Kennedy’s disease (KD), also known as spinal and bulbar muscular atrophy (SBMA), is a rare, adult-onset, X-linked recessive neuromuscular disease caused by CAG expansions in exon 1 of the androgen receptor gene (AR). The objective of the French national diagnostic and management protocol is to provide evidence-based best practice recommendations and outline an optimised care pathway for patients with KD, based on a systematic literature review and consensus multidisciplinary observations.The initial evaluation, confirmation of the diagnosis, and management should ideally take place in a tertiary referral centre for motor neuron diseases, and involve an experienced multidisciplinary team of neurologists, endocrinologists, cardiologists and allied healthcare professionals. The diagnosis should be suspected in an adult male presenting with slowly progressive lower motor neuron symptoms, typically affecting the lower limbs at onset. Bulbar involvement (dysarthria and dysphagia) is often a later manifestation of the disease. Gynecomastia is not a constant feature, but is suggestive of a suspected diagnosis, which is further supported by electromyography showing diffuse motor neuron involvement often with asymptomatic sensory changes. A suspected diagnosis is confirmed by genetic testing. The multidisciplinary assessment should ascertain extra-neurological involvement such as cardiac repolarisation abnormalities (Brugada syndrome), signs of androgen resistance, genitourinary abnormalities, endocrine and metabolic changes . In the absence of effective disease modifying therapies, the mainstay of management is symptomatic support using rehabilitation strategies (physiotherapy and speech therapy). Nutritional evaluation by an expert dietician is essential, and enteral nutrition (gastrostomy) may be required. Respiratory management centres on the detection and treatment of bronchial obstructions, as well as screening for aspiration pneumonia . Non-invasive mechanical ventilation is seldom needed. Symptomatic pharmaceutical therapy includes pain management, endocrine and metabolic interventions. There is no evidence for androgen substitution therapy.The French national Kennedy’s disease protocol provides management recommendations for patients with KD. In a low-incidence condition, sharing and integrating regional expertise, multidisciplinary experience and defining consensus best-practice recommendations is particularly important. Well-coordinated collaborative efforts will ultimately pave the way to the development of evidence-based international guidelines. Kennedy’s disease (KD), or X-linked Spinal and Bulbar Atrophy (SBMA), is a rare neurodegenerative disorder. The diagnostic possibility is typically raised when an adult man presents with slowly progressive lower motor neuron symptoms associated with signs of androgenic dysfunction such as gynecomastia –3. The gKennedy’s disease is caused by CAG repeat expansions in the AR gene resulting in polyglutamine (polyQ) expansion in the AR protein. Expansions larger than 38 CAG trinucleotide repeats result in the formation of a pathological protein called polyQ-AR . It shouPolyQ diseases are characterised by the dysfunction and subsequent neuronal death of specific cell populations and the accumulation of toxic intracellular proteins . The toxNo disease-modifying therapy is currently available, but deciphering the pathophysiology cascade of KD allowed the development of a number of promising therapeutic strategies , 10–13. Kennedy disease is a low-incidence condition that is well documented worldwide. A haplotype study of 123 patients revealed that pathological CAG expansions the humans are not the result of a single founding event, but had emerged in several parts of the world independently . ComprehTable An inverse correlation exists between CAG repeat numbers and age of symptom onset . If non-A number of transgenic animal models have been successfully developed to aid KD research. The AR-65 model, carrying 65 CAG repeats showed a mild phenotype compared to the AR-120 (120 repeats) which exhibited both motor and behavioural symptoms. The motor symptoms observed in AR-120 were associated with spinal alpha-motor neuron degeneration, without evidence of cerebral changes . In anotMotor and sensory manifestationsMuscle weakness is a key clinical feature of the disease; it is present in 97% of cases and usually manifest around the age of 35–40. Higher repeat numbers are associated with younger age of onset, but no association has been found between repeat numbers and rate of progression , 47, 48.Lingual fasciculations are a common feature of KD , 54 and Neuropsychological abnormalitiesThe link between cognitive deficits and KD is not well established despite sporadic reports –65, and Endocrine changesEndocrine involvement stems from partial androgen insensitivity and often precedes neurological manifestations. Gynecomastia may be present in up to 73–78% of male KD patients , 30. It Metabolic alterationsIn a large Italian series, 41% of patients had abnormally high fasting serum glucose levels , but thiBone involvementIn a KD series, 5% of patients had femoral osteoporosis, 36% lumbar and/or femoral osteopenia measured by bone osteodensitometry (59). Compared to healthy subjects, mean bone mineral density (BMD) in KD patients was lower in the femur and preserved in the lumbar vertebrae. Decrease BMD may be secondary to relative inactivity due to lower limb weakness. However, there is a lack of correlation between motor disability and lumbar BMD. It is also noteworthy that up to 65% of KD patients have vitamin D deficiency. The role of partial androgen resistance remains to be explored.Cardiac involvementPotentially life-threatening conduction abnormalities have been repeatedly reported , 30 maniGenito-urinary disordersA large study identified a considerable frequency of genitourinary disorders among 73 KD patients using the International Prostate Symptom Score (IPSS) questionnaire . ModeratElectrophysiologyThe electrophysiological features of KD encompass diffuse, chronic neurogenic changes and fasciculations beyond the regions overtly affected on clinical assessment . An impoMuscle biopsyMuscle biopsy is not commonly performed and is seldom necessary to establish the diagnosis. It typically reveals both myopathic  and neurogenic (angular fibres or type grouping) changes . These aSerum markersIncreased creatine kinase (CK) levels may be detected in 80 to 94% of KD patients, often in association with increased transaminases 24). CK values range from 31 to 4955 IU / L, with an average serum level of 863 IU / L  . CK valu and may ImagingFew dedicated imaging studies have been performed to investigate cerebral alterations in KD . ImagingThere are rare reports of bulbar and spinal amyotrophies without CAG triplet expansions in AR gene. An autosomal dominant non-X-linked form has been reported with spinal and bulbar involvement with associated gynecomastia . In clinIn the absence of effective disease-modifying therapies, the mainstay of management is symptomatic support; pain management, physiotherapy, speech therapy , gastrosThe identification of the genetic underpinnings of KD has paved the way for robust in vitro studies, then to the development of in vivo models –131 whicThe general practitioner has a central role to identify the initial symptoms of KD and promptly refer the patient to a neurologist to initiate the appropriate investigations and to confirm the diagnosis. The initial evaluation is typically performed in a neurology department, preferably at a tertiary referral centre for motor neuron diseases, with the assistance of other medical specialists; endocrinologists, geneticists, ENT specialists, pulmonologist, cardiologists, dieticians, and rehabilitation specialists. A number of other health care professionals are also indispensable for the evaluation and supportive management of KD, such as clinical psychologists, neuropsychologists, physiotherapists, occupational therapists, dieticians, speech therapists and social workers.A family history suggestive of X-related inheritance should be sought but may not always be present.The commonest presentation is the constellation of progressive motor deficits in an adult man around the age of 40, typically affecting the lower limbs proximally, with fatigability when walking, difficulty climbing the stairs, in conjunction with cramps and fasciculations. Postural tremor of the upper limbs can sometimes precede the motor manifestations. Signs of bulbar involvement, dysarthria, dysphonia, and dysphagia and/or laryngospasm usually present later in the course of the disease but would be suggestive of the diagnosis if they are present in combination with limb weakness. The diagnosis should be suspected based on the constellation of a range symptoms and neurological findings which are presented in Table Gynecomastia, which is usually bilateral and symmetrical, is a common early clinical cue which is supportive of a suspected diagnosis. Other signs of hypogonadism, such as erectile dysfunction or infertility, may also constitute initial symptoms, but they typically only raise the suspicion of KD if they are associated with frank neurological deficits. Abnormally high serum creatine kinase (CK) is seldom indicative as it may be caused by a plethora of other medical conditions. CK values of 2–4 times the normal level can be observed, but this is not specific to KD. Similarly, a moderate raise in transaminases  is often observed but not specific.ElectrophysiologyThis is an essential part of the diagnostic work-up and electrophysiological findings need to be carefully interpreted in the context of clinical findings. Diffuse and chronic neurogenic changes are found with widespread fasciculations. Electrophysiological abnormalities typically extend well beyond the region affected clinically, unravelling extensive subclinical involvement. An electrodiagnostic cue is the decrease of sensory amplitudes (sensory neuronopathy) in a non-length-dependent pattern in association with the above motor anomalies.Genetic testingKD is caused by an abnormal CAG triplet expansion in exon 1 of the AR gene on the X chromosome. The diagnosis of KD is established above a repeat number of 38. In suspected cases, a blood sample should be sent to a molecular genetics laboratory, accompanied by a request document, a family tree, a consent form signed by the patient and a signed consultation request. It is preferable that genetic testing takes place in certified laboratory. The result must be communicated by a qualified practitioner during a formal consultation allowing plenty of time for questions and offering the opportunity to ask further questions on follow-up. The risk of passing on the mutation to male members of the family must be discussed with clarity. Specific local guidelines may exist on how to communicate genetic results to those affected and a signature may be requested from the patient to acknowledge that the results have been communicated. Institutional and national legal and ethical frameworks may govern local genetic counselling procedures.Differential diagnosesThe main differential diagnosis of KD is amyotrophic lateral sclerosis (ALS), which carries a worse prognostic outlook than KD. ALS differs from KD in a much faster evolution, the presence of upper motor signs, the absence of sensory neuropathy and the lack of endocrine manifestations Table . Other dBreaking the news of the diagnosis should take place in a quite institutional environment with no distractions by an experienced physician who can dedicate sufficient time to answer any questions about the implications of the diagnosis will patience, empathy and humanity. Following the consultation, it is paramount that the patient’s general practitioner is sent a formal report. It is also essential that a follow-up appointment is organised to allow the patient and the caregivers to ask further questions and to evaluate the patient’s understanding of the diagnosis. The discussion of the foreseeable disability, projected rate of progression, management options and lack of effective pharmaceutical interventions should be balanced, factual and frank. Beyond discussing therapeutic options, initial consultations should set realistic goals, put a long-term management plan into place to allow efficient adaptation to the disease. Instead of merely conveying factual medical information, active listening, offering support, getting to know personal, social and professional circumstances are vital to establish trust and develop individualised adaptation strategies.Evaluation of neurological signsA focused neurological examination informs the choice of mobility aids, occupational therapy interventions and helps to enlist the help of the appropriate allied health care professionals. Proximal lower limb weakness is a cardinal symptom in the vast majority of cases leading to difficulty getting up from a sitting position, climbing the stairs and overall poor mobility. Muscle strength testing alone underestimates the functional disability experienced by the patient and it also overlooks the fatigability associated with the condition. Dysphagia impedes the oro-pharyngeal processing of the alimentary bolus and may result in apprehension of eating and adverse nutritional consequences. Choking episodes are a rare occurrence, but dysphagia can lead to recurrent aspiration pneumonias nonetheless. Dysarthria typically remains relatively mild and seldom leads to the loss of oral communication and reliance on augmentative and alternative communication aids. A number of disease-specific and generic instruments have been validated to assess limb and bulbar disability , 128. ThRespiratory and nutritional evaluationRespiratory involvement is often subclinical and may manifest either as an inspiratory weakness or weak cough due to additional abdominal wall muscle involvement. Respiratory insufficiency may become apparent after lower respiratory tract infection or following a surgery. It can be complicated by acute respiratory insufficiency, requiring hospitalisation, intensive care or transient respiratory support. Specialist respiratory advice should be sought in cases of orthopnoea, evident diaphragmatic involvement, productive cough, coexisting chronic obstructive pulmonary disease, and recurrent upper respiratory tract infections. The initial respiratory assessment should include formal spirometry in both sitting and lying positions with the measurements of maximum respiratory pressures (PImax and PEmax) and a sniff nasal inspiratory pressures (SNIP). Cough weakness may be suspected based on reduced inspiratory and expiratory pressures, but must be confirmed by peak cough flow measurements. Early morning arterial blood gas analysis and overnight night oximetry are also part of the respiratory work-up.Nutritional evaluationFormal nutritional assessment should begin with the recording of anthropometric data; weight, height, body mass index (BMI); tissue body composition (fat mass and lean mass) using validated scales and instruments such as the bioimpedancemeter. Standardised food preference and dietary surveys also help to discuss diet adjustments, increase caloric intake and choose food supplements.Endocrine and metabolic evaluationGynecomastia is evident on clinical examination. If it is unilateral, ultrasound or mammogram should be considered to exclude an underlying neoplastic process, If there is a clinical suggestion of hypogonadism based on the clinical history  or evidence of testicular atrophy or gynecomastia a typical hormone panel would should include: total testosterone level, estradiol level, luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels at baseline, and gonadotrophin-releasing hormone (GnRH). Unlike in other motor neuron diseases , fecundiCardiac evaluationA 12-lead ECG should be recorded on each newly diagnosed KD patients as a first line screening for repolarisation abnormalities, such as the Brugada pattern, which is characterised by coved-type ST elevation from V1 to V3 leads. This ECG pattern may be indicative of increased risk for potentially life-threatening ventricular arrhythmias. ECG should ideally be reviewed by a cardiologist and additional tests such as Holter-monitoring, even monitors, loop recorders, echocardiograms may be required.Bone assessmentsAs bone mineralisation abnormalities have been repeatedly reported in KD, a baseline bone densitometry scan (DEXA) and serum tests for 25-OH vitamin D, calcium and phosphate are also recommended.Erectile dysfunction is not the only genitourinary symptom of KD, and additional urodynamic evaluation may be needed obstructive symptoms are reported.A formal genetic counselling session will specifically discuss the risk of family members developing KD and the projected age of onset in those at risk. The X-linked recessive mode of transmission should be explained with clarity and genetic screening should be offered to family members at risk. Those at risk will be informed that only a CAG repeat number above 38 is likely to lead to the clinical spectrum of KD. The clinical manifestations of a repeat number between 35 and 37 are difficult to predict, but the clinical profile of affected family members may serve as a pointer. Genetic counselling will also inform couples at risk regarding the probability of passing on this genetic variant to their children. During counselling it is explained that there is no direct father to son transmission and that sons of female carriers are at 50% risk to inherit the genetic abnormality. Implications for prenatal or pre-implantation diagnosis are also explained during genetic counselling.In the absence of effective disease-modifying treatments in KD, management centres on supportive interventions for the spectrum of neurological, respiratory, nutritional, endocrine, metabolic or cardiac symptoms associated with KD. The overarching objective of any intervention is to maintain independence, autonomy and dignity irrespective of physical disability while respecting individual care preferences. Key management strategies include:- Passive or active mobilisation physiotherapy to prevent the painful musculoskeletal complications of poor mobility.- Preserving autonomy by helping patients to adapt to physical disability through individualised occupational therapy  and mobility aids, such as wheelchairs, sticks, walking aids, orthoses, stair lifts etc.- Individualised speech therapy to preserve oral communication in patients with dysarthria.- Teaching compensation strategies for swallowing disorders, such as adopting a safety posture, slow swallow, small boluses intake, avoidance of talking while eating etc.- Monitoring nutritional status, dietary modification to suit individual bulbar performance, initiation of food supplementation, high calorie supplements and vitamins, adjusting food textures (avoidance of dry crumbly foods), changing food consistency with thinkers if needed (fluids). Considering gastrostomy placement in sever dysphagia (rarely needed).- Monitoring respiratory function and anticipation of respiratory tract infections, initiation of cough-assist, breath stacking, non-invasive ventilation if needed.- Management of extra-neurological complications, endocrine, metabolic and cardiac disorders; androgen resistance, hypogonadism, diabetes, dyslipidaemia, arrhythmias etc.- Offering education sessions to patients and caregivers by social workers re: genetic risks, prognosis, financial advice, car adaptations, government grants, home modifications, equal opportunity employers.- Offering psychological support to patients and caregivers re: adaptation, coping, and outlook.The management should ideally be coordinated by a neurologist at a centre specialised in motor neuron diseases and a general practitioner in the community. The neurologist confirms the diagnosis, breaks the news and coordinates the care throughout the course of the disease. The management however is strictly multidisciplinary and involves geneticists, endocrinologists, respiratory physicians, dieticians, ENTs, cardiologists, and rehabilitation physicians. The general practitioner ensures that the patient is linked in to a specialist centre, maintains a dynamic partnership with the neurologist and manages intercurrent symptoms, such as infections, diabetes etc. Hospital and community-based allied healthcare professionals, such as physiotherapists, occupational therapists, speech therapists, dieticians and social workers perform regular evaluations, and help the patient to adapt to disability to maintain independence and autonomy. Psychological support by an experienced clinical psychologist should be offered at the time of diagnosis and offered throughout the course of the disease. Specialist nurses affiliated with motor neuron disease centres also often offer invaluable advice and support to patients and caregivers and can assist with medical and administrative challenges. Patient organisations and charities offer additional support in the patient’s community or at a national level, by providing educational sessions, telephone helplines, websites, maintaining a network where patients and caregivers can interact and share information. Unlike in other motor neuron diseases , specialBefore prescribing of any drugs, the increased risk of cardiac repolarisation abnormalities should be carefully considered. If there already is ECG evidence of an underlying repolarisation abnormality, a cardiologist should be consulted about the potential proarrhythmic effect of the new drug.The pharmacological management of painMuscle cramps cause significant discomfort and quinine derivatives and magnesium are commonly prescribed. Even in the absence of established repolarisation disorders, mexiletine, a sodium channel blocker, should only be considered after consultation with cardiology should only be considered after consultation with a cardiologist regarding risk/benefit ration and to put careful monitoring in place. Pain due immobility and skin breakdown at pressure sites are other common cause of pain and the choice of analgesics should follow local guidelines and depend on tolerability of the side-effect profile of specific medications. Paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), gabapentin, pregabalin, tramadol, selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCA) are just some of the pain modulators used in KD, but the choice of specific drugs has to be guided by comorbidities  and life style factors . Any pharmacological treatment must be initiated after, or used in conjunction with non-pharmacological interventions, such as physiotherapy, mobilisation, massage, and occupational therapy. Alternative non-pharmacological interventions such as acupuncture may also be trialled depending on individual patient preferences.Treatment of fatigue and mood disordersFatigue is a very common symptom, and is likely to be multifactorial due to muscle weakness, sedating medications, subclinical respiratory weakness, poor sleep or poor caloric intake. Accordingly, treatment will depend on the key aetiology, and the targeted correction of underlying factors may ameliorate fatigue. Modafinil or levocarnyl are often tried to help generalised fatigue. Psychological support should be offered to patients and caregivers, as patients face considerable uncertainty, may feel helpless during the course of their disease, and generalised anxiety is not uncommon. Patients and carers should be screened for frank depression and a combination of pharmaceutical and non-pharmaceutical interventions may be beneficial. Short course anxiolytics may be considered keeping the risk of dependency in mind. Antidepressants are usually prescribed more liberally, but side effects  and response to therapy need to be carefully monitored.Endocrine and metabolic managementThere is no evidence to support androgen replacement therapy in KD. The treatment of gynecomastia is surgical and a referral for a surgical consultation is typically only offered on the patient’s request. Insulin resistance and diabetes should trigger careful monitoring (HBa1C) and pharmacological treatment. The first line treatment of dyslipidaemia is dietary adjustments and statins should only be used judiciously. There is no established risk for additional myopathy associated with statin therapy in KD, but the risk/benefit ratio has to be assessed on a case-by-case basis depending on the severity of the dyslipidaemia and the vascular risk profile. Vitamin D deficiency needs rigorous substitution. Osteoporosis should be managed by current guidelines and pharmacological interventions are not KD-specific.Rehabilitation and assistive devicesPhysiotherapy should be initiated at the time of diagnosis to prevent complications related to limb weakness, limited range of motion and gait impairment. It has to be carefully tailored to individual disability, life-style, occupation, and fatigue. Physiotherapy can be beneficial in a home setting, in private practice, in a hospital, or in a specialist centre. Physiotherapy focuses on the maintenance of articular range of motion either by passive or active mobilisation and must be pain free, but is sometimes performed following analgesic administration or massages. Frequent pauses are offered during physiotherapy to prevent fatigue. Forms of ‘mechanotherapy,’ passive movements with motorised devices and motor electrostimulation with pulse generators are contraindicated. The aim of respiratory physiotherapy is the prevention of respiratory tract infections, bronchial obstruction, and phlegm mobilisation. These may include manual techniques, such as ‘breath stacking’ and instrumental interventions such as the use of cough assist machines (insufflator - exsufflator).Speech therapy rehabilitation should be initiated at the onset of the first bulbar symptom. It should be tailored to the specific deficits of articulation, phonation or swallowing. Speech therapy entails both passive and active exercises to mobilise the relevant oropharyngeal muscles. Postures facilitating safe deglutition and prevent aspiration are also thought to patients and caregivers during the speech therapy sessions.An expert occupational therapy assessment is required after KD is diagnosed. Interventions will be guided by individual preferences, life-style, home environment, driving needs, and working environment. Occupational therapy will focus on autonomy with regards to activities of daily living; mobilising, washing, dressing, feeding, writing, driving etc. To facilitate independence in routine daily activities assistive devices will be recommended to suit individual support needs. Occupational therapists typically recommend a range of aids and devices which can be tried before deciding which one to use. These typically include wheelchairs, electric chairs, mobility scooters, stair lifts, special keyboards, remote controls, raised toilet seats, taps with large handles, adapted kitchen utensils, large mobile phones etc. The occupational therapists will train the patient and caregivers how to use new aids safely and confidently. Home visits are important elements of individualised occupation therapy to evaluate home circumstances and consider optimal technical solutions for the patients specific needs; home automation, video bells, smart devices, chair lifts, walk-in showers, toilet adjustments, electric beds etc. The implementation of technical aids and home adaptations will be facilitated through an established infrastructure with reputable suppliers and fitters. Patient advocacy groups, charities and patient organisations often provide advice, information and funding regarding home modifications.Nutritional managementFollowing a thorough nutritional assessment after the diagnosis is established; the dietician will provide expert advice on food supplements to facilitate adequate protein, energy and vitamin intake. For patients with dysphagia, consistency adjustments, texture changes, thickening powders, and gelled water may be recommended. Appropriate dental care is also indispensable to for satisfactory oral intake. Oral candidiasis is not uncommon due to the combination of atrophic tongue changes and insulin resistance, and careful mouth hygiene is required to prevent painful fissuring. Meticulous dental care, mouthwashes with antiseptics and antifungals are often recommended. Nutritional management must take the endocrine sequelae of the disease into account, especially dyslipidaemia or diabetes. Enteral nutrition, through gastrostomy may occasionally be needed and options include percutaneous endoscopic gastrostomy (PEG) or radiologically inserted gastrostomy (RIG) tubes. Main indications to consider enteral nutrition include: (1) unintentional weight loss greater than 10% of the baseline weight, (2) a (BMI) indicative of malnutrition (BMI < 18.5 18–70 years or BMI < 21 if older than 70), (3) considerable risk of aspiration pneumonia, (4) excessive time to finish meals impacting on social life. The risks and benefits of gastrostomy placement should be discussed with patients and caregivers, including the risk of local infections (cellulitis), need for tube changes, and the potential but remote risk of peritonitis. The practicalities of feeding should also be discussed with an experienced dietician, such as bolus versus overnight pump feeds, tube changes, the importance of tube flushing, cleaning the gastrostomy site and monitoring for infections, crushing medications or using syrup forms through the tube, and the option of continued oral intake even if a gastrostomy regime has been set up. In patients with respiratory compromise (RIG) may be preferable to PEG due to the lower risk of complications.Respiratory managementIntermittent laryngospasm is not uncommon, reported in up to half of the patients. They can cause considerable anxiety, but they are relatively benign. Provoking factors such as gastroesophageal reflux should be aggressively treated with antacids. Respiratory management includes physiotherapy with drainage and positioning interventions. Insufflator - exsufflator devices (“cough assist” machine) may be needed to help the clearance of tracheal and bronchial secretions. Non-invasive mechanical ventilation is seldom required, and is best initiated after a joint neurological-respiratory consultation based on overnight pulse oximetry readings and early morning arterial blood gas analyses. Oxygen therapy should only be considered in a palliative management setting as without pressure support it may lead to reduced respiratory drive.Cardiac managementBrugada syndrome can be identified based on a screening ECG, ambulatory ECG monitoring (Holter), signal averaged ECG, or invasive electrophysiological studies. It is imperative that the management of Brugada syndrome is coordinated by a cardiology team specialised in arrhythmia or cardiac electrophysiology. The risk for potentially life-threating ventricular arrhythmias, such as ventricular fibrillation (VF) or polymorphic ventricular tachycardia (PVT) needs to be stratified and implantable cardioverter defibrillator (ICD) devices should be considered. Preventive pharmacological interventions are less favourable, and quinidine is only prescribed in selected cases in patients who have ICDs. Life-style modifications should also be recommended in Brugada syndrome to decrease the risk for VF/PVT, such as avoiding strenuous exercise, excessive alcohol consumption, and certain medications such as high-dose paracetamol. For high-risk patients who had been defibrillated several times by their ICDs, radiofrequency catheter ablation is an invasive therapeutic option.The governing concepts of caring for patients with KD should include the following:- Understating the practical implications of motor disability .- Screening for and foreseeing potential complications .- Responding dynamically to progressive changes.- Initiating symptomatic treatments, supportive care, psychosocial care in a timely manner.- Accompanying the patient and caregivers in their journey throughout the disease.- Provide advice, information, support, education throughout the course of the disease.- Linking in the patients with the relevant advocacy groups, charities, support groups.- Offer genetic counselling for the patient and relatives.Patient follow-up is the joint responsibility of the general practitioner and neurologist and is ideally coordinated from a tertiary reference centre. KD care is fundamentally multidisciplinary, involving the general practitioner, neurologist, geneticist, endocrinologist, pulmonologist, cardiologist, rehabilitation specialists, nutritionist, ENT, specialist nurses, physiotherapist, occupational therapist, speech therapist, dietitian, clinical psychologists and social workers. Given the relatively slow evolution of the disease, the various specialists are involved in the patients care at different stages of the disease depending on the clinical symptoms.In the absence of distressing new symptoms, routine clinical follow-up is organised every six months to assess functional impairment, review symptomatic treatment  and adjust rehabilitation strategies . Functional rating scales (SBMA-FRS) are not considered particularly sensitive to track subtle motor decline longitudinally. Routine follow-up reviews also provide an opportunity to screen for new extra-neurological manifestations, such as diabetes, genitourinary problems, metabolic disorders, cardiac disorders etc., serum creatinine is not optimal to screen for renal impairment as levels may remain in normal range despite decreased glomerular filtration due to concomitant muscle volume loss and poor dietary intake. Cystatin C measurements are superior to detect renal impairment as it is independent of muscle mass, gender, age, and there is no lag between kidney injury and cystatin rise . RespiraWhile best practice recommendations and management guidelines have been repeatedly published for ALS in the US, Europe and Japan, no such guidelines exist for Kennedy’s disease despite similarities in diagnostic challenges, heterogeneity of manifestations and the wide spectrum of motor and extra-motor symptoms. Dedicate KD management guidelines not only raise awareness of a low-incidence neuromuscular condition, they draw attention to the range of extra-neurological manifestations associated with the condition and provide a framework to anticipate and screen for serious cardiac and complex endocrine manifestations. KD-specific best practice recommendations provide guidance to the complex supportive needs of the condition and emphasise the importance of well-timed multidisciplinary interventions. As with other progressive neurodegenerative conditions, the governing principle of KD care is the maintenance of independence, preservation of autonomy, dignity and prevention of serious medical complications. Given the low-incidence of KD and the multi-organ, multi-system involvement, best practice recommendations are best proposed by large consortia the members of which actively participate in the care of KD patients. The lack of effective disease-modifying therapies, absence of validated biomarkers, potentially life-threatening cardiac and respiratory complications and the paucity of clinical trials add to the urgency of publishing consensus management recommendations. While our recommendations cover the most stereotypical presentations and possible complications, considerable clinical variations exist which require flexible, dynamic multidisciplinary interventions especially in the presence of comorbid medical conditions. This protocol is therefore not exhaustive and merely provides a framework for KD management.In the context of an orphan disease, these guidelines provide a reference care pathway for patients with KD both for general practitioners and general neurologist who may be less familiar with the condition. This protocol will need to be regularly updated based on emerging scientific findings, especially therapeutic advances, such as gene therapy. There are important lessons to learn from international initiatives, such as the European Group for KD , 12. ColThe protocol is based on currently available scientific evidence and provides a consensus statement for the care of KD patients Fig. . The mulTwo investigators (EB and PFP) have first performed an independent literature search. They reviewed the available international literature using standard databases  to evaluate evidence for the efficacy of specific interventions. They graded the level of evidence according to the French Health Authority guidelines  Table 55. The paThe working group decided to update the background section of the document which was provisionally finalised in March 2017 to include scientifically relevant new publications in the field. The updated scientific section was meticulously reviewed again and approved by the multidisciplinary group.The list of the topics addressed is presented in Table Additional file 1.


However, all allogeneic grafts require immunosuppression. HLA-donor-matching, reduces, but does not completely eliminate, the need for immunosuppression, and is currently investigated in a clinical trial for PD in Japan. Since immune compatibility is very important in all areas of transplantation, these approaches may ultimately be of less benefit to the patients than an autologous approach. By using the patient’s own somatic cells, reprogrammed to induced pluripotent stem cells (iPSCs) and differentiated to mDA neurons immunosuppression is not required, and may also present with several biological and functional advantages in the patients, as described in this article. The proof-of-principle of autologous iPSC mDA restoration of function has been shown in parkinsonian non-human primates (NHPs), and this can now be investigated in clinical trials in addition to the allogeneic and HLA-matched approaches. In this review, we focus on the autologous approach of cell therapy for PD.Parkinson’s Disease (PD) is a progressive degenerative disease characterized by tremor, bradykinesia, rigidity and postural instability. There are approximately 7–10 million PD patients worldwide. Currently, there are no biomarkers available or pharmaceuticals that can halt the dopaminergic neuron degeneration. At the time of diagnosis about 60% of the midbrain dopamine (mDA) neurons have already degenerated, resulting in a depletion of roughly 70% of striatal dopamine (DA) levels and synapses. Symptomatic treatment  can initially restore DA levels and motor function, but with time often lead to side-effects like dyskinesia. Deep-brain-stimulation can alleviate these side-effects and some of the motor symptoms but requires repeat procedures and adds limitations for the patients. Restoration of dopaminergic synapses using neuronal cell replacement therapy has shown benefit in clinical studies using cells from fetal ventral midbrain. This approach, if done correctly, increases DA levels and restores synapses, allowing biofeedback regulation between the grafted cells and the host brain. Drawbacks are that it is not scalable for a large patient population and the patients require immunosuppression. Stem cells differentiated  The clinical movement disorder syndrome of Parkinson’s Disease (PD) occurs due to a progressive loss of midbrain dopamine (mDA) neurons. In fact, most patients remain free of clinical motor symptoms until the PD pathology has already reached an advanced stage with most (∼60%) of the selectively vulnerable dopamine (DA) neurons dysfunctional or dead, and with a consequent depletion of roughly 70% of striatal DA levels and synapses . For thiOther new modalities being explored for PD include gene therapy and cell therapy . Gene thDue to a lack of biofeedback and synaptic control in all current pharmacological therapies, they eventually lead to dyskinesias or other side-effects see . TherefoThe cell-based therapy approaches in PD aim to replace nigrostriatal DA terminals lost by the disease process, with fetal or stem cell derived DA neurons placed directly into the caudate-putamen, and potentially also in substantia nigra. Cell replacement therapy with mDA neurons in PD addresses both the motor symptoms of PD, as well as L-dopa-induced dyskinesias. In the most successful cases , the reqCell replacement therapy using DA neurons for PD in the clinic, has so far utilized ventral mDA neurons derived from fetal sources. More recently, attempts to replace missing DA neurons in PD preclinical models have evolved from this innovative and complex fetal DA cell transplantation method toward a potential scalable method that depends on stem cell-derived DA neurons . The repInduced pluripotent stem cells (iPSCs) provide several advantages over embryonic stem cells (ESCs) as a cell source for cell replacement in PD and other disorders, including the ability to use patient’s own cells, or HLA-matched cells and thus reduce (HLA-matched) or eliminate (autologous iPSCs) the need for any immunosuppression. Immune compatibility is universally known to be very important in all fields of transplantation. Immune suppression is not a trivial matter and may underlie some of the variability previously reported in clinical trials of fetal derived DA neuron transplantation . Indeed,Another approach to avoid the need of immune suppression is the generation of a universal donor cell that will evade the immune system either by HLA engineering or immune cloaking strategies . These ain vivo using virus technology. The current approaches for PD aim to convert astrocytes to DA neurons  data in non-human primates (NHPs) showing functional recovery and long-term survival of autologous transplanted iPSC-derived DA neurons. However, in this parkinsonian NHP model, unilateral autologous transplantation provided POC data for the long-term functional recovery of PD-like motor symptoms (increased daytime activity and reduction of time taken to complete a skilled motor task) for up to at least 2 years . Behavioprimates . From thprimates  showed tprimates .iPSCs, when exposed to a mixture of small molecules, can be differentiated toward mDA neuron fate . Protocoin vitro 17. Therefore, it can be used together with FoxA2 as an indicator of midbrain dopaminergic neurons and the percentual co-positivity of the two can be set as a positive cellular marker criterion for mDA cell transplantations. In cases where only progenitor cells are transplanted one must rely on additional markers to determine dopaminergic progenitors and predict future dopaminergic cell content  have sporadic forms, and the genetic forms of PD are relatively rare. However, even in cases where the patients have underlying cellular problems due to genetic variants, they have surviving functional DA neurons for the majority of their life, in some cases up to >60 years of age, before any noticeable degeneration that results in functional impairment occur. Even in severe familial genetic cases , PD does not present for 30 years or more. Therefore, it is both logical and reasonable to assume that even the most severe, rare genetic forms would, after transplantation of new young cells, have highly adaptive functional DA neurons for synaptic signaling for at least 20–25 years. In fact, both rodent  and NHP There are several advantages of the autologous cell therapy approach over allogeneic or MHC matching ; Table 1(1)Basic biology of cell integration and recognition: Autologous neural cell transplants potentially are better integrated, have better axonal networks (networks  and havenetworks . A relatnetworks .(2)Rejection by immunological mechanisms at cellular and synaptic levels: A primate study demonstrated clear benefits to the use of autologous transplants rather than allografts in both cell survival and immune response The health risks to the patient recipients: Patients with compromised immune system are always considered high risk recipients for systemic immune suppression for any amount of time. Immune responses as observed with allografting or xenografting can be detrimental to transplant function  drives up the cost of the cell production step. However, when looking at the total healthcare cost, this conventional view is not necessarily true . An inted higher . The read higher . The higTO, PH, JS, and OI wrote this 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.


Psychological stress can cause adverse health effects in animals and humans. Accumulating evidence suggests that psychological stress in female mice is associated with ovarian developmental abnormalities accompanied by follicle and oocyte defects. Oocyte and early embryonic development are impaired in mice facing psychological stress, likely resulting from hormone signalling disorders, reactive oxygen species (ROS) accumulation and alterations in epigenetic modifications, which are primarily mediated by the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-ovarian (HPO) axes. The present evidence suggests that psychological stress is increasingly becoming the most common causative factor for female subfertility. Here, we review recent progress on the impact of psychological stress on female reproduction, particularly for oocyte and early embryonic development in female mice. This review highlights the connection between psychological stress and reproductive health and provides novel insight on human subfertility. Psychological stress in humans usually refers to uncomfortable ‘emotional experiences’ accompanied by predictable biochemical, physiological and behavioural changes or responses . GeneralThere are two classes of psychological stress, acute and chronic, which can also be divided into disconnected and persistent psychological stress , 6. As rPresently, growing evidence suggests that psychological stress is involved in a series of biological events that place strain and pressure on systems that may cause certain reproductive system diseases –16. InveAs highlighted above, a large amount of studies has indicated a certain causal relationship between psychological stress and female reproduction; however, the mechanisms underlying the effects of psychological stress on female reproduction are far from fully understood. Here, we focus on research advances of psychological stress on oocyte and early embryonic development in female mice, as well as the mechanism by which this psychological stress impacts female reproductive development and fertility.Generally, the embryo becomes implanted into the proximal endoderm and initiates early development. Around embryonic day 6.5 (E6.5), some ectodermal cells transform into the precursor cells of primordial germ cells (PGCs) . With thIn the mouse, fertilization is achieved when a haploid sperm merges with an oocyte to form a diploid zygote, which is the starting point of new life . FollowiCurrently, the chronic unpredictable mild stress (CUMS) model is widely accepted for psychological stress studies, especially in oocytes and early embryonic development. The CUMS paradigm consists of a series of mild and unpredictable stressors, including restraint, isolation or crowded housing, food or water deprivation, disruption of the dark-light cycle, and dampened bedding. Although different patterns of stress responses were triggered by various responses in animals, no invasive physical procedure or tissue trauma was allowed in psychological stress models –41. ImpoOocytes are largely influenced by psychological stress. The number of atretic antral follicles increased in mice under psychological stress, which was accompanied by impaired follicular development due to a lack of corpus luteum, pyknotic granulosa cells, and an irregular oestrous cycle . Tan andUsing different stress animal models, psychological stress was found to inhibit both secondary and antral follicular development, as well as increase follicular atresia, which may be due to the suppressed expression of growth and differentiation factor 9 (GDF9) in mice . SimilarGerminal vesicle breakdown (GVBD) is the key event conferring oocyte quality . FollowiRat studies revealed that psychological stress decreased the number of secondary and antral follicles . Rats inGiven the sensitive nature, an early embryo is more vulnerable to prenatal stress than at later stages . AccordiApplying a novel psychological stress model (mice were placed in oblong micro-cages in which they could not turn around) also resulted in reduced rates of blastocyst formation and cell counts per blastocyst both in vitro and in vivo. Notably, the number of young and their birth weights from stressed donors decreased significantly compared to those of control donors after embryo transfer , which wExisting studies have shown that the HPA and HPO axes are involved of the effects of psychological stress on oocytes and early embryonic development. Generally, the activation of HPA and HPO axes activation triggers gamma-aminobutyric acidergic (GABAergic) signalling by stimulating CRH neurons and GnRH neurons, respectively, in the paraventricular nucleus (PVN) of the hypothalamus , which iIn terms of HPA-mediated signalling pathways, CRH neurons activated in the hypothalamus can stimulate the pituitary to synthesize and secrete adrenocorticotropic hormone (ACTH), which subsequently induces glucocorticoid production (corticosterone in mice) by the adrenal cortex . IncreasAs reported, glucocorticoids affect ovarian function in multiple ways. The primary mechanism is through inhibiting the synthesis and release of GnRH in the hypothalamus, which further results in reduced LH and FSH in the pituitary. Glucocorticoids are mainly present in hypothalamic neurons and ovaries, which can affect the production of testosterone by regulating the glucocorticoid receptor (GR) or directly inducing apoptosis, thereby further affecting female reproductive function . In addiNumerous studies have examined the effects of glucocorticoids on reproductive function. Mouse serum cortisol and corticosterone (two biomarkers for stress and depression) levels are closely correlated in terms of their dynamic levels throughout the oestrous cycle . In streHow does the HPO axis affect reproductive development when psychological stress occurs? Like the HPA signalling pathway, when the body is under psychological stress, CRH can inhibit the secretion of GnRH in the hypothalamus, thereby reducing the synthesis and release of FSH and LH in the pituitary  and MGCs after in vitro maturation (IVM) were significantly higher, indicating that oocyte incompetence caused by psychological stress may be due to the latent apoptotic programme initiated by increased CRH levels. Moreover, the more CRH that interacts with the CRH receptor 1 (CRHR1) on thecal cells and MGCs, the greater the possibility of an imbalance between E2 and P4 by decreasing the availability of insulin-like growth factor 1 (IGF1) and BDNF, and the greater the possibility that oocyte competence will be eventually reduced. CRH also reduced blastocyst formation rates, and supplementation with the CRHR1 antagonist antalarmin further confirmed the results in CCs .Apart from hormonal imbalance caused by psychological stress, the compromised antioxidant status also adversely affects ovarian function due ROS accumulation . StudiesRecent studies have indicated that the generation of OS because of ROS accumulation, which reduces oestradiol-17β biosynthesis in the ovaries, triggers apoptosis in most granulosa cells and disrupts the developing follicular oocytes . OS can During mammalian development, epigenetic modification, including DNA methylation, histone modification and small non-coding RNA, is essential for early germ cell development and the generation of functional gametes , 92. In A substantial amount of evidence has revealed a causal connection between psychosocial stress events and epigenetic modifications , 95. In In this review, the effects and potential mechanisms of psychological stress on oocyte and early embryonic development in female mice are highlighted. Impacted oocyte development (including maturation and ovulation) and an increased number of atretic follicles were found in mice exposed to psychological stress, and embryonic development (including preimplantation/peri-implantation development) was affected, leading to lower implantation rates, teratogenic outcomes and even miscarriages. In terms of mechanism, psychological stress could affect the HPA and HPO axis, which are major pathways that alter the level of hormones and directly generate OS. Further, these axes indirectly induce apoptosis and necroptosis, ultimately reducing oocyte quality and the reproductive outcome of female mice. Moreover, the impact of epigenetic modification should never be neglected in maternal psychological stress models. In conclusion, animal studies have elucidated the adverse effects of psychological stresses on the neuroendocrine system and have provided novel insights into the mechanisms of ovarian dysfunction and infertility caused by psychological stress in humans.


Circular RNAs (circRNAs) are genome transcripts that are produced from back-splicing of specific regions of pre-mRNA. These single-stranded RNA molecules are widely expressed across diverse phyla and many of them are stable and evolutionary conserved between species. Growing evidence suggests that many circRNAs function as master regulators of gene expression by influencing both transcription and translation processes. Mechanistically, circRNAs are predicted to act as endogenous microRNA (miRNA) sponges, interact with functional RNA-binding proteins (RBPs), and associate with elements of the transcriptional machinery in the nucleus. Evidence is mounting that dysregulation of circRNAs is closely related to the occurrence of a range of diseases including cancer and metabolic diseases. Indeed, there are several reports implicating circRNAs in cardiovascular diseases (CVD), diabetes, hypertension, and atherosclerosis. However, there is very little research addressing the potential role of these RNA transcripts in the occurrence and development of obesity. Emerging data from in vitro and in vivo studies suggest that circRNAs are novel players in adipogenesis, white adipose browning, obesity, obesity-induced inflammation, and insulin resistance. This study explores the current state of knowledge on circRNAs regulating molecular processes associated with adipogenesis and obesity, highlights some of the challenges encountered while studying circRNAs and suggests some perspectives for future research directions in this exciting field of study. Whole-genome sequencing studies reveal that our genome comprises approximately 3 to 3.2 billion base pairs of DNA, but merely 1–2% of those pairs correspond to the annotated exons of protein-coding genes. The remaining 98–99% have been referred to as “junk DNA” or “dark matter” with no obvious function in the cell . AccordiAs stated before, there are different types of ncRNA transcriptomes with varied functions; among the most relevant are small ncRNAs such as miRNAs (18–24 nucleotides (nt.)), lncRNAs (>200 nt.), and circRNAs (median length is ~530 nt.). In recent years, considerable attention has focused on circRNAs, which are distinguished from their linear counterparts by the unique structure of covalently closed continuous loop lacking 5′ cap and 3′ poly-adenylated tails . This feArthrobacter luteus (ALU) elements and inverted repeats complementation, lariat-driven circularization (exon skipping), and RNA-binding-protein (RBP) mediated models [Contrary to conventional splicing forming a linear RNA, circRNAs are generally derived from precursor mRNA back-splicing, a molecular event in which a downstream 5′ splice site is joined to a downstream 3′ splice site to form a covalently closed circular structure . Even thd models . Based od models ,11,13  . HoweverAlthough the exact function of most circRNAs is still ambiguous, several studies have indicated that circRNAs may control multiple biological processes via a variety of mechanisms. They can serve as miRNA sponges, which in turn influence target mRNA translation ,22. In oANKRD52) and sirtuin 7 (RIRT7) respectively, through interaction with Pol II elongation complex [In addition to circRNAs found in the cytoplasm compartment, a fraction can accumulate inside the nucleus (ciRNAs and EIciRNAs) where they control gene expression at the transcriptional level. These intron-retaining circRNAs can interact with upstream promoters, RNA polymerase II (Pol II), and other proteins of the transcription machinery to regulate their parental gene expression in some circumstances ,30,31. F complex . circEIF complex . In addi complex .circANRIL) sequesters pescadillo homologue 1 (PES1) which is an essential 60S-preribosomal assembly factor to impair rRNA maturation, resulting in apoptosis [circRNAs can also serve as protein decoys or antagonists to influence gene expression and cellular function. In line with this, RNA-binding proteins (RBPs) harbor specific sequences to bind their specific RNA targets and regulate several cellular and molecular processes . The intpoptosis . circFoxpoptosis . Additiopoptosis , but thepoptosis .Although circRNAs have been defined as a distinct class of ncRNAs that do not code for proteins, intriguingly, recent studies have indicated that some circRNAs may have an unexpected protein-coding potential , when reIn addition to the above-mentioned functions, it has been suggested that circRNAs found in these extracellular vesicles could serve as essential messengers for inter-cellular/inter-tissue cross-talk as released exosomes can be taken up by other cells ,44,45. IAlthough the state of the current knowledge of circRNAs biology is at a very early stage, mounting evidence points to their role as master regulators of gene expression in many diseases including metabolic disorders. In accordance with this observation, a growing number of studies revealed the dysregulation of circRNAs in association with the pathophysiology of several diseases such as diabetes, hypertension, cardiovascular diseases (CVD), and other metabolic perturbations ,49. For Obesity and its metabolic consequences have been considered as one of the most threatening health burdens of modern times. Multiple investigations have brought forward evidence that obesity is a complex condition with multiple etiologies which develop as a joint effect of a variety of factors such as biological, genetic, social, environmental, and behavioral determinants ,57. The Evidence for a large contribution of genetic variation to inter-individual differences in body mass index (BMI) comes from twin, human linkage, and association studies of large cohorts. Heritability estimates for BMI range from 31–90% across different family studies , leavingDespite the established link between circRNAs and several metabolic diseases, investigations on the potential connection between circRNAs and adipogenesis remain rare. Currently, there are few emerging studies extending the scope of the disease-relevant role of circRNAs to obesity and underlying mechanisms. Hence, a review of examples in the literature, suggesting key regulatory roles of circRNAs in many biological processes associated with obesity, including adipogenesis and adipocyte differentiation, is discussed next.Animal adipose tissue. Emerging evidence from in vitro and in vivo animal studies suggest that circRNAs are expressed in adipose tissues and may modulate adipogenesis and lipid metabolism. In this respect, Li and colleagues identified several circRNAs differentially expressed in the subcutaneous adipose tissue of Large White pigs and Laiwu pigs [Bubalus bubalis) [Bos grunniens) adipogenesis [iwu pigs . A furthiwu pigs   . In the ogenesis . In cattogenesis . Moreoveogenesis . CollectHuman adipose tissue. The past two years have witnessed a significant increase in the number of studies determining the function of circRNAs in human adipogenesis and obesity. In a study involving visceral adipogenesis, as many as 4080 circRNA species were found to be differentially expressed in human visceral preadipocytes (HPA-v) versus HPA-v that were induced to form adipocytes; among them, 2215 and 1865 circRNAs were significantly up- and downregulated, respectively [ectively . Furtherectively .In order to screen circRNAs involved in adipogenesis and obesity, Arcinas and colleagues analyzed the transcriptome of human and mouse visceral and subcutaneous fat by RNA sequencing methods . In thiscircANRIL). Genetic variants at the ANRIL gene have been linked with increased risk for T2DM, atherosclerotic CVD, coronary artery disease, myocardial infarction, and obesity [ANRIL promoter methylation at birth is associated with increased cardiovascular risk [ANRIL loci could be a marker for later adiposity. Collectively, the results from the above studies demonstrate that several circRNAs are differentially expressed in adipose tissue and support a significant role of these RNA species in the regulatory networks of adipogenesis. However, the precise role that circRNAs play in fat deposition and lipid metabolism remains elusive. Deeper understanding of molecular mechanisms controlling the expression of these RNAs species is critical to identify new targets for prevention of adipogenesis and therefore occurrence of obesity and obesity-related metabolic disorders.Another circRNA that has attracted substantial attention for its role in various physiopathological processes is circular antisense noncoding RNA at the INK4 locus  which was downregulated in both peritoneal macrophages and adipose tissue macrophages from high-fat diet-fed obese mice . MoreoveIn another study, it was observed that circARF3 (ADP-ribosylation factor 3) functions as an endogenous miR-103 sponge to inhibit miR-103 activity, resulting in an increase of TNF receptor-associated factor 3 (TRAF3) expression and accordingly alleviates inflammation in mouse adipose tissue . SubsequObesity and inflammation have been associated with several complications including T2DM, CVD, hypertension, and stroke . In thisUnlike white adipocyte tissue (WAT), which primarily stores lipids, brown adipocyte tissue (BAT) can promote energy metabolism by decreasing adiposity and increasing energy expenditure. Loss of BAT activity may contribute to obesity and development of IR. Hence, WAT browning has gained considerable attention for its potential to reverse obesity and related metabolic complications . A varieSo far, several miRNAs have been identified and characterized to govern WAT browning process ,110. MorcircRNAs are increasingly being recognized to play essential roles in several diseases including metabolic disorders. They are also emerging as a novel regulatory layer in adipogenesis and lipid metabolism involved in the development of obesity. Yet a number of key questions remain: i) While the studies discussed above have confirmed that circRNAs display altered expression patterns in adipose tissue and obese individuals, the cell types and tissue origin of circRNAs in obesity are not yet fully explored. This is very challenging because obesity is a complicated condition involving many tissues and organs including the muscle, pancreas, liver, and adipose tissue. In addition, there is growing evidence that WAT is heterogeneous, and adipocytes are only part of the adipose deposit. Furthermore, different types of adipocytes have differing metabolisms and their ability to communicate with other metabolic organs through sending out various signaling molecules and possibly ncRNAs may contribute to the regulation of systemic energy homeostasis differently ,115. TheTo sum up, circRNAs have recently emerged as a class of ncRNAs with multifaceted roles in the cell. Emerging evidence from in vitro and in vivo experimental studies indicates that circRNAs are involved in the regulation of adipogenesis and obesity. However, the ongoing efforts to better understand the role of circRNAs in adipose tissue and metabolics must include the above-mentioned considerations as they may help accelerate their clinical research.


Diabetic keratopathy (DK) is a common, but underdiagnosed, ocular complication of diabetes mellitus (DM) that has a significant economic burden. It is characterised by progressive damage of corneal nerves, due to DM-induced chronic hyperglycaemia and its associated metabolic changes. With advances in corneal nerve imaging and quantitative analytic tools, studies have shown that the severity of diabetic corneal neuropathy correlates with the status of diabetic peripheral neuropathy. The corneal nerve plexus is, therefore, considered as an important surrogate marker of diabetic peripheral neuropathy and helps in the evaluation of interventional efficacy in the management of DM. The clinical manifestations of DK depend on the disease severity and vary from decreased corneal sensitivity to sight-threatening corneal infections and neurotrophic ulcers. The severity of diabetic corneal neuropathy and resultant DK determines its management plan, and a step-wise approach is generally suggested. Future work would focus on the exploration of biomarkers for diabetic corneal neuropathy, the development of new treatment for corneal nerve protection, and the improvement in the clinical assessment, as well as current imaging technique and analysis, to help clinicians detect diabetic corneal neuropathy earlier and monitor the sub-clinical progression more reliably. Diabetes mellitus (DM) is a chronic metabolic disorder, that is characterised by the increase in blood glucose, due to insulin deficiency from the destruction and loss of insulin-producing pancreatic b-cells Type 1) or as a consequence of both insulin resistance and “relative” impairment in insulin secretion Type 2) . Th. Th39]. The morphology and distribution of corneal nerves can be visualised with different types of staining techniques. Conventional staining techniques, such as gold chloride, silver staining and methylene blue, are now less commonly used because they require a high level of technical skill. Also, their sensitivity to show nerve patterns is low . ImmunohThe corneal subbasal nerve plexus lies in a single plane parallel to the corneal surface, and its density is, therefore, easier to be evaluated with IVCM compared to that of stromal nerves that are distributed throughout the stroma in a three-dimensional pattern . MoreoveThe relationship between corneal neuropathy and DPN has been described. Petropoulos et al. reported that corneal nerve fibre density, branch density, and nerve fibre length differed significantly between control subjects and type 1 and type 2 diabetic patients, and the corneal nerve metrics worsened with increasing severity of DPN . FurtherThe corneal nerve plexus has also been used as a biomarker to determine interventional efficacy in the management of DM. Corneal nerves have been shown to regenerate in diabetic individuals after adopting measures to improve glycaemic control, especially HbA1c ,48. In tCorneal nerves provide trophic support to various cells that constitute the cornea by secreting biologically active mediators, collectively known as neuromediators, including neurotrophins, neuropeptides, and neurotransmitters . These nThe neurotrophic role of corneal nerves maintains a healthy cornea and promotes corneal wound healing . SeveralDM causes a decrease in the concentration of neuromediators . Hence tThe clinical manifestations of diabetic corneal neuropathy vary with disease severity. NK is a manifestation of diabetic corneal neuropathy that may result in corneal hypoesthesia, dry eye, recurrent corneal erosions, non-healing corneal epithelial defects, neurotrophic ulceration and vision-threatening corneal infections .NK is a disease that is related to alterations in corneal nerves, leading to impairment of their sensory and trophic functions, with a consequent breakdown of the corneal epithelium, as well as affecting health and integrity of the tear film, epithelium and stroma . Its repThe clinical evaluation of a patient with diabetic corneal neuropathy involves taking a detailed history, corneal sensitivity assessment, slit-lamp biomicroscopy evaluation for the ocular surface integrity with vital stains and tear film function, as well as IVCM imaging on corneal nerves.The patient’s medical and surgical history should be probed to rule out conditions other than DM that could be associated with the development of NK. Other concurrent ocular manifestations specific to the aetiology would also help in the differential diagnosis. However, the essential components of clinical manifestations of diabetic corneal neuropathy are not different from those, due to other causes of NK that have been summarised in It is well known that corneal sensitivity decreases in diabetic patients and its degree of loss correlates with the severity of DM . The evaCorneal esthesiometers have been used widely in clinics for the quantitative assessment of corneal sensitivity . Among tw/v solution of fluorescein sodium  To promote corneal epithelial integrity and avoid its breakdown; (2) to improve health and quality of corneal epithelium; and (3) to prevent progression to stage 2 NK.For stage 1 NK, discontinue all topical medications if possible, except preservative-free artificial tears or ointment to avoid toxic keratopathy from preservatives. Reducing concurrent inflammation with the use of topical non-preserved steroids, non-steroidal anti-inflammatory drugs (NSAID) or ciclosporin is also indicated. However, topical steroids should be used with caution because they may increase the risk of secondary microbial infections . LikewisThe treatment goals of stage 2 NK include re-epithelialisation of the denuded stroma and prevention of corneal infections and stromal lysis. These intervention aims can be achieved by the following therapeutic modalities.In some patients, the leading edge of the healing epithelium may become heaped, which may prevent corneal epithelial migration across the epithelial defect. Debridement of rolled edges of the neurotrophic ulcer promotes corneal re-epithelialisation by triggering the healing response in the surrounding epithelium .Corneal or scleral therapeutic contact lenses can promote ocular surface integrity as they (1) decrease the trauma from the eyelids (2) create a reservoir of therapeutic agents and lubricants between the contact lens and cornea, as well as increase their retention time on the ocular surface. However, therapeutic contact lenses should be cautiously used in patients with NK as reduced, or absent corneal pain sensation might mask an early sign of corneal infections .Over the last decade, there has been an increased interest in the use of autologous serum eye drops to treat persistent corneal epithelial defects in patients with stage 2 NK who are unresponsive to conventional medical treatment because of superior efficacy in comparison with traditional lubricants . AutologPlatelet-rich plasma (PRP) also contains biologically active proteins and growth factors and has been used as a therapeutic agent to promote wound healing and regeneration of the ocular surface. Some studies have demonstrated that PRP had better efficacy than autologous serum eye drops as it healed those persistent epithelial defects where topical autologous serum drops had failed ,97.® and ProkeraTM, which consist of a combination of AM and a contact lens that can easily be slipped into the eye, have also gained attention [Amniotic membrane (AM) is a biological tissue that has been used by ophthalmologists for the management of a variety of ocular conditions, including neurotrophic corneal ulcers a. While ttention .AM has three distinct layers: Epithelium, basement membrane, and stroma. The basement membrane comprises of collagen IV and VII, laminin and fibronectin that facilitate epithelial cell adhesion. In contrast, the stromal part contains various growth factors, anti-inflammatory factors, tissue-inhibitors of matrix metalloproteinases and anti-angiogenic factors. The complex interaction of biological mediators assists in the resolution of neurotrophic corneal ulcers ,98. SeveEyelid closure to narrow the interpalpebral fissure is the cornerstone in the management of NK, to eliminate blink-related trauma to the healing epithelium and to reduce evaporative tear loss . MoreoveConjunctival flaps may be useful in the management of non-healing corneal epithelial defects where medical management has failed because they provide vascular blood supply and serum-derived growth factors to the non-healed area ,107,108.NGF eye drops have become a promising therapeutic modality for the treatment of NK. Clinically, it promotes corneal epithelial healing, improves tear function and stimulates corneal nerves regeneration . SeveralIn neurotrophic corneas, a secondary microbial infection could delay the healing of persistent corneal epithelial defects c. It mayNK could progress to stage 3, where patients may end up with a corneal perforation and/or corneal stromal melting. Hence, the management aims at preventing corneal stromal lysis and corneal perforation . AlthougIn addition, topically administered biological polymers, such as matrix-regenerating agent (RGTA), have also been proposed for the management of severe NK. RGTA promotes corneal healing by providing binding sites for growth factors and avoids stromal proteolysis .Clinicians and researchers are striving to identify potential biomarkers and new treatment strategies for diabetic corneal neuropathy. The advancements in corneal imaging and development of innovative clinical tests may help the eye care professionals to detect corneal neuropathy early and to monitor its progression.Tears are easily obtainable, and the use of tear biomarkers to predict or stratify an ocular condition is gaining significant importance. A correlation has been found between the tear biomarkers that are involved in corneal health, such as IGF-1 and SP and IVCM findings in diabetic patients ,122,123.IGF-1 is an important component of the tear film proteome and has potent neuroprotective functions . In diabTear SP may be another potential biomarker for diabetic corneal neuropathy. SP is a key neuropeptide that is secreted by corneal nerves. It maintains corneal epithelial integrity by mediating epithelial migration, proliferation and differentiation via the neurokinin-1 receptor . In diabRecently, Meera and colleagues explored the role of 31 tear biomarkers for screening of DPN. MMP-9 and tumour growth factor-α (TGF-α) levels in tears were higher in patients with DPN compared to patients without DPN, but the difference was not significant. The authors concluded that inflammatory tear biomarkers were regarded as suboptimal standalone tools for detecting DPN as the AUC was only 65%. However, combining tear analysis (MMP-9 and TNF-α) with corneal esthesiometry measurement (cut off 5.8 mm) could improve the AUC to 84% .With growing interest in the treatment of diabetic corneal neuropathy, development of new therapies to promote and maintain ocular surface integrity, as well as corneal neuronal health, is imperative. The systemic and topical therapeutic approaches, as well as gene and cell-based therapies that have been tested and suggested in recent years, are summarised in 2), hence scanning on multiple areas may be required if clinicians intend to depict the nerve network over the whole cornea. Wide-field or large-area corneal scanning, as well as montaging techniques, have the potential to circumvent this [Corneal confocal imaging is a rapid and non-invasive tool to evaluate the severity of diabetic corneal neuropathy, as well as response to treatment. However, costly equipment, limitations of the current image acquisition systems and analytic technology, have limited the widespread adoption of IVCM in routine clinical practise, as well as screening programs for diabetic neuropathy. The commercially available IVCM scans a small area of interest , Oculus Keratograph 5M  and LipiView II  that reliably determine the production and stability of the tear film, maybe useful.Diabetic keratopathy affects 47–64% of patients during the clinical course of DM and can have a significant economic burden. Chronic hyperglycaemia and its associated metabolic changes result in corneal neuronal degeneration. Recent advancements in corneal nerve imaging and software have allowed quantitative evaluation of the morphology of corneal nerves, and emerging scientific evidence has established that DM-induced corneal neuropathy correlates with changes in peripheral nerves. Hence, the corneal nerve plexus may be regarded as a surrogate marker of DPN. The clinical manifestations of diabetic corneal neuropathy vary with disease severity and range from decreased corneal sensitivity to neurotrophic ulcers that have a risk of vision-threatening corneal infections. The management of DK depends on its severity, and a step-wise approach is generally suggested. Future work would focus on exploring the potential biomarkers and treatment strategy, as well as new innovative clinical tests and imaging modality to detect diabetic corneal neuropathy early and to monitor its sub-clinical progression.


Ananya program aimed to support the GoB to improve reproductive, maternal, newborn and child health and nutrition (RMNCHN) statewide. Here we summarise changes in indicators attained during the initial two-year pilot phase (2012-2013) of implementation in eight focus districts of approximately 28 million population, aimed to inform subsequent scale-up.The Government of Bihar (GoB) in India, the Bill and Melinda Gates Foundation and several non-governmental organisations launched the Ananya interventions were not implemented. We analysed changes in indicators across the RMNCHN continuum of care from baseline to midline in intervention and comparison districts using a difference-in-difference analysis.The quasi-experimental impact evaluation included statewide household surveys at two time points during the pilot phase: January-April 2012 (“baseline”) including an initial cohort of beneficiaries and January-April 2014 (“midline”) with a new cohort. The two arms were: 1) eight intervention districts, and 2) a comparison arm comprised of the remaining 30 districts in Bihar where Ananya; two-thirds (n = 13) of secular indicator changes were in a direction expected to promote health. Statistically significant impact attributable to the Ananya program was found for 10% (five of 51) of RMNCHN indicators. Positive impacts were most prominent for mother’s behaviours in contraceptive utilisation.Indicators in the two arms were similar at baseline. Overall, 40% of indicators (20 of 51) changed significantly from baseline to midline in the comparison districts unrelated to Ananya program had limited impact in improving health-related outcomes during the first two-year period covered by this evaluation. The program’s theories of change and action were not powered to observe statistically significant differences in RMNCHN indicators within two years, but rather aimed to help inform program improvements and scale-up. Evaluation of large-scale programs such as Ananya using theory-informed, equity-sensitive (including gender), mixed-methods approaches can help elucidate causality and better explain pathways through which supply- and demand-side interventions contribute to changes in behaviour among the actors involved in the production of population-level health outcomes. Evidence from Bihar indicates that deep structural constraints in health system organisation and delivery of interventions pose substantial limitations on behaviour change among health care providers and beneficiaries.The ClinicalTrials.gov number NCT02726230. The Sustainable Development Goals (SDGs) and recent calls for Universal Health Coverage (UHC) have reaffirmed global commitments to ensure affordable and equitable access to high-quality health services for all people. Strengthening primary health care (PHC) systems has been well-established as a necessary condition for achieving these goals . MoreoveImproving PHC system performance in LMICs remains a major global health challenge -5. PoorlGovernment-managed PHC systems are central to the provision of RMNCHN services at scale in many LMICs, including in India and the state of Bihar. Despite significant out of pocket private expenditures , high leThere is a robust body of evidence assessing the impacts of multiple RMNCHN interventions delivered through PHC platforms, including (a) community health workers, (b) health facilities, (c) social and behavioural change communication programs, (d) women’s self-help groups (SHGs), and (e) other community-based organisations -27. WhilSure Start) involved a partnership between PATH and the Government of Uttar Pradesh and generated significant improvements in care-seeking and healthy behaviours through community-level interventions, including communications, strengthening of local health committees, and mobilisation and mentoring of FLWs , measles immunisation , fully vaccinated , and use of a postpartum intrauterine device for contraception . Thus, changes in indicators associated with contextual factors unrelated to Ananya were mixed, but overall favoured improvements in indicators in the direction of health promotion. These changes were also accounted for in DID analyses . No significant change attributable to Ananya was seen for four delivery indicators, ten postnatal care indicators, five variables reflecting child nutrition, and eight child immunisation indicators. Four of 14 family planning indicators improved significantly as a result of Ananya interventions. There was a significant three ppt increase in postpartum tubal ligation (P = 0.026) and significant increases in use of any modern method of contraception among mothers of younger children 0-5 months  and for mothers who had more than one child , with the largest increase in use of oral contraceptive pills (five ppt) although this change was borderline in significance (P = 0.06). The increase in contraception was significant among mothers of female children  but not among mothers of males.Some improvements in DID estimators were seen for ANC and birth preparedness, postnatal care, child immunisation and family planning ((P = 0.017) and immediate breastfeeding (within one hour of birth) (P = 0.032) attributable to the Ananya program. Among private facility births, there was a 27 ppt increase in applying nothing to the cut umbilical cord (P < .001). No significant changes in practices attributable to Ananya were seen for home births.Ananya program interventions by restricting our analyses to maternal respondents who received either two or more antenatal FLW home visits in the last trimester ((P = 0.038) improvement in exclusive breastfeeding but a 15 ppt (P = 0.04) decrease in identification of a skilled attendant for delivery among home births ((P = 0.006) increase in exclusive breastfeeding but an 11 ppt (P = 0.046) decrease in immediate wiping and drying of the newborn after delivery   of DID estimators were significant after FDR adjustment for multiple comparisons. Improvement was greatest for indicators of family planning, which showed significant increases in 29% (four of 14) of indicators and accounted for 80% (four of five) of all indicators showing significant improvements. This might reflect relatively uniform, low levels of most family planning indicators at the beginning of the program. Only one statistically significant improvement was seen for antenatal and birth preparedness (FLW home visits), and none for delivery care, postnatal care, child nutrition or immunisation. Three of the five indicators showing improvement reflected mother’s behaviours in utilising modern contraception. Among sub-samples of infants by place of birth, improvements were found for cord care in public and private facility births but not for home births, and immediate breastfeeding improved in public but not private facilities. Overall, no improvements attributable to the Ananya program were seen in postnatal care practices among home births. There was limited evidence – only for exclusive breastfeeding – that antenatal or postnatal FLW home visits were associated with improvements in delivery care or newborn care, although this result must be viewed with caution given the possibility for selection bias in that characteristics of women who received these visits could have differed across the Ananya program and the comparison districts.Few significant improvements in RMNCHN indicators could be attributed to the In other analyses, we found that social and behavioural change communication interventions led by BBC Media Action showed more robust and consistent improvements in desired behaviours among mothers who were exposed to mHealth interventions ; howeverJanani Avam Bal Suraksha Yojana (JBSY) program provided a cash transfer to women to incentivise facility deliveries [Ananya program area could result overall in an over-estimation of program impact. Thus, given the varying magnitude and pace of improvement of health measures in Bihar during this period, the DID design of this evaluation was critical for assessing the attributable effect of the Ananya program on RMNCHN behaviours.In Bihar (and across India), there were substantial secular declines, based on population-level survey data , in maternal mortality ratio and smaller but steady reductions in infant mortality rate, neonatal morality rate, under-5 mortality rate and total fertility rate (Table S4 in the liveries . These dAnanya coupled with the short, two-year midline in the context of a planned five year initative. The Ananya interventions sought to saturate the health system at community and, to a lesser extent, at facility levels and through outreach by rolling out a number of interventions through various delivery platforms [Ananya management structure with intensive support to GoB implementation may have yielded more consistent and higher magnitude effects. Further, the midline evaluation was collected during the period when GoB implementation was transitioning to scale-up and thus intensity of implementation and Ananya program support to the GoB may have already been declining [Ananya did not focus on complementary efforts such as providing nutritional supplements or promoting increases in household purchasing power that – when coupled with FLW counseling on complementary feeding and nutrition – might have generated more positive impact in this domain.Interpretation of evaluation results must consider the large scale and ambitious scope of latforms . Timing eclining . AdditioAnanya pilot study area to characterise motivational mechanisms among ASHAs in Bihar [The evaluation design was not capable of identifying specific demand-side barriers to adoption. For example, babies being breastfed within one hour of birth for home deliveries decreased by four ppt, but we do not know if the constraint to adoption pertained to knowledge, attitude, skills, efficacy, or social norms. We conducted a realist evaluation in two districts of Bihar outside the in Bihar . FindingOther than two randomised controlled trials implemented during this period ,20, it iThe Lancet Global Health Commission on High-Quality Health Systems in the SDG Era [Collaborative efforts such as the PHC Performance Initiative  and The  SDG Era  seek to  SDG Era . Similar SDG Era , and the SDG Era . Cost-efAnanya which are comprised of multiple interventions and require great coordination among stakeholders, additional system-level approaches, tools, and research methods might also be applied, which recognise PHC systems as complex adaptive systems in which technical solutions alone are not adequate to induce the adoption of innovations [To complement more traditional public health evaluations, program designers could utilise evaluation designs such as realist evaluations, which seek to discern “what works, for whom, in what respects, to what extent, and how” . Given tovations . Popularovations . Researcovations ,58.Ananya during its pilot implementation period. Encouraging signs were seen in select RMNCHN indicators, but ultimately the duration and intensity of implementation were insufficient to achieve large-scale, statistically significant improvements in most health-related indicators. Of note, the evaluation provided early evidence of encouraging improvements in family planning uptake from very low baseline levels, due to program inputs. The finding of a significant increase in contraception among mothers of female children but not among mothers of males requires further investigation, and underscores the importance of bringing a gender lens to RMNCHN programming inputs and evaluations [Ananya offer the opportunity to advance the research agenda for PHC performance improvement at scale, and provide practical guidance to policymakers and practitioners seeking to invest in improving the performance of PHC systems in LMICs. This evaluation well illustrates the importance of taking secular changes into account and reinforces the need for theory-driven, gender- and equity-sensitive, policy-relevant, mixed-methods evaluations of large-scale health programs that inform action to improve primary health care system performance.The Mathematica evaluation offers an important contribution in its use of DID estimators to control for secular changes that impact health, and its broad assessment across the continuum of care and delivery platforms, in order to reliably analyse the contribution of luations . Impact luations . Evaluat


The coronavirus disease 2019 (COVID-19) pandemic has rapidly evolved and imposed extraordinary challenges to health care systems worldwide. Health systems in high-income countries have been overwhelmed due to severe COVID-19 infections, even though it causes serious illness in a relatively small fraction of patients who contract the virus. Therefore, it is expected that fragile health systems in African countries like Malawi will be highly vulnerable to the anticipated surge in severely ill patients with COVID-19.Management of severe COVID-19 infection entails intensive monitoring and use of specialized medical equipment by clinical professionals including those with nutrition expertise like dietitians. To date, one of the major challenges faced in the implementation of public health measures in African countries has been inadequate nutrition for citizens living under the poverty line. In Malawi, clinical nutrition care is a crucial yet underdeveloped component of health care, hence, it is important to anticipate challenges exerted by COVID-19 on delivery of nutrition services.Malawi, a landlocked low-income country with a population of almost 19 million, registered its first case on April 2, 2020 and had 3709 confirmed cases including 103 deaths as of July28, 2020. Like other countries globally, the COVID-19 response in Malawi has consisted of a myriad of interdisciplinary approaches aimed at case prevention and case management. The absence of a specific treatment for this novel virus has called for pragmatic prevention and management strategies based on clinical and public health experience. The preventive approaches aimed to reduce transmission rate include promotion of handwashing and physical distancing also in form of lockdowns. However, the appropriateness, effectiveness, feasibility, and sustainability of these measures are unknown and questionable particularly in low-resource settings like Malawi, the only country to announce a lockdown and cancel it before its start. In this paper we discuss the anticipated challenges in providing adequate nutrition and preventing malnutrition-related morbidity and deaths in the public health system in Malawi.Inadequate nutrition remains a global health problem, having the highest prevalence and impact in low- and middle-income countries (LMICs). The bidirectional relationship between nutritional status and immunity poses a likely threat of COVID-19 pandemic exacerbating the burden of global malnutrition.Nutritional status is expected to be a highly important factor related to outcomes of patients with COVID-19. It has been documented that major causes of morbidity and mortality in COVID-19 patients are secondary to complications of acute respiratory syndrome related to prolonged Intensive Care Unit (ICU) stay .Non-communicable diseases (NCDs) like obesity, diabetes, and hypertension are also now known risk factors for poor clinical outcomes in people hospitalized with COVID-19 . With anTo achieve COVID-19 nutrition recommendations outlined by various authorities in nutrition practice, countries must already have adequate human resource capacity in place. In settings such as Malawi where there are only 11 clinical dietitians in the country, a lack of human resource in clinical nutrition provision is anticipated to rank high on the list of challenges.A study by Bunyani et al  in LilonIn the absence of a COVID-19-specific clinical nutrition response, hospital malnutrition will likely increase in both COVID-19 and other patients in low-income settings like Malawi. Literature shows  that 20%In addition to this, the feeding of patients within hospitals in Malawi largely depends on food prepared and served by a patient’s designated guardian, to supplement inadequate hospital meals. Guardians are typically allowed to visit a hospitalized patient three times per day. However, due to the World Health Organization recommendation of physical distancing, visits have been banned at hospitals. These restrictions will negatively affect the availability of food for patients, resulting in an increased risk in malnutrition amongst hospitalized patients with either COVID-19 or other conditions as a result of inadequate intake.Aside from the effects of COVID-19 on the adult population, we forecast the presence of indirect negative effects on child health and nutrition. This could be attributed to numerous factors which may include ill caregivers failing to provide adequate nutrition through breastfeeding (though it is currently recommended to continue breastfeeding even in mothers with COVID-19), health care failures associated with movement restrictions, economic disruptions, and limited food access. Further to this, efforts made by already fragile health systems to prepare for COVID-19 at the possible expense of other health services, which may include food security and nutrition programs, may also contribute to the rise in severe acute malnutrition admissions.Due to the novelty of the COVID-19 pandemic, many assumptions about its potential effects on other health services have been extrapolated from other contexts. For example, the Ebola outbreak in West Africa caused a health care shutdown, which resulted in outpatient care coverage declining by approximately 27% . In IndiPhysical distancing, which is currently promoted in Malawi, could inadvertently cause a rise in poor management of NCDs from a lack of access to nutritious foods combined with low physical activity. Furthermore, income losses related to market diversity restrictions, movement restrictions may also contribute to a decline in diet quality, especially as more nutritious foods are often costlier than energy-dense foods.To address misinformation, related to how COVID-19 is transmitted and treated, advocacy and risk communication through health literacy campaigns should also include nutrition education. As shown by evidence from the WHO , campaigDeriving from lessons learned from the Ebola crisis in West Africa, we also agree that the public health response should aim to maintain utilization of routine health services . We commTo complement the recruitment of nutrition personnel, we propose the initiation of training for nutrition management in pandemics for all frontline workers especially in a setting such as Malawi where clinical nutrition specialists are scarce. Moving forward, LMICs such as Malawi also need to invest in inclusion of standard enteral and parenteral feeding products in the essential medicines list, which become particularly important for severe infections such as COVID-19 and future outbreaks.