Obstructive sleep apnea is a potentially dangerous condition with significant risks of comorbidities if left untreated. It represents a cardiovascular risk factor in the general population, and a higher prevalence is observed in patients already suffering from cardiovascular diseases. The gold standard treatment, continuous positive airway pressure, is not always accepted or tolerated. The mandibular advancement device represents an alternative treatment that we propose to implement in our study. The objective here is to first present a brief review of the topic. Due to poor evidence in the field, we propose a pilot study to evaluate the effect of a mandibular advancement device in patients with cardiovascular disease who are not treated for their sleep pathology in order to improve their therapeutic management. Obstructive sleep apnea (OSA) leads to hypoxemia, sleep fragmentation with excessive daytime sleepiness, reduced quality of life, and altered neurocognitive performance . In the The prevalence of OSA in cardiac patients is higher than the prevalence observed in the general population.Several studies have shown that OSA is a cardiovascular (CV) risk factor and is associated with cardiovascular events  . In patiContinuous Positive Airway Pressure (CPAP) is and remains the gold standard therapy for moderate to severe OSA . HoweverHowever, the large trials, including SAVE (Sleep Apnea cardiovascular Endpoints), failed to prove the benefit of CPAP in the reduction of cardiovascular events. Indeed the SAVE study  enrolledResults highlight that CPAP did not prevent cardiovascular events but improved health-related quality of life . HoweverMandibular advancement devices (MAD) have emerged as the leading alternative to CPAP. MAD is a noninvasive and appropriate treatment for patients who are intolerant of CPAP and may be comparable to CPAP in mild disease .Oral appliances (OA) protrude the mandible during sleep to maintain upper airway patency and include a titratable mechanism that allows for a gradual protrusion. Their principle is to increase and stabilize the oropharyngeal and hypopharyngeal airway space by repositioning and maintaining the lower jaw in a forward position during sleep ,19.With MAD, the upper airway occurs in both the lateral and the anteroposterior dimension due to the anterior displacement of the base of the tongue, epiglottis, and soft palate with OA ,20.Various authors propose recommendations to use the MAD in patients with mild to moderate OSA as a therapeutic alternative following a failure or refusal of CPAP for severe OSA. The MAD treatment follows a dental check-up and is carried out by dentists with training in sleep medicine ,22.A number of trials have shown comparable effects of MAD and CPAP in OSA patients with regard to symptoms such as daytime sleepiness. Recently, studies revealed similar beneficial changes in cardiac autonomic function during the day, especially in blood pressure  and reveA randomized controlled trial concluded that CPAP and MAD may have similar effectiveness in reducing the risk of fatal cardiovascular events in patients with severe OSA . SeveralIn 2021, a study by Xu L. et al. found no significant difference in the average hours of use between CPAP and MAD . In 2020CPAP and MAD also demonstrate an effect on other criteria, including daytime sleepiness, quality of life, and blood pressure . MAD is However, there are some contraindications to the placement of MAD, and the patient’s oral condition will determine the feasibility of MAD. Indeed, teeth that are too dilapidated will represent a temporary contraindication to the placement of MAD. If more care is required, the feasibility will then be re-evaluated.The ideal dental conditions for the placement are: healthy, retentive teeth (the orthosis clips onto the teeth), non-mobile, with a healthy periodontal support, all the teeth present or a small number of missing teeth, a mouth opening greater than 35 mm, a mandibular propulsion of at least six mm, an absence of musculo-articular pathology, and an absence of gag reflex.Periodontal disease may increase the risk of cardiovascular disease. Periodontal disease can cause tooth mobility due to loss of bone support and tooth loss, which can even contraindicate the placement of MAD .Periodontal diseases, infectious pathologies of the supporting tissues of the teeth, lead to gingival inflammation, irreversible bone loss, and therefore mobility of the teeth. This pathology is more frequent in cardiac patients and may therefore represent a contraindication to the establishment of MADs.https://www.clinicaltrials.gov (accessed on 17 June 2022) 90 studies appear (85 MAD and OSA).When we searched the keywords “sleep apnea syndromes” and “oral appliance”, currently on Of these 90 studies, only 3 relate more specifically to the cardiovascular field and focus on the influence on the primary prevention of an ischemic stroke, on the effect of atrial fibrillation, and on the impact of MAD on cardiac remodeling. This last study seems to be the most relevant because it is a randomized interventional study.To date, there are no studies on mandibular advancement orthoses and periodontitis, or on other cardiac conditions and sleep apnea, which explains our interest in this subject.The aim of our work is to assess the oral status of patients with OSA at risk of developing heart disease. This oral condition will then make it possible to validate the feasibility of an orthosis in patients who have failed or refused CPAP treatment.We propose a study assessing the management by MAD in a cohort of patients with CVD, proven OSA, and CPAP failure. A first oral examination prior to any inclusion will determine the existence of periodontal disease, given the major correlations between periodontal disease and cardiovascular risk. Indeed, in this population, the prevalence of periodontitis in patients with OSA “was 77–79% depending on the definition used” which is almost 4 times higher than the general adult population ,37. ThisDuring the inclusion phase, a detailed oral examination  and a dedicated complementary exam (panoramic radiograph and teleradiography) will be carried out in order to validate the feasibility of this management by MAD on stabilized periodontal terrain. This study will allow us to determine specific predictive factors for the effectiveness of MAD and identify characteristics of patients who respond well to MAD therapy. In addition, quality of life will be evaluated by self-questionnaires and an analysis of cardiac monitoring parameters . After MAD placement, regular follow-up is necessary two times per year in order to check the oral status of patients and record the occurrence of adverse effects of MAD.This study demonstrates the importance of and may make possible multidisciplinary care  for people with OSA:On the one hand, there is OSA, the diagnosis of which is still a challenge in this population.On the other hand, to show the importance of restoring oral health in this at-risk population for maintaining overall health .The role of the dentist in screening for OSA: he sees a large number of patients every day and plays an important role in screening for this underdiagnosed pathology. A questionnaire given in the waiting room, the questioning at the beginning of the consultation, the exobuccal examination, and the intraoral examination can make it possible to suspect OSA, and thus the practitioner can refer the patient to a specialized doctor.The non-management of OSA following a failure or refusal of CPAP represents a real public health problem because of the potentially serious risks of associated comorbidities.It would be necessary to be able to inform and sensitize the patients to the alternative to CPAP, which is the MAD.The sleep doctor must be able to guide his patients in the event of treatment failure or refusal.-Patient failing to comply with or refuses CPAP-MAD can be proposed as secondary therapy -○good dental condition ,○absence of infectious foci○sufficient number of teeth○no tooth mobility○mouth opening greater than 40 mm○mandibular propulsion of at least 5 mm○no psychiatric illness○no progressive temporomandibular dysfunctions○no significant gag reflexesFeasibility conditions: elements to observe-The sleep doctor informs the patient of the modalities of this therapeutic alternative.-Placement of the MAD and regular follow-up with a dental surgeonReminder/table with items to check:


Cancer represents a very grave and quickly growing public health problem worldwide. Despite the breakthroughs in treatment and early detection of the disease, an increase is projected in the incidence rate and mortality during the next 30 years. Thus, it is important to develop new treatment strategies and diagnostic tools. One alternative is magnetic hyperthermia, a therapeutic approach that has shown promising results, both as monotherapy and in combination with chemo- and radiotherapy. However, there are still certain limitations and questions with respect to the safety of the systemic administration of magnetic nanoparticles. To deal with these issues, magnetoliposomes were conceived as a new generation of liposomes that incorporate superparamagnetic nanoparticles and oncological pharmaceuticals within their structure. They have the advantage of targeted and selective drug delivery to the diseased organs and tissues. Some of them can avoid the immune response of the host. When exposed to a magnetic field of alternating current, magnetoliposomes produce hyperthermia, which acts synergistically with the released drug. The aim of the present review is to describe the most recent advances in the use of magnetoliposomes and point out what research remains to be done for their application to chemo-thermal therapy in cancer patients. Cancer represents a very grave and quickly growing public health problem. It deteriorates the quality of life of patients and is the first cause of mortality worldwide. In 2021, there were 20 million new cases and 10 million cancer-related deaths. The highest incidence in men was for lung, prostate, colorectal, stomach, and liver cancer, and in women for breast, colorectal, lung, cervix, and stomach cancer. The countries with low to median income are disproportionately affected by cancer, and they will carry the burden of 70% of cancer-related deaths by the year 2040, according to the World Health Organization (WHO) and the International Atomic Energy Agency (IAEA) [Chemotherapy is one of the pillars of cancer treatment, as are radiotherapy and surgery. Over 100 agents are currently used as antineoplastic drugs, and many more are still under investigation. Unfortunately, the great majority of these drugs lack specificity towards cancer cells. Consequently, they are toxic not only to tumor tissue but also to healthy tissue and organs, especially those with a rapid rate of proliferation . Moreover, chemotherapy drugs tend to be toxic to organs involved in their metabolism and elimination. The variability in the toxicity of antineoplastic drugs is dependent on their mechanism of action and target.The lack of selectivity of conventional anticancer drugs has limited the maximum allowable dose and thus impeded their capacity to accumulate sufficiently in the target tissue. Many of the adverse effects are associated with their distribution in healthy tissue. Additional problems of importance are the pharmacokinetic profile, biodistribution, and chemical instability of a drug ,3.The physiology of an organism is altered by cancer and other pathological conditions. The altered organism in turn substantially modifies the pharmacokinetics of drugs taken. In the case of neoplasms, solid tumors are similar to an organ in their structure but are more heterogeneous and complex. There is a notable difference in the quantity and composition of the extracellular matrix of a tumor compared to that of healthy tissue . The eleSince drugs reach their target site by the systemic route, the pharmacological response of the tumor is influenced directly or indirectly by the vasculature. The blood vessels of tumors are characterized by a greater dilation and quantity of ramifications as well as a lack of orderly growth. Moreover, these vessels are compressed by tumor cell growth, their vascular endothelium has fenestrations, their basal membrane is discontinuous, and their blood flow is disorganized and variable. All the aforementioned factors increase resistance to blood flow and give rise to an abnormal distribution of blood and consequently of nutrients and oxygen in the tissue of a given tumor. Thus, some regions of tumors commonly present hypoxia, acidity, and a distinct metabolic activity, a microenvironment that leads to a lesser accumulation of therapeutic agents . In respAmong the new breakthroughs in oncological treatment is the use of nanotechnology for the elaboration of liposomal systems as transporters of therapeutic agents . AdditioLiposomes, first described during the 1960s, are defined as spherical vesicles of nanometric size that form when phospholipids or similar amphipathic lipids are hydrated or exposed to an aqueous environment . They arAs systems for the release of drugs, liposomes are often capable of improving the therapeutic index by increasing the concentration of a drug in tumor cells and/or decreasing its toxicity for healthy tissue. Various antineoplastic drugs have been successfully formulated by utilizing liposomes as vectors . The verIt has been shown that liposomes are not completely innocuous even though the components utilized in their elaboration are generally considered non-toxic due to their natural and semisynthetic origin. A variety of adverse effects and immunogenic reactions have been reported after the administration of commercial formulations of liposomes ,14. AddiAs a result of the discontinuous vascular endothelium found in a tumor , liposomes are capable of passively accumulating in a tumor by means of the enhanced permeability and retention (EPR) effect. Also favoring the accumulation and retention of liposomes at this site is the lack of lymphatic drainage in tumor tissue  Once in The pharmacokinetic profile and biodistribution is quite different for drugs encapsulated in liposomes compared to their free form. The encapsulated drugs essentially follow the pharmacokinetics and biodistribution of the vector (the liposome). The pharmacokinetic parameters of liposomes depend on the dose and route of administration as well as their physicochemical properties, including size, surface charge, composition of the phospholipidic bilayer, and the modification of the liposomal surface through the binding of distinct compounds ,19,20,21Conventional liposomes administered intravenously are rapidly recognized by the reticuloendothelial system and removed from circulation, accumulating mainly in organs such as the liver and spleen , thus reOther modifications have been made to liposomes with the aim of generating transport systems with more specific purposes, leading to greater therapeutic efficacy. For example, some function as theragnostic agents (therapy + diagnosis) or combine therapies  .The therapeutic value of elevating the temperature above normal, of a part or the whole body, to the treatment of a disease has been of interest for thousands of years. This concept known as hyperthermia has become an important focus of cancer research since the discovery of the radiosensitizing action of heat two or three decades ago. Around 4000 scientific articles have been published on inducing hyperthermia for the treatment of cancerous tumors.Upon being exposed to elevated temperatures (≥41 °C), cells are irreversibly damaged, especially their proteins. Cell damage caused by thermal shock includes the decomposition of the cytoskeleton, denaturation of cytoplasmic proteins, loss of membrane receptors, and damage to membrane integrity. Cells are reportedly more thermosensitive in the S or M phase of the cell cycle , at acidThe first effect observed with an increase in temperature in tissues is a greater blood flow as a response to dissipating heat. However, the limited possibility of greater blood flow in a tumor hinders the dissipation of heat through this mechanism. As the temperature rises and the exposure time lengthens, edema and vascular lesions may occur . StudiesIn addition to the cytotoxicity detected in preclinical models, hyperthermia at temperatures over 42 °C has generated a reduction in tumor blood flow, thus impeding the arrival of oxygen and nutrients. As a consequence, acidosis and damage to the tumor vasculature were found, resulting in the swelling of the endothelium, flow of plasma fluid to the interstitial space, micro-thrombosis due to the activation of hemostasis, and a change in the viscosity of blood cell membranes. At the same time, no damage was exhibited by the vasculature of normal tissue.Contrarily, tumors treated with moderate hyperthermia  show a greater blood flow and therefore higher levels of oxygen. This can enhance the efficiency of radiotherapy and chemotherapy. The former is more effective with a higher concentration of oxygen, while the latter is more effective with greater blood flow, which increases the probability of the accumulation of a therapeutic agent in a tumor ,29.In vitro studies have demonstrated that hyperthermia and chemotherapy act synergically on tumor cells. Maurici et al. (2022) reported that hyperthermia increases the cytotoxic effect of 5-fluorouracil, gemcitabine, and cisplatin in pancreatic cancer cell lines. There are several mechanisms by which hyperthermia could help increase the cytotoxic effect of antineoplastic agents . MoreoveThe use of hyperthermia as a part of oncology treatment has increased in the last years; however, there is a controversy about its effectivity. Quenet et al. (2021) did not find a significant difference in global survival with the use of hyperthermic intraperitoneal chemotherapy in comparison with the use of cytoreductive surgery only. For that reason, more studies are needed on the use of hyperthermia as an oncology treatment .The principal limitation of clinical hyperthermia has been the design of equipment and methodologies to increase the temperature locally and uniformly in tumor mass without affecting the surrounding healthy tissue. In recent years, much research has focused on resolving this problem in order to improve the efficacy of treatment. The principal hyperthermia techniques were local hyperthermia, regional and entire body .Hyperthermia of the entire body has been accomplished in distinct manners, the main one being the exchange of heat to the body from external sources. This occurs with the use of thermal garments or blankets, immersion in a hot water or wax bath, and perfusion of blood at elevated temperatures. Apart from the high risk of systemic toxicity , a limited and temporal response has been observed in patients .Regional perfusion has been utilized to treat well-localized tumors, particularly in the case of sarcomas and melanoma of the extremities. Intracavitary perfusion has been investigated as well and has found high toxicity . With otTo address this situation, new techniques for generating heat have been developed. One such technique is oncothermia, which involves iron oxide nanoparticles together with a magnetic field. Nanoparticles at a certain dose are focused only on the tumor , and they are activated by a radiofrequency modulated at 13.56 MHz induced between two plan-parallel electric condenser plates embracing the tumor area between two electrodes . The modIron oxide nanoparticles are an attractive material for biomedicine because it is possible to control their size, and the particles are easily manipulated during synthesis . AdditioConsidering their great capacity to interact with biological systems, these nanoparticles are important elements for the transport of drugs to tumors. After loading iron oxide nanoparticles with anticancer drugs, it is possible to conjugate them with antibodies to achieve binding to specific receptors on the surface of tumor cells. The result is a therapy targeted in a controlled manner by an external magnetic field to obtain a substantial accumulation of the therapeutic agent in the target tumor tissue ,40.The heat generated by magnetic nanoparticles in the presence of an alternating magnetic field is focused on tumor tissue. This minimally invasive technique, known as magnetic hyperthermia, aims to locally increase the temperature of tissue. The superparamagnetic nanomaterials are administered to the organism intravenously and targeted to the site of the tumor by means of external magnetic fields. Subsequently, the application of magnetic fields of alternating current make the nanoparticles vibrate and therefore heat is produced . With thDuring the process of reorientation, energy is released mainly through the processes of Néel relaxation (reorientation of the magnetic moment) and Brown relaxation (rotation of the nanoparticles) ,42. The To generate the necessary magnetic field to increase and control the temperature during the hyperthermia with nanoparticles, there are commercial heat inducers , such as3O4/PNIPAM/5-Fu@mSiO2-CHI/R6G) [Among the formulations that have been elaborated with iron oxide magnetic nanoparticles are those conjugated with the peptide CREKA and coated with dextran , and a tCHI/R6G) . In the CHI/R6G)  or prostCHI/R6G) .3O4) and maghemite (γ-Fe2O3), are among the most common nanomaterials used to promote hyperthermia through magnetism. They have both been investigated in relation to biomedical applications for diagnostic purposes, serving as contrast agents for magnetic resonance imaging (MRI) [Two iron oxide nanoparticles, magnetite (Feng (MRI) ,51. One ng (MRI) .Iron oxide nanoparticles (IONPs) are the only nanomaterial approved by the FDA for clinical use. They have low toxicity and are highly biodegradable and biocompatible. These nanoparticles are relatively unstable with low solubility and bioavailability and a strong tendency to aggregate. Additionally, their magnetism is lost to oxidation. Thus, they need to be functionalized, meaning that functional groups with hydrophilic ligands must be added to allow them to be stabilized and transported through the blood without aggregating, disassociating, opsonizing, losing magnetism, or entering into chemical reactions capable of changing their structure and properties. Therefore, iron oxide nanoparticles are coated with polymeric matrices.Thermosensitive coatings made of nanoparticles have been coupled to drugs, in which case the coatings serve as vectors to target the drugs to tumor cells. This leads to a maximum drug concentration in tumor tissue and a minimum of adverse effects. The hyperthermia generated by these nanoparticles upon exposure to an alternating magnetic field causes death exclusively to cancer cells .Iron oxide nanoparticles are classified as superparamagnetic or ferromagnetic in accordance with their size. The most commonly used in nanomedicine are superparamagnetic nanoparticles, with a diameter of 10–20 nm. They have been employed as contrast agents for MRI studies and as transporters for the controlled release of drugs to tumors. In the latter role, it has been possible to functionalize them with different coatings, including polyacrylic acid , dextranIron oxide nanoparticles (IOPNs) are very often synthesized as oleate-coated species to prevent oxidation and loss of magnetism. During loading into liposomes, they are heated at temperatures ranging from 400 to 600 °C and washed to remove the oleate coating and let them to be able for functionalization ,60,61. HThe distribution in organs and the pharmacokinetics of iron oxide nanoparticles depend to a great extent on their physicochemical properties, such as size, morphology, surface charge, and the presence or absence of molecules bound to their surface. These properties are capable of substantially changing the behavior of nanoparticles in the organism. Among other experimental variables that can influence the pharmacokinetics and biodistribution of this type of material are the routes of administration and the variations between animal models and humans.For research on the treatment of cancer, some of the routes of administration most commonly evaluated are intravenous, oral, and intratumoral. The immune system is known to respond rapidly to the presence of free nanoparticles in an attempt to eliminate them from the bloodstream, regardless of the via of administration. The most important mechanism of elimination is the phagocytic activity of cells of the reticuloendothelial system in certain organs, especially the liver and the spleen, where the greatest accumulation of free nanoparticles is found ,66. WhenThe circulation half-life of nanoparticles varies from a few minutes to various days, depending on their coating. The instability of the size of nanoparticles caused by their aggregation also plays an important role in their rate of clearance from the organism. If nanoparticles have a sufficiently small size (<10 nm), they can be rapidly eliminated in the kidney by filtration . The mec50) of up to 300–600 mg/kg of body weight has been found. For particles stabilized with biocompatible molecules as dextran, the LD50 has reached 2000–6000 mg/kg [Iron oxide nanoparticles are generally considered as safe, biocompatible, and nontoxic. For particles without any coating, a lethal dose (LD00 mg/kg . HoweverThe majority of synthesized magnetic nanoparticles exert toxicity by means of the production of reactive oxygen species (ROS), which varies in accordance with their physicochemical properties . Moreove® being the first approved therapy in Europe based on iron nanoparticles for the treatment of brain tumors [In the last years, the use of iron oxide nanoparticles has recently been extensively studied both in vitro and in vivo in different types of cancer, as well as in clinical trials, with NanoThermn tumors . A clinin tumors .The few magnetic nanoparticle formulations approved for clinical use have demonstrated a safe toxicological profile in patients ,76. It iGiven the advantages of the use of liposomes and magnetic nanoparticles in cancer therapy, we can expect that the combination of both could be more effective in cancer treatment. Considering the advantages of liposomes such as biocompatibility, reduced toxicity, biodistribution and stability, this system could be used as a coating for magnetic nanoparticles.Liposomes capable of incorporating magnetic nanoparticles have colloidal structures, which are formed when IOPNs are surrounded by a bilayer of phospholipids. These structures, denominated magnetoliposomes, were described for the first time in the 1980s by Kiwada et al. (1986) , and sinIn the first type (classic) of magnetoliposomes, a center of iron oxide of ∼15 nm in diameter is surrounded by a lipid bilayer. These do not have an aqueous internal cavity, given that this site is occupied only by iron oxide. The second type of magnetoliposomes, developed later, are unilamellar vesicles with a diameter of 100–500 nm. They have many magnetic particles from 1–10 nm in their central aqueous cavity. Usually prepared for extrusion, they are defined as extruded magnetoliposomes. Their principal advantages include the facile modulation of their size and their capacity to contain hydrophilic molecules in the central aqueous space .The ferromagnetic nanoparticles of iron oxide used in the fabrication of magnetoliposomes have a diameter under 50 nm and should be coated with peptides or other molecules to avoid their aggregation and obtain stable aqueous suspensions. Because they have a relatively small magnetic dipole capable of conferring superparamagnetism, they are designated ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs). When an external alternating magnetic field is applied and then removed, they do not present any remnant magnetism, which constitutes their main characteristic. Consequently, it is not necessary to demagnetize them.Magnetoliposomes can be modified to bind to immunoglobins G and E and utilized in the diagnosis of hypersensitive reactions in patients with respiratory allergies. They are often used as contrast agents in MRIs due to their capacity to darken the low-intensity regions in the field of interest, thus providing an improved delimitation of the tissues or cells in the image. It is possible to carry out this type of study with classic and extruded magnetoliposomes.In the field of drug transport, magnetoliposomes have excellent biocompatibility and amphiphilic properties and are easily manipulated to attain the desired variation in size. To increase specificity, they are elaborated with antibodies against ligands expressed on the surface of target cells, such as antigens in renal carcinoma, that are not expressed on healthy cells. To prolong circulation in the blood and avoid the reticuloendothelial system, magnetoliposomes are prepared with PEG chains coupled to the surface to prevent opsonization and elimination by macrophages, making them a type of stealth liposome. Extruded magnetoliposomes are preferable for transporting polar drugs, which can be easily encapsulated in their aqueous cavity. Because the classic form of magnetoliposomes does not have an aqueous cavity, drugs require pre-hydrophobization before being encapsulated.As drug transport systems, one of the advantages of magnetoliposomes is their capacity to accumulate in tissues, both passively and by the guidance of external magnetic fields to the target site. In 2006, Fortin-Ripoche et al. loaded liposomes with nanocrystals of maghemite and magnetically targeted them to xenografts of prostate cancer developed in nude mice. They then assessed the accumulation of the liposomes through MRI studies. The authors found a 7–8 fold increase in the accumulation of liposomes with, versus without, magnets placed on the skin of the tumors . In 2009In recent years, the pharmacokinetics and biodistribution of liposomes and magnetoliposomes have been studied, since the pharmacokinetic profile is necessary to predict the effectiveness of these formulations . EarlierThe third use of magnetoliposomes is to combine chemotherapy treatment with magnetic hyperthermia. Synergism is known to exist between hyperthermia and the conventional treatments of chemotherapy and radiotherapy ,85 FigurAnother application of magnetoliposomes is in the controlled release of the encapsulated agents. In these cases, hydrophobic nanoparticles are generally employed, being embedded in the phospholipid bilayer of the liposomes. Diverse polymers are coupled to the nanoparticles to make them thermosensitive. As a consequence, they break open at a certain temperature and release the encapsulated drug. The drugs encapsulated in magnetoliposomes can also be released by utilizing magnetic fields of alternating current that create heat and cause the magnetic nanoparticles to modify the permeability of the lipid membrane in such a manner that a greater amount of the drug passes through it . In the To date, diverse formulations of magnetoliposomes loaded with antineoplastic drugs have been developed and evaluated in preclinical tests. Cardoso et al. (2022) elaborated a magnetic nanosystem loaded with doxorubicin, finding an enhanced release of the drug in conditions of hyperthermia and in an acidic environment . Hence, 3O4 magnetic thermosensitive liposomes in combination with an alternating magnetic field for heating could achieve a synergistic anti-tumor effect of chemotherapy and heat treatment [In 2010, a formulation of thermosensitive magnetoliposomes loaded with doxorubicin and targeted to folate receptors was prepared by Pradhan et al. (2010). It was examined in vitro in HeLa (cervix cancer) and KB cells in the presence of a fixed magnetic field (a magnet), exhibiting a greater uptake of doxorubicin in cells compared to that found with non-magnetic liposomes. Magnetic hyperthermia reached temperatures of 42–43 °C and was synergistic with the formulation in producing cytotoxicity . In the reatment ,97.Another formulation of magnetoliposomes loaded with curcumin was elaborated and evaluated by Hardiansyah et al. (2017). The authors quantified the capacity of the liposomes to release the drug and the efficiency of the treatment in combination with chemotherapy and hyperthermia. Hyperthermia was induced by a magnetic field. The results showed a significant increase in the release of the drug when the formulation reached 45 °C and synergism between hyperthermia and the drug in producing cytotoxicity on MCF-7 cells .During the last decade various preclinical tests and clinical trials have demonstrated that hyperthermia in combination with cisplatin and other platinum analogs can have a synergistic effect ,101,102.Using a target for cancer cell receptors in magnetoliposomes is a strategy that has been studied. Cintra et al. (2022) reported that folate-target magnetoliposomes loaded with doxorubicin were more cytotoxic for folate receptor overexpression cells . In receGreat progress has been made in the use of nanotechnology to elaborate magnetoliposomes as systems of transport and release of oncological agents. However, there is still work to be done to make these advances materialize into more effective anticancer treatments. Future studies are necessary to design new and better magnetic nanoparticles that assure heating efficiencies, in specific areas of tumors or deeper tumors, under the application of alternating magnetic fields. Furthermore, novel technologies and materials for thermosensitive magnetoliposomes must be developed to achieve a good magnetic targeting effect, that stimulates heat and thus guarantees a better on-demand drug release and their internalization into tumor cells, reducing drug distribution in normal tissue.The application of two or more drugs is a common practice used in cancer treatment to achieve synergistic effects. However, adverse effects may also be potentiated in these patients; therefore, the development of magnetoliposomes that combine magnetic hyperthermia with two or more anticancer drugs will represent an important advance for the benefit of cancer patients by increasing the efficacy of oncological drugs and reducing their adverse effects.Another area of interest in the topic of magnetoliposomes is their diagnostic application, through functionalization with some radiopharmaceuticals, which must continue to be explored to improve magnetic resonance imaging techniques or to develop new diagnostic methods.Given the implications that the use of magnetoliposomes will have on health, it is important to support the safety and efficacy of these systems through pharmacokinetic and bioavailability studies. To date, the scarcity of information on preclinical pharmacokinetics indicates the need for future research that guarantees an increase in the circulation time of magnetoliposomes in the organism, in addition to ensuring their interactions with tumor cells, leading to significant improvements in the clinical outcome.


One specific type of bacteria, Bifidobacterium longum subsp. infantis, (B. infantis) is uniquely equipped with a repertoire of genes encoding enzymes capable of taking up, hydrolyzing and metabolizing the complex glycans of human milk. This combination of a distinct food supply and unique genetic capability shapes the composition and metabolic products of the entire microbial community within the lower intestine of breast fed infants. The intestinal microbiome dominated by B. infantis, shields the infant from the growth of gram negative enteropathogens and their endotoxins as a clear health benefit. The world is facing unprecedented challenges to produce a food supply that is both nourishing, safe and sustainable. Scientists need to guide the future of agriculture and food in response to these 21st century challenges. Lactation provides an inspiring model of what that future research strategy could be.The origin of lactation and the composition, structures and functions of milk's biopolymers highlight the Darwinian pressure on lactation as a complete, nourishing and protective diet. Lactation, under the driving pressure to be a sustainable bioreactor, was under selection pressure of its biopolymers with diverse functions acting from the mammary gland through the digestive system of the infant. For example, milk is extensively glycosylated and the glycan structures and their functions are now emerging. Milk contains free oligosaccharides; complex polymers of sugars whose stereospecific linkages are not matched by glycosidic enzymes within the mammalian infant gut. These glycan polymers reach the lower intestine undigested. In this microbe-rich environment, bacteria compete to release and ferment the sugars  The world is facing an urgent challenge: transform the existing agriculture and food enterprise into a sustainable, nourishing and health-promoting system. A daunting problem is the lack of knowledge of what we should eat. While necessary, obtaining all of the essential nutrients is not sufficient to health. The tools are emerging to measure diet as a complex ensemble of biomolecules at specific concentrations , 2. WhatAs the life sciences advance with powerful new tools of biology and genomics, of big data and artificial intelligence, we are faced with many challenges, from demographics to emerging pathogens. Ideally, a goal of health is prevention. The aim is to understand biology: how to intervene pro-actively, build individual defenses and protections that prevent the development of disease. Prevention is challenging. Interventions must act on healthy individuals. There is not the simplifying focus of disease diagnostics, there is no disease to diagnose. What targets improve performance, while protecting and preventing diseases in healthy individuals? The cost-benefit ratio is different. If one is suffering from a disease, then the costs of reversing that disease are tangible, quantifiable and specific. The risk of side effects of disease therapeutics can be evaluated within a context. What costs are justified to prevent a disease that one is never going to get? Even more profoundly, an intervention that lowers the risk of one disease but increases the risk of another is a hollow prevention. What scientific strategy would allow investigators to understand how to improve the health of healthy individuals, to act on preventing all diseases and to do so without putting any individuals at risk?via diet, milk. The combination of cost to the mother and advantage to the infant has yielded the rosetta stone for scientific discovery of nourishment, and of the entire principle of diet. Milk nourishes healthy infants, guides their development, protects them from biological and chemical threats and equips them for the complex environments that they will face, life long. This article describes the implementation of a research strategy based around lactation as a scientific focus.The biological history of mammalian lactation is a process of evolutionary selection of the output of that tissue: milk, sculpted by infant survival and long term genetic success. Mammalian mothers literally dissolve themselves to make a complete and comprehensive diet for their infants. From the earliest pre-mammals, secreting fluids from a hyperactive sweat gland , generatA basic strategy to study milk is summarized in The tools to understand lactation are from genomics to physiology. Whole genome sequencing provides the basic knowledge set. The challenge is to identify and annotate genes associated with lactation. The goals for lactation genomics were propelled by a diverse group of scientists participating with the International Milk Genomics Consortium . The divMilk is a challenge for analytical chemistry. From small molecules to entire cells, milk is a cornucopia of biomolecules varying in size and concentration by orders of magnitude. All the essential nutrients are in milk, each present within a matrix that enhances their bioavailability and controls their chemical reactivity. These matrices that enhance bioavailability impede the characterization of the molecules analytically. Every class of biopolymer is present in milk, all the substrates and intermediates in their synthesis. Milk oligosaccharides were typical. Entire methodological platforms had to be developed for this one biopolymer class alone . OligosaThe scientific investigations to discover biological actions of milk require that the components be available as purified research materials in quantities and purities maintained in their native conformations for the multiple assays by which investigators address their hypotheses. Also, human milk is a rare and valuable material and simply accessing milk as research material is and should be a process of regulatory, safety and ethical formalities. Combinations of traditional separation technologies and bioguided separations were needed . StrategThe evolutionary history of mammalian lactation is remarkable across all of biology. Once begun, the complex interplay between the composition of epithelial secretions and the success of offspring set in motion a Darwinian engine of diet for protection and nourishment of the mother-infant dyad . The chaGlycans are abundant across the tree of life and the most abundant biopolymer in the biosphere . DespiteThe oligosaccharides of human milk have been attractive to scientists because they are free, abundant (1-2% w/v) and yet indigestible by the neonate. They are perplexing to annotate: why would mothers “dissolve themselves” to produce these biopolymers in such abundance? The scientific challenges posed by this apparent paradox propelled laboratories to pursue the analytical platforms to identify and annotate them .Bifidobacterium  only Bifidobacterium and Bacteriodes species grew to high cell densities yet, growth was strain specific (B. bifidum and B. longum subsp. infantis (B. infantis) strains. In these same growth conditions even isolates of B. longum subsp. longum and B. breve showed poor growth and strains of B. adolescentis, and B. animales were unable to grow on HMO  have the unintended consequence of preventing the transfer of commensal organisms as well. The first indications of the outcomes of that environment emerged in studies comparing the explicit inoculation of candidate organisms. Studies used in-vivo administration of B. infantis to premature infants fed either formula or breast milk. Breast milk-fed infants, when supplemented with B. infantis saw increases in fecal bifidobacteria and decreases in γ-Proteobacteria compared with a formula-fed group  University of California, Davis, NIH  and Training postdoc .The authors co-founded the company Evolve Biosystems.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Adolescents are a unique population with significant unmet health needs. They are often excluded from research that may benefit them as they are perceived as vulnerable and needing protection from research participation. For Research Ethics Committees, conflicting positions in statutes, regulations and ethical guidelines about who provides informed consent for adolescent involvement in health research can be a significant barrier to approving adolescent research. For researchers, the requirement for parental/guardian proxy consent or prolonged approval processes may potentially result in the exclusion of those adolescents most vulnerable and at risk, particularly if issues such as gender-based violence, gender identity, sexuality and sexual practices are in question.To describe the challenges to adolescent research and suggest strategies to address these.We consider the legal and ethical framework in South Africa regarding the consenting age for adolescents in research, outline the challenges and, using examples of best practices, suggest strategies to address the current conundrum.We suggest three principles to guide Research Ethics Committees on their approach to reviewing health research involving adolescents. Strategies to develop ethically acceptable approaches to adolescent research and consent processes are described, which include community involvement. We elaborate on examples of nuanced approaches to adolescent research.The inclusion of adolescents in research is critical in informing appropriate and effective health services for this vulnerable population, whilst providing an opportunity to link them into care and services where relevant. It is a time of heightened vulnerability as choices about future, friendship, sexuality, gender identity, and substance use are negotiated. With an evolving capacity to make sound decisions and participate in promoting their own welfare, the needs and vulnerabilities of pre- and early (10–13-years-old), middle (14–16-years-old) and late adolescents (17–19-years-old) vary.3Adolescence, defined by the World Health Organization and Statistics South Africa as those 10–19 years old, is a transitional stage from child- to adulthood.4 The vulnerabilities and needs of adolescents and adolescent girls, in particular, often remain unaddressed. Large numbers of unsafe abortions and a high risk of pregnancy-related mortality occur, with 11% of the global births in girls occurring before their 18th birthday.7 Health services for adolescents are increasingly recognised as a priority in low- and middle-income countries,8 as it is during adolescence that the foundations for adult health and well-being are laid, underpinning the health and well-being of subsequent generations.Globally 1.2 billion adolescents make up 16% of the world’s population, with 90% living in developing countries, where they make up 23% of the population.10The unique health needs of adolescents are seldom addressed, a situation which is further exacerbated by their exclusion from research. Exclusions may occur as adolescents require a different and unique approach to that of adults, perceived to be vulnerable, needing protection from possible risks of research involvement, and perceived to be incapable of autonomous consenting with good understanding. Ironically, although ethical considerations regarding adolescent involvement should be a balancing act between protection from research harm and inclusion in research that may bring benefit, these ethical issues have themselves become a barrier to adolescent inclusion in research. In South Africa, conflicting positions in statutes, regulations, and guidance on who provides informed consent for adolescent involvement in health-related research has become a significant challenge and consequently a barrier. This situation is exacerbated by misunderstandings of adolescents’ cognitive abilities and capacity to provide informed consent, valuing of protection over inclusion, institutional self-protection by Research Ethics Committees (RECs) and antiquated attitudes about adolescents not holding equal rights to adults.10 Moreover, the frequent exclusion of adolescents from research is compromising their health and well-being.12 In this article, we consider the legal and ethical framework in South Africa with regard to the consenting age for adolescents in research. We outline the challenges related to differing requirements of legislation and guidelines and, using examples of best practices, suggest strategies to address the current conundrum.This situation is no longer tenable, as RECs find themselves increasingly in unenviable positions and researchers are frustrated.National Health Act (NHA).13 These norms must be read in conjunction with other pieces of legislation which set standards relating to child and adolescent health. In addition, and overlapping the law, are ethical obligations to health research.Health research is regulated by legal norms set out in the 13 which requires mandatory consent from the parent or guardian. If the minor has the ability to understand, he or she consents (not assents), together with the parents or guardian.13 The significance of a minor’s consent and not assent is borne out by the discussion below which underscores capacity to consent rather than an age-dependent consent framework. There are no permissible exceptions to parental/guardian consent with respect to proxy consent and waiver of consent.Research involving minors is governed by section 71 of the NHA,14: (1) Regulation 4.1 states that research with minors should only take place when adults are not appropriate participants for the research; if the research poses no more than a minimal risk to the minor; if the research poses more than a minimal risk, that it has a direct benefit to the minor; or where the research poses more than minimal risk and has no direct benefit to the minor, it may contribute to generalisable knowledge of the health condition being studied; (2) Regulation 2 establishes the 2015 Department of Health Guidelines on Ethics in Health Research as the mandatory minimum benchmark for health research, thereby recognising the legal force of the Guidelines. It stipulates that health research be undertaken with ‘appropriate consent processes’, but gives no guidance on how the inconsistency in consent approaches for minors’ participation in research in the NHA, Regulations and Department of Health Ethical Guidelines should be addressed.The NHA is complemented by two provisions from the 2014 Regulations that relate to research with human participantsChildren’s Act, in contrast to the NHA, recognises the decision-making autonomy of children as human rights bearers, based on their evolving maturity and mental capacity to participate in decisions that affect them.16 In other words: children, as persons and constitutional rights bearers with an evolving capacity for individual autonomy, have the right to make their own decisions regarding matters that affect them, provided they display sufficient maturity. Examples of context-specific interventions where children’s consent is recognised in the Act include, amongst others, access to contraceptives, medical treatment and HIV testing. Similarly, the Choice on the Termination of Pregnancy Act provides that children do not need parental consent for termination of an early pregnancy.17The Children’s Act does not regulate research involving minors it does not offer direct guidance in resolving the different consent approaches for minors. However, it is counter-intuitive to allow children to independently access services that impact their sexual, general, and mental health, but deny them the opportunity to participate in research which may benefit their health individually and collectively, on grounds of diminished capacity and autonomy.As the mandatory parental or legal guardian consent requirement allowing for REC discretion when the participation of minors is considered.11 They provide that, in specific instances: (1) a parental substitute may be appointed to provide consent; and (2) the minor themselves can consent independently to research participation. For example, for studies about sexual activity or substance abuse it may be ethically justifiable and appropriate for mature minors (e.g. 16 years and older) to independently consent to research participation as the involvement of parents/guardians may potentially result in social harm to the minor or may result in the failure of adolescents to participate because of their fear of disclosure. The guidelines recommend prior engagement with community role players to justify minors’ independent consent and that RECs may grant a waiver of the requirement of written parental permission. In these cases, the process should be carefully documented.The Department of Health Ethical Guidelines state that minors should participate in research only if the research is relevant to them, cannot be achieved without their involvement, and is in their best interests with minimal or negligible risk of harm. These guidelines are to some extent aligned with the NHA on minors’ consent for research, but deviate from the NHA’s As Regulation 2 of the 2014 Regulations has endorsed the Ethical Guidelines as the minimum legal standard for research with human participants, section 71 of the NHA, the 2014 Regulations and the Ethical Guidelines are all legally binding. However, as the legislation and guidelines provide conflicting stipulations with respect to the consent process for research, we suggest four principles to guide RECs on which legal instrument should prevail in reviewing health research involving minors.20 The Constitution endorses the Bill of Rights as the cornerstone of democracy in South Africa and furthermore directs courts to promote the object, purport and spirit of the Bill of Rights.20 Consequently, an interpretation of the NHA, regulations and the Children’s Act should strive to give effect to and promote the aims and values of the Constitution and the Bill of Rights, which in the case of children’s consent would favour an interpretation that acknowledges the evolving decisional autonomy of children. The Children’s Act’s recognition of children’s decisional capacity is more attuned to the Bill of Rights and its interpretation is hence to be preferred above that of the NHA. Secondly, if there is a conflict in the provisions of two statutes dealing with the same subject (e.g. children’s consent), the general rule in South African law is that the later provision should be followed.22 Not only was the Children’s Act promulgated after the NHA, but it gives better effect to children’s rights in general, as well as to their autonomy. Thirdly, since rules of statutory interpretation provide that any conflict between a prevailing act and any of its regulations be resolved in favour of the prevailing act,23 this would technically favour the NHA’s interpretation over the interpretation in its (2014) Regulations. However, as pointed out above, since the NHA’s interpretation is inconsistent with the Constitution and the Bill of Rights with regard to children’s autonomy, the recommended legal position regarding children’s consent to research should be the position captured in the 2015 Guidelines, whose interpretation supports and promotes the autonomy of children. Fourthly, the Constitution mandates the consideration of international law in the interpretation of the Bill of Rights, which includes international agreements such as the United Nations Convention of the Rights of the Child signed by South Africa in 1993, requiring an interpretation of national legislation that is aligned and compliant with international law.24Firstly, where legal provisions on a specific issue may lead to conflicting interpretations, an attempt should be made to harmonise the interpretations in a manner that is aligned with the values enshrined in the Constitution or the Bill of Rights.30The United Nations Convention of the Rights of the Child recognises children as rights holders, draws attention to their protection and provision of rights, the obligation to consider their best interests and their evolving capacities to make sound decisions and participate in promoting their own welfare. Although it does not refer specifically to research, its articles are flexible enough to address participation in research. Numerous other international documents have also addressed the issue of minors and research and the main themes emerging from these documents are: (1) children are people in their own right and have a right to have a say and be heard, including in the context of well-planned, ethical research; (2) involvement of children in any kind of research should take place in partnership with caring, skilled adults who provide appropriate support and guidance; (3) research should focus on understanding and improving children and adolescents’ lives and circumstances; and (4) a participatory approach in which children are included in the research process should be promoted.10 Instead, it proceeds on the basis that children have a fundamental right to benefit from scientific advances and, to fulfil this right, discussion and debate is needed with RECs and researchers on how to do this in an ethical and principled manner.The ongoing legal uncertainty as to whether the NHA imposes a strict mandatory parental consent approach or whether it can be interpreted in a purposive manner to align it with the norms in the Regulations and national Ethical Guidelines remains contentious. This article does not address this issue as authors have written about it elsewhere.The inclusion of adolescents in research is needed to advance their health. The strategies detailed below to develop ethically acceptable approaches to adolescent research and consent practices are illustrated in Reform: Regulatory, policy and ethical guidance reform are needed to facilitate research involving adolescents. A minimum is closer alignment between the legal and ethical requirements.Collaboration between RECs: Research Ethics Committees need to collaborate and work together to promote ethical standards, facilitate decision-making around ethical challenges, and through a consensus derived approach standardise approaches to adolescent research within an enabling framework. The generation of a publicly available ‘ethics repository’ of resources to support all stakeholders in adolescent research would develop this capacity in South Africa.Dialogue and feedback between researchers and RECs: To develop a common understanding, opportunities for feedback and dialogue between researchers and RECs need to be established. This would provide an opportunity to inform RECs of the positive and negative experiences of independent minor consent processes if parental consent is waived. This feedback may be required as part of the approval process to ensure real-time monitoring, accountability, and learning. Additionally, reporting back ongoing research findings and adolescent-informed community stakeholder experiences and recommendations would facilitate the amendment of consent approaches to protect the best interests of adolescent participants in an iterative fashion.Community engagement: This is addressed in the section below and should be operationalised.Adolescent-informed engagement: Adolescent-informed engagement strategies are needed to guide research involving adolescents from different sociocultural backgrounds with divergent views of when parental consent is acceptable or necessary. Consent procedures may need to be tailored to accommodate the diverse needs and preferences of adolescent participants.18 Thirdly, how can both youths and adults be engaged to ensure their input and participation throughout the study process? Trained Community Advisory Boards (CABs) that involve youth/minors may achieve this, but in their absence, can community participation be ensured? Fourthly, standard operating procedure documents for serious health issues need to be developed, detailing referral procedures to support structures, for instance, for minors diagnosed with sexually transmitted infections including HIV and those who become pregnant, together with mandatory reporting procedures for abuse and neglect of minors, and under-age sexual activity. Fifthly, timely and continual dialogue with RECs to protect adolescents whilst facilitating their participation in research.Before embarking on research with minors, researchers need to ensure they are familiar with the complexities of parental consent and how these are addressed in the NHA, subsequent regulations and the Ethical Guidelines. These will provide guidance in addressing the issues that need to be considered . Firstly18 Based on the principle that individuals are interrelated and decisions are made within a social context, the purpose of community engagement is to assess whether parents and the wider community are supportive of minors’ involvement in the research without explicit individual-level parental consent. Community engagement should never be tokenistic or seen as an ancillary component of the research process; it should be authentic, objective and effective. Through the exchange of research ideas and community opinions throughout the research process, new and mutually beneficial connections will develop, benefitting the research agenda.32One of the requirements for independent consent by minors in the Ethical Guidelines is prior engagement with ‘participating community role players’ with tangible evidence of such engagement.34 For adolescent research, stakeholders could potentially include parents, foster parents, guardians, adolescents of the relevant age range including transgender people and sexual minorities, representatives of child-headed households, teachers, principals and social workers. In addition, key decision-makers  may need to be included to facilitate the eventual translation of research findings into policies and practices. Researchers need to be aware of the socio-economic context and power relations which result in competing interests, priorities and structural coercion threatening the legitimacy and ethical conduct of the research.36Community engagement is challenging, as even a definition of community is contentious. Five defining characteristics of communities have been suggested: locus, sharing, joint action, social ties, and diversity; but as communities are increasingly heterogeneous and dispersed, community engagement should involve different strategies and be as inclusive as possible.31 Most guidance is based on a CAB model, where CABs create a forum through which questions, concerns, and community needs can be raised; the feasibility of protocols determined; bidirectional sharing of information to facilitate understanding of the research and the community channelled; culturally acceptable recruitment strategies identified; and, ultimately, research support generated among the broader community. The Tygerberg research Ubuntu-inspired community engagement (TRUCE) model  model  details BOX 1Eight steps for successful community engagement.Identify potential communities through social mapping.Establish the scope of community engagement.Approach communities early.Co-create strategies for community engagement.Acknowledge and respect co-ownership of knowledge.Recruit and engage communities at each stage of research.Evaluate and adapt community engagement strategies.Discuss and disseminate results after the research is completed.Source: Moodley K, Beyer C. Tygerberg research Ubuntu-inspired community engagement model: Integrating community engagement into genomic biobanking. Biopreserv Biobank. 2019;17(6):613–624. https://doi.org/10.1089/bio.2018.0136Research protocols should include a description of community engagement activities, the roles, responsibilities and skills of various parties, training needs, how feedback will be given to the communities, together with innovative ways of involving the community during the dissemination of information, including publications and conference presentations.37One of the first South African studies involving adolescents in HIV vaccine research highlighted requiring parental/guardian consent as a barrier to the enrolment of high-risk adolescents; careful consideration of the consent approach is advisable.38 The design of these approaches is developed in consultation with well-established adult and youth CABs including representative ages, populations and stakeholders’ input, guidance from ethical and legal experts to ensure protective ‘safety nets’ are in place, and open and ongoing communication with RECs. Depending on the study, adolescents are given the option to involve a trusted adult or parent/guardian, and a parental proxy consent form provided. Some examples of these studies, together with the different reasons for waivers of parental consent, are described in The Desmond Tutu HIV Centre has been conducting clinical research with adolescents since 2003 and has developed a nuanced approach to consent, depending on the nature of the study and age of the adolescents participating in the research. A ‘one-size-fits-all’ approach is not possible, and each study requires an individualised, context-specific exercise.43 In addition, a quarter of sexually active adolescent girls contract a curable sexually transmitted infection annually.44In early November 2021, Statistics South Africa released a report on pregnancy in South Africa. There were over 1 million babies born in 2020, of which 34 587 were born to girls ≤ 17 years old and 600 to girls aged 9 and 10. Eighty per cent of HIV infections occurring in adolescents in sub-Saharan Africa occur in girls 15–19 years of age, where the prevalence of HIV in adolescent girls and young women is four times higher than in young men, with one-third screening positive for mental health and substance abuse problems.We as a country are failing to protect our girl children and adolescents and every possible measure must be taken to address this situation as a matter of urgency. Our efforts are more likely to be effective if evidence-based interventions are employed. Firstly, the NHA should be amended to take into consideration the United Nations Convention of the Rights of the Child’s provisos on the rights of children and their evolving capacities to make informed decisions. Secondly, the National Heath Research Ethics Council needs to work together with RECs to standardise approaches to adolescent research to ensure adolescents are not excluded from research that will benefit them. Thirdly, researchers and RECs need to work together so that a more informed position based on the experiences of parental waivers of consent is developed. Essentially, what is required is to balance child protection with the facilitation of ethical child and adolescent research. In the meantime, researchers, communities, and ethics committees must find ways to include adolescents safely and ethically in relevant and justifiable research.By investing in adolescent health, we are investing in the health and productivity of future generations. The inclusion of adolescents in research is critical in informing appropriate and effective health services for this vulnerable population whilst providing an opportunity to link them into care and services where relevant. While it is critically important to acknowledge adults in gatekeeping roles for protecting adolescents from potential harm, it is equally important to respect adolescents’ right to privacy and their evolving capacities to take autonomous responsibility for their health and health decisions.


The increase of centralization developments in primary and secondary care practices may cause the organizational needs to increase as well, as the practices grow in size. This continuous change is observed in different stages in various countries since, from the perspective of a physician, it is reinforced by the benefits it adds to flexible work configuration, professional exchange and specialization. However, in order to benefit from the joint practice system, the proper managerial skills of practice managers are required, as doctors are not naturally prepared to fulfill such tasks. This study thus aims to gain insight into physicians' views in group practices and acquire a greater understanding of expectations towards practice management and the emerging role of practice managers (PM).th and March 17th 2021 by the Association of Statutory Health Insurance Physicians of Baden-Württemberg, Germany. Bivariate and multivariate analyses were applied to characterize the expectations of physicians towards practice management.A cross-sectional study design was employed which utilized an anonymous online questionnaire. In total, 3,456 physicians were invited to participate in the study between February 8The survey yielded 329 replies . 50% of the participating practices already had a PM employed. In general, these practices were larger than practices without a PM. Most physicians (85%) considered a medical background to be essential for the task of a PM. While practices without a PM considered it important for PMs to have medical qualifications, practices with a PM favored qualifications in business administration. 77.2% of physicians preferred to educate and recruit PMs out of their current practice staff. Competence in organizational tasks, such as coordination of tasks and quality management, was considered to be an essential skill of a PM and had the highest agreement levels among those surveyed, followed by staff management of non-physicians, billing, bookkeeping, staff management of physicians and recruiting. Based on multivariate regression analysis, larger practices valued the role of a PM more and were more likely to employ a PM. Notably, the effect that size had on these items was more substantial for generalists than specialists.The benefits and importance of PMs as well as the potential for delegation are recognized, in particular, by larger practices. The positive feelings that physicians who already employ PMs have towards their contribution to ambulatory care are even more significant. Pre-existing medical support staff has been identified to be the most desirable candidates for taking on the role of PM.The online version contains supplementary material available at 10.1186/s12913-022-08199-5. A gradual shift in the structure of medical practice can be observed in several countries, such as the United States of America, Taiwan, Great Britain, Denmark, Italy and Germany. Larger group practices are increasingly replacing solo practices . This deNewly qualified German physicians prefer to work part-time and seek employment over being self-employed. This originates from a desire for more flexibility, fewer organizational tasks, and a focus on work-life balance –6. JointOn the one hand, joint practices offer several synergies , 10: MinThere is no standard definition of a practice manager (PM) in the German healthcare system. The title of PM is not officially regulated and neither are its qualifications. Previous studies comparing the educational possibilities of German PMs identified a proliferated landscape of educational options . GeneralCompetency based frameworks such as the CanMEDS Framework are used worldwide in under- and postgraduate training and included management and organizational topics . In GermAs the core of a physician’s field of expertise will likely remain to be medicine, it can be argued that the role of dedicated PMs will gain more importance. Furthermore, the specialized managerial knowledge of PMs will be required to be adequately prepared for the challenges of larger practices to reap the benefits these practices promise –19. OtheThis research paper aims to explore practice management from the perspective of physicians and identify the desired qualifications, relevant tasks and organizational characteristics for PMs in Germany. Furthermore, by researching the perspectives of physicians, a more complete picture of the evolving role of a PM can be gained in order to develop a more standardized profile for PMs.A cross-sectional study design was employed, which utilized an anonymous online questionnaire with 32 items to ascertain physicians' perspectives as potential employers of PMs. The questionnaire contained closed questions and questions with the option for open-ended answers. The questions focused on the qualifications, backgrounds, and skills of prospective PMs as well as tasks delegated to the role. Additionally, questions were included to find out what the minimum number of physicians and what the rate of patient turnover would have to be in order to justify a PM. Essential demographic characteristics were also collected .The questions built upon the explorative qualitative interviews with physicians, which contained information on potentially relevant practice management topics as well as a PM’s role . The queAfter creating the questionnaire, it was piloted within the Association of Statutory Health Insurance Physicians and the Institute of Family Medicine in Lübeck via a think-aloud process. This process included two general practitioners and four senior staff members in the association . The latter group has gathered a deep understanding of practice managerial aspects through a close exchange with practices regarding organizational procedures, legal aspects, personnel issues, and billing. The questionnaire was amended and selectively altered in tone and focus according to the received feedback.The questionnaire’s target group were physicians in a southwestern federal state of Germany (Baden-Württemberg) located in practices consisting of more than three physicians. Such practices can be characterized as larger organizations within the practice landscape of this area. No specialists were excluded from the survey, since practice management is relevant for all kinds of specialists within the physician population, in addition to the fact that larger-scale practices may have multiple specialists present. Furthermore, all legal forms of cooperation present in German outpatient care were included.th 2021 via e-mail by the Association of Statutory Health Insurance Physicians of Baden-Württemberg, followed by two separate reminders in two-week intervals.The contact information for the questionnaire was sourced from the Association of Statutory Health Insurance Physicians of Baden-Württemberg, of which all physicians in the outpatient care sector must be members. The dataset thus included all physicians in the federal state who met the criteria of working at a practice that consisted of more than three physicians. 4.465 physicians out of about 21.000 that met the criteria. As the questionnaire was distributed via e-mail, the 3.456 physicians who had an e-mail address were selected for the online questionnaire. The initial contact was made on February 8Descriptive statistics were applied to explore the general prevalence of specific qualifications among PMs and indicate tasks delegated to the PM’s role. Frequencies were used for items which scaled nominally, while means and standard deviations were used for numerical discrete variables.Additionally, a comparative analysis of groups within the total sample was conducted in order to explore the differences between physicians who worked in practices which employed a PM and those who worked in practices who did not. We considered practice size, specialty, the physician’s expectations and the general perceptions of the PM role, the desired qualification profile and the relevant tasks of PMs to be significant characteristics. The physicians were split into two groups of generalists and specialists. The generalists’ group included general practitioners and pediatrics , 23. Phy testing .Finally, two multivariate regression analyses were applied to estimate the associations between physicians’ characteristics and perspectives, and (1) the assessment of the importance of a PM for the practice as well as (2) the likelihood, whether a PM was present or not. Since a six-point Likert scale measured the importance, an Ordinal Logistic Regression Model was estimated. In order to estimate the likelihood for the presence of a PM, we applied a Binary Logistic Regression Model. In both models, we specified the number of physicians in a practice, the specialty group , and other covariables  as regression variables. Furthermore, for each regression, an interaction effect between the number of physicians in the practice and the specialty group was specified to analyze whether the latter moderated the effect of the practice size.th March 2021, equating to a response rate of 9.5%. The gender distribution within the survey was almost equal between males and females, with some respondents identifying as non-binary , while practices with an employed PM had fewer concerns. Both groups of practices rated the need for continuous education as necessary, but the practices which had a PM rated it slightly higher. Finally, relatively few concerns about non-medical task delegation were reported, with more favorable views towards PMs held by those working at practices where they were already present.When considering the expected effects of PMs on physicians and their work, 88.1% reported that saving time is essential for a PM’s employment. Physicians with a PM rated the time-saving potential higher than other physicians (93.3% vs. 82.3%). When considering suitable practice managers, 77.2% preferred to educate and recruit PMs out of their current practice staff. The risk of conflict with external PMs was perceived as a slight risk. The practices without a PM present perceived risk more strongly.Table Task coordination and quality management are the organizational tasks which have the highest agreement levels among those questioned. This is followed by staff management  of physicians and non-physicians, billing, bookkeeping and recruiting. Recruiting of non-physicians and staff management of physicians have the lowest agreement levels. Staff management of non-physicians and recruiting of non-physicians are potential tasks for a PM which have stronger agreements in practices with a PM present.In Table The estimated coefficients were very similar across the different models. The gender and the age of the physicians was not associated with either dependent variable. Physicians who believed that a PM had the potential to reduce their workload, evaluated the importance for the practice higher and were also more likely to work in a practice with a PM. Another determining factor for the acceptance of a PM was found to be the task of recruiting non-physicians. Differences between both models could be observed for the following tasks: staff management of non-physicians and bookkeeping. While staff management of non-physicians was positively associated with the importance of a PM, it had no correlation with the likelihood of the presence of a PM. Physicians who regarded bookkeeping as an important task for a PM were less likely to work in a practice with a PM.The results of the estimated practice size effects underlined the previous finding that the bigger the practice size tended to be, the higher that practice rated the importance of a PM. The likelihood for the presence of a PM was also higher in larger practices. Further, both practice size effects were stronger for generalists.This research aims to explore the expectations and perceptions of current group practices concerning practice management from a physicians’ perspective. The analysis identifies PMs’ desired qualifications, relevant tasks, and organizational characteristics. Thereby a more comprehensive picture of the evolving role of a PM can be obtained.Our results show that larger practices rate practice management as more important than smaller ones. Larger practices are also more likely to employ a PM and, thus, share a more robust perception of the importance of a PM. This can be interpreted as a sign of a PM’s positive effect on the personal time and efficiency gains for physicians. Nevertheless, it also emphasizes the need for interpersonal relationship management and managerial tasks in larger practices , 25, 26.Furthermore, our regression results suggest that the likelihood for a PM and its rated importance increases for generalists more strongly with practice size than for specialists. A possible reason could be that the increase in practice sizes might introduce more complexity into the practices of generalists than in the practices of specialists. PMs thus seem more important for generalists if developing into more centralized practices. It is of note that practices, which employed a PM, had a smaller threshold with regards to the number of physicians and non-physician staff that justified the hiring of a PM than practices who did not. Physicians without experience regarding PMs might be overestimating the practice sizes whose management could benefit from a PM. This seems in line with the fact that physicians are primarily educated in medical tasks, not managerial endeavors . There iHowever, larger practices and practices with a PM also prefer business administration and public administration specialists in addition to the medical staff for the role of PM. Having first-hand experience with PMs and their complex tasks may lead to a more positive view of managerial professionals taking on the role. This is in line with findings from the UK, where PMs do not predominantly require a medical background . The potAn international scoping review found that while group practices improve physicians’ quality of life, the higher stress caused by the more complex interpersonal/staff relationships is a disadvantage . In a GeOur results also confirm that larger practices have fewer concerns about delegating non-medical tasks. Therefore, the delegation of operational tasks is central to the PM’s role. The presence of a PM positively affects the willingness to delegate tasks such as the recruitment and staff management of non-physicians. However, the recruitment and management of physicians as well as the bookkeeping are less likely to be delegated. Physicians still want to be personally involved in these critically important tasks. Generally speaking, task delegation requires the delegator and the recipient of the tasks to trust, collaborate and communicate with confidence in each other in order to benefit from the process –33.Overall, the findings highlight that physicians have clear preferences regarding PMs' practical tasks and educational background, thus shaping the emergent role and who fulfills it.Lastly, there are no differences between men and women in the data. This is surprising, as systematic differences in various dimensions between the sexes have been documented previously .There is little quantitative research done into practice management, the role of PM, and opinions towards it. Nevertheless, our results give insights into physicians’ perceptions when considering a PM for their practices. Overall, the study has yielded a rather low response rate of 9,5%, amounting to 329 replies. The response rate is within an expected range, considering the target audience . The phyMale and female respondents provided equal representation within the survey, giving confidence to the findings in this regard. The risk of a self-selection bias exists, with maybe only those who are already interested in the subject participating in the survey. Furthermore, practices without e-mail were not able to attend the survey. Moreover, employers and employees were both included as participants. Therefore, it is not possible to separate the specific employer perspective in this regard. However, it can be assumed that regardless of their respective status, both groups of physicians would have experiences and opinions on the topic as a result of working in larger practices.Lastly, there is the matter of considering internists to belong to the group of specialists. In 2020, 1929 (53%) of the 3609 internists have been practicing as primary care physicians in the federal state Baden-Württemberg . HoweverIt might be rewarding to contrast the expectations physicians have of PMs with the curriculum of the institutions which are offering practice management qualifications. Another critical factor is understanding the effects of a PM on cost-effectivity and the monetary benefits of delegation in group practices. Finally, it would be of interest to quantify the possible model of cost reduction within the healthcare system due to the employment of PMs on a larger scale.Centralization developments offer physicians a more flexible work configuration, professional exchange, and specialization in ambulatory care practices. At the same time, the increased organizational needs of larger practices necessitate the establishment of practice management routines. The physicians surveyed in this study recognized the benefits of employing a PM. As a result, PMs’ acceptance is higher and the presence of PMs is more frequent in larger practices than in smaller ones. The task delegation is also more prevalent in practices with a PM. Physicians, however, are hesitant to delegate critical tasks such as the billing and management of the physician staff. Regardless, specialized education is required to enable medical or administrative staff to take on management tasks and alleviate operational and interpersonal pressure from physicians. The purpose of a PM is, after all, to realize managerial potential and alleviate tasks from physicians.Additional file 1. Translated_Questionnaire. The original German version of the questionnaire was used to identify desired qualifications, tasks, and organizational characteristics of practice managers as part of the cross-sectional survey among group practice physicians in Germany.


The global need for energy has grown in tandem with mankind’s development and spread. This has resulted in an increase in the use of fossil energy sources, a decline in these sources and an increase in pollution, necessitating the search for renewable energy sources. One of the important ways to reduce pollution resulting from the increasing consumption of fossil energy is to enhance the sources of solar energy, of which photovoltaic cells (PV) are one of its most important tools. Therefore, it was necessary to pay attention to improving its efficiency for it to become a promising source of clean energy. PVs turn solar energy into electricity; however, the amount of electricity generated decreases as the temperature of the cells rises in response to the sun’s heat. Cooling of the optical surfaces is one of the most important elements to consider while running solar PV systems to obtain maximum efficiency. The electrical efficiency of PVs is enhanced when suitable cooling technology is used, and the rate of cell breakdown is reduced over time, extending the life of the PV panels. There are many materials used to remove unwanted heat in PV cells, and in recent years, the focus has been on integrating nanomaterials in specific proportions with traditional cooling materials such as water to improve their thermal properties. As a bio-material that is environmentally friendly, renewable, sustainable, inexpensive and has high mechanical properties, cellulose nanocrystals (CNCs) are one of the most promising materials for improving the properties of cooling materials for cooling PV cells and improving their performance. Fossil fuels produce more than 80% of the world’s energy. Combustion residues of these fuels negatively affect the environment by producing acid rain and causing global warming, which increases rapidly with development and increases in the world population because of the increasing demand for energy ,2,3, so This paper summarizes a set of research related to enhancing the efficiency of photovoltaic cells by controlling their temperature by cooling them using different ways and materials, which strengthens their position as a clean and environmentally friendly energy source.PV panels convert solar energy into electricity. However, if the temperature of the cells rises owing to the sun’s temperature, the output of electricity falls. Therefore, different cooling techniques were used for solar cells to control their temperature, as shown in 2.1Improving the generation of clean energy by cooling techniques to reduce environmental effects.2.2Improving solar cell’s low efficiency.2.3The use of cellulose nano-crystal (CNC) nanofluids as a cooling material.In this work, we divide reviews of previous studies according to the reasons that prompted researchers to work on developing the performance of photovoltaic panels as a promising source of energy and a suitable alternative to fossil energy. This review is divided into three areas:It is clear from the total research reviewed in this paper that the percentage of research interested in using nanocellulose in thermal applications, which is shown in Because of the increasing demand for energy and the excessive use of traditional energy sources, this has led to an increase in environmental pollution due to emissions from burning fuels. Cooling solar cells increases their potential to create clean energy and use it as an alternative to traditional polluting energy sources.Researchers provided an in-depth analysis of the design components of a concentrated photovoltaic thermal, heat transfer medium and new application sectors in this paper. The findings show that CPVT systems are a promising system for producing high amounts of clean electrical and thermal energy that are in line with the seven sustainable development goals by using this energy in a variety of thermal applications such as space heating and cooling, desalination, electrical energy generation, greenhouses and so on ,72,73. OIn comparison to alternative kinds of cooling, it was found that the efficiency of the systems in producing energy depends on the type of material used, and all the arrangements proved to be more important solutions for delivering superior thermal and electrical efficiency systems , thus serving as a promising source as an alternative to fossil energy that gives rise to air pollution and an increased earth temperature ,74,75. S2), into the environment more effectively than pure heat pumps by producing more energy. The performance of the integration of the Kalina cycle with CPVT for a multi-generation and hydrogen production system was investigated utilizing air and water as a cooling medium and three distinct mass flow rates. According to the findings of these studies, electricity, hydrogen and hot air production were increased. These kinds of systems would be used to minimize pollution in the environment because the emissions will decrease significantly [Researchers ,81,82 loficantly ,84.The steady increase in population numbers and the need to address the problem of food insecurity in some countries made some researchers search for quick, effective and environmentally friendly ways to dry food, as the drying process consumes energy intensively, and the use of fossil energy in the drying process increases pollution. In these cases, the focus was on improving the performance of solar energy systems to provide the appropriate energy ,86,87. OMore than 50% of the solar radiation falling on PV cells turns into thermal energy rather than electricity . This maSeveral ways for cooling the PV module, such as the PV/T air-heating manifold and water-cooled PV/T, have been introduced and used. The heat transfer process from PV modules should be improved; the operating temperature must be reduced to improve the system’s efficiency. A hybrid PV/T solar system is one method for cooling the PV panels. It consists of a cooling system connected to a solar PV panel, so the hybrid model can be considered as two different mechanisms, one providing electrical energy and the other producing heat , which is used to warm the cooling medium . It was There is a lot of research that has studied the possibility of cooling photovoltaic cells using different materials such as phase change materials (PCM), salts, oils, nanomaterials and metallic materials with different thermal conductivities. In the same line, many researchers have also focused on improving the performance of PV cells by cooling them via traditional methods using air and water. Because air is a less efficient coolant medium than water, water cooling functions at higher temperatures. It allows for more efficient waste heat recovery by utilizing it for household water heating or air conditioning. A coolant is a liquid or gas that is used to lower and regulate the system’s temperature. A good coolant has a high thermal capacity and a low viscosity that is inexpensive, chemically inert, non-toxic and does not corrode the cooling system. In order to benefit from the thermal energy absorbed from the PV panels, they are cooled and heat is extracted from them, which is reflected on their overall efficiency and increases their electrical efficiency, which is negatively affected by heat.Researchers worked to address the effect of the efficiency of photovoltaic cells on temperature by working on cooling them in different ways. Cooling by air was one of the first and simplest methods used, which a group of researchers used in different ways and conditions. The results indicated a modest perspective because thermal air capacity is low, but there are advantages to the use of air, as it is used directly in buildings without heat exchange; the problems of fluid leakage are also not as critical when using air, and the problems of corrosion and freezing do not exist ,98,99. AAs seen in So, examination of the performance of photovoltaic cells cooled with nanofluid improves the heat transfer coefficient, PV power and PV efficiency and therefore improves the overall efficiency of the system ,90,113. Some researchers successfully developed tools to increase the performance of solar cells by using concentrated solar energy to obtain the largest amount of solar radiation that can be received from these cells. The increase in solar radiation is accompanied by an increase in temperature, and thus cooling the cells is very important in these cases to avoid damage and a sharp decline in their efficiency. Multi-junction solar cells are also chosen for high concentration ratios due to their good performance at high operating temperatures. The results showed that high sun radiation and the volume flow rate of the cooling fluid have a significant influence on PVT performance, according to the research ,118,119.Nanofluids are the most recent advancement in modern technology for enhancing the performance of engineering equipment and machinery . The nanCNCs have attracted the attention of business and academia due to their unique qualities, which include their cheap cost, renewable resource extraction, minimal toxicity and high mechanical properties. This made some researchers conduct studies to find out the possibility of improving the thermophysical properties of cooling fluids by adding crystal nano cellulose at various concentrations and temperatures to them and using these materials in different applications. The results experimentally and theoretically indicate that thermal conductivity increases as the CNC volume concentration and temperature increase, so CNC is a promising material in industrial, electronic, and thermal applications ,63,64. S2O3/CNC composite nanofluids enhancement improved with the temperature and volume concentration, according to the researchers [Furthermore, nano cellulose and aluminum oxide hybrid nanofluids as a novel coolant for car radiators was examined experimentally by Naiman et al. (2019). The thermal conductivity of the resultant fluid improved significantly, and the thermal conductivity of Alearchers .2O3 and CNC) to the basic fluid of a solar collector and compared their effects on its thermal performance. They came to the conclusion that flat plate solar collectors’ energy gains and thermal efficiency had increased. For (0.5 percent) Al2O3, the greatest efficiency was approximately (2.48 percent), while for (0.5 percent) CNC nanofluids, it was around (8.46%) [Other researchers have been interested in incorporating nanocellulose with other compounds to form nanocomposites and have studied their properties and investigated their performance as a superior heat transfer nanofluid than base fluid coolant at various concentrations and temperatures as depicted in  (8.46%) .From the previous studies, it is clear that the use of PV cells has become one of the best ways to produce clean electric power in recent years and to increase the production of electricity while reducing the cost of solar systems and reducing the area on which the PV panels are installed. Even though interest in renewable energy sources has grown in recent decades, solar energy’s proportion of worldwide energy (power) output remains below 2.5 percent , as showThe temperature of the PV cell rises when the radiation intensity is high, lowering its efficiency and increasing the risk of damage. Therefore, it is necessary to cool these cells by exposing them to a coolant medium (coolant system).After a thorough examination of the subject of PV cells and their evolution over the previous decades, as well as previous studies that looked into different ways to improve the efficiency of PV systems and different methods and materials to cool them so that their temperature does not exceed the required limit, water is one of the best materials used for cooling because of its availability, easy storage, cheapness and the fact that it can be used in relatively high pressures and temperatures and has a high thermal capacity.However, it is possible to work on improving water’s mechanical and thermal properties by adding nanomaterials to it, which will positively affect its performance. This also applies to other cooling materials so that their properties can be improved by adding certain materials to them or merging them with each other. There are many tools and materials used to get rid of unwanted heat in PV cells, and in recent years, the focus has been on integrating nanomaterials in certain proportions with traditional cooling materials such as water to improve their thermal properties. The use of nanomaterials in cooling depends on their availability, price and environmental friendliness. Its efficiency by improving the properties of cooling liquids depends on the size of its components, the volume ratio and its stability in the liquid, in addition to the temperature.Cellulose nanocrystal (CNCs) are one of the promising materials in improving the properties of cooling materials that can be used in PV cells’ cooling, and this is reflected in the performance of it, as this material is considered a bio-material that is environmentally friendly, renewable, sustainable, inexpensive and has high mechanical properties.