Blood cancers are a group of diseases with thus far frequently poor prognosis. Although many new drugs, including target therapies, have been developed in recent years, there is still a need to expand our therapeutic armamentarium to better deal with these diseases. Integrative hematology was conceived as a discipline that enriches the patient’s therapeutic possibilities with the use of supplements, vitamins and a nutritional approach aiming at improving the response to therapies and the clinical outcome. We will analyze the substances that have proved most useful in preclinical and clinical studies in some of the most frequent blood diseases or in those where these studies are more numerous; the importance of the nutritional approach and the role of the intestinal microbiota will also be emphasized. Starting a few years ago, “integrative hematology” has been used to define a multi-systemic approach to blood diseases that differs from integrative oncology . In factAlthough similar in some ways, oncology and hematology are quite different. First of all, hematological cancer has an immune deregulation common to all cancers, but also has an intrinsic alteration of immune function, as neoplastic cells often coincide with those of the immune system. Therefore, acting in an immunological sense is often even more complex and difficult in this case, and it can cause hesitation on the part of the professional for fear of stimulating the pathological counterpart as well.Secondly, there is a prognostic aspect. Some blood cancers have a better prognosis than most solid ones or, in any case, have a chronic course, for example Hodgkin’s lymphoma , forms of indolent non-Hodgkin’s lymphoma  or even some myeloproliferative neoplasms in which the life expectancy is equal to that of a normal individual  .Last but not least, in hematology, some diagnostic tools (such as lymphocyte typing or even simple blood counts) or therapeutic tools such as bone marrow or peripheral stem cell transplantation are used in which the manipulation of the immune system plays a main role and its fragility during treatment is even greater, so much so that a deep knowledge of it cannot be ignored for a good therapeutic strength.In this review, we will address tools that can be used on a scientific basis in addition to conventional therapy, without compromising its effectiveness.We will review the main hematological pathologies from a clinical point of view by analyzing which are the remedies offered by integrative medicine that, in the scientific literature, proved to be valid in specific cases.Unfortunately, in most cases, available data are preclinical, in vitro and on animal models, while there are currently few clinical trials ongoing or concluded that involve the use of these substances in hematological patients.Although discouraging, this is also an incentive, because revisions such as the one that follows are more than necessary to help us identify which one of the available remedies is the most useful and urgent to test in daily clinical practice.In conclusion, the microbiota’s role and the nutritional approach in this patient setting will be examined.Myelodysplastic syndromes (MDS) are a miscellaneous group of diseases characterized by an ineffective myelopoiesis linked to clonal dysplastic aspects of the stem cell and a consequent peripheral pancytopenia, generally not responsive to growth factors and also characterized by transfusion refractoriness. These diseases are far more frequent in the elderly, affecting 1 in 3000 people over 70 years old. They can evolve into acute myeloid leukemia. Treatment with hypomethylating agents such as azacitidine is indicated for high-risk patients. To treat other patients, if eligible, allogeneic stem cell transplantation should be taken into consideration as it is the only potentially curative tool to date .Vitamin K2: Vitamin K2 has been shown to improve cytopenia in this patient setting. By acting on the SXR receptors present on myeloid cells, it stimulates their differentiation (confirmed by an increase in CD11b and CD14); it would also have an antiapoptotic effect on erythroid cells . A multiThese preliminary data were confirmed in a recent meta-analysis .The relationship between vitamin K and hematopoiesis has recently been confirmed by the observation that the use of vitamin K antagonists can compromise the bone marrow microenvironment, possibly with increased MDS risk .Coenzyme Q10 (CoQ10): Some evidence suggests the efficacy of CoQ10, at a dosage of 1200 mg/daily, in causing not only hematological but even cytogenetic remissions .The rationale for using this substance is that plasma CoQ10 concentration decreased in an untreated MDS group compared to controls; this could be related to the mitochondrial dysfunction and systemic inflammation [A more recent study showed, in fact, a significant impairment of mitochondrial respiration in peripheral blood cells in low-risk MDS; the utilization of CoQ10 and carnitine improved not only mitochondrial function but also cytopenia and quality of life .It is currently unclear which patient setting could benefit most from this substance but, given the lack of side effects, we believe it makes sense to use it in all patients with myelodysplastic syndrome, also in consideration of anecdotal data on marked improvement in patients with sideroblastic anemia and mitochondrial myopathy .Eicosapentaenoic acid: Given the finding of high levels of TNF-α and IFN-γ in patients’ serum , it seemVitamin D: Low levels of vitamin D have been associated with some cancers in many observational studies; however, vitamin D deficiency is very common in the general population, so it is difficult to determine what its actual impact is in the potential for the onset of cancer . PardanaFinally, some data seem to show that, even in the absence of a true therapeutic response, the intake of vitamin D contributes, in any case, to a reduction, desirable in these patients, of the progression of acute leukemia, probably due to its differentiating properties .Curcumin: In recent decades, much research has shown that curcumin, a component of Curcuma Longa root, has pleiotropic activity due to its ability to modulate many intracellular signal molecules . Multiple clinical studies in recent years have tested its pharmacokinetics, safety and efficacy in many diseases including neoplastic disease, highlighting safe doses up to 12 g/day .However, there have been few clinical trials in hematological patients. One of these (NCT00247026) aimed precisely at the myelodysplastic patient in order to investigate the effectiveness of this nutraceutical in association with CoQ10.Unfortunately, this study was closed prematurely so the results are not known.From a preclinical point of view, however, there is evidence that curcumin can act as a chemosensitizer and increase the of arsenic trioxide through the downregulation of survivin. Arsenic trioxide actually had not demonstrated great efficacy when used alone in these patients (transient remissions in 20–30% of patients) at the expense of a moderate toxicity. The combination of the two would, therefore, prove to be an effective strategy in targeting myelodysplastic cells but, above all, that share of leukemic stem cells most likely responsible for the chemoresistance in this context of patients with an action, therefore, at an epigenetic level .Melatonin: The regulatory effect of melatonin on blood cell proliferation has been known for many years and, in particular, its ability to increase hemoglobin and platelets in conditions in which cytopenia was also due to different causes . There iWithania Somnifera: The antineoplastic role of withaferin A  has been known for some time, and the first study that documents it dates back to 1958 . LeukemiAcute myeloid leukemia (AML) is the second form of leukemia by incidence; its onset increases with age, being very frequent in the elderly  and rare in children (<10% of cases).It is a clonal disorder of stem cells characterized by impaired proliferation of cells in an early differentiation stage (myeloblasts) and non-maturation of the various lineages with consequent peripheral pancytopenia. Standard treatment consists of induction and consolidation chemotherapy. Allogeneic stem cell transplantation then follows, if the patient is eligible. In older or unfit patients, target therapy (including the use of azacitidine and venetoclax) is the first choice. However, this pathology has a poor prognosis, with an OS of 5 to 21% .Epigallocatechin 3 gallate (EGCG): The antiproliferative effect of EGCG on leukemic blasts has long been known . More reAn important observation is that a marked effect of EGCG is evident on promyelocytic leukemia cell lines  and it sAscorbic acid (AA): The now-outdated discovery that leukemia cells depended on AA for their survival had led to dissuading from the use of this substance . However2O2-mediated apoptosis already at very low doses (<5 mmol), when normal cells are insensitive to this effect even at doses of 20 mM, probably due to a difference in cellular permeability to extracellular H2O2 as well as the characteristic absence of catalase in leukemia cells. The increase in H2O2 could determine glutathione’s oxidation and also increase ROS [Against this controversial background, new studies have concluded that the antitumor effect is expressed through a paradoxical pro-oxidant action against cancer cells, an action opposite to that which occurs in normal cells. AA induces Hease ROS .Another molecule that appears to play a key role in the antiproliferative action of AA is hypoxia-inducible factor 1α (HIF1α), already known to play an important biological role in both myeloid and lymphoid leukemias: HIF1α is actually activated in leukemic cells even in the absence of hypoxia.AA inhibits HIF1α both by increasing its degradation and by inhibiting, through nuclear factor kappa B (NFκB), its transcription and, precisely, the inhibition of this factor seems to play a crucial role in its antileukemic effect. If we also consider that HIF1α regulates the expression of vascular endothelium growth factor (VEGF), we understand how the effect is probably very large and also involves the medullary microenvironment in which the blast cell grows . FinallyThese preclinical data added to the clinical, although still limited, efficacy of AA in some patient settings and a lack of important side effects even at large doses  support Curcumin: The powerful and eclectic antitumor action of curcumin is also confirmed in AML, where its important chemo-sensitizing role is added.Curcumin has also shown good hypomethylating action in myeloid leukemia by means of the downregulation of DNMT1, which results in a reduction in tumor growth in in vivo models . In leukBusulfan (a drug widely used in pre-transplantation stem cell conditioning regimens) also shows little activity against these chemoresistant CD34+ leukemic cells, but curcumin, in the same case, has been shown to increase busulfan-induced apoptosis. This synergistic action could allow a reduction in the required clinical dose of busulfan, with the aim of reducing mortality related to transplant toxicity, as suggested in the conclusion of the study by Weng et al . This isIn line with this approach, the synergy of curcumin with cytarabine leads the authors of this study to suggest that the combination of the two substances would make it possible to reduce the cytotoxicity profile at the same time as the IC50 .Even in an animal model, curcumin administered in the 20 days prior to the injection of etoposide accentuates its action, reducing the number of bone marrow leukemia cells compared to controls, and increasing the percentage of mature granulocytes and erythrocytes compared to the etoposide-only group. This confirms a protective factor this substance provides to healthy cells against the etoposide’s cytotoxic potential .Aloe vera: Traditional medicine attributes many properties to aloe vera (Barbadensis Miller); its leaves are 98–99% water and 1–2% pharmacologically active compounds. It has proved to have immune-stimulating, anti-inflammatory and antioxidant properties . Its antVitamin D: Epidemiological studies have long suggested an anti-neoplastic role of vitamin D, and these observations were confirmed by evidence from tissue cultures and animal models.In hematological diseases, vitamin D is often lower than in healthy controls ; low levIn acute leukemia, there was a significant difference in LFS between patients tested at diagnosis and those tested at the time of relapse: the lower values at diagnosis are, in fact, more predictive of a bad response and an aggressive disease than those performed at recurrence, making vitamin D a potential marker of prognosis in patients with acute myeloid leukemia .Since this is an agent that has showed differentiating and immunomodulatory capacities in the hematopoietic system, it seems it could act at multiple levels and have a beneficial role in guiding the differentiation of leukemia stem cells (LSC), that is to say, the niche of stem cells not sensitive to chemotherapy as they are not in the active phase of proliferation and responsible for relapse. This hypothesis arose from the observation that normal stem cells have a greater number of receptors for vitamin D (VDR) than committed or already differentiated cells. Unfortunately, this does not occur in LSC, where the VDR receptors are lower than those found on normal stem cells. Therefore, vitamin D and its analogues do not appear useful for this purpose, although the epigenetic effect mediated by the acetylation of histones and the hypomethylating effect of some VDR receptor ligands could, in part, contribute to a reduction in the niche of chemoresistant cells .It is interesting to note that vitamin D can enhance the effect of cytarabine, especially in association with carnosic acid (antioxidant extracted from rosemary); the increased apoptosis of leukemic blasts in this experiment is limited to neoplastic cells while the normal bone marrow population is preserved, and this is certainly a considerable aspect .This phenomenon often occurs with the use of so-called “supplements” actually used in integrative medicine, and it is an additional weapon that allows us to use these substances with an added value, which is to enhance the toxic effects of the chemotherapy on neoplastic cells without worsening the toxicity for the whole organism.Withania Somnifera: We have already mentioned this traditional Indian herb, used for centuries in Ayurvedic medicine for its anti-inflammatory, neuroprotective and immune-modulatory properties. In leukemic cells, its antiapoptotic effect has been confirmed: withaferin A triggers early generation of ROS, loss of mitochondrial membrane potential with release of cytochrome c and activation of caspases 3 and 9, simultaneous to activation of the extrinsic pathway, as demonstrated by increased caspase 8 activity . AnotherMelatonin: As already explained with regard to myelodysplastic syndromes, the use of high-dose melatonin (starting from 20 mg daily) has proved useful not only to reduce chemotherapy-induced cytopenia but also that intrinsic to the disease, although the mechanism of action is not clear .In addition to this action, however, melatonin has also immunomodulating and antitumor effects.Cancer patients have lower hormone levels than healthy controls and chemotherapy itself causes a reduction .2O2 on myeloblastic cells, saving the healthy ones and, thus, protecting them from damage from chemotherapy [Melatonin reduces the growth of leukemic myeloid cells through increased mitochondrial release of cytochrome c, activation of caspases 3 and 9 and downregulation of BCL2 . It alsootherapy .It does not interfere with the major chemotherapeutics used in hematology such as cytarabine, daunorubicin and etoposide, even enhancing the effect of the latter . FinallyResveratrol: Resveratrol  is a non-flavonoid phenol, naturally produced by many plants  as a defense against pathogens such as bacteria or fungi.It has antioxidant properties, protects the cardiovascular system and has effects that mimic caloric restriction. Its antitumor effect manifests itself through interference with the mitochondrial respiratory chain and an increase in ROS; actually, the effect is hormetic and the substance can act as a pro-oxidant or anti-oxidant based on the concentrations reached and the type of cell involved. The available data on hematological cancers are sufficient. As regards myeloid leukemia cells, resveratrol induces cell death even in cells resistant to FAS-mediated death, suggesting apoptosis independent of FAS and also of caspase 8. At the same time, a downregulation of BCL2 was highlighted.It also reduces the cardiotoxicity of arsenic trioxide, a drug used in acute promyelocytic leukemia, showing promise for its use in this patient setting .From a clinical point of view, the effect of resveratrol on insulin-like growth factor 1 (IGF1) and its binding protein (IGFBP-3) is very interesting: 40 subjects took the substance for 29 days and the levels of the two plasma molecules dropped in all the volunteers. IGF1 is known to be elevated in several types of cancer. It could be assumed that a supplement acts positively if it reduces this indicator. Indeed, a similar effect from resveratrol is certainly promising .Sulforaphane: Sulforaphane is an isothiocyanate found in plants of the cruciferous family, deriving from the hydrolysis of glucosinolate compounds by the enzyme myrosinase . Epidemiological observations drew attention to this substance, highlighting a reduced incidence of cancer in those who consumed a greater daily quantity of cruciferous vegetables. The action of isothiocyanates is to inhibit phase I enzymes, protect against the formation of DNA adducts and induce detoxification phase II enzymes. The antineoplastic activity seems to be attributable to the modulation of intracellular signals such as MAPkinase and cyclin B1. Moreover, they could also be involved in the inhibition of histone and COX2 acetylation. This action is also confirmed in leukemia cells, where it triggers apoptosis via the FAS and mitochondrial pathways. Additionally, it is capable of inhibiting proliferation under hypoxic conditions and creates an oxidative environment, inducing DNA damage and activation of Bax and p53 . It acceChronic lymphocytic leukemia (CLL) is the most frequent type of leukemia in the Western world, with a maximum incidence peak between 60 and 70 years.Only 15% of patients are younger than 60 years at diagnosis. In 95% of cases, it is characterized by the clonal expansion of a mature B lymphocyte that accumulates in the peripheral blood and lymphoid organs (spleen and lymph nodes), resulting in variable lymphocytosis, splenomegaly and lymphadenopathy. The disease has a very heterogeneous clinical course: the diagnosis is often random and some patients remain symptomatic and stable for years without any therapy, while others develop early symptoms and have a progressive disease. the latter can now often also benefit from chemo-free treatments, such as anti-bcl2 or Bruton kinase inhibitors, which allow an excellent depth of response and a longer PFS to be obtained . Due to Curcumin: In CLL, B lymphocytes show a constitutive activation of NFκB; even in this pathology, therefore, the use of this spice can have a rationale. Some studies confirm that curcumin does, in fact, induce apoptosis in CLL B cells, with an EC50 four times lower than that observed in normal mononuclear cellstheThe simultaneous reduction in NFκB at the nuclear level suggests that the action of turmeric is exerted precisely on this molecule, likely through the inhibition of the phosphorylation of IkB. Curcumin also increases the levels of vincristine-induced apoptosis in these cells .Beyond the preclinical data, it is interesting to underline the presence in the literature of a case report in which complete remission, both hematological and molecular (persistent after 3 years), was obtained, with the use of curcumin and EGCG only  for theiEpigallocatechin 3 gallate (EGCG): In a 9-year cohort study involving 42,000 people, the intake of green tea was shown to be inversely associated with the risk of developing lymphoproliferative neoplasms .The first anecdotal evidence of spontaneous remissions in patients who took this preparation on their own initiative  paved thThe first study demonstrated good tolerance of the substance up to the highest doses (4 g per day), as well as detecting a reduction in lymphocytosis and lymphadenopathy in the majority of patients .The subsequent phase II study with the same extract dosage showed an overall response of 70%, regardless of the patient’s prognostic factors.Although it is not clear whether these satisfactory results will translate into a slowdown in the progression of the disease or a delay in the start of chemotherapy in the future, this is certainly very promising evidence . AlthougAscorbic acid (AA): AA showed in vitro therapeutic activity against CLL B cells at doses clinically achievable by AA oral administration (250 μM), sparing healthy cells and also having a synergistic interaction with approved targeted therapies . AA cytotoxicity involved pro-oxidant damage and caspase-dependent apoptosis .Resveratrol: Resveratrol is able to induce apoptosis in B lymphocytes of CLL patients, sparing normal cells and showing synergy of action in vitro with purine analogues such as fludarabine. The action of resveratrol takes place in these cells due to its paradoxical pro-oxidant effect, as demonstrated by the increase in SOD and DNA damage.These results are greater in patients’ cells with positive prognostic factors or with limited disease, suggesting that this substance may have a more significant role in early-stage or in better-prognosis disease .Vitamin D: The results of the EPIC study do not show an inverse association between levels of vitamin D and lymphoproliferative diseases in general. Nevertheless, the same analysis shows that CLL detaches itself from this trend, and higher levels of vitamin D in the blood are linked to a reduced risk of developing the disease . Low vitThe association of this hormone with a reduced TTT leads us to think that its impact is not only immunoregulatory and differentiating in general terms, but acts precisely on this type of neoplastic cell. Proof of this is the fact that vitamin D receptors are highly expressed on pathological B lymphocytes compared to normal ones, and that pharmacological doses of this substance induce in vitro apoptosis of CLL B lymphocytes through activation of caspases 3 and 9 .An Italian group also analyzed the prevalence of vitamin D deficiency in patients with Binet’s stage A CLL, showing low levels of vitamin D in most cases: about 80% of patients had values below 25 ng/mL, and this correlated with a very short TTT . ClinicaMelatonin: The relationship observed between CLL’s incidence and changes in the circadian rhythm is very interesting. In particular, there seems to be a greater likelihood of developing CLL among workers who work rotating night shifts, particularly after 20 years of work . These dMonoclonal gammopathies are characterized by an abnormal proliferation of plasma cells in the bone marrow with consequent increase in the production of an antibody protein called monoclonal component (MC) consisting of an antibody, more frequently IgG, more rarely IgA or IgM, and a type of light chain, K or λ, mild (<10% medullary plasma cells) in the case of monoclonal gammopathy of uncertain significance (MGUS) or frankly pathological (>10% medullary plasma cells) in the case of multiple myeloma (mM). The disease represents 10% of hematological diseases, second only to non-Hodgkin’s lymphomas. It is more frequent in the elderly, while only 2% of patients are under 40 years of age at the time of diagnosis. In these cases, unfortunately, the disease already shows a more aggressive course. Neoplastic cells produce inflammatory cytokines which, together with the bone marrow expansion itself, are the cause of the osteolytic lesions typical of the disease and bone pain. Other distinguishing symptoms are renal failure  and anemia. Remarkable progress in our understanding of the pathobiology of MM has changed the treatment paradigm. Thanks to new drugs such as proteasome inhibitors, immune-modulators, monoclonal antibodies and CAR T cells, median OS has improved dramatically, and it is currently about 6 years .Curcumin: This substance, whose use is, by now, undoubtedly useful in neoplastic patients, also shows some notable specific effects in MM.First of all, there is the inhibition of NFκB, in addition to what is already used in practice with Bortezomib and other proteasome inhibitors. It testifies to what extent the regulation of this metabolic pathway has given MM an advantage in terms of response.It also downregulates Interleukin 6, the protagonist cytokine in this disease and inhibits osteoclastogenesis by inhibiting RANKL .In in vitro and murine models, it increases chemosensitivity to dexamethasone, doxorubicin and melphalan, and synergizes with the action of bortezomib and thalidomide . It has Two clinical trials published to date have evaluated the efficacy of curcumin in monoclonal gammopathies.k/λ ratio  by 35 and 36%, respectively, as well as the markers of bone resorption [The first study involved 26 patients with MGUS treated with 4 g daily of curcumin, and showed a reduction in the monoclonal component in 50% of patients in whom this was of moderate entity (>2 g/dL), in parallel with a reduction in markers of bone resorption . This vesorption . AlthougA more recent study involved 15 patients, with the aim of verifying the effect of curcumin combined with either an immunomodulatory drug or proteasome inhibitor instead of dexamethasone in patients intolerant to the latter. It was shown that curcumin, 3–4 g daily, may act as a steroid-sparing agent in patients with MM who are intolerant of Dex, with an excellent tolerability profile .Clinical trial number NCT04731844 is still ongoing. It aims to determine whether the supplement of curcumin plus peperine can prevent or delay the progression of prostate cancer, monoclonal gammopathy of unknown significance or low-risk smoldering myeloma into a more aggressive cancer .Sulforaphane: This isothiacyanate deriving from Cruciferae has been shown to have an action similar to Bortezomib in inhibiting the degradation of IkB (the Nkb inhibitor), and, finally, shows synergy with dexamethasone, doxorubicin, bortezomib and melphalan. In animal models, it leads to a reduction in disease burden and an increase in survival .Epigallocatechin 3 gallate: The apoptotic effect of EGCG on MM cells appears to derive from the stimulation of ROS and the reduction in peroxiredoxine levels (antioxidant molecule), as well as a selective interaction with the much higher laminin receptor 1 in patients with MM compared to controls, whose absence cancels out the apoptotic effect of EGCG .The interaction of EGCG with Bortezomib has been studied and is the subject of controversy: in 2009 two contradictory scientific papers were published.The first affirmed the ability of EGCG to antagonize the effect of bortezomib on inhibiting the proteasome in both in vitro and in vivo models, at concentrations also easily obtainable in humans, so as to conclude by dissuading the association of the two substances.Although EGCG is able to inhibit the proteasome, this would not occur in the presence of bortezomib; EGCG inhibition of bortezomib could be explained by its binding to bortezomib’s boronic acid .In the second work, however, this assumption was denied on the basis of the evidence of a synergistic effect between the two substances, attributable to a higher dosage of EGCG and bortezomib used, according to the authors . These dResveratrol: Resveratrol, in addition to inhibiting apoptosis and enhancing the action of Bortezomib, also has a marked antiangiogenic action through the regulation of various factors such as VEGF, matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-9 (MMP9). It also inhibits the constitutive activation of STAT3 and NFκB, overcoming an important mechanism of chemoresistance and, again, synergizing with Bortezomib and Thalidomide . HoweverVitamin D: Even in the case of MM, there seems to be a relationship between this hormone and the probability of the onset of the disease: patients with MM have a greater deficiency of vitamin D and this deficiency appears “alarming” in patients with bone lesions . SpecifiThe already known correlations between low levels of vitamin D, and increased C-reactive protein is also confirmed in patients with MM. Therefore, it is an additional negative prognostic marker. The lower levels are, in fact, also linked to a more advanced stage of diagnosis . BortezoIt has been observed that macrophages associated with myeloma (MAMs) display a defective vitamin D pathway; since vitamin D increases CD38 expression on plasma cells, enhancing binding of CD38-targeting antibodies, the ability of lenalidomide and pomalidomide to restore the vitamin D pathway explains the synergistic effect of lenalidomide and vitamin D in enhancing the efficacy of MAM-mediated cytotoxicity, and poses an important rationale for vitamin D supplementation during therapy with anti-CD38 and immunomodulatory drugs .Interestingly, there may be interference in the immunoassay measurement of 25 (OH)-vitamin D due to paraproteins from MM, so vitamin D levels may appear higher than their actual value.Ascorbic acid: Although AA appears to reduce Bortezomib neurotoxicity by allowing the recovery of damaged Schwann cells , it has Quercetin: Quercetin is a flavonoid present in many vegetables and fruits, with well-known anti-inflammatory and anticancer properties. Its antiproliferative activity has also been demonstrated in some hematological diseases: in multiple myeloma, its action is expressed through various mechanisms that determine the arrest of the cell cycle and the induction of apoptosis, including the downregulation of c-myc expression, upregulation of p21 expression and activation of caspase-3 and caspase-9. One of the main mechanisms of inhibition of MM cell proliferation, the upregulation of PTPRR , has recently been demonstrated . In a xeCannabinoids: Cannabinoids are natural compounds found in the cannabis plant with demonstrated effects in chronic pain and chemotherapy-induced nausea and vomiting . In MM, The role of organic solvents, chemotherapy, ionizing radiations and viruses in the pathogenesis of some hematological neoplasms is clear; the impact of food on the incidence of these diseases is less evident.Even the World Cancer Research Fund has not yet stated a convincing relationship between blood cancers and lifestyle.However, some observations on the metabolic and molecular pathways shared by hematological cancer cells suggest a rationale for recommending the same nutritional guidelines already applied to cancer patients . These rBesides some controversial aspects previously mentioned, it seems appropriate to take into account other features.In hematological patients undergoing chemotherapy, but especially undergoing a transplant procedure, prolonged neutropenia may occur; it is common practice to advise against raw food to avoid the risk of infectious complications.There are no approved guidelines on what patients can eat and what neutropenic patients should avoid while undergoing chemotherapy: the so-called neutropenic diet varies in its composition from one institution to another. What is usually found is the recommendation to avoid raw fruit and vegetables with the aim of reducing the risk of infection. However, this could prevent the important role that these foods can have in providing vitamins and antioxidants, as well as in the reconstitution of a good gut microbiota and an adequate intestinal function, itself impaired by chemotherapy and the lack of fiber in the diet. A recent meta-analysis concluded that a neutropenic diet cannot reduce the risk of infection and mortality in cancer patients with neutropenia .Currently, the most suitable approach seems to be that of paying attention to the handling of food, advising the patient not to consume food prepared in unsafe environments such as fast food restaurants, cafe or buffets, where meals remain exposed for a long time.Another worthy consideration is that these patients often have important mucositis, especially in the context of the transplant procedure. This side effect, in addition to causing discomfort and suffering to the patient, can limit the intake of food with non-negligible consequences, in particular malnutrition, weight loss and the risk of sarcopenia. Sarcopenia is a negative prognostic factor in the hematological patient. In MM, for example, a reduction in muscle mass is not only very frequent, but is a valid predictor of poor prognosis . It is lThe role of the gut microbiota (GM) in contributing to the pathogenesis and progression of many diseases, including cancer, is currently under intense investigation .The impact of GM is also increasingly emerging in blood diseases. More and more studies are concentrating on differences between healthy and sick people in the composition and diversity of GM at diagnosis, as well as the effect of drugs used for therapeutic purposes or preventive antibiotic therapy in causing altered proportions in the dominant microbial species and in the production of metabolites . An imbalance of bacterial populations was observed at diagnosis compared to controls in patients with acute lymphoblastic leukemia (ALL), especially less bacterial diversity . GreaterFurthermore, chemotherapy, together with the important use of preventive antibiotics, profoundly modifies the mucosa and the GM structure. The alpha diversity of pediatric patients with ALL is reduced after induction chemotherapy, although it is not clear whether the major influence is due to the chemotherapy itself or to the type of antibiotic therapy. This change in the GM is also predictive of the risk of infectious complications, a risk particularly associated with the increase in some taxa of the phylum Protebacteria, such as Enterococcaceae and Streptococcaceae ,130. A rOn the other hand, bacteria can influence the effectiveness of chemotherapeutic agents: the antitumor action of platin treatment is radically reduced in germ-free mice, whereas Lactobacillus acidophilus supports the anticancer action of cisplatin ,133. In Even in hematopoietic stem cell transplantation (HSCT), an important and often the only therapeutic weapon in hematological patients, the diversity of the GM has an impact on the outcome as well as on the incidence and severity of graft-versus-host disease (GVHD), while the abundance of some bacterial species such as Blautia proved protective. The depletion of Blautia after 10 days of parenteral nutrition, as well as the consequent alteration of the production of short-chain fatty acids, emphasizes the impact of the type of nutritional support in these patients .GM modifications can contribute to the incidence of infections and pneumonia in HSCT: for instance, patients with Escherichia coli and Klebsiella pneumoniae bloodstream infections show concomitant gut colonization with these bacteria, suggesting that intestinal alteration may be the starting point of septic complications.This knowledge provides the rationale for outlining therapeutic strategies that could consist of the use of probiotics, prebiotics, antibiotics, fecal metabolites, fecal transplantation and a microbiota-oriented nutritional approach. These tools can be useful not only in reducing the risk of infection, GVHD and mortality in hematological patients, but also in mitigating the side effects of therapy such as diarrhea, nausea and chemotherapy-induced vomiting, with the important aim of improving the quality of life of patients.p = 0.009) and a reduction in the use of antimicrobial agents (26.6% versus 53.3) (p = 0.03) [A small prospective study performed by Reyna-Figueroa et al. in patients with ALL and AML aimed to use Lactobacillus Rhamnosus to mitigate the gastrointestinal side effects of chemotherapy. Indeed, patients experienced a reduction in nausea, vomiting and diarrhea (30% versus 63%) ( = 0.03) . Further = 0.03) .Manipulating the composition of the microbiota through procedures such as fecal microbiota transplantation, both as a preventive and therapeutic strategy, could influence the intestinal ecosystem even more with local and distant beneficial consequences such as the restoration of bacterial diversity or the reduction in GVHD. Although intriguing results were produced by case reports, the administration of living microorganisms to immunocompromised patients with altered intestinal permeability is still a matter of debate, and further studies are needed to evaluate the real advantage of this procedure in HSCT recipients ,138. TheButyrate, a fecal metabolite produced through fiber fermentation by GM, has already demonstrated an antiproliferative action on colon cancer cells mediated by the inhibitory action of histone deacetylase. The same mechanism seems to underlie the inhibition of lymphoma proliferation in mice fed a high-fiber diet .In 2019 Planko et al. showed that patients with MM who obtained a negativity of minimal residual disease, an important target for increasing the patient’s PFS, had higher abundance in the stool of Eubacterium hallii, a butyrate-producing bacterium. This finding suggested a link between the composition of the GM and the depth of the response . More reBlood cancers, while accounting for just over 6% of all cancers, are a very heterogeneous and numerous group of diseases, in some cases very different from each other in terms of pathogenesis and clinical behavior.In drafting this review, it was decided to select only a few based on the greater frequency in the adult population (as in the case of chronic lymphocytic leukemia or acute myeloid leukemia), on the limited effectiveness of standard treatments, which calls for the finding of new strategies (myelodysplastic syndromes) or, finally, on the existence of interesting clinical trials (multiple myeloma). A major limitation of integrative hematology is, in fact, the scarcity of clinical studies available and this is a gap that, in our opinion, deserves to be filled. Most of the studies we have and that we collected in this review are in fact preclinical studies: we are well aware of these limitations. Unfortunately, we can consider this a pioneering discipline: we have little consolidated data at our disposal and what we have must, therefore, be known and exploited to the fullest extent to allow us to also progress in clinical research. We know that in vitro studies are not always representative of what happens in vivo, but they are a starting point from which we can take inspiration to look for new ways in the approach to the patient, armed with a good background knowledge of the biochemistry and biology of the carcinogenesis process as well as the pathology’s clinical aspects.In this review, we focused on the anticancer action of the substances studied, but this too is clearly a limitation and we are fully aware. The tumor process is a complex process in which the modulation of the immune system and its interactions with the microenvironment certainly has a key role, in its pathogenesis when dysregulated as well as in its care when well-modulated.This is another aspect to consider in drafting therapeutic proposals.We have identified some substances based on the data available and their use will become highly recommended in daily practice when it is supported by clinical trials.The advantage of using these substances is manifold. First of all, they can be used in stages of disease in which there is not yet an indication for chemotherapy treatment, such as in early stages of chronic lymphocytic leukemia, thanks to their good tolerability and safety. In this way, we would be able to delay the start of a more aggressive therapy as much as possible, with all the benefits that this entails for the patient.Another desirable advantage is given by the synergy of some substances with chemotherapy with the aim of increasing their effectiveness. Additionally, we should consider that many patients use these substances regardless of the scientific evidence, often without informing the hematologist.In this review, we have considered only some of the substances known for their potential antineoplastic effect: here we also had to select, but many other substances are good candidates for evaluation and use in the hematological field. Finally, greater importance should be given to nutritional aspects, in prevention but especially during the disease, to improve GM performance and reduce the risk of sarcopenia.All these observations lead us to consider this first revision work of the literature as just a beginning.Therefore, the same therapeutic proposals that we have drawn up and summarized in


As the world’s population is aging and there is a shortage of sufficient caring manpower, the development of intelligent care robots is a feasible solution. At present, plenty of care robots have been developed, but humanized care robots that can suitably respond to the individual behaviors of elderly people, such as pose, expression, gaze, and speech are generally lacking. To achieve the interaction, the main objectives of this study are: (1) conducting a literature review and analyzing the status quo on the following four core tasks of image and speech recognition technology: human pose recognition, human facial expression recognition, eye gazing recognition, and Chinese speech recognition; (2) proposing improvement strategies for these tasks based on the results of the literature review. The results of the study on these improvement strategies will provide the basis for using human facial expression robots in elderly care. Many developed countries are currently faced with issues brought about by changing population structures as societies age. These issues include significant increases of life expectancy and elderly populations. Statistical data of the global population in 2019 indicated that the average global life expectancy was 72 years in 2019, with 74.2 years for women and 69.8 years for men [As the world’s population is aging and there is shortage of sufficient caring manpower, the development of intelligent care robots is a feasible solution. The development of care robotics around the world has primarily been focused on assistive devices, as well as on providing assistance in social interaction. Examples of these robots include FujiSoft’s PALRO care robot from Japan, which focuses on care support; the NAO robot by France’s Aldebaran, which is a humanoid robot focusing on interaction; the Kirobo Mini, which is a small companion robot developed by Toyota; the PARO developed by Japan’s National Institute of Advanced Industrial Science and Technology, which is a seal-type robot utilized in the care of older people with dementia. Additionally, Pepper is a multi-functional robot capable of emotional expressions, which is produced by Taiwan’s Hon Hai Precision Industry, and Zenbo is a household companion robot developed by Taiwan’s ASUS Corporation. Although a plenty of care robots have been developed, humanized care robots that can suitably respond to the individual behaviors of elderly people, such as pose, expression, gaze, and speech, are generally lacking. In order to implement a humanized care robot, this research has two main objectives: (1) to conduct a literature review and status analysis of the four core tasks of image and speech recognition technology: human pose recognition, face detection, eye gazing recognition and Chinese speech recognition; (2) to propose improved strategies for these tasks. The discovery of these improved strategies will provide the basis for the use of expressive robots in elderly care.This study attempts to realize four core tasks with image and speech recognition technology: human pose recognition, human facial expression recognition, eye gazing recognition, and Chinese speech recognition. These tasks will lay the foundation for creating the functionality of expressive robots in elderly care. What follows is a review of the literature on these four tasks.Body gesture is one of the fundamental skills of a person. The postures of the human body are always changing in daily life, each one representing the appearance state of a person. Real-time interpretation of the significance behind each state could lead to many applications, such as personal safety and behavior prediction. Thus, making human pose recognition is a popular subject of investigation.Traditional methods of image recognition include the least-square method, a globally convergent iterative method, and simplified linear solutions , which aIn recent years, deep-learning architectures such as the convolutional neural network (CNN) and long short-term memory (LSTM) have paid wider attention to, and have been utilized in, developing the recognition capabilities of care robots. Human facial expressions are key to social interaction and form the basis of non-verbal human communication. Taking elderly care as an example, one must learn to communicate and interact with elderly people through eye contact, expressions, and body language. Traditionally, there are two widespread methods for classifying human facial expressions. The first method is based on the Bayesian classifier, which classifies an unknown facial expression based on known data of human facial expressions. For example, the hidden Markov model (HMM)  evolves Our study will adopt a convolutional neural network (CNN) as our deep learning model . The arcEyes are so called the “window to the soul” and are the primary means for understanding how information is obtained through the gaze. Recently, eye tracking technology has been widely researched to better analyze the target fixation point for eye gazing.The development of eye tracking has gone through numerous advances. Rapid advancements in computer graphics have promoted the development of highly sophisticated eye tracking systems, and greatly enhanced the application of eye tracking research in psychology and related fields. Therefore, the study on eye tracking has become a benchmark of modern psychology research.Eye gazing image recognition technology serves as capturing the images of eye movements and converting them to image coordinates, including the pupil positions and fixation points . EssentiSpeech recognition is the ability of a computer to receive and process vocally spoken commands, which is known as automatic speech recognition (ASR) . After cAfter decades of development, speech recognition technology has been infused with other word processing technology. This technology is referred to as natural language processing (NLP) . In the The technology that converts the predicted answers to spoken voice is called “text to speech” (TTS) technology. Conventionally, text-to-speech can be realized via two methods: concatenative speech synthesis and parametric speech synthesis . CurrentIn this study, researchers played the role of testers to propose the most optimal solutions for the development of care robots, drawing from the results of the literature review of image and speech recognition technology to fulfill the four core research tasks. Aside from using the traditional method for gazing tracking, all other tasks will be achieved through deep-learning techniques to conduct human pose recognition, facial expression recognition, and Chinese speech recognition. The systemic processes, frameworks, algorithms, and outcome examples of each respective technique will be described in order below.According to statistics, the probability of accidental falls occurring increases with age. Elderly people falling has become the third major cause of chronic disability for elderly people. Therefore, we propose a process of the human pose image recognition system used in care robots, which is shown in The purpose of pre-processing elderly images is to train the human pose recognition model used in care robots. First, a camera recorded the movements of elderly people. Then, we used a toolkit to detect the positions of the key joints of the human body in 3D space. The data were then converted to a vector for training. Different from most datasets of pose recognition, this research collected a sequence of movements that occur within 30 frames of a video as one training data input. Lastly, the data were labeled with five common poses of the elderly, as shown in The deep-learning architecture used in this study utilized three layers of LSTM . In the Extracting Haar-like features from a human face imageThere are three major procedures in the recognition of human facial expression images, which are described as follows:Haar-like features are digital image features used in object recognition. Its name is originated from its similarity to the Haar wavelet, and it was the first method that could extract human facial features in real time . In this2.Recognizing facial expression images by a convolutional neural network3.Locating the human face and displaying the facial expression recognition resultFirst, we employed the C++ library called Dlib to detect human faces of an input image. For a detected human face, 68 landmarks were then labeled using a dynamic optical flow approach  as shownAccording to the intercept theorem, one can calculate the horizontal coordinates from the center of an eye to the target fixation point for gazing. The horizontal offset of the camera lens can be compensated with a constant. x axis:Taking the left eye as an example, Equation (1) is used to calculate the coordinates of the gaze target fixation point on the Here, S is the state space for the HMM. Assuming there are k states, and the initial state is I, then i transitioning to state j, t observations with k as the final state. Additionally, k.After receiving the speech of elderly people and generating text, the Chinese words were segmented with Jieba, which utilizes the HMM and Viterbi algorithm. From Equations (2) and (3), In this study, the HMM and Viterbi algorithm were utilized to compute the text of elderly Chinese speech and output the most possible word sequence via Equation (4), so as to obtain the final results of Chinese word segmentation. When We used the CBOW model to identify speech meaning in the elderly. The CBOW is a neural network as shown in The gTTS library was employed to convert text to speech, so the care robot can respond with speech. Essentially, gTTS adopts Google text-to-speech API, which uses WaveNet to generate a speaking voice. The core architecture of WaveNet is the dilated causal convolution, which is a deep learning model to generate raw audio. Such a model performs that the string replies of a care robot serve as the input to carry out speech synthesis. It can emit human-like voice to make inanimate robots behave more humanly.After multiple field tests and verification, this study proposes optimal solutions for the four core tasks of the care robot. The following sections evaluate the test results of human pose recognition, facial expression recognition, eye gazing recognition for live videos, as well as those of the Chinese speech recognition for live audios.To simulate the human pose recognition test scenario for elderly people, we illustrate a behavioral flowchart of the care robot encountering the elderly as shown in In this study, we adopted the LSTM architecture to implement the human pose recognition module. It not only achieves good recognition accuracy, but it also effectively improves the lack of continuity between frames and the costly operation of a CNN-based human pose recognition model. To evaluate the efficacy of the care robot for elderly people, we filmed many videos that took place in an indoor environment and verified the accuracy of the falling recognition. The care robot only considers the largest target (an elderly person) in the lens. For the convenience of evaluation, each 30-frame shot of a video acts as a single pose datum. Over the course of developing the human facial expression recognition model used in the care robot, we employed the FER-2013 dataset for training and verification. During the process of model training, we evaluated the convergence of the model through the loss function of the categorial cross entropy as expressed in Equation (5).In this study, we randomly sampled 100 images from the aforementioned dataset. To evaluate the recognition efficacy of the care robot for elderly people, we filmed many videos that took place in an indoor environment and verified the accuracy of the eye gazing recognition. The following example is the close-up video (length: 30 s) of an elderly man, and we randomly chose the last 100 frames to test. To simulate a Chinese speech recognition test scenario for the elderly, To evaluate whether the SpeechRecognition library used in the study is capable of Chinese speech recognition, we adopt the Common Voice dataset  to verifIn the Common Voice dataset, our SpeechRecognition package is able to achieve a WER of 13.21% which is considered a satisfactory result. We observed that the Common Voice dataset contains a certain percentage of erroneous data that increases the wrong results and increases WER; for example, microphone noise completely drowns out the human speech, or some phrases are spoken in Cantonese. Based on the experiments, it seems that the SpeechRecognition package is reliable and accurate in recognizing the Chinese speech of elderly people.After reviewing the literature and proposing strategies for improvement, we applied image and speech recognition techniques to accomplish four built-in functions developed for care robots currently. These functions are human pose recognition, human facial expression recognition, eye gazing recognition, and Chinese speech recognition described as follows.We used a video camera to simulate the height and inclination angle of the eyes of a care robot to record elderly people’s posture images that are then used to train the human pose recognition model. The MediaPipe framework is used to detect the positions of the major human body joints in 3D space and convert them into a vector for detecting a fall event. Through the LSTM-based architecture of the elderly fall detection model, there are five kinds of human poses that can be recognized: walking, squatting, sitting, lying down, and falling.Human face images captured by the camera equipped on the care robot were put into the convolutional neural network that mainly consisted of four convolutional layers for training. From this, the trained model can conduct recognition of elderly people’s facial expressions, including seven kinds: anger, disgust, fear, happiness, sadness, surprise, and neutral.For the human face image captured by the camera, landmarks were labeled to locate human eyes and calculate the coordinates of the gaze target fixation point via a formula deduced from geometry relationship between eyes and a target. The gazing recognition results include eyes closing, gazing to the left, the right, and at the center.The Chinese speech from elderly people was received by the microphone equipped on the care robot and converted into words and sentences. They were then segmented and passed through a CBOW model to predict the middle words using surrounding context words. This allows the key meanings of elderly people’s spoken phrases to be obtained. Based on the results of phrase prediction, text for specific key phrases is generated and then converted into human-like speech as output.Although we have obtained preliminary results on the four functions built for care robots, there remains room for improvement. The following is the brief descriptions of future work for further implementation of human pose recognition, human facial expression recognition, eye gazing recognition, and Chinese speech recognition.Because the deep learning model of human pose recognition is too large, it cannot be effectively used under the condition of system integration. Therefore, in future work, this study will continue to optimize the architecture of the human pose recognition model and strive to improve its accuracy.At present, the deep learning model used in the facial expression recognition of this study already has complete functions. Therefore, we will focus on the integration of the system, try to reduce the misjudgment of facial expression image recognition, and do our best to improve the potential performance delay due to integration.In this study, traditional image recognition methods are used for eye gazing recognition. While they serve the purpose, there is still room for improvement. We will continue to perfect the techniques for eye gazing recognition and improve the system integration performance to avoid interference from executing the other three tasks.In terms of system integration, it was found that multi-threading interferes with Chinese speech recognition most frequently. We will continue to investigate how the care robot can engage in fluent speech interaction with elderly people in the case of multi-threading, and collect more scenario script examples for our Chinese speech database.


Africa is the last region to incorporate family physicians into its health systems. They are still a relatively new concept in many countries, small in numbers and deployed in a variety of ways. There is a need for more evidence on their contribution to African health systems to guide policymakers.African Primary Health Care and Family Medicine Journal in 2021.The aim of this study was to review the special collection of short reports on the contribution of family physicians to African health systems, published in the Seventeen short reports from eight countries were qualitatively and thematically analysed in ATLAS.ti. Codes, which were derived inductively, were organised into categories according to the World Health Organization’s primary health care monitoring framework.In the domain of health system determinants, family physicians made little contribution to governance, adjustment to population health needs or financing. They did, however, contribute substantially to the capacity of the health workforce, supply of equipment, functioning of the health information system and use of digital technologies. In the domain of service delivery, they strengthened the model of care and championed systems for improving the quality of care. This translated into improved availability and utilisation of services, core functions of primary care, quality of care and patient safety.Family physicians described their important contribution to service delivery in district hospitals and primary health care. This should lead to improvements in outcomes and impact for the health system. Their contribution to the concept of resilient facilities and health services needs further exploration. Given the huge need for strengthening district health services in the African region, it seems surprising that health systems are slow to incorporate family physicians.Africa is probably the last region in the world to incorporate family physicians into its health systems.2 The impact of family physicians is therefore low, and deployment has not yet gone to scale. Policy and decision-makers may be confused about the roles of family physicians in the African context and unsure as to whether the return on investment is worthwhile.3 Some assume that the proposed model of care is that of Europe or North America, where family physicians are the main primary care providers, and they dismiss family medicine as impractical and unaffordable. Others would rather invest in the training of medical specialists for central and tertiary hospitals, leaving PHC in the hands of community health workers, nurses and midlevel health workers. Others may even assume that family physicians are most appropriate to the private sector.The supply of family physicians in African countries is typically limited, and many countries have only recently initiated training programmes.4 Family physicians, in our context, work in the district or primary hospital as much as in PHC.5 They are not usually the first-contact primary care provider but key members of multidisciplinary PHC teams. They may act as clinicians for more complicated patients, consultants to the team, capacity builders and leaders of clinical governance. In the district hospital, they have similar roles and often fill important skill gaps, particularly in rural and remote locations. Whilst African family physicians may share similar values to their colleagues in high-income countries, their roles and required competencies may differ considerably.6The World Organisation of Family Doctors in Africa produced a consensus statement on African family medicine several years ago.7 In the region, it is difficult to evaluate their contributions because of the small numbers, unclear responsibilities and varied positioning in the health system. Their strengths as generalists and capacity builders have been identified but mostly in terms of perceptions and qualitative studies.5It is clear that evidence-based policymaking requires evidence, and there is a need to provide evidence of the contribution of family physicians to African health systems. In South Africa, early research has shown the impact they can make through their various roles, and district managers have recognised their contributions, particularly in district hospitals.African Primary Health Care and Family Medicine journal publishes such evidence in the region. The editorial team were aware of the fact that family physicians in different countries were making significant contributions to their health systems but not reporting on these contributions through research projects. Therefore, the journal put out a call for short reports so that family physicians could narrate their stories and make their contributions visible. Where possible, these stories were supported by locally collected evidence. The journal published 17 short reports in 2021 from eight countries . The structures and inputs are viewed as the necessary health system determinants that are required for the processes and outputs of service delivery. Service delivery is responsible for the achievement of the outcomes and impact under health system objectives. Each domain of the logic model is then broken down into subdomains as shown in The framework is structured in a logic model that flows from structures, inputs, processes, outputs and outcomes to impacts 25. The sThe author performed the analysis and is also the editor-in-chief of the journal. He was responsible for reviewing and making decisions on all the articles accepted for the special collection. Therefore, he was already familiar with the articles prior to the analysis. Although he conducted the review alone, the analysis was validated by the corresponding authors of the included articles.Communities were characterised by high morbidity and mortality with low life expectancy:22. The health of the Somaliland population is poor. Life expectancy is estimated at 53 and 56 years for males and females, respectively. One in seven children dies before their fifth birthday, and one in 18 women has a lifetime risk of death during pregnancySeveral reports observed an increase in noncommunicable diseases such as diabetes and hypertension. Vulnerable groups, such as older persons, homeless people or those with disabilities, were also present in many communities. Conflict and civil war in several countries had undermined health services. The topography impeded access to PHC in remote and rural areas, where health care workers were also harder to attract and retain. Several of the reports outlined responses to the coronavirus deasese 2019 (COVID-19) pandemic. Many health services were characterised by high workloads, limited time and constrained human resources.Health workforces were limited in their ability to manage the burden of disease. For example, primary care providers might struggle with managing chronic or complex health conditions, rational prescribing and person-centred care. As a result, patients might bypass PHC or be inappropriately referred:18 Challenges in gatekeeping, as well as limitations in resources, time and training, often limit the ability of rural health care providers to appropriately address chronic diseases and complicated cases.were] travelling to Kampala, the capital city, in search of health care services because of the lack of skilled medical personnel.20 (Northern Uganda)Many patients  programme, FM is playing an active role to help create a culture of learning and refection in the health system.12 Through the VDL  with a vital opportunity to practice integrating primary care practice and public health. They also develop their leadership skills by developing an intervention for a locally identified health problem.13 (Kenya)This provides [This] demonstrates how primary care facilities can improve NCD management, the FM registrars … are distinguishing themselves as capable and efficient leaders of health care.18  was used for referrals to specialist care and the Mpilo programme [it is an app and not a programme] to coordinate transport for the homeless:Technology was used to assist with coordination of care between primary and secondary levels. For example, a family physician was the gatekeeper for a new referral system to cardiology using e-mail; in another setting, the Vula programme  and Clearspace Labs developed a telemedicine platform. “Virtual Care” used an encrypted video consultation which greatly enhanced care for people with COVID-19 infection as compared to the previously used telephone consultation.8 (Ghana)In June 2020, NMC . Improving coordination of care across the primary–secondary care interface requires building relationships of mutual respect and trust and overcoming ‘professional tribalism.23 Subsequent to the meeting, both FPs and medical officers reported an improved referral experience to VHW  graduates are routinely doing C-sections contributes to achieving the highest priority objective of the health services: to reduce maternal, neonatal and child mortalities.22 The fact that 15 , in-hospital neonatal mortality decreased from 53% to 10%, major surgeries performed increased from 530 to 1620, maternity admissions increased from 2700 to 3313 and babies delivered increased from 1872 to 2967.20 (Northern Uganda)As a result of these improvements [rural district] hospital, we completed 966 cases in the one available theatre. All had theatre notes, surgical safety checklists and information on all these procedures were available digitally.10 During my last year at the  is a residential care facility that offers medical and residential care to 160 severe and profoundly disabled adults.14 This report describes the virtual support provided by two family physicians to a mental health care institution in Tshwane, during the first wave of the pandemic in 2020. [In addition, the presence of a family physician could improve access to the next level of expertise by ensuring appropriate referrals and improving the timeliness of appointments. Their specialist training enabled them to negotiate and collaborate with specialists at the referral centre. In one example, family physicians were able to directly book patients for CT scans at the referral hospital, because they were recognised as having appropriate clinical decision-making skills.Quality care: The previous examples of clinical governance activities illustrated tangible improvements in access to care, comprehensiveness, coordination, continuity, person-centredness, equity, adherence to clinical standards, responsiveness to patients’ needs, safety and timeliness of access to secondary care.The contribution of family physicians was mainly in the domain of service delivery in both district hospitals and PHC. They made a substantial contribution to the models of care and to establishing systems of quality improvement and patient safety. This translated into improved access to and availability of services close to communities. They also improved all of the core primary care functions such as first-contact accessibility, comprehensiveness, coordination, continuity and person-centredness. There were several examples of improved effectiveness, efficiency, equity, safety and timely access to the next level of expertise. Their contribution to resilient health services and facilities was not as evident.They had some influence on the health system determinants, particularly the inputs to service delivery. In this domain, their main contribution was in improving the capability and motivation of the workforce and creating a supportive learning environment. In addition, they supported the development of health information systems and the use of digital technologies. They had little engagement with the more structural components of the health system.These reports from multiple countries in East, West and Southern Africa illustrate that family physicians improve service delivery through three key roles:as clinicians and consultants to health care teamsas capacity builders of health care teams and clinical trainers to future health professionalsas leaders of clinical governance who improve the quality of care and patient safety.26 but are clearly illustrated and confirmed in these reports from diverse contexts.These roles were conceptualised previously,Family physicians appear to bring a systems viewpoint, leadership skills and a sense of agency to strengthening district health services. These higher-order competencies are vital to health care teams at district hospitals and in PHC. Whilst it is clear that family physicians make their contribution through teamwork, their leadership may well be critical to improving service delivery. This review of short reports provides additional evidence of the need for including family physicians in health care teams. In many cases, the family physician was located at the district hospital but reaching out to support the PHC services in the catchment area.25 and the World Health Assembly has previously included them in its definition of the PHC team.27 This review provides concrete examples of their contribution in the African context in both low- and middle-income countries. Most governments in the African region have signed the Astana Declaration and made a renewed commitment to strengthen PHC.28 This review shows the promise of family physicians as an intervention across the whole service delivery domain.The WHO framework document notes that family physicians are of particular relevance to PHC,It is not surprising that the reports showed little impact on the structural domain of the health system, as this is usually the responsibility of national and subnational policy- and decision-makers. The inputs required for service delivery are also usually the responsibility of managers at district and facility level.29 Family physicians may need to develop new alliances with the disciplines of public health and emergency medicine to prepare for and adapt to the likelihood of these events.The one subdomain of service delivery where their contribution was less was that of resilient services and facilities. The emphasis on resilience is relatively new and is particularly relevant in the face of challenges such as the COVID-19 pandemic. In the future, climate change and extreme weather events will also test the resilience of health workers in PHC.The reports commented only briefly on the outcomes and impacts of the changes to service delivery. This is not surprising as changes to these would be longer term and require formal research to measure. Family physicians were able to report on what they had done, seen and, to some extent, measured at the local level. The purpose of the data collection was to allow family physicians to narrate their stories without the need for a formal research study.The review is based on 17 short reports that intended to showcase the contribution of family physicians. These reports may not be typical of all family physicians in the region and could be overly optimistic. Nevertheless, the reports came from a wide variety of countries, both urban and rural contexts, as well as from low- and middle-income settings. The reports did not have the scientific validity of a well-formulated research study, although family physicians did provide supportive evidence when available and described their contributions in detail.30 Whilst health care workers at other levels, such as community health workers, can provide some of the needed coverage, family physicians are needed to ensure quality and the availability of comprehensive services at the community level.By synthesising the key themes from these multiple short reports, this review provides a more reliable and valid analysis of the contributions of family physicians than one report by itself. The picture that emerges suggests that family physicians can make a substantial difference to the performance of PHC and district health services. The evidence distilled here should encourage policymakers to invest in the training and deployment of family physicians in their health systems. Universal health coverage requires both coverage and quality.Family physicians can make a substantial contribution to African PHC and district-level service delivery. They improve the models of care, enhance systems for quality improvement, improve access and availability of care and build the capacity of the workforce. They particularly strengthen the core primary care functions of first-contact accessibility, comprehensiveness, coordination, continuity and person-centredness. This review adds additional evidence that in the African context, family physicians are an essential human resource in health care teams. Policymakers on the continent should consider whether family physicians can help them to realise their political commitments to strengthening PHC.


This special issue highlights advances in the availability of radionuclides for medical application based on developments of the production methods using ion beam and separation technologies. MEDICIS-Promed, a project funded within the H2020 framework program of the European Commission, aimed to train young scientists to provide the basis for novel production methods and for systems for personalized medicine, combining functional imaging and treatments based on radioactive ion beam mass-separation.MEDICIS is an extension of the ISOLDE class A laboratory at CERN. It is a facility dedicated to the production of radionuclides for research in the medical field. It comprises an irradiation station located in the beam dump of the HRS target station, a remote handling system, an isotope mass separation system and a simple radiochemistry laboratory .Martinez Palenzuela et al., details of the MEDICIS beam lines are provided. It consists of a simple target station and related beam optics, along with a slit system and an isotope collection system. The required modifications to operate a laser ion source with a (laser-) beam window and impact of the modified magnetic field homogeneity are described. Operated with 1+ ion sources suitable for Radioactive Ion Beams used in ISOLDE, a mass resolving power dm/m~400 is simulated and experimentally verified with a VADIS ion source, allowing to achieve enrichment factors of x1,000–10,000 as shown with subsequent examples of this topical Frontiers article, enabling the production of radionuclides with high molar activities, e.g., Tb, Sm, or Er, that was not possible until then.In Duchemin, Ramos et al., an overview of the operation of MEDICIS as a collaboration with external institutes is provided, starting with a 1st Radioactive Ion Beam commissioned in 2017. The operation of the facility with proton irradiations in 2018, with external sources provided by neutron irradiation in reactors and proton irradiation in cyclotrons during 2019–2020 in LS2 is described. The separation of small batches of radionuclides implanted in gold foils coated with zinc allowed to show the potential of the facility and collaboration—providing non-conventional radionuclides both for diagnostic and therapeutic applications. More specifically, radio-lanthanides were produced, as well as alpha emitting and Auger emitting radionuclides such as 225Ac and 165Er. They were shipped across Europe, including UK partners such as NPL and researchers in Lisbon, depending on the half-lives of the radionuclide under consideration. 149Tb, with its ~4 h half-life, must follow similar logistics constraints as 18F and was shipped to the neighboring CHUV research groups in Lausanne.In Gadelshin et al.. Reaching 50% and more, it matches the best efficiencies achieved to date for radioelements investigated in facilities using the ISOL method, demonstrating the proper implementation of the new MELISSA source with 2 Ti:Sa lasers used in combination.The newly started MELISSA laser ion source allowed to extend the scope and the efficiency of the radionuclide beams separated from different targets. With its element specific scheme developments, it reached high efficiency with stable elements such as Er, Tb, Yb, Ac as shown in Heinke et al. and Talip et al., in which the target irradiation and later the separation performances are shown for 167Tm and 169Er. 169Er is a well-known radionuclide applied in nuclear medicine for radiosynovectomy. However, its scope of application had been limited because of its very low specific activity, preventing its use in targeted molecular therapy and in the field of theranostics.A few examples are provided by 153Sm by Van Voorde et al. is another example for which its application in nuclear medicine is restricted to pain relief treatments used for bone metastases of advanced stage prostate cancer. Its high molar activity grade made available by mass separation has allowed the synthesis of radiopharmaceuticals such as 153Sm-DOTA-HSA in a proof-of-concept experiment, paving the way toward the application of this radionuclide with suitable half-life, imaging properties as well as therapeutic properties to be tested and compared to, e.g., well-known 177Lu-PSMA radiobioconjugates presently investigated in several clinical trials.67Cu with deuteron beams on 70Zn targets is presented by Nigron et al. and Duchemin, Cocolios et al., respectively. High energy beams and targets with limited enrichment factors lead to the production of radionuclidic impurities which are quantified there to find the best parameters to reach high activity, purity, and manage the required associated chemical or mass separation steps.The production and related cross-sections of terbium radionuclides with high energy proton beams on tantalum targets and of Penescu et al. extends the scope of the present topical Frontier issue to external radiotherapy, considering the diagnostics potential of PET-emitting 11C ions for treatment and dose distribution monitoring. While the success of treatments with Carbon-ions relies on the proper delivery of the dose to targeted tumors while preserving organs at risk, this paper reviews the requirements for facilities able to combine a 11C source with present-day operating synchrotron treatment facilities such as CNAO or MEDAUSTRON. In particular, the coupling of a medical cyclotron to such facility allows to develop the appropriate acceleration scheme with high efficiencies required to translate the cyclotron produced batches of 11C toward treatment and diagnostics hadron pulses.D'Onofrio et al. described the evaluation of a DOTA-Tetrazine, and its radiolabelling with trivalent metals, exemplified by 90Y and 111In. Their compound allows the application for pre-targeting approaches which have found applications especially in the context of using antibodies for targeting.In advancing applications derived from novel radionuclide production approaches there are essential steps also in the development of novel radiopharmaceuticals toward their clinical application. This covers aspects of modifying suitable targeting molecules for radiolabelling. In an interesting approach Cassells et al. describe radiolabelling experiments with 161Tb, using albumin as a model of a heat sensitive molecule and evaluated their stability in vitro, finally proposing DOTA, DOTAGA, and NETA derivatives as being suitable for terbium-radioisotopes.Optimization of radiolabelling procedures is also an important step in the development of novel radiopharmaceuticals, especially when sensitive targeting molecules are involved. Many trivalent radiometals included in this special issue require heating steps for conventional radiolabelling approaches which are not compatible with many targeting molecules. Pouget and Constanzo provided a mini review of revisiting the radiobiology of targeted alpha therapy. Even though it is recognized the alpha particles are highly cytotoxic producing complex DNA lesions and therefore the cell nucleus is seen as the primary target, recent research has shown that this paradigm is no longer valid and that alpha therapies are also effective in larger tumors or when a ligand carrying the alpha-emitter only binds to the cell surface. Also, bystander effects and immunological responses are increasingly recognized to play an important role for radionuclide therapy approaches, which is excellently summarized in this review. This, however, not only holds true for alpha emitters but also for other novel radionuclides emitting low energy electrons .Besides extensive testing of target interaction of novel radiopharmaceuticals, it is also essential in particular in the context of novel approaches in Theranostics to consider the biological effects in relation to the specific radiation emitted. In this context Maietta et al. use Monte Carlo simulations for novel terbium radioisotopes, which can be expanded to other radionuclides, and allows simulation doses in different exposure scenarios, from which relevant coefficients can be derived.Even if a new radiopharmaceutical has been developed and characterized preclinically, also logistics should not be forgotten, in particular considering the shipment of highly radioactive materials both in the context of the radiopharmaceutical preparation, but also for the clinical application. In the case of novel radionuclides there are limitations due to conservative radiation transport safety approaches when no coefficients are available to calculate the appropriate shipment category. In their paper Decristoforo et al. discuss the main regulatory framework for novel radionuclides and the hurdles involved. They identify the limitations in the current legislation, in particular in relation to the legal definitions of radionuclides for pharmaceutical applications. Within the PRISMAP project the requirements for pharmaceutical standardization and harmonization in the context of developing radiopharmaceuticals using novel radionuclides, including those derived from new ion beam applications, have been summarized and specified  or brachytherapy applications .Closer to clinical application, Naskar and Lahiri present the theranostic quadruplet of terbium radionuclides (152Tb and 155Tb for diagnostics and 149Tb and 161Tb for therapy) which have promising applications, provided they can be produced in suitable quantities and adequate purity. The authors describe production pathways and show the role of CERN MEDICIS with spallation technique coupled with mass separation as a possible way to contribute to this endeavor.Finally, Overall, this special issue on Advances in Radioactive Ion Beams for Nuclear Medicine provides an excellent overview with examples from different aspects of research areas involved in the translation of novel radionuclide production methods to clinical applications in Nuclear Medicine.TS, CD, and JP wrote the first article draft and revised the article. All authors contributed to the article and agreed with the last version to be accountable for the content of the work.The authors acknowledge the financial support of the E.U. through the MEDICIS-Promed program (grant agreement No. 642889) and the PRISMAP program (grant agreement No. 101008571).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Beira, the biggest city of Mozambique’s Sofala province, was struck by Cyclone Idai on 14 March 2019, with devastating impacts. The floods along with the cyclone destroyed road infrastructure and health facilities and disrupted primary health care (PHC) service delivery. In addition, destruction of farmland and food stocks resulted in malnutrition; the abundance of water fostered the reproduction of mosquitos, exacerbating the burden of malaria; and problems with water and sanitation led to epidemics of cholera. The exact role and contribution of human-induced climate change is very difficult to quantify, but there is little doubt that climate change is driving more frequent and severe cyclones, such as Idai. Considering the current climatic changes, it is expected that climate hotspots such as Beira will only experience more frequent extreme weather events. In these settings, with high risks but low adaptive capacity, dedicated efforts are required to strengthen PHC with a focus on preparedness for disasters. This should entail community awareness and education, strengthening infrastructure and service provision, as well as collaboration with important stakeholders across other sectors.Using a case study approach, this article contributes climate resilient PHC for better preparedness to service continuity. This article reports the experiences and expertise of Dr Priscilla Felimone, complemented with available scientific literature. Dr Priscilla Felimone is a family physician, currently working at the provincial health service of Sofala province in Beira.1 The total population is around 530 000 people, according to the 2017 national census.2 The Ndau and Sena tribes are the most prominent in the area, and Ndau, Sena and Portuguese are the main languages spoken.Beira is the biggest city of the Sofala province in Mozambique, situated on the coast of the Indian Ocean .1 The to4 This means there is no intermediate level of care in Beira, and all patients are referred from PHC to the central hospital.The health system consists of four levels of healthcare. Primary health care (PHC) comprises the first and second levels, and there are in total 176 health facilities in Sofala province. Beira has a central referral hospital (fourth level) but no provincial hospital (third level).In Beira there are 18 PHC centres, each responsible for a dedicated section of the population. This means that patients preferably access services at the PHC centre they are allocated to but are not sent away if they consult at a different PHC centre. All health services are provided for free, except medication, which is provided for a fixed rate. There is no distinction in service provision based on nationality. In each PHC centre, there is a variety of health professionals. At least one medical doctor is present, but large PHC centres can employ up to four doctors. Nurses, technical officers and community health workers work alongside the doctors and complete the minimum 15–20-person staff mix in each centre, but the staff count can reach up to 100.5 An intersectoral approach includes participation of community leaders and specific stakeholders that collaborate on early prevention, preparedness and recovery responses. In line with this, a community comanagement committee is established in each centre for early detection of health problems in the community. The focus of service provision is health promotion and disease prevention.As entrenched in the Alma Ata declaration, PHC operates on five main principles, including intersectoral collaboration.Under normal circumstances, there is a seasonal burden of disease in Beira. Respiratory diseases and related mortality increase during the cold season, between May and November. In the warm season, vector-borne diseases, such as malaria, are most prominent. Mortality from HIV, AIDS and hypertension are high in adults. In children, the mortality rate is highest for respiratory diseases. However, mortality and morbidity changed drastically during Cyclone Idai.When Cyclone Idai struck Beira on 14 March 2019, the entire community, including the health professionals, had very limited awareness of what could happen and were unprepared. Therefore, the effects were devastating for the entire population.7 The PHC centres had moderate to severe infrastructural damage, and the roads to access them were also badly damaged. As a result, patients and staff could not get to the PHC centres. Not only were the patients unable to attend the PHC centres, but many were afraid to go. This led to a decrease of PHC service delivery.Across Mozambique, over 1000 people were killed, and in Beira about 90% of the city’s infrastructure was destroyed because of the cyclone and flash floods.The usual daily patient count dropped from 200 to 300 percent to about 20–25 patients in the direct aftermath of the cyclone. As people from the middle and upper classes were better protected because of safer housing conditions, the patients who consulted the centres were often the most vulnerable people, desperately seeking health services for critical injuries. Health workers could not provide services to the best of their capacity, as the infrastructure was destroyed and transport possibilities were very limited, although routine basic service delivery was continued as much as possible in tents and field hospitals, for example from humanitarian organisations such as the Red Cross.Many health workers had to live at the PHC centres to maintain services and were overstressed because of the increasing workload. In addition, as local people were relocated to other areas, once these were considered safe, displacement put an extra burden on the PHC centres in those safe areas.8 Problems with sanitation and water management led to cholera outbreaks.10 Water inundation, because of the floods, created better breeding conditions for mosquitos, and as a result, malaria  had an increased wave of infections.The long-term impacts of the cyclone and floods were seen through changes in the burden of disease. The floods destroyed farmland and led to shortages of food, with an increase in malnutrition. Exemplifying the malnutrition was an outbreak of pellagra, a disease that was not present before the cyclone.11 In the months before the cyclone hit, there had been a long-lasting drought and extremely high temperatures, which were intensified by climate change.12 As a result of this, the land was more susceptible to flooding, with water running off rather than sinking in. In addition, sea level rise because of climate change contributed to more extensive flooding. All factors combined indicate the important role of climate change on the impact of Cyclone Idai.13The exact role and contribution of human-induced climate change is very difficult to quantify. However, Cyclone Idai was not at all an isolated incident, and climate change is a strong risk factor. The sixth assessment report of the Intergovernmental Panel on Climate Change, Working Group 2  stated that climate risks appear faster and with an increased frequency, intensity and duration of extreme weather events, including droughts, marine heatwaves, cyclones and floods.15 Another key implication relates to the ongoing provision and resilience of services. This implies a need for protocols and plans of how to adapt and reorganise services in case of such emergencies. Strategies to maintain patient transport, services and supplies are fundamental and might include the availability of helicopters.16 Building strong intersectoral relationships and community engagement will enable collaboration to maintain services in the face of such disasters.17 Lastly, to ensure access to PHC, efforts are needed to prepare for the challenges related to displacement of populations and increased demands for PHC in areas receiving the population. Collecting data on PHC performance during such events and on the number of migrants entering or leaving the area would prove useful for this purpose.Better preparedness of PHC for such disasters is essential. Primary health care must help communities to be more aware of the risks of extreme weather events and what to do. In terms of infrastructure and equipment, everything should be adapted to withstand disasters, which will ensure full operability in case of adverse events. For example, telecommunication equipment and cables should be protected to maintain the functioning of the emergency warning system; an alternative electrical power source should be available in a secure and accessible place; a permanent water supply should be available to provide 60 L of water per resident patient per day; and the medical and laboratory equipment should be protected for the impacts of disasters.Considering the current climatic changes, it is expected that climate hotspots such as Beira will only experience more frequent extreme weather events. For this reason, it is argued that in these settings with high risks but low adaptive capacity, dedicated efforts such as raising community awareness, adapting infrastructure and equipment and building intersectoral relationships are required to strengthen climate-resilient PHC.