Care that places the relief of suffering at its core, affirms life and does not hasten nor postpone death, but regards dying as a normal process, according to World Health Organization (WHO).Care that is individualised: the person or patient is its core focus. The recipient is someone who has been diagnosed with a chronic, life-threatening illness that is no longer responsive to curative treatment, for example, cancer, irreversible end-stage end-organ failure, HIV infection and related disorders unresponsive to available treatment, et cetera.■‘End-of-life’ care is an aspect of palliative care that specifically refers to the care of persons estimated to have a life expectancy of ≤ 12 months, according to the National Council for Palliative Care, United Kingdom.Care that is directed towards the control of distressing symptoms including the relief of pain:■‘Total Pain’ – this concept refers to pain that cannot be adequately controlled without addressing its contributory factors, namely, physical, emotional, social and spiritual factors.■Under-use of and insufficient access to opioids however characterises opioid use in Africa and other low-income countries. Palliative care offers appropriate access to opioids without the risk of addiction and within the context of a professionally competent team. .42The opioid-use crisis – inappropriate opioid use is a major contributor to the opioid addiction crisis currently reported from high- and middle-income countries. Care that is provided by a team. The team is multidisciplinary and comprises nurses, doctors, paramedical persons, for example, physiotherapists, counsellors and accredited members of the religious community. The patient and their personal support network  are advisors to the team and receive support from the team. The team has a leader who takes responsibility for the totality of care, plans specific therapy, prescribes medication, completes medico-legal forms, et cetera. This is usually a medical doctor.■Team care is intended to integrate the medical, practical, psychological and spiritual aspects of care in a system that promotes as active a lifestyle as possible until death. Team care provides support for the patient’s family or partner, et cetera, during the illness and through the time of bereavement.Care that is not restricted by the patient’s age and is not restricted to a particular access point, such as a local clinic, district hospital or tertiary level medical centre. The 2017 National Draft Policy Framework and Strategy Paper on Palliative Care, Department of Health, South Africa (SA), envisages access to palliative care for all South Africans who are in need. detectable viral load while on ART is usually a sign of treatment failure or poor viral control. These persons are also at increased risk of HIV-related morbidity and mortality.Human immunodeficiency virus infection is incurable. About 770 000 people died of HIV worldwide in 2018. More than two-thirds of these died in Africa . Although Statistics South Africa has recorded some improvement in the overall survival, HIV-related levels of morbidity and mortality remain high. Mortality is greatest among those not on antiretroviral therapy (ART), that is, either naïve to ART or those who have stopped taking medication and are outside of care. Mortality is also high in the first year after the start of ART. Of South Africa’s 7.97 million people living with HIV (PLWHIV) in 2019, only 4.94 million are on ART. A No palliative care: Access to formal palliative care within either the public or private health sector in much of Africa including SA, is extremely limited. Few currently access this care  and vaccination against influenza, the pneumococcus, hepatitis B and regular clinic visits form the routine background of care. From time to time, this routine is interrupted by disease. This necessitates a shift in the emphasis of care. Palliation becomes an option for those with incurable conditions, such as a central nervous system (CNS) lymphoma, disabling stroke, renal and liver failure, et cetera. For PLWHIV who live longer, the diseases of old age, for example, chronic lung conditions, diabetes, cardiovascular disease, bone fragility, neurocognitive decline, and the non-AIDS defining cancers, emerge. Indeed, these conditions generally appear a decade or more before identical disease affects uninfected peers .Tm Tool , discusses clinical ‘evidence-based’ support for approaches to HIV-related pain syndromes: this is summarised in the ‘Managing the HIV sick’ section. The analgesic drugs are presented in The core activity of the palliative care team and its clinician(s) is the relief of suffering. Pain, particularly chronic pain lasting ≥ 3 months, is experienced by the majority of PLWHIV before death. A formal approach to the assessment of both acute and chronic pain underlies its successful management see . Pain coThe ‘hidden cancer epidemic’ refers to the growing number of HIV-infected cancer patients in Africa. Cancer and the HIV epidemic are interlinked. Uncontrolled plasma (HIV) viral load increases the risk of malignancy. AIDS-defining malignancies were described in the 1980s and 1990s but are still widespread throughout sub-Saharan Africa today. In the era of ART, the risk of non-AIDS defining cancers is also increasing. Universal Test and Treat (UTT) and the 90-90-90 by 2020 initiatives of the WHO and the UNAIDS, will help to reduce risk in the long term if successful.However, at this time, oncology and radiotherapy on the African continent face multiple challenges: poor and ageing infrastructure, insufficient numbers of skilled professionals, inconsistent data collection, the huge rural–urban divide, empty drug shelves and constant drug stockouts, et cetera. This section briefly reviews this subject. Answers to the palliation of HIV-related cancer include greater access to prevention, for example, vaccination against the Human Papilloma Virus (HPV) and the broader reach of cervical health assessments in women, vaccination against Hepatitis B and the improved early diagnosis of cancer and the rapid referral to cancer curative treatment services. Closer collaboration between Africa’s oncologists, radiotherapists and HIV clinicians is needed if any of this is to be achieved.The science of cannabinoid use as an adjuvant in HIV-related palliative care is new. Although South Africa has recently legalised cannabis for medical use, supporting data are largely observational and subjective. Definition 1. According to the National Policy Framework and Strategy Policy on Palliative Care, Department of Health, South Africa, 2017–2022:as needed, from birth until death, and should be accessible at all levels of the health care service. Palliative care cuts across all health programmes in the delivery of services.1 The care of the dying is as old as the practice of medicine itself Source: Shaner DM. Suspending ethical medical practice. N Engl J Med. 2010;363:1988Definition 2. According to the World Health Organization (WHO):Affirms life and regards dying as a normal process.Neither hastens nor postpones death.Provides relief from pain and other distressing symptoms.Integrates the psychological and spiritual aspects of patient care.Offers a support system to help patients live as actively as possible until death.2Offers a support system to help the family cope during the patient’s illness and during the experience of bereavement.Palliative care is an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention, treatment and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial or spiritual. Palliative care:Definition 3. End-of-life care: This refers to healthcare, not only of a person in the final hours and days of his or her life, but more broadly care of those with a terminal condition that has become progressive and incurable . The National Council for Palliative Care, United Kingdom, states that end-of-life care is given to persons ‘likely to die within 12 months’. Several commentators make the point that end-of-life care is not identical to palliative care, that is, end-of-life care is a final phase within the broader provision of palliative care. Nonetheless, its starting point is sometimes difficult to identify.The principal goal of palliative care is the relief of suffering. This is done through individualising care – addressing symptoms, controlling pain, listening to the patient, responding to fear and anxiety, incorporating families and the patient within a competent, professional and resourceful team, and bereavement support for the patient’s loved ones. A defining characteristic of palliative care is the notion of total pain, the recognition that pain cannot be alleviated completely unless all contributing factors that inform the patient’s life experience are addressed. Palliative care is team work. The team comprises a range of medical, nursing, paramedical and psychosocially trained health and community workers. The leader is usually a senior palliative care-trained clinician. The South African National Policy Framework on Palliative Care envisages that these teams will be accessed by patients – including those who are human immunodeficiency virus (HIV)-positive – at the community, district and regional levels in free-standing clinics and at all district, secondary and tertiary-level hospitals across the country. These proposals are currently aspirational, however, as significant barriers to implementation still exist: approval and financing, recruitment and staffing, education and training, et cetera.The individual matters. The process of palliative care is just, non-judgmental and given to all irrespective of colour, creed or class. ’The relief of suffering is considered one of the primary ends of medicine by patients and the general public’.3Yet patients and their families do not necessarily agree with health workers on the means to this end.3‘In the care of the dying, patients and their friends and families do not divide suffering into its physical and nonphysical sources the way doctors, who are primarily concerned with the physical, do.’Palliative care recognises this divide and addresses it by taking all causes of suffering into account when aligning the goals of the patient with that of the caregiver and healthcare system. A consultative, multi-disciplinary approach forms the basis of this model of care.4 It was estimated that 56% were on antiretroviral therapy (ART) yet viral control could only be confirmed in 45%. Although 95% of pregnant women had accessed ART, mother-to-child transmission of HIV in 2016 still resulted in 12 000 newborn infections. The 2017/2018 SA Human Sciences Research Council’s (HSRC) report, released in July 2018, estimated that 7.9 million South Africans are now living with HIV, an increase of 1.6 million over the past 5 years; 70.6% are taking ART; and 87.5% of PLWHIV aged 15–64 years on ART have suppressed viral loads. The number of new cases among women aged 15–24 years has remained high since 2012 and is three times that of their male peers, while the overall prevalence of HIV among South Africans was 14%. Prevalence rates were higher in the provinces of KwaZulu-Natal (KZN), Mpumalanga (MP), the Free State (FS) and the Eastern Cape (EC), with rates of 18.1%, 17.3%, 17.0% and 15.3%, respectively.5 Notwithstanding these numbers, new HIV infections have fallen by 44% since 2012 and HIV testing has been on the rise.The Joint United Nations Programme on HIV and AIDS (UNAIDS) reported in 2016 that 7.1 million South Africans were HIV-positive.7The evolution of the South African epidemic has meant that many who are infected yet undiagnosed and ART naïve, or who have defaulted on ART in the past, now present to hospitals and clinics with symptomatic disease, namely, the HIV-sick. It is estimated that as many as 40% – 60% of the beds in the public hospitals in KZN, Gauteng, MP and FS are occupied by PLWHIV.8Few, if any, state hospitals offer a formal palliative care service and despite access to ART since 2005, mortality from HIV-related diseases remains high. Of the 14 431 patients who died in Soweto’s Chris Hani Baragwanath Hospital from 2006 to 2009, 64% of the men and 82% of the women were HIV infected. More than 90% of those dying between the ages of 30–40 years were HIV infected.9 The dominant regional pathogen of the HIV-infected patients is Mycobacterium tuberculosis. All who died of TB had disseminated infection at the time of their death. The first 90 days following the start of ART, namely, ‘early-ART’, is a key risk period for death from TB. The recovering immune system has been implicated in these deaths, namely, the immune reconstitution inflammatory syndrome (IRIS) as the likely cause or complicating event in these deaths.10A small but well-analysed autopsy group from the Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) is reported in 11Models of palliative care vary. Three models that are frequently encountered by the HIV clinicians in South Africa (SA) are briefly discussed in this section.In this model , little 14 , chronic renal failure, heart disease et cetera, experience a slow but progressive downhill trajectory. Each new episode of disease or hospital admission compromises organ function further and moves the patient towards the end of life.20 The model in Chronic lung disease (CLD) is a problem for long-term survivors of HIV-infection.1 During this period, emphasis gradually moves from the curative to the palliative, as dictated by the changing needs of the patient and family  and continues until a time after death when bereavement support is provided to the family members of the deceased.mily see .21 While the availability of ART has brought great benefits, many still unfortunately die. Under normal circumstances, the clinician’s mandate is the restoration of a patient’s health and well-being which begins with obtaining a medical history, the examination of the patient, the formulation of a probable diagnosis, investigation, the start of remedial therapy, the monitoring of the response, a review of laboratory or radiographic data and the confirmation of the diagnosis. Patients want and need to feel better and good symptom control is the shared ground of curative and palliative medicine. It addresses the immediate needs of those who suffer. A recent randomised controlled trial (RCT) of palliative care in patients with advanced non-small-cell lung cancer found that this intervention reduced depression, improved quality of life and produced a short but significant 3-month survival advantage.22Patients on ART who regain normal or near-normal immune activity and whose viral count is ‘undetectable’  have life expectancies similar to that of their uninfected peers.3) and give past medical histories that suggest advanced immune suppression, namely, previous TB, recurrent bacterial and other infections and unexplained weight loss.23 Despite adherence to therapy, INRs remain at an increased risk of disease and death notwithstanding years of documented viral suppression.24 No dependable treatment currently reconstitutes the blood compartment with CD4 cells in this group of patients. Attempts to address this situation by changing background ART in those who are virologically suppressed have not been successful and this is mainly discouraged. Where the patient’s usual medication may be incriminated, for example, AZT or trimethoprim-sulfamethoxazole, alternative drugs should be tried.For most people, ART preserves and restores immune function and extends survival. However, in every HIV clinic, a small group of patients fail to reconstitute CD4 cells despite ART and viral control. These ‘immune non-responders’ (INRs) are often older (> 45 years), start ART late, begin ART at a very low CD4 nadir/baseline , malignancies and rheumatological conditions such as systemic lupus erythematosus (SLE), rheumatoid arthritis and drugs that are used to control these conditions.In addition to this group are those HIV-infected with identifiable causes of immune suppression, for example, steroid use, alcohol abuse, herbs such as the ‘African potato’, chemotherapy, infections such as TB and Management of the comorbid condition or removal of the offending toxin, for example, alcohol or steroids, may improve the immune response of these patients. The likelihood of cannabinoid use influencing the human immune system either negatively or positively is currently unknown. If these agents are indicated for the palliation of symptoms, it seems reasonable to continue to monitor CD4 response as per the usual intervals recommended in current ART guidelines.26 Another observational study that included data from South, Central and West Africa found that age, gender and baseline CD4 cell count continued to predict death at 6, 12, 24 months and beyond while taking ART.27 These factors indicate the need of palliative care but are not to be used to define ‘therapeutic futility’, that is, the discontinuation of active care. In every circumstance, the patient must be treated with dignity and respect and every attempt made to correct the underlying life-threatening process and to offer where possible, life.While all should be able to access the costlier components of a palliative care service, for example, admission to hospice and home nursing, it is acknowledged that the capacity of palliative care services in SA is limited. Who are in greatest need? No randomised, controlled palliative care trial addresses this question directly. Nevertheless, several observational studies have identified associations that provide some answers see ; these i28 However, given the potential for ART to reverse underlying disease in the HIV-infected – the Lazarus effect – the absolute score must be viewed with caution. The usefulness of the Karnofsky score as a measure of impending mortality in this group of patients has not been established  are used in the United Kingdom and have been applied to patients with HIV and cancer.29 The tool is not specific to HIV and does not consider the role of ART and the curative potential of the treatment in several life-threatening infections, for example, sulfonamides in cerebral toxoplasmosis and Pneumocystis jiroveci pneumonia (PJP), TB drugs in disseminated TB, antifungals in cryptococcal meningitis (CM), et cetera.The Support and Palliative Care Tools A low BMI  prediction of survival (death) following the start of ART. Although the data reflect the experience of high-income countries and examine the risk of death in patients already on ART, the database is large, the index has wide applicability and its predictive value is superior to individual and composite indices currently in use.32 Most of the indices used in this system, with the exception of baseline hepatitis C virus (HCV) serology, are routinely performed in the public sector in SA. Local HCV prevalence is low (viz. 3% – 5%) and the absence of this index in the calculation of the score is unlikely to influence the result (see This scoring system (Veterans Aging Cohort Study – VACS index)33 ‘[a]ny attempt at prognostication that does not address whether the patient has had an adequate trial of ART would be ill-informed and inaccurate’.According to Merlin et al.,33 although no similar timeline has been formally adopted in SA. While the VACS index has definite merit, it was not intended to answer the question of eligibility to specialised hospice benefits, namely, home care and hospice admission. The SPICT tool has wide applicability but fails to take in the reversal of clinical disease on ART. This committee recommends the use of the SPICT tool where ART is unlikely to improve outcome, for example, end-stage cancer and irreversible end-organ failure, or where current or future ART is judged by the medical and palliative care team to be futile. With regard to patients in SA’s private sector, provision of palliative care and hospice benefits is addressed in and supported by the South African Medical Schemes Act 131 of 1998.35 At this time, it is recommended that Medical Schemes utilise the SPICT tool when considering the reward of hospice benefits and/or the ≤ 6 month estimated survival time as practised in the United States. However, the patient must be on ART or switch to active ART if treatment failure has been confirmed and where ART remains a therapeutic option. Every HIV-infected person should be given the opportunity to access ART and enjoy its benefits. Where a patient refuses to take ART, yet requires hospice admission, addressing the patient’s immediate need is of primary importance and the question of starting ART can be postponed.In the United States, an estimated life expectancy of ≤ 6 months is a sufficient reason to access hospice support,36, p. 2232)Of all treatment modalities reviewed, the best evidence for pain reduction averages roughly 30% in about half of treated patients, and these pain reductions do not always occur with concurrent improvement in function. These results suggest that none of the most commonly prescribed treatment regimens are, by themselves, sufficient to eliminate pain and have a major effect on physical and emotional function in most patients with chronic pain. 60402-9Pneumocystis jirovecii pneumonia; CCM, Cryptococcal meningitis.ART, antiretroviral therapy; FBC, full blood count; U&E, urea and electrolytes; LFT, liver function test; HBV, hepatitis B virus; HCV, hepatitis c virus; TB, tuberculosis; PJP, 31 Pain in HIV-infected South Africans is likely to accompany an identifiable clinical cause and the most valuable contribution the HIV and palliative care physician can make to pain management is to identify the cause and treat it. The severity of the pain must be documented: ask the patient to describe the pain and to rate it on a scale of 0 = ‘no pain’ to 10 = ‘the worst pain I have ever experienced’. Can the pain be fitted into a recognisable pattern, for example, peripheral neuropathy, post-herpetic neuralgia and meningeal irritation, or is it associated with a specific site or organ, for example, perianal ulcers and bedsores, pulmonary or pleural disease, a tumour such as Kaposi’s sarcoma or a collection of enlarged lymph nodes? While the clinical examination will provide some answers, a pain assessment chart will ensure that no aspect of the pain is omitted 31067-X36 Ideally, the team should offer, in addition to good medical and nursing care, most or all of the following:The control of pain is a priority and must be addressed as soon as the patient arrives at a clinic or the admission ward. Tests to confirm the diagnosis are important but must not be allowed to delay the treatment of the pain, which works best when given by an interdisciplinary team.physical rehabilitationexercise therapycognitive restructuring that emphasises self-management, self-efficacy and resourcefulness, that is, activity rather than passivity, reactivity, dependency and hopelessnessbehavioural treatment, for example, relaxation and/or engagement in activities that enhance functionalityvocational rehabilitation if long-term survival is not in doubtNota bene evidence-based support for opioids as improvers of chronic pain and functionality is weak; therefore, their use must be measured against their risks, for example, addiction, hypogonadism, falls and fractures, depression, overdose and death.36drug management – in particular, the avoidance or reduction of opioid dependency. 38 , aspirin and the non-steroidal anti-inflammatory drugs (NSAIDs) and ending with the opioids or combinations of opioids and non-opioids38 .39 In this assessment, only the following aspects of pain care received unanimous – ‘strong quality, high level’ – support:The 2017 Chronic Pain Guideline of the HIV Medicine Association of the Infectious Diseases Society of America (IDSA) provides an evidence-based evaluation of pain and its management in the HIV-infected people.Any ‘new pain’ in a patient with previously controlled pain needs fresh re-assessment.Acetaminophen and NSAIDs are the first-line agents for the treatment of musculoskeletal pain in persons living with HIV.Topical capsaicin is indicated for chronic HIV-associated peripheral neuropathy in conjunction with additional analgesics and supportive therapies and adequate viral control.Screen all with chronic pain syndromes for depression, that is, direct questioning, via a depression questionnaire and/or through a psychiatric referral.Additional remarks that scored well  but did not secure unanimous support from reviewers included:The re-evaluation of pain among those with a ‘changing experience of pain’.The ‘immediate or early’commencement of ART in those with a sensory polyneuropathy believed to be caused by HIV infection.Gabapentin, with dose escalation up to a maximum of 2400 mg daily po in divided doses, is recommended as the first-line oral treatment of chronic HIV-associated neuropathic pain (the authors note that somnolence occurs in 80% and can be problematic). The serotonin-noradrenaline reuptake inhibitors, tricyclic antidepressants and pregabalin received only weak or moderate support.Despite the absence of RCTs in HIV-related pain syndromes, Alpha-lipoic acid (ALA) received support for neuropathic pain treatment in view of its confirmed role in diabetic neuropathy, a condition that also targets the peripheral nerves.36Opioid analgesics are not indicated for first-line control of neuropathic pain or chronic pain syndromes. Tramadol, a combination opioid, that is, a serotonin + noradrenaline reuptake inhibitor + a µ-opioid agonist, received support, however, for use in several non-cancer pain syndromes, including osteoarthritis, fibromyalgia and the neuropathic pain syndromes.Opioid therapy is often the treatment of choice for patients with cancer and those having moderate to severe pain.39 Although the WHO analgesic ladder recommends different opioids for different levels of pain, for example, codeine for moderate pain and morphine for severe pain, cautious dose escalation using the initial opioid may avoid an unnecessary switch.40 Morphine can be given by several routes and subcutaneous, intramuscular and intravenous injection should be considered for those unable to swallow. Fentanyl is given by injection and transdermal skin patch but is not widely available to public sector patients in SA. Unwelcome respiratory complications can be avoided with careful monitoring of opioid dose increases, which is particularly important where patients and families have expressed a desire for a pain-free yet lucid end to life.Drug–drug interactions are important to note. Many drugs used in pain control, for example, opioids, benzodiazepines, antidepressants and sedatives, are substrates of the cytochrome P450 (CYP450) family of enzymes. Strong inducers or inhibitors of CYP450 will reduce (inducers) or potentiate (inhibitors) serum levels (efficacy and toxicity) of these drugs. Several antiretrovirals (ARVs) – especially the non-nucleoside reverse transcriptase inhibitors , protease inhibitors (PIs – inhibitors) and drugs commonly used in the management of the HIV-sick, for example, rifampicin (inducer) for TB, carbamazepine and phenytoin sodium (inducers) for seizures, will influence the activity of substrates of this enzyme pathway see .41 should not be withheld from people in need in low- and middle-income countries (LMICs), for example, Africa and Asia. The authors of a recent Lancet Commission on Palliative Care and Pain Relief provide data to show that this happens:The non-medical use of prescription opioids, which has become a major public health issue in the United States and Europe,42 (p. 1391)The fact that access to such an inexpensive, essential and effective intervention – opioid use for pain relief – is denied to most patients in LMICs and in particular to poor people – including many poor or otherwise vulnerable people in high-income countries – is a medical, public health and moral failing and a travesty of justice.The Commission notes that the 10 health conditions that result in the largest numbers of patients seeking palliative care in LMICs, namely, malignancy, cerebrovascular disease, lung disease, injuries, TB, premature birth, HIV, liver disease, non-ischaemic heart disease and dementia, also account for about 95% of days of serious health-related suffering reported in these countries.43 In situations of inadequate food intake and altered food metabolism, weight loss may become severe. With every 1% increase in unintentional weight loss from the baseline measurement, there is a detectable increase in the risk of death of the HIV-infected patient.44 The lower the BMI, that is, below the normal value (BMI 18 kg/m2 – 20 kg/m2), the greater the risk.45Increased resting energy expenditure (REE) is a persistent accompaniment of HIV infection despite the use of ART.Possible clinical conditions include:oesophageal candidiasis and cytomegalovirus (CMV) infection and ulceration.Disease of the mouth and upper gastrointestinal tract (GIT), for example, TB (drug-resistant TB) or MAC. Drugs: Chemotherapy, lopinavir/ritonavir.Anorexia. Consider medication, tumour and occult infection, for example, Food insecurity. Particularly among refugees, migrants and the poor.GIT-TB or MAC, tumour of the GIT. Send repeated stool samples (× 3) for parasites: Cryptosporidia, Cystoisospora spp. Poorly controlled HIV infection = HIV enteropathy.Malabsorption, for example, chronic diarrhoea, end-stage HIV, TB, MAC and CCM.Infection, particularly tumour.Disseminated Hormonal deficiencies, for example, Addison’s disease, hypothyroidism and hypogonadism.(Bold indicates conditions that are frequent among the HIV-infected patients.)Management: The HIV clinician will look for treatable causes but as the patient approaches death, symptomatic treatment will take priority. Start ART if the patient is treatment naive or check for resistance if on ART and the VL is detectable. Glucocorticoids, for example, dexamethasone 2 mg daily po or IV–4 mg daily po or IV, can be considered at the end of life as the risk of additional immunosuppression is unlikely to influence the outcome. Steroids are often given to stimulate the appetite and/or to counter the fatigue and weakness of the final illness. Vigilance is indicated if steroids are given for a prolonged period of time and patients should be monitored for hypertension, hyperglycaemia, gastrointestinal bleeds, fluid retention, proximal myopathy, confusion and psychosis. Testosterone has benefited hypogonadal individuals with fatigue46 and the stimulants, modafinil and armodafinil, have had success in reducing fatigue in small RCTs, but caution is advised in view of limited data and the risk of drug abuse.31 Invasive procedures, such as nasogastric feeding and percutaneous endoscopic gastrostomy, are discouraged at the end of life but may be considered where a reversible condition has been identified. Ensure good nursing, keep the oral mucosa clean, moist and wet and mobilise the indigent patient where possible. Avoid bedsores and treat oral thrush with topical nystatin drops 2 mL – 5 mL ‘swish and swallow’ five times a day or oral fluconazole 50 mg – 100 mg daily until the infection clears. If oesophageal candida is diagnosed, give oral fluconazole 100 mg – 200 mg daily for 7–10 days. A short course of IV amphotericin B can be considered if the patient is unable to swallow the fluconazole. Treat oral and oesophageal Herpes simplex aggressively, prescribe oral acyclovir (public sector) or valaciclovir (private) if the infection is mild and confined to the mouth and IV acyclovir for disease that is extensive, virulent or involves the oesophagus. Continue treatment until the infection has cleared, usually for 7–10 days, and control the pain that often requires strong analgesia, for example, codeine or tramadol. Food should be liquidised or very soft to minimise oral pain while the infection is acute.46 Disease at any of these sites may be responsible for cough; however, in HIV-infected patients, cough usually directs attention to the lung. An acute cough lasts from a few days to a few weeks and a chronic cough lasts for ≥ 8 weeks.47The anatomic connections that control the cough reflex link the upper and lower airways to afferent and efferent neural connections within the brain.Symptoms of dyspnoea and cough include the following:Bacterial pneumonia: Productive cough, fever, chest pain, sudden onset and acute history. Aspiration pneumonia is frequent at the end of life.Pulmonary TB (PTB): Productive cough, haemoptysis, chest pain, fever, night sweats, weight loss, chronic history or past history of TB, and TB contact history.PJP: A dry incidental chronic cough, worsening dyspnoea with effort, later dyspnoea at rest, severe hypoxia at rest, worsens with exertion, little or no fever, minimal chest pain, profound fatigue and exhaustion, tachycardia and unrelenting tachypnoea. Often a bedside diagnosis!■PJP: Poor prognosis. The persistence of hypoxia or respiratory failure, tachypnoea and tachycardia despite treatment, no decrease in baseline LDH level with treatment, worsening of the chest X-ray (CXR) on treatment, elevated Acute Physiology and Chronic Health Evaluation (APACHE) II score.49■PJP: Prevention. Initiation onto ART soon after the initial infection with HIV and prophylactic use of trimethoprim-sulfamethoxazole with all baseline CD4 cell counts < 350 cells/mm3 are recommended.51■PJP: Ethics. The decision to admit to the intensive care unit (ICU) and to ventilate usually rests with the ICU clinician or resident pulmonologist; however, this action may be futile, that is, it does not guarantee success or survival. The palliative care team must make itself familiar with this scenario in order to provide wise support (insight and understanding) to patients and colleagues and, where possible the death of a patient in the ICU and on a ventilator should be avoided. This is a source of great suffering for patients and their loved ones, although it is best managed through discussion with the patient, family and friends before the urgent need of ICU admission and ventilation arises.47Causes of dyspnoea and cough include the following:Acute infection: Trachea-bronchitis, pneumonia .Chronic infection: Bronchiectasis, chronic lung infection , fungi , protozoa (toxoplasmosis) and rarely helminths.Airway diseases: Asthma, chronic bronchitis, postnasal drip.Diseases of the parenchyma and vessels of the lung: Chronic interstitial lung disease, emphysema, sarcoidosis, pulmonary vascular disease, namely, embolic, vasculitis, pulmonary hypertension.Tumour: Primary and secondary tumours of the lung and chest cavity.Cardiovascular disease: Left ventricular failure, right-sided endocarditis.Anaemia: Severe dyspnoea, Hb < 8 g/dL.GIT: Acid reflux, aspiration pneumonia (cough often at night).lactic acidosis , renal tubular acidosis (tenofovir disoproxil fumarate): Tachypnoea and dyspnoea but with normal oxygenation (p02), chest auscultation normal, CXR clear.Metabolic acidosis: Diabetic ketoacidosis, Drugs: Angiotensin-converting enzyme (ACE) inhibitors (cough).Bold indicates conditions that are frequent among the HIV-infected patients.) lung disease whether from previous TB or from COPD, may not be reversible and will require palliation. Blood gas measurements, blood transfusion, intubation and ventilation are likely to be inappropriate when death is imminent. Supportive care such as oxygen, bronchodilators, steroids and antimicrobials may be prescribed if indicated and diuretics may be needed to treat pulmonary oedema and fluid overload. Opioids are regarded as the treatment of choice for dyspnoea in the context of end-of-life care. These can be given safely, that is, without the risk of respiratory depression, if titrated carefully with attention to dose and response.38 In addition, the careful use of benzodiazepines may relieve anxiety associated with breathlessness and asphyxiation.38Specific end-of-life therapies include the following:Morphine: 5 mg po– 10 mg po every 30 min as needed until the patient is comfortable, or IV 2 mg – 4 mg every 30 min to 1 h as needed until the patient is comfortable.Oxygen: Adjust to achieve satisfactory saturation and subjective relief of dyspnoea.Non-pharmacologic measures: Support, relaxation and breathing exercises, et cetera.Causes of dry mouth include:Poor oral immunity: Often a sign of advanced HIV and AIDS with or without HIV-associated dementia (HAD); poorly controlled diabetes mellitus, gingivitisoral candidiasisInfection: Chronic parotitis, salivary duct obstruction , extensive Autoimmune: Sjögrens syndromeDrugs: Anticholinergics, alpha- and beta-blockers, diuretics, calcium channel blockersPost-irradiation, for example, cancer of the head and neck.Bold indicates conditions that are frequent among the HIV-infected patients.), stop offending drugs (above), artificial saliva.Nausea is defined as the subjective feeling associated with the action of vomiting. Identify and treat the cause, including the common associations mentioned below:Gastroenteritis, intestinal diseases Abdominal conditions: CNS disease, for example, meningitis and raised intracranial pressure (RICP); Anxiety and fear; cardiac, for example, acute myocardial infarction; endocrine, for example, pregnancy, diabetic ketoacidosis; pancreatitis; end-organ failure, for example, renal (uraemia), liver disease, adrenal failure (Addison’s disease)General causes: Middle ear and ARVs ; antimicrobials ; chemotherapy (oncology); digoxin; opioids; alcohol-intoxication, et cetera.Drugs: Bold indicates conditions that are frequent among the HIV-infected patients.), glucocorticoids (e.g. methylprednisone), dexamethasone or with cannabinoids (e.g. tetrahydrocannabinol) (see Section 7).Suggested end-of-life treatment:Bowel obstruction: Octreotide 100–200 µg subcutaneous injection 3 times a day or 100–600 µg per day in an IV infusion. Should a nasogastric tube (NGT) be placed? Where the likelihood is that this will provide little or no improvement and where the expectation is that death is within hours or a few days, it is more humane to withhold NGT and maximise alternative forms of symptomatic relief.Dexamethasone 4 mg po/IV–8 mg po/IV daily: maximum 16 mg daily.Gastroparesis:Metoclopramide 10 mg po/IV–20 mg po/IV every 4–6 h: maximum 100 mg per day.Elevated intracranial pressure:Dexamethasone 4 mg po/IV–8 mg po/IV daily: maximum 16 mg daily.Unspecified cause but including chemotherapy:■Metoclopramide 10 mg po/IV–20 mg po/IV every 4–6 h: maximum 100 mg per day.■Haloperidol Oral: 1.5 mg–5 mg 2–3X per day IV: 0.5 mg–2 mg every 8 h.■Ondansetron 8 mg po 8 h as needed.■53Dexamethasone 4 mg po/IV–8 mg po/IV daily: maximum 16 mg daily. Usually combined with other anti-emetics.This is defined as infrequent emptying of bowel or rectum often with a sensation of incomplete evacuation. It is seldom secondary to a significant medical problem.Acute or recent onset: Local problem .Chronic: Irritable bowel syndrome; hypothyroidism; hypercalcaemia; pregnancy; chronic CNS disorders ; drugs .Bold indicates conditions that are frequent among the HIV-infected patients.) including vegetables and fruit. The following medicines can be tried: lactulose, psyllium, bisacodyl and fleet enemas. Management must be expectant and preventive.Suggested end-of-life care:Senna 2–4 tabs (8.6 mg sennosides per tab) or 1–2 tabs as a single daily dose or in two divided doses per day. Do not exceed 100 mg per day.Bisacodyl suppository: 10 mg given rectally per day as needed.Fever in someone with HIV infection usually suggests an infectious complication. The constellation of fever, cough, weight loss and night sweats in an HIV-infected person in Africa indicates a heightened suspicion of tuberculosis. However, TB must be confirmed as it is a treatable, transmissible disease and its presence puts others at risk. Even at the end of life, TB must be diagnosed, treated and controlled and it is particularly important to check whether the disease is drug-resistant or not . Even in the context of palliative care, patient isolation and infection control measures must be implemented.If fever is part of an end-of-life infection, such as an aspiration pneumonia, the patient and his or her family may resist the idea of prolonging the inevitable with antibiotics and active interventions. The task of the palliative care team is to assist the patient to face the inevitability of death yet at the same time the team must agree to do all that it can to minimise suffering, that is, to support the patient. This is where the palliative care physician and team provide what is frequently missing from the wards of our South African hospitals as death should be about healing even when the latter is not delivered by way of pills, lines and procedures.Management: Treat the cause when a fever is indicated. Paracetamol, aspirin, NSAIDS and sometimes steroids may assist in controlling it, while tepid sponging, a fan and oral fluids may help to alleviate the patient’s distress. Avoid paracetamol in patients with liver disease. Antimicrobial therapy that is not directed at a particular pathogen or a likely diagnosis is unlikely to be helpful at the end-of-life. Prophylactic trimethoprim sulfamethoxazole is recommended if the baseline CD4 count is < 350 c/mm3 and/or an AIDS-defining illness (or WHO stages 3 and 4 disease) is present.50Suggested end-of-life care:Paracetamol/acetaminophen650 mg po/pr–100 mg po/pr or IV every 4–6 h as needed: maximum daily dose = 4 g.Naproxen 250 mg po bid–500 mg po bid (short course × 2–3 days. Can be repeated).Human immunodeficiency virus infects the human brain. This occurs during the first few weeks following acquisition of the virus and establishes a chronic but usually low-grade infection which persists for the remainder of the individual’s life. Neurological consequences are frequent but generally mild or asymptomatic and usually well controlled with ART. If the patient is naïve to ART or if the virus in the CNS has become resistant to ART, the function of the brain will be impaired for example, HIV encephalopathy. The latter is a life-threatening and dementing process characterised by motor-slowing, abnormal movement  and progressive cognitive decline. Human immunodeficiency virus also attacks the peripheral nervous system (PNS) and is responsible for a painful symmetric sensory polyneuropathy that leaves the individual wheelchair and bedbound and in constant pain. These conditions will usually respond to viral suppression with ARVs tailored to treat the CNS infection. Treatment with ARVs is warranted even in the context of palliation.54 as detailed in Several of the following conditions need to be considered in the HIV-infected patient with serious neurological disease,Management: Treat the cause where identified. Is the patient on ART (efavirenz)? TB drugs (Isoniazid)? Is the HIV infection controlled in the serum and in the CSF?Suggested end-of-life care:Lorazepam for anxiety: 0.25 mg po or IV–2 mg po or IV or S/C every 4–6 h as needed. Increase the dose to 5 mg if necessary.Haloperidol for delirium: 0.5 mg po or IV–1 mg po or IV every hour as needed. When symptoms have settled, give the daily total dose in 3–4 divided doses through the day.60 On the back of this, the growing numbers of HIV-infected persons with cancer, a so-called ‘hidden cancer epidemic’ in LMICs, is of concern.62 More than a decade ago, South African researchers recorded the prevalence of several cancers among HIV-infected South Africans63  than in high-income regions for example, Europe and North America (46%).ns63 see . Odds raEstablishing early linkage to care, particularly to palliative and HIV care, is essential if the goal of improved survival and the relief of suffering is to be reached. However, several hurdles must be overcome:Late presentation. Stigma, misunderstanding and denialism continue as barriers to early detection of HIV and cancer. Patients present at an advanced HIV stage, naïve to ART, with a low baseline CD4 level and multiple competing diagnoses.Delays in receiving cancer treatment. Large number of patients, few or inadequately skilled staff, insufficient specialists and unsupportive management cause delay in treatment. In many instances, patients die before test results return and before a link with oncology and radiotherapy is made. Thirty African and Asian countries have no radiotherapy machines and in many LMICs, oncologists, if present, are restricted to the largest cities.66Laboratory support. Obtaining reports, for example, biopsy (histology) results, in the public sector in SA is plagued by long delays, while histology reports in the private sector return within a couple of days, and oncology referrals in the public sector cannot be processed without the confirmatory histology. In the absence of histological confirmation, patients die while awaiting their test results or while awaiting their oncology appointment.HIV and cancer therapy. Chemotherapy in Africa and SA’s public sector is frequently characterised by the ongoing use of drugs that are no longer viewed as optimal in developed regions.67 Problems include post-chemotherapy neutropenia, HIV immunosuppression, antimicrobial resistance, frequent drug stock-outs and drug–drug interactions between cytochrome P450 substrates, inducers and inhibitors, and ARVs.How can the HIV-infected cancer patient be better served?Prevention■Tobacco use control■Hepatitis B vaccination■Hepatitis C serology and access to directly acting antivirals (DAAs)■Human papillomavirus (HPV) vaccination■Cervical and anal Pap smears■The early introduction of ART. Uncontrolled plasma (HIV) viral load is associated with the increased risk of malignancy in the HIV-infected cancer patients.69Baseline determination of HIV status of every cancer patient. Survival of the HIV and cancer patient requires access to ART and long-term suppression of HIV.71Linkage to care. The ethos of this care is holistic, that is, oncology, HIV-caregivers and the palliative care team work together in the support of the patient.Collaboration is needed between oncology and radiotherapy and the disciplines of HIV/infectious diseases and palliative care. Cancer care in SA must be sensitive to the needs of the HIV-infected people, and greater collaboration between HIV, palliative care physicians and oncology and radiotherapy specialists must take place if weak links in healthcare delivery are to be strengthened. Antiretroviral drugs and regimens are constantly changing, drug–drug interactions and toxicities are common, and secondary infection with opportunistic microbes frequently occurs. A team approach is required to improve the survival outcome in this group of patients.72 An observational study in > 3000 cancer patients found that cannabis improved sleep, anxiety and depression levels and reduced the fatigue, nausea and vomiting caused by chemotherapy.73 A report of 198 HIV-infected ‘heavy’ cannabis users found reduced activation of inflammatory markers compared with non-cannabis using controls; however, there is clearly a need to better clarify the role of the cannabinoids in evidence-based, well-planned RCTs of the HIV-infected and uninfected people.74 The 2016 Johns Hopkins-Lancet Commission on Drug Policy and Health makes the additional point: ‘At a time of policy-level concern about dependence on prescription opioids, a few ecological studies suggest that greater access to cannabis could reduce use of opioids for pain relief’.75South African courts have recently legalised cannabis for medical use. Data on HIV-infected people are sparse and restricted to observational reports, and although the use of these compounds is widespread both in Africa and globally, the hostility to its use is slowly changing. Nonetheless, data are beginning to emerge see .72 An ob72Cannabinoid side effects are common, usually dose-dependent, that is, higher doses tend to produce more side effects, and are often specific to individual compounds see . These s72:With regard to the role of cannabinoids in the palliative care of HIV-infected patients, several ‘unknowns’ remain, for exampleIndications for use of cannabinoids require urgent clarification.The pharmacokinetics and pharmacodynamics of cannabinoids in people naïve to and those with prior exposure (to cannabinoids) in the context of palliative care. Does this differ? Do cannabinoid-exposed people require a higher dosing of cannabis?Drug–drug interactions between the cannabinoids, ART and TB drugs have minimal or no data.Which route of administration should be recommended: oral, inhaled (smoked)?It was the general belief in the 1980s that a vaccine and cure would have been found by the end of that decade or at the latest, that is, the middle of the 1990s. That did not occur, and the HIV epidemic is now firmly rooted in southern African soil. Antiretroviral therapy has transformed the infection into a chronic, manageable disorder yet the condition remains incurable. About 8 million HIV-infected South Africans need care and will die from or with the virus. Their suffering is the concern of these guidelines as many will require palliative care see .78The ‘total pain’ that accompanies suffering arises from multiple causes. Analgesics alone do not effectively control this pain although palliative care teams throughout the country’s health service would go a long way to answer this need. Even highly motivated teams require funding, organisation and the support of colleagues and government in a country where its public health is in trouble: underfunded, overcrowded, ageing facilities in need of renewal and a department facing extraordinarily high levels of litigation.75Developing a discipline of palliative care and fitting it into this failing system at this time will be a testing experience, but it must happen. Somehow.TM tool.The private sector must find a reliable tool that funders can use when providing capital for home nursing and hospice admission. A life expectancy of 6 months or less is a widely used rule of thumb in the United States, although available models are generally insensitive to the gains of ART and the treatment of opportunistic disease. No local RCTs answer this question; nonetheless, our recommendation has been to follow the US approach and use the 6-month probability of survival or the SPICTThe defining treatment ethos of HIV and ID clinicians is curative. There is no conflict between curative and symptomatic management provided the goal to treat suffering is central to care. Is there a time where curative care is no longer appropriate? Is there a time to let go of ART? Yes. Those of us who are hospital-based clinicians encounter these questions daily in our wards and clinics. The answers are not usually found in textbooks but at the patient’s bedside.


N = 169) and 57.3% were females (N = 227). Their ages ranged between 25 and 72 years . Participants answered a questionnaire that assessed psychological flexibility, mindfulness, sources of stress at work and health benefits. In a bivariate analysis, managerial factors (MF), relationships, and intrinsic factors are partially negatively related to psychological and physical health; whereas, multivariate analyses show that psychological flexibility does not moderate the relationship between psychological and physical health. Instead, mindfulness is strongly and consistently correlated to psychological and physical health. Employees who show psychological flexibility, are more likely to show greater openness to the acceptance of setbacks in the working environment and to carry on their valued living and working path. This seems to correlate positively on individual wellbeing. Data show that a flexible and mindful attitude toward difficult psychological events aids responsiveness to changes and the ability to work more effectively.Research in organizational psychology emphasizes the idea that wellbeing and productivity outcomes are influenced both by individual differences  and work environment characteristics . Evidence on the effectiveness of psychological interventions for stress is currently unclear. To date, research on psychological flexibility in workplaces has not been systematically conducted in Italy. We investigated its relevance in the context of the Italian health care system. In this study, the relationship between sources of stress at work and its outcomes in terms of psychological and physical health are explored. Furthermore, the moderating effect of psychological flexibility and mindfulness on psychological and physical health are investigated. Four hundred and eleven health workers from a Sicilian hospital, with different job positions were recruited, of which 42.7% were males ( Psychological flexibility is defined as being in contact with the present moment, fully aware of emotions, sensations, and thoughts, welcoming them, including the undesired ones, and moving in a pattern of behavior in the service of chosen values. In simpler words this means accepting our own thoughts and emotions and acting on long-term values rather than short-term impulses, thoughts, and feelings that are often linked to experiential avoidance and a way to control unwanted inner events . AcceptaThere is good empirical evidence that targeting psychological flexibility with an ACT protocol is beneficial for a range of clinical disorders including anxiety, depression, and post-traumatic stress disorders , and witResearch in healthcare settings has mostly focused on organizational aspects around workplace conflict and safety perception such as workload, relationship to management, colleagues, work position, and home. Studies have largely neglected to investigate the role of factors associated with Psychological Flexibility patterns, which have been related to adaptive responses to heavy stressors, both in terms of frequency and intensity, like those found in hospitals .1.Occupational stress is a serious health issue affecting organizations and employees. Over the last few years in Italy, many changes have occurred in workplaces that led to organizations focusing more on work-related stress. The introduction of a specific law on safety in the workplace, Dlg. 81/2008 (recently updated in July 2018), made it mandatory for organizations to carry out work-related stress risk assessments, and implement, when necessary, actions aimed at preventing, reducing, and eliminating sources of risk 1.2.Nowadays in all working contexts there is an increased awareness of the negative impact of stress on the physical, psychological, and social health of individuals . In the Stress and Psychological Flexibility are two intertwined constructs. In In the last decades, the idea of wellbeing counteracting work related stress has been linked not only to the individual employees’ characteristics  but also the whole organization itself, conceptualized as a complete organic system. Organizational wellbeing is thus related to all organizational aspects including climate, culture, and performance.In healthcare settings, contact with ailing patients and their relatives represents an emotionally complex situation which, if not properly managed, may in the long-term threaten the psychological health and quality of life of healthcare workers and consequently negatively impact their performance. In this context, healthcare workers’ inner states  are fundamental to how these stressors are handled. Attempts to avoid thoughts, feelings, and emotions that occur under various stressful conditions in hospital settings have been found to relate to stress, absenteeism, depression, and ineffective communication or interpersonal relationships, rather than a lack of technical skills . In the An increasing number of studies on experiential avoidance and thought suppression point to the fact that mental health and everyday behavioral patterns of action are influenced more by the way people relate to their thoughts and feelings than by their actual form  . For exaPsychological flexibility is founded on the six core ACT processes: defusion, acceptance, present moment, self-as-a-content, values, and committed action. ACT uses acceptance and mindfulness strategies to develop committed behavior change by increasing it. Where the established operational definition offered by On the other side of psychological flexibility there is inflexibility. Experiential avoidance is the process at the core of the empirically based conceptualization of psychopathology in the ACT model . In ACT Within this theoretical framework and application in organizations, ACT  is proviSimilar results were obtained by Another interesting result that emerges from research data is the link between psychological flexibility and the construct of job control, defined as the perceived ability to exert influence over one’s work context to make it more rewarding and less threatening. It is therefore important to analytically assess the conditions under which stress occurs both to guide the choice of the type of intervention to be implemented, but also to clarify to trainers and trainees the current situation and modifications that can be obtained. To accomplish this integrated assessment, numerous tools are available in literature .Different studies  have alsBased on recent risk management theories, there is a need for specific plans aimed at identifying, analyzing, assessing, and constantly monitoring the possible risks of stress in the workplace, in order to prevent or avoid damaging effects. Risk management is a recursive process, where initial identification of risk factors is followed by periodic cycles of evaluation and interventions to progressively optimize organizational aspects that reduce risk and increase the wellbeing of employees .In general, the results of these studies within organizational contexts highlight how ACT-based interventions, which build psychological flexibility positively influence individuals and make them more aware and responsive to change and enable them to work more efficiently. More flexible workers are therefore able to notice, with greater openness, opportunities where they can express their valued pattern of behavior in the workplace and this seems to correlate positively on their individual wellbeing . Thus, iIn our study, we aimed to investigate the relationship between sources of stress in the workplace, focusing more specifically on managerial factors (MF) such as both power and decision, relationships at work, intrinsic factors and, psychological and physical health. Furthermore, the moderating effect of flexibility  and mindThe present study aimed to investigate how flexibility and mindfulness buffer the relationship between MF, both power and decision, relationships at work, intrinsic factors, and psychological and physical.The following hypotheses were proposed:Managerial factors, both decision (H1) and power (H2), relationships (RF: H3), and intrinsic factors (JF: H4) are negatively related to psychological and physical health.Flexibility will moderate the relationship between MF (power: H5 and decision: H6), relationships (RF: H7), and intrinsic factors (JF: H8) on psychological and physical health.Mindfulness will moderate the relationship between each independent variable: Managerial decision (H9), managerial power (H10), relationships at work (H11), and intrinsic factors (H12) on psychological and physical health.z value was equal or over ± 3, then, according this criterion  The Internal Review Board (IRB) of the Faculty of Human and Social Sciences at the “Kore” University of Enna approved the present research. The data were collected from February to December 2017. All participants were asked to complete a questionnaire, with 411 workers choosing to participate (95% response rate). Missing data were analyzed and outliers were screened in the dependent variables  to test research hypotheses for each record. No missing data were over 5%, no records were deleted according to this criterion . We stanriterion  no outliN = 169) males and 57.3% (N = 227) females. Their average age was 49.16 years (SD = 8.65). Sixty-seven (19.5%) of them were physicians, 148 (43.1%) nurses, 44 (12.8%) administrative staff, three (0.9%) psychologists, 14 (4.1%) hospital staff, and 167 (19.5%) other health professions. Tenure average was 15.42 (SD = 8.63) years. The characteristics of the sample are reported in Respondents comprised 42.7% (N = 650) versus 27% (N = 370) being physicians.Although the sample is strongly weighted toward nurses who comprise 43.1% of the sample , it reflects the distribution of the hospital workforce with around 48% being nurses , relationships at work (RF: 10 items) and intrinsic factors (JF: 9 items). Examples of item themes are: Lack of power and influence, management or supervision of other people’s work, having too many things to do. We re-phrased some of the OSI items to reflect direct statements. The response scale ranged from 1  to 6 . Coefficients alpha assessment of scale reliability was 0.80.•Individual consequences of stress – sub scales: Psychological (PSYTH: 18 items) and physical (PHIT: 12 items) health; both deriving individual scores. Examples of PSYTH items are: During the day, there are moments when you feel worried, upset, useful, confident. We re-phrased some of items to reflect direct statements. Examples of PHIT items are: Did you notice any symptoms over the last 6 months, like lack of appetite, or headache, or noise. The response scale ranged from 1  to 6 . Coefficient alphas were 0.79 for the PSYTH sub-scale and 0.85 for the PHIT sub-scale.MAAS – Mindfulness Attention Awareness Scale  is a 15-AAQ. II – The Acceptance and Action Questionnaire - II  focuses Participants were also asked to provide information on socio-demographic characteristics, such as gender , age, school grade, and occupational history that may be associated with psychological stress, including: type of contract (such as long-term or fixed-term contract), time of contract (full or part time), work position, shift work, years of service, hours of service for day .p < 0.05. Hypothesis testing (main effects and moderation) was conducted using Structural Equation Modeling (SEM). Data analysis was performed by using SPSS version 22.0, including the AMOS statistical package.Before testing our hypotheses confirmatory factor analysis (CFA) and descriptive analyses were computed. CFA was conducted to examine the factorial structure of the measures used in this study through maximum likelihood estimation. Descriptive analyses  were computed to pre-investigate the data as shown in Confirmatory factor analyses affirmed that seven construct measures could be treated as unidimensional, and one as bidimensional with fit indices satisfying standard criteria  >0.90, Confirmatory factors analyses results are reported below:2 = 35.531, df = 19, p = 0.012, χ2/df = 1.870, CFI = 980, TLI = 0.970, SRMR = 0.034, and RMSEA = 0.046), when the covariance error between two pairs of similar items in the same factor was specified. The composite reliability was 0.80.CFA supported the one factor structure , when the error covariance between four pairs of similar items in the same factor was specified. The composite reliability was 0.79.CFA supported the one factor structure , when the latent factors were allowed to covary. The two managerial power and decision factors were, respectively, constituted by five and four items. The value of the composite reliability was 0.78 for managerial power and 0.74 for managerial decision.CFA supported the two factors structure . The composite reliability was 0.81.CFA supported the one factor structure . The composite reliability was 0.74.CFA supported the one factor structure . The composite reliability was 0.79.CFA supported the one factor structure . The composite reliability was 0.85.CFA supported the one factor structure .Means (M), standard deviations (SDs), and bivariate correlations for the measured variables are presented in r correlation coefficients between socio-demographic indexes and the psychological variables were statistically significant for: gender and managerial decision, psychological health, physical health, gender, years of experience in organization, and physical health.The Bravais–Pearson’s With regard to the correlations among the psychological constructs: managerial decision, managerial power, relationships, and intrinsic factors showed a significant positive correlation with psychological and physical health; managerial decision, managerial power, relationships, and intrinsic factors were significantly and positively correlated with each other and negatively correlated with mindfulness. Flexibility was not correlated with any psychological constructs.The correlation between socio-demographic indexes  and social-psychological variables was significant (and positive) only for managerial factor (decision and power) and research unit. Managerial factor was negatively correlated with gender. Research unit was negatively correlated with intrinsic factor of work (JF). All other relationships with socio-demographic variables were not significant.Inter-correlations among OSI variables , showed a significant positive relationship with mindfulness and both dimensions of health, but not with flexibility. With respect to mindfulness interaction, results showed a significant positive relationship on all two dimensions of health .Correlations among such aggregates were calculated in order to examine discriminant validity, determining that all constructs in the model are distinct from each other. All the correlations were below the threshold of 0.80 as suggested by In order to explore the research hypotheses on the causal relationships among variables, we used structural equation modeling. Before testing SEM, we performed an Anova test between two different samples  that could have different patterns in physical and psychological health. Then, we tested three alternative models because with the SEM we can only evaluate the degree to which a measurement or path model is consistent with data. A perfect fit is usually trivial because the model includes all possible paths between all pairs of variables e.g., . As the p < 0.05. No statistical differences emerged for Psychological and Physical Health in the two sample groups .An Anova was performed to test subsamples differences in dependent scales’ scores; significance was verified for The first model included the main effects of independent variables .The second model considered the moderating effect of flexibility on the relationship between each independent variable  on psychological and physical health .The last model considered the moderating effect of mindfulness on the relationship between each independent variable  on psychological and physical health .p < 0.001) and physical health ; (ii) Relationship both on psychological  and physical health ; (iii) Managerial decision both on psychological  and physical health  and; (iv) Managerial power on both psychological  and physical health .Positive relationships emerged between the following variables: (i) Intrinsic factors both on psychological , the overall model fit does not provide evidence of an acceptable model. The goodness of fit was evaluated on the basis of the criteria specified from different authors. Such indices are the Tucker Lewis Index  on psychological and physical health. In order to run these models, an interaction term was computed in the model between flexibility and each independent variable, by calculating the multiplication of the standardized variables.p < 0.05), thus H5, H6, H7, and H8 were not supported.The results did not show a significant effect of the interactive term on flexibility ; (ii) Relationship on psychological health . For lower levels of mindfulness, the relationship between managerial decision on psychological health and the relationship between psychological health and relationship  is positive and significant .For higher levels of mindfulness only a moderation effect emerged for the following relationships: (i) Managerial decision on psychological health  and for the second one .These results were confirmed by a good overall fit of the structural model, as evidenced by indices for the first model , where they may be associated with more positive psychological adjustment to stress. Our data partially supports this hypothesis, demonstrating a positive and significant correlation between the effect of independent variables .The second model tested the moderating effect of psychological flexibility on the relationship between MF (power and decision), relationships, intrinsic factors, and psychological and physical health . In this case, our data did not support this hypothesis and showed no significant effect.The last and third hypothesis that mindfulness moderates the relationship between each independent variable  on psychological and physical health . Our data supported this hypothesis, demonstrating a significant effect of the interactive term on mindfulness.Mindfulness is one component of the ACT model related to the left and central processes in the so called hexaflex of psychological flexibility. The second tested model did not offer support for the moderating role of psychological flexibility, while the third model supported the moderating role of mindfulness. This might be viewed as contradictory though it could be explained by several factors. One could be relevant to the 10-item version of the scale, used in the study, which potentially has some drawbacks that led the authors to eliminate three of them in its latest version . In addiM = 3.99 on a scale from 1 to 6), while flexibility was low . So, mindfulness varied enough to play a role as a buffering variable, at least on psychological health. Furthermore, in this context no difference between subsamples were detected. All workers in the hospital perceived a low level of psychological  and physical health  and those, presumably, is given by a relatively good organizational climate.Further, mindfulness showed a high level in this in this study and specific context (To overcome those issues related to the AAQ-II as a broader measure of flexibility, To date, research on psychological flexibility and ACT in workplaces has not been systematically conducted in Italy. Our study provides further evidence that psychological flexibility is a transcultural construct  and thatIn line with literature, overall our data shows the emergence of an association between all the occupational stress factors and individual and organizational symptoms of occupational ill-health in hospitals. ACT-based interventions, for example, found, enhanced psychological flexibility with a beneficial impact in improving job control . By promMindfulness-base ACT protocols have also been shown to be effective in preventing stress-related health issues. Acceptance and Commitment Therapy  is one oThere are some limitations to this study. Generally, it provides partial support to the research hypotheses. Limitations need to be better addressed in future research by using tools such as the WAAQ or the 7-item AAQ to better investigate work-specific and more general aspects of psychological flexibility. Results should be interpreted with caution because of the use of a cross-sectional survey which is not sufficient for establishing a causal relationship. Another limitation of this study was the sampling of work positions with response rates being lower than ideal. This was owing to service contingencies and being an emergency hospital, where not all wards had the available time to take part in the survey. Results may have been affected by specific features of the investigated unit. This research aims to include those departments which were not part of this study. For more complex designs, including intervention studies and cohort designs, larger samples would be required and would allow more sophisticated statistical analysis. We would also like to draw attention to the fact that our sample did not include ethnic and cultural diversity. Our work is not unique in this, but it is an important consideration for future research, particularly in the development of interventions which may be more prone to participant effects, and in which cultural variation may impact patient-perceived acceptability and effectiveness. Thus, for all these limitations, experimental studies are particularly needed.TR and GP conceived and designed the experiments. DB analyzed the data and helped the co-authors conceive and design the research. TR contributed the analysis tools. GS critically reviewed the manuscript. TR wrote the manuscript.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.


Access to food is a basic necessity, and food insecurity may impair the individual’s well-being and health. Self-rated health measurements have frequently been used to assess population health. Little is known, however, as to whether food security is associated with self-rated health in low- and middle-income settings. This study aims at analyzing the association between food security and self-rated health among non-pregnant women of reproductive age in a rural Nicaraguan setting.Los Cuatro Santos in northwestern Nicaragua. Fieldworkers interviewed women about their self-rated health using a 5-point Likert scale. Food insecurity was assessed by the household food insecurity access (HFIAS) scale. A multilevel Poisson random-intercept model was used to calculate the prevalence ratio.Data was taken from the 2014 update of a health and demographic surveillance system in the municipalities of The survey included 5866 women. In total, 89% were food insecure, and 48% had poor self-rated health. Food insecurity was associated with poor self-rated health, and remained so after adjustment for potential confounders and accounting for community dependency.In this Nicaraguan resource-limited setting, there was an association between food insecurity and poor self-rated health. Food insecurity is a facet of poverty and measures an important missing capability directly related to health. Hunger and undernutrition were reduced during the Millennium Development Goal era of 1990–2015. However, food insecurity increased from 2013 to 2016, affecting 815 million people with 689 million people severely food insecure. During that three-year period, food insecurity increased from 4.7 to 6.4% (42 million) in Latin America [The second Sustainable Development Goal (SDG) aims to end hunger, achieve food security, improve nutrition, and promote sustainable agriculture by 2030. It includes targets to end all forms of malnutrition during childhood, adolescence, pregnancy, and lactation . TherefoThe Food and Agricultural Organization defines food security as “a situation that exists when all people, at all times, have physical, social and economic access to sufficient, safe and nutritious food that meets their dietary needs and food preferences for an active and healthy life” . There aStudies in the United States have shown an association between food insecurity and reduced well-being, mental health problems, depression, hypertension, hyperlipidemia, and sleep deprivation . The mecSelf-rated health (SRH) is a proxy measure of health and well-being constructed from individual answers to the question “In general, would you say that your health is excellent, very good, fair, or poor?” Reporting poor to fair health is associated with increased risk of future mortality. This association has also been documented in low- and middle-income countries , althougHealth and well-being is not comprehensively achieved under an economic welfare framework. Single macroeconomic monetary poverty measures used by the World Bank, such as Gross Domestic Product per capita, which classifies nations into high-, middle- and low-income countries, or the proportion of people living below the poverty line, are useful for international comparisons. For an improved understanding of the multi-dimensionality of poverty, other measures and theories, such as the capability approach, are suggested. The capability approach to poverty, initially developed by Amartya Sen, focuses on individuals, and prioritizes the freedom of choice a person has in life to achieve desired outcomes and utilities . This apThe aims of this study were to measure the prevalence of food insecurity and the level of self-rated health in women of reproductive ages in four communities in northwestern Nicaragua, and to analyze whether food security as a capability at the household and community levels was associated with women’s self-rated health.Los Cuatro Santos  reported severe food insecurity among 36% of mothers to children below three years of age in 2009 [Nicaragua is classified as a lower middle-income country. Poverty dropped from 42.5 to 29.6% from 2009 to 2014, which may have contributed to achieving the food security target, halving the number of hungry people in 2015 , 26. How in 2009 . Another in 2009 . As the Los Cuatro Santos are four rural municipalities in northwestern Nicaragua. In this area, a Health and Demographic Surveillance System (HDSS) was established in 2004 with a baseline survey covering socio-economic information, population composition, births, deaths, and in- and out-migration. After the baseline, three follow-up surveys were performed in 2007, 2009 and 2014 including data on social and demographic changes. In the HDSS 2014 update there were around 25,000 inhabitants, with 25 % of the population being women of reproductive age.During the last two decades, local development strategies were implemented, including a wide range of facilitated community based activities. It is plausible that these initiatives have improved the economic, environmental and health situation in the area . For insThe 2014 follow-up survey in the HDSS included information on food security and self-rated health of all women of reproductive age (15–49 years). Women with physical or mental conditions that made interviews difficult were excluded (0.3%). We also excluded pregnant women from the present study (4%). For the purposes of this study, the design is cross-sectional.The nine-item household food insecurity access scale (HFIAS), version 3, was used . The resAs women’s health and wellbeing are included in the 2030 SDG targets, we collected data on self-rated health in this population in the 2014 HDSS update [In each household, information was collected on education, age, and employment status of each inhabitant. The education of the women in this study was grouped into three categories: illiterate or not completed primary school, completed primary school or not completed secondary, and completed secondary school or beyond. Age was measured in years at the time of interview and categorized as less than 20 years, 20–29, 30–39, and 40 years or more. The employment status of women was classified as employed or unemployed.The information on selected household characteristics  and assets  was analyzed by principal component analysis (PCA) and summarized into a wealth index, which was weighted for the number of members residing in the household . The scoPrevalence data were summarized as percent with 95% confidence intervals. The prevalence of poor self-rated health was analyzed by levels of food insecurity and other background characteristics. The lower-bound Cronbach’s alpha and its one-sided 95% confidence interval were computed to determine the internal consistency of the household food insecurity scale. A value of Cronbach’s alpha of 0.7 or higher was considered reliable . Chi-squWe considered women nested within communities. The self-rated health of women might be correlated within their communities. Therefore, we implemented a hierarchical modeling approach to analyze the association of food security as a capability with women’s self-rated health. The unadjusted and adjusted prevalence ratio and its 95% confidence interval were determined by random-intercept Poisson regression analyses .Three models were developed. The first, the null model (no variables included in the model), identified variability across communities of the self-rated health outcome. In the second model, the exposure variable food insecurity was added, and finally, in the third model (full model), the covariates were incorporated to determine adjusted estimates and identify changes in variance between communities. The median prevalence ratio (MPR) was determined to assess the variability between communities by comparing two women from two randomly different communities . The fol−1(3/4) corresponds to the 75th centile of the cumulative distribution of the normal standard distribution with a mean 0 and a variance 1. If MPR is approximately equal to 1, then the community variation is not relevant. P-values < 0.05 were considered as significant for the association analyses. No evidence was found for multicollinearity based on the variance inflation factor (VIF) greater than 10 criteria (VIF = 1.61). The statistical analyzes were performed using Stata 15.0.The value “exp” is equivalent to 2.7172, ψ is the contextual level variance, and ɸA total of 5866 completed records of non-pregnant women of reproductive age residing in 71 communities were included in the analyses after excluding missing records . The average age was 29 (standard deviation 9.94) years and over half were 15–29 years. Few women were illiterate or had not completed primary education (5.5%) and few were employed (9.6%)  was 89.1% . The Cronbach’s alpha of the household food insecurity scale was 0.90 with a 95% one-sided confidence interval of 0.90, indicating a high internal consistency.Overall, 4.3% of women rated their health as very good, 3.2% good, 44.6% average, 42.3% bad and 5.5% very bad Fig. . The proThe results of the regression analysis using community as a cluster variable are shown in Table Los Cuatro Santos. The results also suggested lower self-rated health at higher levels of food insecurity. This association was found across the different communities.Food insecurity affected nine out of ten households in In the area, food insecurity was still at a high level, although reduced over the last five years. For instance, the proportion of severely food insecure households dropped from 36% in 2009 to 29% in 2014 . Our groWomen who were employed and living in wealthier households had better self-rated health. Self-rated health was reduced by age, which has been found in many settings . DespiteIn this area where access to food is insecure, this must be seen as a lack of capabilities. As shown by Sen and others, when this happens the dignity of poor people is damaged . In our In our study, at least 80% of women perceived lack of access to diverse foods for consumption , a proxy assessment of food quality. Having the resources and opportunities to consume a diverse diet increases the prospects for good nutritional and health outcomes. Nevertheless, it is acknowledged that healthy foods as part of a diverse diet are more expensive than unhealthy foods . This reLos Cuatro Santos HDSS is reportedly of good quality [The data in  quality . In the Local individual-level data have advantages in comparison with the ecological national data frequently used by international agencies. Although the study of causal pathways between different capabilities and health calls for longitudinal analyses, the local level individual data do not suffer from the obvious risks of spurious associations when analyzing ecological data from national statistics. Local data may also be used to initiate and reinforce grassroots strategies to promote development and combat health inequalities, which frequently has been the case in the study area , 42.A high prevalence of food insecurity was associated with poor self-rated health among women in rural northern Nicaragua. Although the mechanisms remain unclear, we analyzed the limited access to food as an important dimension of poverty using the capability approach. Future research is needed to link social development, health, and well-being using longitudinal designs and including other capability indicators.


Objective: It is well-known that the hippocampus presents significant asymmetry in Alzheimer's disease (AD) and that difference in volumes between left and right exists and varies with disease progression. However, few works investigated whether the asymmetry degree of subfields of hippocampus changes through the continuum from Mild Cognitive Impairment (MCI) to AD. Thus, aim of the present work was to evaluate the Asymmetry Index (AI) of hippocampal substructures as possible MRI biomarkers of Dementia. Moreover, we aimed to assess whether the subfields presented peculiar differences between left and right hemispheres. We also investigated the relationship between the asymmetry magnitude in hippocampal subfields and the decline of verbal memory as assessed by Rey's auditory verbal learning test (RAVLT).Methods: Four-hundred subjects were selected from ADNI, equally divided into healthy controls (HC), AD, stable MCI (sMCI), and progressive MCI (pMCI). The structural baseline T1s were processed with FreeSurfer 6.0 and volumes of whole hippocampus (WH) and 12 subfields were extracted. The AI was calculated as: (|Left-Right|/(Left+Right))*100. ANCOVA was used for evaluating AI differences between diagnoses, while paired t-test was applied for assessing changes between left and right volumes, separately for each group. Partial correlation was performed for exploring relationship between RAVLT summary scores  and hippocampal substructures AI. The statistical threshold was Bonferroni corrected p < 0.05/13 = 0.0038.Results: We found a general trend of increased degree of asymmetry with increasing severity of diagnosis. Indeed, AD presented the higher magnitude of asymmetry compared with HC, sMCI and pMCI, in the WH (AI mean 5.13 ± 4.29 SD) and in each of its twelve subfields. Moreover, we found in AD a significant negative correlation  between the AI of parasubiculum (mean 12.70 ± 9.59 SD) and the RAVLT Learning score (mean 1.70 ± 1.62 SD).Conclusions: Our findings showed that hippocampal subfields AI varies differently among the four groups HC, sMCI, pMCI, and AD. Moreover, we found—for the first time—that hippocampal substructures had different sub-patterns of lateralization compared with the whole hippocampus. Importantly, the severity in learning rate was correlated with pathological high degree of asymmetry in parasubiculum of AD patients. Brain hemispheric specialization is among the central features of functional cortical organization in humans , the most common form of dementia, is a well-known neurodegenerative disorder that presents diffuse lateralized brain atrophies. The same pathological asymmetries were found in the Mild Cognitive Impairment (MCI). Indeed, a large number of morphological-based studies have previously reported a variety of regional abnormalities in hemispheric asymmetry in AD and MCI, including cortical thickness , subiculum and presubiculum hippocampal subfields were selectively involved in AD, and that they were correlated with the mnsesic process.Recently, a growing interest was born on the role of the hippocampal substructures and their relationship with verbal and visual episodic memory in AD  database (adni.loni.usc.edu). The ADNI was launched in 2003 as a public-private partnership, led by Principal Investigator Michael W. Weiner, MD. The primary goal of ADNI has been to test whether serial magnetic resonance imaging (MRI), positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of MCI and early Alzheimer's disease (AD).We selected publicly available subjects from ADNI by filtering text files downloaded from the website. In particular, we used the file containing the conversion of diagnosis for first choosing 100 healthy controls (HC), 100 Alzheimer's patients (AD) and 100 stable Mild Cognitive Impairment (sMCI) who did not convert their diagnosis in the follow up. With the same approach, we selected 100 progressive MCI who converted to Alzheimer's (pMCI) within 36 months from the baseline.The second step was to select the visit ID of each subject at the baseline and to obtain demographic, clinical and neuropsychological data at that timepoint, i.e., age, gender, years of education, Mini-Mental State Examination score (MMSE) and Rey's Auditory Verbal Learning Test (RAVLT) scores. The last step was to obtain the subjects' MRI scan id at the baseline from the file MPRAGEMETA.csv. In particular, we selected the first MPRAGE sequence (no repetition), acquired at 3 Tesla.From the ADNIMERGE table, we extracted the age, gender, years of education, Clinical Dementia Rating Sum of Boxes (CDRSB), Mini Mental State examination (MMSE) and the Rey's auditory verbal learning test (RAVLT) scores.Rey's auditory verbal learning test (RAVLT) Rey,  is a welBriefly, the RAVLT consists of presenting a list of 15 words across five consecutive trials. The list is read aloud to the participant, and then the participant is immediately asked to recall as many as words as he/she remembers. This procedure is repeated for 5 consecutive trials . After 30-min of interpolated testing, the participant is again asked to recall the words from the first list .For each of the 400 subjects that we selected from ADNI, we obtained the RAVLT scores from the ADNIMERGE table. Four different summary scores derived from raw RAVLT scores are provided: the RAVLT Immediate , the RAVLT Learning , the RAVLT Forgetting  and RAVLT Percent Forgetting  . Briefly, the main processing steps of Freesurfer included: removal of non-brain tissue (skull stripping) by using a hybrid watershed/surface deformation procedure  and the sum of them  test (p < 0.05). Differences in the gender distribution were assessed with a Pearson Chi-square test (p < 0.05).The statistical analysis was conducted by using the R language 3.3.2 for Macintosh. An analysis of variance (ANOVA) was employed for comparing the age, the years of education, the CDRBS, the MMSE and the RAVLT scores among the four groups. The multiple comparisons problem was accounted by a post-hoc paired comparisons was adjusted by the Tukey's HSD test (p < 0.05).An analysis of covariance (ANCOVA) was applied for finding differences in each of the hippocampal subfields AIs among the four groups, by adding age, gender, years of education and ICV as covariates, as AIs might be not distributed normally .With the aim of exploring the possible lateralization of the hippocampal subfields, a paired Partial correlation, controlling for age, gender, years of education and ICV, was used for exploring the relationship between the neuropsychological tests and the AI values of the hippocampal subfields. In particular, we separately regressed out from the RAVLT scores and the AI values the influence of age, gender, years of education and ICV with a linear regression. Then, we performed a Pearson's correlation between the residuals of RAVLT scores and residuals of AIs.t-tests, ANCOVAs and partial correlations, the statistical threshold of the post-hoc analyses corrected according to Bonferroni: p < 0.05/13 = 0.0038, considering 13 comparisons (the whole hippocampus and its 12 substructures).In paired Table Post-hoc analysis revealed that the MMSE, the CDRSB and the RAVLT Immediate scores were significantly different in all the pairwise comparisons with a RAVLT progressive score reduction from demented to not demented patients.Regarding the RAVLT Learning, the mean values were significantly different among groups, except that for the comparison between HC and sMCI. The mean values of RAVLT forgetting were significantly different among groups, except that for the comparison between HC and sMCI and sMCI and AD. Finally, the mean values of RAVLT Percent Forgetting were significantly different among groups, except that for the comparison between HC and sMCI and pMCI and AD.The asymmetry means values of the hippocampal subfields and of the whole hippocampus are reported by group in Table post-hoc analyses and survived at Bonferroni's correction, between HC and AD, and between sMCI and AD. Significant differences in the asymmetry index of presubiculum were found only between HC and AD. The asymmetry of subiculum was different between HC and pMCI, HC and AD, and sMCI and AD. CA4 and GC-ML-DG showed differences in their asymmetry index only between HC and AD, and sMCI and AD. The molecular layer presented significant differences in the degree of asymmetry between HC and pMCI, HC and AD, and sMCI and AD. None of the pairwise comparisons survived at Bonferroni's correction in the parasubiculum, CA1, CA3, HATA, fimbria, hippocampal fissure and hippocampal tail. For the sake of knowledge, the boxplots in Figure post-hoc comparisons at p < 0.05.ANCOVA results  of eight on twelve hippocampal substructures—CA1, CA3 CA4, GC-ML-DG, HATA, molecular layer, hippocampal fissure and hippocampal tail—as well as in the whole hippocampus, in the four diagnostic groups. Three hippocampal subfields did not present any significant lateralization toward a specific hemisphere in the four groups: the parasubiculum, subiculum, and fimbria. The presubiculum showed a leftward lateralization (left volume > right volume) in healthy controls, stable and progressive MCI, but not in AD, which did not present any significant difference between left and right hemisphere in this substructure. The molecular layer was another hippocampal subfield that did not present a homogeneous pattern of lateralization among our four groups. Even if in HC, sMCI and AD, the molecular layer showed a higher volume in the right hemisphere, in pMCI no statistical differences were found between the right and left hemisphere. The consistent left-less-than-right asymmetry of the whole hippocampus volume in normal subjects, MCI and AD patients, was largely demonstrated by several works summarized in a meta-analysis by Shi et al. . Our resAn interesting result presented in the current work regards the hemispheric alterations of the parasubiculum and its relationship with the verbal memory. Despite the lack of interhemisferic volumetric difference, the AD was the unique group showing a significant correlation between AI and RAVLT learning scores. We found that the more asymmetric was the parasubiculum, the worst was the performance at the rate of learning. It is well known that the decline of hemispheric asymmetry during healthy aging and disease progress represents an impediment to the compensation and interaction between the hemispheres, which badly influence the cognitive functions (Long et al., Some important caveats need to be discussed. Firstly, regarding the automatic segmentation of the hippocampal subfields (Van Leemput et al., In conclusion, our methodology showed that the hippocampal substructures exhibited different sub-patterns of asymmetry and lateralization compared to the whole hippocampus, through the continuum from healthy subjects to MCI and AD. Moreover, we found an increment of the magnitude of asymmetry with the increment of the severity of the diagnosis, where AD patients had the highest values of asymmetry in all the hippocampal subfields as well as in the whole hippocampus. More interestingly, the pathological low rate of learning was correlated with the pathological high degree of asymmetry in the parasubiculum of AD patients, indicating the possibility of using AI as a biomarker for the disease progression.AS: Research project—Conception, Organization, and Execution; Statistical Analysis—Design, Execution, Review and Critique; Manuscript—Writing of the first draft, Review and Critique. RV: Research project—Organization and Execution; Statistical Analysis—Design, Review and Critique; Manuscript—Review and Critique. FN: Research project—Conception, Organization and Execution; Manuscript—Review and Critique. MGV: Research project—Organization; Manuscript—Review and Critique. AC: Research project—Organization and Execution; Manuscript—Review and Critique. AQ: Research project—Organization and Execution; Manuscript—Review and Critique.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.