put on a wound and aid in the healing process by promoting fibroblast aggregation and tissue repair, eating necrotic tissue that otherwise could promote infection, releasing antibacterial substances, and destroying ingested bacteria. Larval therapy has been implemented since the Middle Ages and has been practiced by traditional healers in Asia, South America, Europe, and Australia . In a trInsects are specialized in the synthesis of chemical compounds that function as pheromones, defensive sprays, venoms, and toxins . These cAll examples derive from , which cRegarding their potential to combat T2DM and related complicated disorders, some insects and insect-derived products have been described that may also have medicinal applications. Examples are shown in Thasus gigas) as an alternative treatment for T2DM in Mexico. These insects are consumed and are believed to ameliorate diabetes, but there are no objective data available that indicate this effect. The study of Nallely et al. indicates that some people actually consume the insect as a treatment for diabetes, and 7% of people with T2DM have discontinued their allopathic treatment [Ulomoides dermestoides) as an alternative medicine to treat illnesses, including diabetes [Diagnosis of diabetes in some tribes in Africa is made when ants are seen to feed on a person’s urine . As alrereatment . It is tdiabetes .A molecule that may be useful in combating CVD complications is chitin, an aminopolysaccharide that makes up the exoskeleton of insects. Chitosan, a deacetylated form of chitin, has been shown to have a total and an LDL cholesterol lowering effect in animals and humans. The mechanism for this effect is not yet known, but as little as 1.2 g per day may provide significant reductions in serum cholesterol. Studies suggest that chitosan could accelerate human weight loss if used in combination with a weight reduction diet . SimilarAnticoagulants from leeches and ticks have been investigated for potential use as an anticlotting agent, but insects also contain interesting substances, an example being anopheline, found in the salivary glands of Anopheles mosquitoes, which has an unique thrombin inhibition mechanism that has potential for the design of novel antithrombotics .Recently, the anti-diabetic and anti-obesity effects of functional, active proteins obtained from edible insects were investigated ,55. SeveBee venom has been reported to have good anti-diabetic effects by increasing the insulin level in mouse models . In a smDiabetic nephropathy is a major complication of diabetes. Sustained hyperglycemia can increase the production of free radicals, which can result in oxidative stress, inflammation, and fibrosis in the kidneys . Wang etPogonomyrmex badius ants and which may reduce the risk of coronary heart disease by raising HDL and lowering LDL levels at the same time [The biologically active products are not always synthesized by insects, but instead can sometimes be traced back to associated microorganisms or to plants and even animals . This isame time .In Tanzania, and more generally in sub-Saharan Africa, the prevalence of diabetes is rising, and about 60% of adults aged 20–79 years with diabetes are undiagnosed. As urbanization increases and populations age, T2DM will pose an increasing problem [Given that T2DM is associated with obesity and an unhealthy diet, one approach to battle T2DM and associated disorders such as cardiovascular diseases (CVD) may involve a prevention campaign that implements insects in healthy diets. As shown earlier, insects contain a large proportion of proteins with essential amino acids and the insect fats contain a large fraction of PUFA and fibers. By integrating selected nutritious insects into balanced diets, healthy food may be provided to battle obesity, CVD, and the potential development of T2DM.Between 1961 and 2010, 939 nature-derived approved drugs were developed; none of these were from insects, but rather from plants, marine organisms, microbes, and invertebrates such as leeches . HoweverTo conclude, the geographical location and climate of Africa favors the rich flora and fauna that includes large quantities of insects. In some African countries, insects are eaten, but research on their use for treating different diseases is rare. Only a few studies on insects have been carried out regarding diabetes, and some insect products exhibit antidiabetic activity as well as having bioactivities relevant to the control of risk factors/disorders of diabetes. Future focused and detailed studies of both insects and plants could provide safe standardized natural remedies for diabetes that would be of high value for the local people as the majority are not able to afford modern antidiabetic medicines. In addition, developed countries might learn of new opportunities for treating or preventing diabetes and collaborative scientific studies could lead to the isolation and identification of bioactives, which may lead to more effective medicines with less/few side effects compared to the current antidiabetic medicines.In this review, we attempted to present the perspectives on the implementation of insects as a nutritional preventive and/or as a source for curative approaches in the battle against diabetes and associated complex disorders.


A methodology enabling the customization of shoes for comfort improvement is proposed and assessed. For this aim, 3D printed graded density inserts were placed in one of the critical plantar pressure zones of conventional insoles, the heel. A semi-automated routine was developed to design the 3D inserts ready for printing, which comprises three main stages: (i) the definition of the number of areas with different mesh density, (ii) the generation of 2D components with continuous graded mesh density, and (iii) the generation of a 3D component having the same 2D base mesh. The adequacy of the mesh densities used in the inserts was previously assessed through compression tests, using uniform mesh density samples. Slippers with different pairs of inserts embedded in their insoles were mechanically characterized, and their comfort was qualitatively assessed by a panel of users. All users found a particular pair, or a set, of prototype slippers more comfortable than the original ones, taken as reference, but their preferences were not consensual. This emphasizes the need for shoe customization, and the usefulness of the proposed methodology to achieve such a goal. From a user perspective, comfort is one of the most relevant features in footwear assessment . The demSeveral studies correlate the increase of plantar pressure with pain and discomfort , but up Researchers have been searching for new materials and new ways to build shoes in order to balance the plantar pressure distribution . HoweverDespite all these possibilities, the need for innovative industrial solutions and the advances in material science led to the development of the so-called functional graded materials (FGM) . In the In the context of shoe comfort, Tang and co-workers  recentlyThe objective of the present research is slightly different since it focuses on the development of a methodology that enables to produce, through a simple and automatic way, insole inserts having different densities distributions that can be used to increase comfort. Two main differences can be depicted: (i) the graded density zones are inserts of the insole, enabling, therefore, a simple and fast way to customize it; (ii) the graded density inserts have a continuous structure, automatically generated, not being composed by a juxtaposition of discrete modular elements.Independently of the specific solution to be adopted for promoting a higher comfort, it is clear that it has to act on the three critical zones identified. The hereby proposed strategy is to create insole inserts for these zones. This design decision brings two advantages: (i) it may be used in commercially available shoes, adapted to each individual, easily providing customized solutions; and (ii) for the purpose of this research, it enables testing different solutions in the same pair of shoes. In fact, the customization of the insole focuses on the FFF produced inserts that are placed in the critical zones of conventional insoles. This way, the negative effect of the low printing speeds, typical of FFF techniques, will be minimized since the majority of the insole will still be produced by injection molding.The geometric freedom provided by FFF technique is used to produce inserts with graded flexibility, as a result of an internal filling built with a graded mesh density. Keeping in mind that the objective is to understand which type of structure provides the best comfort, we decided to carry out this research solely focused on the heel zone, since the final conclusions will provide guidelines applicable to the remaining critical plantar zones. The methodology proposed is illustrated in https://www.simplify3d.com/, accessed on 29 March 2021) were used, by selecting the triangular mesh and different filling densities for the internal structure of the samples. The triangular geometry was selected since it facilitates the automatic generation of graded density meshes, as will be described in The design of functional graded structures of the heel inserts was preceded by a simpler research on the effect of the mesh density on the compression behavior of uniform mesh density samples. The expected differences in the compression behavior of the printed samples/structures obtained in this way will enable us to assess the potential of using a single material to obtain different structure properties. For this sake, the capabilities of the Simplify3D slicer software , using Filaflex, a polyurethane based thermoplastic elastomer filament, with Shore A 82. This filament material was selected due to its similarity to the material used to produce the slippers insole that was used as a base structure in the present case study see . The tesCompression tests were carried out in a universal mechanical testing machine, Instron 5959 . A maximum compression head displacement of 8 mm (strain of 64%) and a test speed of 50 mm/min were selected.σ)—strain (ε) curves obtained in the tests are illustrated in E), maximum stress (σmax), i.e., stress at yielding, and strain and displacement at the maximum stress, listed in The stress , i.e., with the same material, different meta-properties for the structure are obtained, which may vary within a wide range. This preliminary study provides, therefore, a relationship between cell size and structure stiffness, an important information to tune local properties of structures having graded mesh densities.the linear region of the stress-strain curve, where the stress increases proportionally to the strain imposed to the material;region where the structure deformation takes place, due to the buckling of the vertical walls, corresponding to a plateau/quasi-plateau region where the strain increases at almost constant stress (the stress at yielding);densification region where the stress starts again to increase, due to the full collapse or crushing of the structure. In these conditions, an almost compact structure is, therefore, being compressed.The typical behavior observed during the compression tests is illustrated in In the present study the cellular structures obtained are of 2D type, but their behavior is similar to that of 3D cellular materials/structures such as, for example, cork , or PolyIn terms of the envisaged application, the inserts will have internal structures capable of withstanding the local plantar pressures without collapsing. In fact, the collapse of the structure would result in very high stiffness and almost no impact absorption capability, inducing discomfort. Therefore, these stresses should not exceed the maximum ones previously identified for each mesh density.The maximum plantar pressure depends on several variables, as person’s weight and foot/floor contact surface, gait attitude, footwear and type of floor and inclination . HoweverAfter determining the effect of using different filling densities, the next step consisted in the generation of inserts with graded mesh density structures adjusted to the plantar pressure distribution. A 12 mm height, similar to that of the compression test samples, was selected for the inserts. The mesh density, variable in this case, resulted from cells sizes between 2 and 11 mm, i.e., in the range previously tested.The first attempts to design inserts with two different mesh densities zones, directly from Simplify3D software, was unsuccessful. More specifically, despite being possible to define sub-zones with different filling densities, the software created a boundary wall at their interface. As a consequence, the mesh was not continuous and the boundary wall would affect the compression behavior of the structure, mostly for the larger cell size cases (lower mesh densities). Furthermore, the cell size varied in a discrete way, with an abrupt change at the sub-zones’ boundary. According to the smooth plantar pressure distribution see , variablUsing the above methodology, the eight different types of heel zone inserts illustrated in Pairs of each insert shown in The original shoes used for comfort assessment are the slippers shown in Prototype slippers, with pairs of inserts placed in their insoles, were subjected to a dynamic impact load test frequently used to assess the cushioning properties of sport shoes insoles . For thi−2 and 32–50% ranges, respectively. Having this into consideration, it may be concluded that all the prototype slippers perform better than the reference ones in what concerns to the maximum deceleration, and that the majority also perform better when the energy return is taken into account. In this last case, only inserts G and H have a lower performance than the reference slippers. Therefore, at this stage the inserts that show the best cushioning properties are E and F, presenting the lower values for maximum deceleration and a good resilience .The reference TPU slippers present the higher value of maximum deceleration. Thus, they are expected to promote the lowest comfort when subjected to an impact. This was anticipated since the insole is totally compact. For the prototype slippers, this value depends on the average density of the inserts and its spatial distribution. Another property shown in In order to verify if there is a relationship between these mechanical properties and comfort perception, the prototype slippers and the reference ones were also tested by a panel of users. The main objective was to determine which of the two main types of structures provides higher comfort and how they compare with the original slippers . The main results of this study are shown in The assessment results were not consensual, and two main groups of users can be identified: those that select as more comfortable the prototype slippers with inserts A to D, valuing their softness and impact absorption capability; and those that valued stability, selecting the prototypes with inserts E to H. As referred in the Introduction, comfort is a subjective concept, which perception is highly dependent on the user. This was confirmed in the present study that clearly strengthens the need for shoe customization. Anyway, all the users considered their specific preferences as more comfortable than the reference  slippers, putting in evidence the potential of the strategy developed in this work to tailor shoes insoles for comfort improvement.In this work, a methodology enabling the customization of shoes for comfort improvement was proposed and assessed. The first step consisted in a study where the selected material, a TPU filament, was employed to print several different uniform mesh density structures, obtained through the use of different printing filling densities. This study showed that the compression behavior of the different structures varied significantly with the filling density, presenting maximum (yield) stresses between 0.05 to 1.7 MPa, and that the smaller cells structure was capable to withstand the maximum typical plantar pressures without collapsing. Thus, it was concluded that the material and the cell size range tested were adequate for shoe insole applications.The next step consisted in generating and printing insole inserts comprising graded mesh density structures for the heel zone, one the of the critical zones in terms of plantar pressure. Graded properties were considered relevant due to the typical patterns of plantar pressure distribution. The graded density structures were generated with an in-house developed methodology that enabled a continuous variation of the cell size and, hence, graded mechanical properties. Eight different pairs of inserts were printed by the FFF technique and embedded in TPU slippers insole. For this sake, the original insoles of these shoes were laser cut, at the heel zone, to create a cavity for the 3D printed inserts. These inserts were of two main types: those having a lower mesh density in the center and higher in the periphery, and those having the opposite mesh density distribution.−2) and reached a minimum of around 160 ms−2 in inserts having a higher density in the center . Concerning the energy return, the recommended range is 32–50 %. In the majority of the cases, both the prototype slippers and the reference ones presented values in this range. The only exceptions were two prototype shoes, in which the inserts had very high mesh density in the center and low mesh density in the periphery.The prototype slippers (those having inserts embedded in their insoles) and an original pair of slippers (the reference case), were mechanically characterized through dynamic impact load tests, and their comfort was assessed by a panel of users. The properties determined in the impact tests were the maximum deceleration, related with the capability to promote comfort, and the energy return, a measure of the resilience, i.e., the impact absorption capability. It was concluded that all the prototype slippers tested had a better performance than the original ones in what concerns to the maximum deceleration. In fact, this value was always lower than the reference value  one. However, their preferences varied. Furthermore, the most promising inserts in terms of mechanical performance were not, definitively, the predominant choice of the users. This emphasizes the subjectivity of comfort perception and the need for shoes biomechanical customization, which can be done via the proposed methodology.In conclusion, slipper or any other type of shoes, can be produced with a special insole  where inserts selected from a set of pre-produced ones can be used. In fact, the present study showed that there is no ‘best insole’ since the preferences of the users varied.


Despite the clear risks of tobacco use, millions of people continue to smoke. Electronic nicotine delivery systems (ENDS), commonly called e-cigarettes, have been proposed as a substitute for those who are unwilling or unable to quit. Current systematic and narrative reviews on the health effects of ENDS use, particularly respiratory and cardiovascular effects, have come to differing conclusions.We conducted two systematic reviews to critically assess and synthesize available human studies on the respiratory and cardiovascular health effects of ENDS substitution for people who smoke. The primary goal is to provide clinicians with evidence on the health effects of ENDS substitution to inform their treatment recommendations and plans. The twin goal of the reviews is to promote health literacy in ENDS users with facts on the health effects of ENDS.These two reviews will be living systematic reviews. The systematic reviews will be initiated through a baseline review. Studies will be evaluated using the JBI quality assessment tools and a checklist of biases drawn from the Centre for Evidence Based Medicine Catalogue of Bias. A narrative synthesis is planned because of the heterogeneity of data. A search for recently published studies will be conducted every 3 months, and an updated review will be published every 6 months for the duration of the project or possibly longer.The baseline and updated reviews will be published in a peer-reviewed journal. The findings of the reviews will be reported in a white paper for clinicians and a fact sheet for people who use ENDS.The substitution of ENDS for cigarettes is one way to potentially reduce the risks of smoking. Clinicians and their patients need to understand the potential benefits and possible risks of substituting ENDS for cigarettes. Our living systematic reviews seek to highlight the best and most up-to-date evidence in this highly contentious and fast-moving field of research.PROSPERO CRD42021239094; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=239094DERR1-10.2196/29084 There are 1.3 billion people worldwide who use tobacco, and more than 7 million of them die annually from its use . For resDespite the clear risks of tobacco use, millions of people continue to smoke. Smoking has pleasurable effects , and somElectronic nicotine delivery systems (ENDS), commonly called e-cigarettes, have been proposed as a substitute for those who are unwilling or unable to quit ,11. A reThere have been 3 recent systematic reviews published on the respiratory effects of ENDS. The study by Bals et al , which wIn addition, 4 narrative reviews on the pulmonary effects of ENDS have been published since 2019; they were conducted with a combination of in vitro, in vivo, emission toxicology, and human studies. The reviewers came to diametrically opposed conclusions regarding the respiratory effects. Gotts et al  and MiyaRecent systematic reviews offer substantially different conclusions on the cardiovascular effects of ENDS, some suggesting harm and others not finding harm, whereas still others stating that there is a lack of evidence. One systematic review of in vitro, animal, and human studies presented the conclusion that “most studies suggest potential for cardiovascular harm” caused by sympathetic nerve activation, oxidative stress, endothelial dysfunction, and platelet activation . AnotherConversely, some reviewers claim that evidence is lacking or insufficient. The NASEM stated that “there is no available evidence whether or not e-cigarette use is associated with clinical cardiovascular outcomes  and subclinical atherosclerosis ” . D’AmariAn umbrella review  , or comparisons with documented smoking outcomes.Outcomes (respiratory): changes in chronic cough, phlegm, wheezing, dyspnea, exacerbations of asthma and chronic obstructive pulmonary disease, or changes in testing, including forced expiratory volume, chest x-rays, and computed tomography scans.Outcomes (cardiovascular): measures of cardiovascular function, including blood pressure, heart rate, carotid intima-media thickness, and coronary artery calcifications, or changes in cardiovascular disease symptoms .We are conducting 2 systematic reviews to critically assess and synthesize available human studies on the respiratory and cardiovascular health effects of ENDS substitution for people who smoke. We will provide an even-handed assessment of the data, considering all health effects, both potentially adverse and beneficial. The primary goal is to provide clinicians with evidence on the health effects of ENDS substitution for people who smoke to inform their treatment recommendations and plans. The twin goals of the reviews include promoting health literacy in ENDS users with facts on the health effects of ENDS with a white paper drawn from the review. These 2 systematic reviews will be conducted with the living methodology to keep the information up to date and complete, as described in the following sections.The protocol conforms to the PRISMA-P  requirements ; the comThese 2 reviews will be living systematic reviews. Living systematic reviews are a recent innovation for conducting systematic reviews that incorporate evidence from studies as they are published ,32. LiviThe Cochrane guidelines  specify The review team comprised RO, the project leader, with extensive experience in conducting literature reviews and a substantial background in tobacco control, tobacco harm reduction, and ENDS. The research team comprised 4 fellows: MAQ, GRMLR, and DCO, each having literature review experience as the first author of a narrative review, and RWMV, who has substantial experience in literature reviews. MAQ and GRMLR are clinicians, and DCO has worked as a pharmacist. MAQ has a background in tobacco control and tobacco harm reduction.The processes that will be conducted to create the baseline reviews are described in the following sections.Study designs selected for the reviews include randomized and nonrandomized controlled trials and clinical trials, prospective and retrospective cohort studies, and case-control studies. A gray literature search was performed. Database searches were performed separately for the cardiovascular and respiratory studies. Supplementary searches were conducted after the database search and after the full paper selection.A search for articles on ENDS not published in peer-reviewed journals was conducted on January 13, 2021, on the websites of 41 cardiovascular medical organizations and 53 respiratory medical organizations . No grayThe databases searched included Scopus, PubMed, and CENTRAL Cochrane Library.electronic cigarettes and e-cigarettes. Vapor or vapor were not used as keywords, as these terms retrieve many chemical studies. Cardiovascular keywords were cardiovascular, heart, circulatory, arterial, and stroke. The respiratory keywords were lung, pulmonary, and respiratory.The keywords used for the search included the following: ENDS keywords were The text fields searched were title and abstract in PubMed; title, abstract, and keywords in Scopus; and trials in Cochrane Library.The search dates were from 2010 to January 31, 2021. The start date of 2010 is the date of publication of the first peer-reviewed research studies on ENDS.The languages searched were English, French, Spanish, and studies in any language with an English abstract.In compliance with PRISMA-P, an example of the search strategy is reported in the The retrievals were entered into EndNote for bibliographic management. Paper retrieval duplicates were removed. There were 374 retrievals cardiovascular outcomes and 703 retrievals for respiratory outcomes.The first exclusion of articles was performed on titles, and where a title was not sufficient for a determination, the abstract was reviewed. There were five categories of exclusion criteria. The first category was article types: editorials, commentaries, letters, news articles, issue introductions, and reviews. The second category was studies that were not peer reviewed, including conference abstracts, unpublished clinical trials, and preprint articles. The third category was articles without an English abstract (except for those in French or Spanish). The fourth category was studies exclusively on EVALI (e-cigarette or vaping product use–associated lung injury) because most EVALI cases were linked to black market tetrahydrocannabinol products not commercial ENDS . The fifThe exclusion process was conducted independently by 2 reviewers, and all discrepancies were resolved by discussion between the reviewers. One study in a nonincluded language was excluded. The number of studies after title and abstract exclusion was 43 cardiovascular outcomes studies and 23 respiratory outcomes studies.As a supplementary search, the reviews discussed in the introduction ,18-28 weThe second process of inclusion and exclusion was a full-paper review. There were 3 inclusion criteria. First, studies were limited to the research designs of randomized controlled trials, nonrandomized clinical studies, prospective or retrospective cohort studies, and case series. Second, a study was required to have either a comparator of participants who smoked combustible tobacco (cigarettes) or a before and after testing of participants who had substituted ENDS for smoking. Third, the study had to report outcome data on cardiovascular or respiratory function or diseases. All 3 aforementioned criteria had to be met for a study to be included.The review team members were trained and supervised on the inclusion criteria on 5 studies. The inclusion and exclusion of studies was conducted independently by 2 reviewers, and discrepancies were resolved by a discussion. The reviewers achieved 95% (63/66) agreement on the inclusion and exclusion of studies. The project leader made the final decision on the studies that were questioned.After this step, the reference lists of all included studies were reviewed for additional studies and were citation chased in Google Scholar. A list of studies excluded during the full-paper review is reported in the The search processes yielded 27 cardiovascular outcomes studies and 19 respiratory outcomes studies that are listed in the The data extraction process is being conducted with a data extraction form. The reviewers were trained using calibration exercises to ensure consistency. Data are being extracted independently by 2 reviewers and will then cross-checked by the reviewers for accuracy and completeness. Any discrepancies in data extraction will be rectified by discussion. The data extraction items were drawn from inventories by JBI and the Cochrane Collaboration ,43. The Two additional examinations of each study are being performed. The first is a check for internal discrepancies in the reporting of data  Multime. The secThe completed data extraction forms will be submitted to the Systematic Review Data Repository at the Agency for Healthcare Research and Quality , an openData from these studies will be reported in two ways. First, individual studies will be presented with a brief narrative description. Second, study tables will be constructed with items from the data extraction and quality assessments (see the following section).A quality assessment of each study is being conducted using the JBI quality assessment tool for its research design . RevieweCatalogue of Bias [Bias is being assessed with observations of biases listed in the Oxford Centre for Evidence-Based Medicine  of Bias  applicabQuality assessment and risk of bias observations are being made concurrently with the data extraction process. Two reviewers are independently performing the quality and bias assessments. Discrepancies will be resolved through discussions between the reviewers. If a consensus is not reached, the final decision will be made by the project leader. No studies will be excluded based on their quality assessment or risk of bias observations. Studies not conforming to the JBI quality assessment items or with observations of biases will be reported in the study tables. These shortcomings will be specified in the data analysis and will be referenced in the discussion section of the reviews.The synthesis will be a narrative synthesis. Owing to the heterogeneity of the study populations and outcome measurements, we anticipate that a meta-analysis will be inappropriate. If sufficient studies are identified as comparable either during the baseline review or for updated reviews, we will develop an additional protocol for a meta-analysis and will add it to the review.The narrative syntheses will have four components. The first will be the findings organized by the study design. The second will be a summary of descriptive statistics for the participants and intervention characteristics. The third will group the findings based on the tests performed, physiological functions, and disease outcomes. The final synthesis will tally studies that have been found to demonstrate quality issues or biases.Three subgroup analyses of testing and disease outcomes will be conducted for (1) concurrent users of cigarettes , (2) populations with prior respiratory or cardiovascular diseases, and (3) ENDS use of a duration of 1 year or longer.Sensitivity analyses will be performed to explore the influence of the risk of bias on the findings. One will be to rerun the third analysis by excluding all studies assessed at a high risk of bias. A set of sensitivity analyses will be performed on groups of studies based on the following types of funding sources and author affiliations: ENDS or tobacco industry, pharmaceutical affiliations, and philanthropic or medical organization affiliations or funding. Publication bias will be assessed using a funnel plot for the test results and disease outcomes.The certainty evidence for each reviews’ findings will be evaluated with the Grading of Recommendations Assessment, Development, and Evaluation framework ,49.A literature search will be conducted at 3-month intervals to retrieve newly published studies. Searches were conducted using the same databases and keywords as the baseline review. Newly published papers will be checked for studies that meet the inclusion criteria. The searches will apply appropriate date limiters to include only those records added to the database subsequent to the last search, allowing for indexing lag time ,32. SearThe first update search will be conducted on or shortly before April 30, 2021. The retrieved studies will be incorporated into the baseline review so that it will be updated when published.The updating search can result in 3 scenarios: (1) no new studies are identified (highly unlikely), (2) new studies are retrieved but the evidence has no impact on the review’s findings, or (3) new studies are found with evidence that significantly impacts the review’s findings. This third scenario will trigger an immediate update of the review ,32. In eBecause a large volume of new studies is expected, we will update the review every 6 months if no studies prompt an earlier revision of the review. Narrative descriptions of the newly included studies and new study table listings were produced by merging them with the baseline review studies. All data analyses will be conducted using the procedures used for the baseline review. Conclusions and recommendations are revised to reflect the addition of new studies.In addition, the search methods will be reviewed annually, or sooner if substantial changes occur that impact the search methodology, such as new search terms or sources. Possible changes to the frequency of the searches will be considered. We will verify that the scope of the review  is reflected in the inclusion of adequate thesaurus terms or changes to database search syntax. Other methodological aspects such as the use of technology enablers will also be reviewed annually.long COVID. No studies in this area have been retrieved from the initial search.One addition to the scope of this review has been made for the COVID-19 pandemic. As tobacco smoking may be a risk factor for more severe COVID-19 disease outcomes, we will include in the reviews any clinical studies on the impact of ENDS substitution for smoking on patients with COVID-19, particularly with regard to The review will be transitioned out of living mode if the research question no longer meets all the 3 criteria justifying the living approach. At that time, we will examine article-level metrics, knowledge translation activities, and the output of new research studies. A practical factor that could result in the end of the living mode is reaching the end of our funding in September 2023. After this period, new funding will be sought to maintain the living mode. If funding is not acquired, we will ask if at least two members of the review team are available as volunteers for 1 year of updates, followed by a final revision of the review. If both of these strategies fail, the review will be transitioned into a traditional systematic review for final publication at the end of the project.The goal of these reviews is to assemble all the available human studies on the respiratory and cardiovascular effects of ENDS in people who smoke. Furthermore, the reviews will assess the quality and potential biases of the studies to foreground the best available evidence. The reviews will identify those studies that demonstrate reporting bias so that the misrepresentation of ENDS health effects can be addressed in the contentious debate around tobacco harm reduction. The living systematic review methodology will keep the evidence current and complete as opposed to a static systematic review that quickly becomes out-of-date due to the rapid pace of publication of ENDS studies.As of March 11, 2021, the literature search has been completed except for the review of the study selection by experts, with 27 studies included in the cardiovascular outcomes review and 19 studies in the respiratory outcomes review. Training on data extraction, quality assessment, and bias assessment processes has been completed. The data extraction process has commenced. The target date for the completion of the reviews is July 2021.Journal of Medical Internet Research Protocols. The baseline and updated reviews will be published in a peer-reviewed journal that agrees to work with the living format for updated editions of the review. The abstracts for the reviews will be translated into as many languages as possible. Announcements of these publications will be sent out on social media platforms .Few protocols contain substantive planning for dissemination or knowledge translation activities beyond the publication of the review in a peer-reviewed journal and conference presentations. Of course, the reviews will be disseminated through these traditional avenues. This protocol has been published as a preprint on medRxiv. Pending acceptance, the project protocol will be published in the In addition, we will write white papers to make the findings of the reviews accessible to clinicians and current or potential ENDS users. The reviews and white papers will be made available for downloading on a dedicated website. The reviews and white papers will be added as references to the relevant Wikipedia pages.For clinicians, a white paper will spell out the treatment considerations of ENDS use drawn from both the cardiovascular and respiratory outcomes from the reviews. As most physicians and health care providers hold erroneous beliefs about the health effects of nicotine itself -53, the For current and potential ENDS users, a white paper with infographics will explain the health effects found in the reviews. The public also hold misperceptions about the health effects of nicotine ,54, so tOur goal with these actions is to achieve a wide dissemination of the findings of the reviews to a wide audience. Standard review publication practices would fail to reach the stakeholders who will benefit from having the evidence presented in a format that is accessible and readily understood.The terrible toll of death and disease from cigarette smoking calls for every effort to stem the tobacco epidemic. The substitution of ENDS for cigarettes is one way to potentially reduce the risks associated with smoking. Clinicians and their patients who smoke need to understand the benefits of substituting ENDS for cigarettes. They also need to be aware of the risks because “research toward uncovering the risks of e-cigarette use is aligned with optimizing harm reduction” . Our liv


Toxoplasma gondii. In this mSphere of Influence article, she reflects on how two papers from the laboratory of Maria Mota, “Host-mediated regulation of superinfection in malaria” by Portugal et al.  and “Nutrient sensing modulates malaria parasite virulence” by Mancio-Silva et al. , made an impact on her understanding of host-pathogen interactions by examining the complex interplay between parasites and their hosts’ nutritional status.Clare Harding works on the metal biology of the parasite  Early in our careers as scientists, we are frequently presented with a simplistic narrative: a pathogen invades, and our immune system fights back. Both parties use the various weapons at their disposal—toxins or specialized killer cells—and, in the end, one army is victorious. However, this story can miss many of the most interesting interactions between the host and the parasite. Armies march on their stomachs, and the same is true for invading microbes: pathogens must acquire sustenance from their hosts to ensure replication and onward transmission. However, both the host and the pathogen are capable of manipulating the availability of nutrients to their advantage. The host can sequester or redistribute nutrients away from the invaders, and pathogens have developed intricate mechanisms to sense and subvert these nutritional changes. The papers I have chosen here reflect some of the complexity of these interactions. Their context is the deadly infectious disease malaria, a major cause of death worldwide, especially of children. Understanding how the malaria parasite acquires nutrients opens the possibility of breaking these supply lines and starving the parasite, preventing its transmission to new hosts.Plasmodium infections at the same time? Using a mouse model of malaria, Portugal and colleagues  of the host. I like how this study paints the typically antagonistic relationship between the host and parasite in a new, more synergistic light. It is not in the parasite’s best interests to replicate too quickly under these stressful conditions since that may kill the host. Instead, the parasite responds by sensing its environment and slowing down, hoping to survive the downturn and transmit to a more amenable battleground.In the second work, Mancio-Silva et al.  address These papers highlight that in many cases it is against the parasite’s best interests to kill the host too quickly. Instead, the parasite senses and responds to environmental conditions, adjusting both its own behavior and the host status to ensure continued survival and eventual transmission.Plasmodium, see the excellent review by Kumar et al. (The work described here, and in other studies from the Mota group, have deeply affected my view of the interactions between the parasite and the host. Although pathogens must outrun host immunity, often causing damage to the host when they do, they also depend on their hosts in a number of complex ways. I find the interface between pathogen growth, nutrient acquisition, and the status of the host fascinating. The papers here touch on only a few aspects of nutrient sensing. For a recent account of r et al. . However