Neuromyelitis Optica (NMO), or Devic’s disease, is an immune-mediated, usually relapsing, central nervous system (CNS) demyelination disorder associated with optic neuritis and transverse myelitis. It is characterised by the presence of longitudinally extensive transverse myelitis (LETM) and antibodies against water channel aquaporin-4 (AQP4-immunoglobulin G [IgG]). The term NMO spectrum disorder (NMOSD) includes patients with limited forms of NMO who are at risk of recurrence. Often patients with NMO or NMOSD have an associated systemic autoimmune disease, most commonly systemic lupus erythematosus (SLE) or Sjogren syndrome (SS) or a related profile of non-organ-specific autoantibodies. The intriguing aspect of coexisting NMOSD and SLE is whether they are independent diseases that can coexist with each other or the serological findings specific to both diseases in a patient is a non-specific finding of no prognostic or therapeutic concern. We have presented two cases of NMOSD coexisting with SLE and based upon the existing evidence in the literature we present that the two conditions are independent of each other, and, at times, it can throw a therapeutic challenge to any clinician. It also includes patients with coexisting autoimmune disorders.3 The presence of AQP-4IgG in patients with the first episode of LETM is a strong predictor of its relapse or occurrence of optic neuritis in more than 50% of patients within 12 months.4Neuromyelitis Optica (NMO) or Devic’s disease is an inflammatory central nervous system (CNS) disorder char-acterised by the presence of three or more vertebral segments longitudinally extensive transverse myelitis (LETM) and serum antibodies against water channel aquaporin-4 (AQP4-immunoglobulin G [IgG]).6 Customarily, patients with transverse myelitis and non-organ-specific autoantibodies have been classified as disease-associated transverse myelitis, irrespective of the fact that the disease has clinically manifested or not.8Patients with NMO or NMOSD often have an associated autoimmune disease, most commonly systemic lupus erythematosus (SLE) or Sjogren’s syndrome (SS), or a related profile of non-organ-specific autoantibodies.There is no consistent opinion whether NMOSD and SLE/SS are independent diseases that can coexist with each other, or the serological findings are non-specific and AQP-4IgG or non-organ-specific antibodies can be seen in either condition. However, this differentiation has significant implications for the management of the two groups of diseases and, at times can be a therapeutic challenge when they coexist and are active in the same patient simultaneously. Here we present two cases of NMOSD coexisting with SLE and we have discussed the clinical implications subsequently.Figure 1). There was no obvious cord swelling or atrophy or post-contrast enhancement. MRI of the brain was normal. Her blood counts and biochemical parameters were unremarkable. A detailed evaluation at our institute revealed a history of polyarthralgia with morning stiffness of one hour duration, hair loss for the last one year and malar rash for which rheumatology consultation was sought.Our first case is a 27-year-old female patient who became symptomatic with pain in the lower abdomen and lower back on the same day followed by severe paraesthesia in the lower limbs. Four days later, she developed acute painful retention of urine and loss of bowel sensation, paraparesis, and loss of sensation to all modalities below the level of the umbilicus by the fifth day. She had a progressive course of illness and became bedridden with a complete inability to move her lower limbs. She was evaluated by a neurologist and a clinical diagnosis of transverse myelitis was made. Magnetic resonance imaging (MRI) of the spine showed long segment involvement of the spinal cord at dorsal vertebral levels 4 to 6 (D4-D6) with well-defined intra-substance T2 and short-tau inversion recovery (STIR) hyperintensities and seen to involve the central and both halves of the cord, sparing the dorsolateral part  with normal leukocyte and platelet counts. Erythrocyte sedimentation rate (ESR) was raised , however, C-reactive protein (CRP) was normal (0.7 mg/L). She had proteinuria without any active sediment (24-hour urinary protein 1140 mg). Cerebrospinal fluid (CSF) analysis showed the presence of raised leukocytes (30 leucocytes/ml) with lymphocytes predominance and a mild increase in proteins . Other tests on CSF were normal .9 The patient was diagnosed as a case of SLE .10 However, due to the presence of LETM in MRI, there was a strong suspicion of NMOSD. Anti-AQP-4IgG antibody test by immunofluorescence was requested, and it turned out to be positive. Thus, the patient also fulfilled the international consensus diagnostic criteria for NMOSD, 2015.11 Involvement of the optic nerve was ruled out by a normal fundus, visual evoked potential, and MRI brain.Rheumatological evaluation of the patient showed positive anti-nuclear antibody (ANA) by indirect immunofluorescence (IIF) using Hep-2 cells and positive anti-double-stranded DNA antibody (dsDNA) positivity. Serum complements were normal. Lupus anticoagulants (LAC) were not present . Anti-neutrophil cytoplasmic antibodies (ANCA) were negative. Other tests including serum angiotensin-converting enzymes (ACE), and serological markers for Human Immunodeficiency Virus and hepatotropic viruses were normal. However, kidney biopsy revealed International Society of Nephrology/Renal Pathology Society (ISN/RPS) class V lupus nephritis.The patient was treated with methylprednisolone pulse followed by high dose oral prednisolone and B cell depletion therapy (rituximab). Significant improvement was achieved within two to three weeks with recovery of muscle strength to enable her to ambulate up to a hundred meters with minimal support. At five years of follow up patient had a complete recovery of neurological deficit and resolution of proteinuria.Figure 2). It was predominantly seen in the central region of the spinal cord and involved most of the cross-sectional area. No post-contrast enhancement was seen. It was associated with swelling of the cord and mild prominence of the central canal. On further evaluation she exhibited the presence of anti- AQP-4IgG antibody by immunofluorescence. Anti-myelin oligodendrocyte glycoprotein (MOG) antibody was negative. CSF oligoclonal band was absent while CSF IgG was raised . No other abnormality was noted in CSF analysis. Her serum complements (C3 and C4) and CRP were normal and there was no proteinuria. A radiogram chest revealed no abnormality. Other haematological and biochemical parameters were normal.Our second patient was a 34-year-old female. She was diagnosed to have SLE seven years ago when she presented with neuropsychiatric symptoms and discoid lupus erythematosus (DLE). She was doing well on azathioprine and hydroxychloroquine (HCQ) till 10 days before the presentation when she developed acute onset numbness over the left half of the body from mid-chest downward, weakness of left lower limb and acute retention of urine. Her symptoms gradually progressed to have numbness on the right half of her body as well and she developed weakness of neck muscles and trunk. On clinical examination, she had a loss of sensation to all modalities below T8 spinal level with grade 3/5 power in left lower limb and grade 0/5 power in right lower limb in all muscle groups. There was hypotonia and reflexes were diminished. There were no other manifestations to suggest SLE flare. MRI of the whole spine revealed long segment T2/STIR hyperintensity with swelling of the cord extending from the cervicomedullary region up to the axial level of the D12 vertebral body (She was diagnosed as a case of NMOSD and was given five days of pulse methylprednisolone (1000mg each). Due to a suboptimal response, it was followed by five cycles of plasmapheresis. For the maintenance phase, she was given rituximab. At the time of discharge, she could hold the neck of the pillow, could sit on the bed with little support and power in her hands had recovered. She could change sides on her own, left and right lower limb power was 4/5 and 2–3/5, respectively, and sensory loss was improving.Here we have presented two cases of SLE with LETM and AQP-4IgG positive status. Our Case 1differs from Case 2 in the manner that on the presentation itself, she fulfilled the classification criteria for both NMOSD and SLE (with lupus nephritis class V), while in Case 2, NMOSD was detected on the background of a long-standing SLE (without any evidence of active SLE).Case 1 gave us several diagnostic and therapeutic challenges. Firstly, is the transverse myelitis a part of CNS manifestation of SLE or is it NMOSD coexisting with lupus nephritis? Does the treatment of transverse myelitis in SLE and NMOSD differ? If yes, should we treat transverse myelitis following the guidelines for the treatment of CNS lupus or NMOSD? If the existing evidence mandates treatment of NMOSD, in the prevailing circumstances, how should we manage the lupus nephritis class-V? We reviewed the literature to overcome this dilemma and we have discussed our opinion as below.st line therapy - azathioprine or rituximab; second-line therapy - Mycophenolate mofetil (MMF) or Methotrexate or Mitoxantrone; third-line therapy - combination therapy (combination of steroids plus cyclosporine A or methotrexate or azathioprine) or Tocilizumab.12 Due to relatively higher rates of failure, cyclophosphamide is recommended only in case of failure or non-availability of other immunosuppressive therapy.12It includes treatment of acute episodes as well as prevention of recurrences. While prednisolone is the accepted recommendation for an acute episode, choices of a preventive agent are: 113 Refractory cases can be subjected to immunosuppressive therapy in which intravenous cyclophosphamide has been found to be more effective than azathioprine or MMF.14 If vasculitis is possible pathogenesis for the CNS manifestation, high-dose prednisolone is recommended, followed by early institution of cytotoxic therapy for which, again, cyclophosphamide has been found to be more effective than other immunosuppressants..14 Once vasculitis has been controlled by cyclophosphamide, it can be substituted by another medication to maintain remission.14CNS manifestations of SLE consequent to thromboembolic pathology is treated with high dose prednisolone or pulse methylprednisolone and anticoagulation.15 Though the LUNAR trial failed to achieve the primary endpoint in cases of proliferative lupus nephritis, it has been reported to have a promising effect in several case reports and observational studies in membranous lupus nephritis.17Mycophenolate mofetil and prednisolone remain the first-line treatment of ISN/RPS class V lupus nephritis, while calcineurin inhibitor alone or in combination with MMF is emerging as an alternative.Thus, following the review of available literature, we concluded that if myelitis is secondary to NMOSD, the acute phase is treated by methylprednisolone and refractory cases should undergo rescue plasmapheresis. In the maintenance phase, azathioprine and rituximab become the first choice while cyclophosphamide is not recommended due to poor response. Conversely, if myelitis is considered to be the manifestation of SLE, cyclophosphamide becomes the preferred choice over rituximab and azathioprine.18 They also found that anti- AQP-4IgG antibody is not present in other conditions associated with severe myelopathy  or optic neuropathy. Moreover, the pathogenic role of anti- AQP-4IgG antibody in NMO is strongly supported by the presence of AQP-4 at the exact site of the NMO-typical vasculocentric deposition of immunoglobulins and products of complement activation in human NMO spinal cord lesions and selective loss of AQP4 immunostaining in all NMO lesions.20 Based on these pieces of evidence, they concluded that NMO and SLE are overlapping disorders that may coexist in some patients and the presence of non-organ-specific antibodies in patients of NMOSD who are positive for AQP-4IgG antibodies may reflect a more intense autoimmune response and such patients are at risk of developing other autoimmune disorders.20Sean J Pittock et al. in their study published in 2008 observed that anti- AQP-4IgG antibody is strongly associated with NMO, and SLE patients without a history of transverse myelitis lacked these antibodies.21 It has a significant therapeutic consequence which can be explained by a hypothetical situation. If our first case had ISN/RPS class IV LN, it would have mandated treatment for the same with either MMF or cyclophosphamide, which is not the drug of choice for NMOSD maintenance therapy. In such a condition, a combination of MMF with rituximab would have been a better choice. Our second case did not have any evidence of active lupus when she was diagnosed with NMOSD, so, we treated our patients with rituximab which is the first line long term therapy for NMOSD. The therapeutic import of the viewpoint mentioned above also holds relevance when newer drugs are being used to treat NMOSD. Eculizumab, a humanised monoclonal antibody against C5 complement was approved by United States Federal Drug Agency (USFDA) for maintenance therapy of NMOSD.22 Inebilizumab, another B cell depleting agent and satralizumab, an interleukin-6 (IL-6) inhibitor, have also been approved by USFDA for treating NMOSD in maintenance phase.22 Eculizumab has rarely been reported to be beneficial in special circumstances in patients with SLE.23 IL-6 inhibitors did not show any clinically meaningful response in trials.25 Although the B cell depletion with belimumab is an approved treatment for SLE, the evidence for other B cell depleting agents is insufficient or still emerging.26 Thus the therapeutic dilemma endowed with a coexistent NMOSD and SLE with its varied complications is likely to persist in near future.Because of this evidence, we concluded that transverse myelitis in our patient was secondary to NMOSD and SLE was a co-existing condition and in any such condition wherein LETM with AQP-4IgG antibodies coexists with SLE, the transverse myelitis should be treated as part of NMOSD. A similar opinion has been promulgated by other reports as well.It can be emphasised that all cases of transverse myelitis or optic neuritis associated with the presence of any connective tissue disease or non-organ-specific antibodies, should be evaluated for the presence of anti- AQP-4IgG antibody. This antibody is highly specific for NMOSD and puts the patient at the risk of recurrence of myelitis or optic neuritis. Since recommendations for the treatment of NMOSD may differ from those of co-existing autoimmune condition, careful planning of treatment is required.


Childhood maltreatment (CM) is recognized as non-specific risk factor for the onset of various psychiatric disorders and is associated with a greater severity in their clinical presentation and poorer treatment outcome. These data suggest that maltreated people with eating disorders (ED) may be biologically other than clinically different from non-maltreated people.Aim of the present study was to investigate cortical thickness (CT), a possible biomarker of neurodevelopment, in people with ED with or without history of CM and in healthy women.Study participation was proposed to patients consecutively admitted to the adult ED outpatient centre of the University of Salerno. Twenty-four healthy women, 26 with anorexia nervosa (AN) and 24 with bulimia nervosa (BN) underwent a 3T MRI scan. All the participants completed the short form of the Childhood Trauma Questionnaire (CTQ). All neuroimaging data were processed by FreeSurfer. Maps of CT were computed in order to perform a vertex-by-vertex analysis. CT maps underwent a general linear model analysis to evaluate differences among groups. Age and body mass index (BMI) were included as nuisance covariates.Based on CTQ cut-off scores, 12 participants with AN and 12 with BN were identified as maltreated and 14 participants with AN and 12 with BN as non-maltreatment. All healthy women were “non-maltreated”. Therefore, participants were split in 3 groups: 26 maltreated participants with ED, 24 non-maltreatment participants with ED and healthy control (HC). Compared to HC, maltreated people with ED showed lower CT values in the left rostral anterior cingulate gyrus, while compared to non-maltreatment people with ED showed lower CT values in the left superior frontal, in right caudal middle frontal and in right superior parietal gyri. No significant differences emerged in CT measures between HC and non-maltreatment people with ED.Present findings show for the first time that in adult people with ED childhood maltreatment is associated with cortical thinning in areas implicated in the modulation of brain processes that are acknowledged to play a role in the psychopathology of ED.None Declared


Men in sub-Saharan Africa are less likely than women to initiate antiretroviral therapy (ART) and more likely to have longer cycles of disengagement from ART programmes. Treatment interventions that meet the unique needs of men are needed, but they must be scalable. We will test the impact of various interventions on 6-month retention in ART programmes among men living with HIV who are not currently engaged in care (never initiated ART and ART clients with treatment interruption).We will conduct a programmatic, individually randomised, non-blinded, controlled trial. ‘Non-engaged’ men will be randomised 1:1:1 to either a low-intensity, high-intensity or stepped arm. The low-intensity intervention includes one-time male-specific counseling+facility navigation only. The high-intensity intervention offers immediate outside-facility ART initiation+male-specific counselling+facility navigation for follow-up ART visits. In the stepped arm, intervention activities build in intensity over time for those who do not re-engage in care with the following steps: (1) one-time male-specific counselling+facility navigation→(2) ongoing male mentorship+facility navigation→(3) outside-facility ART initiation+male-specific counselling+facility navigation for follow-up ART visits. Our primary outcome is 6-month retention in care. Secondary outcomes include cost-effectiveness and rates of adverse events. The primary analysis will be intention to treat with all eligible men in the denominator and all men retained in care at 6 months in the numerator. The proportions achieving the primary outcome will be compared with a risk ratio, corresponding 95% CI and p value computed using binomial regression accounting for clustering at facility level.The Institutional Review Board of the University of California, Los Angeles and the National Health Sciences Research Council in Malawi have approved the trial protocol. Findings will be disseminated rapidly in national and international forums and in peer-reviewed journals and are expected to provide urgently needed information to other countries and donors.NCT05137210.5 May 2023; version 3. Identifying efficient linkage strategies for men (IDEaL) provides male-specific differentiated models of care aimed to improve men’s antiretroviral therapy outcomes. We specifically focus on building trusting relationships with healthcare workers and developing client-led, individualised strategies to overcome barriers to care.IDEaL will test the impact of a stepped intervention for men. This approach promises to improve the efficiency and reach of HIV programmes for men as the highest-resource interventions will only be received by the minority of men who are most in need.IDEaL develops and tests a male-specific counselling curriculum that, if effective, could easily be taken to scale. Findings from the study will identify critical components for male-specific counselling, especially among men who struggle to be retained in HIV care.IDEaL interventions do not change facility characteristics that may act as barriers to men’s use of facility-based services. IDEaL focuses on providing outside-facility services for reaching men.Men in sub-Saharan Africa (SSA) are under-represented in HIV programmes.3One contributor to men’s poor HIV outcomes is an increased risk of disengagement from care. Engagement in ART programmes is not static—many ART clients cycle through care, starting and stopping HIV care multiple times throughout their lifetime.14Men who disengage from HIV programmes (either after testing HIV positive or after enrolling in HIV care services) are frequently described as a difficult and ‘hard-to-reach’ population.Some men may require male-specific interventions to facilitate engagement in HIV care. Men have less exposure to HIV services than womenDifferentiated service delivery (DSD) models are now being developed to improve men’s ART engagement throughout SSA.Identifying efficient linkage strategies for men (IDEaL) trial is an individually randomised control trial aimed to test the impact of various interventions on ART (re)initiation and 6-month retention among men living with HIV who are not currently engaged in HIV care in Malawi. We will compare a stepped intervention against low-intensity and high-intensity interventions to assess the impact of the stepped intervention on men’s use of ART services over time . Secondary objectives are to understand the effect of a stepped intervention on: (1) ART initiation; (2) the presence of adverse events ); (3) intervention acceptability and (4) cost-effectiveness.IDEaL is a programmatic, individually randomised, non-blinded controlled trial design. We will recruit men from 13 high-burden health facilities in Malawi using medical chart reviews to identify men who are living with HIV but not engaged in HIV care.Individual men will be block randomised using R by a biostatistician using a 1:1:1 ratio to either the stepped, low-intensity or high-intensity study arm using a computer-generated program. Participants will be randomised in blocks of 3 and 6, depending on the number of men available for recruitment at each facility. After enrolling in the trial and completing a baseline survey, men will be assigned to a study ID based on the randomisation list. Study IDs will be linked with the preassigned blocked randomisation and preloaded into the tablet device, but will be unknown to the study staff until survey and randomisation modules are completed and saved, ensuring randomisation cannot be manipulated by the study staff. Once finalised, the randomisation results will appear on the tablet device as a picture, and will be shown to the participant to maximise transparency and study buy-in.The effectiveness of the stepped intervention will be compared with a low-intensity intervention  and orientation to the ART clinic and procedures) and with a high-intensity intervention . Across all arms, men who do not (re)initiate ART will continue receiving follow-up visits for up to 3 months, depending on preferences of the client. The number of intervention visits delivered for each participant will be documented.Participants randomised to the low-intensity arm will be traced in the community and receive a one-time, one-on-one male-specific counselling session, using client-centred service techniques.The male-specific curriculum is developed specifically for this trial. Ministry of Health counselling materials are adapted to meet the specific needs of men, based on formative in-depth interviews, focus group discussions and a systematic literature review. Adaptations will include exploring topics of most concern to men in Malawi . The materials will also include language and pictures that resonate with men , and male-specific case studies of challenges men face and how they overcome them. The adapted male-specific counselling curriculum will be developed into a standardised counselling flip chart .Men who wish to (re)initiate ART will be offered facility navigation and facility-based services. Participants will be escorted to the facility (if desired), orientated to the ART clinic procedures and introduced to other HCWs who routinely work at the facility. Facility navigation is intended to facilitate a positive experience for men by helping them feel comfortable and confident navigating clinic spaces. Men may access all ART clinical services at the health facility (but counselling described above will be provided in the community). The client will be responsible for all transport costs related to return to the facility in all study arms.Participants who do not (re)initiate care within 14 days will be offered follow-up counselling every 2 weeks (up to 3 times) until participants (re)initiate care or inform the counsellor that they do not wish to be contacted.Participants in the high-intensity arm will be offered community-based male-specific counselling by HIV counsellors (described above), and offered ART (re)initiation outside facility (either at home or another location in the community of their choice). Those who choose outside-facility ART initiation will be referred to a male study nurse who will meet participants one on one at times and locations that are convenient for participants. The nurse will offer a brief counselling session, reviewing key topics from male-specific counselling curriculum that are most relevant to the individual participant. Nurses will then conduct WHO staging. Individuals classified as WHO stage 3 or 4 will be referred  to the nearest public health facility for additional services. Participants classified as WHO stage 1 or 2 will be given same-day ART. At their 4-week follow-up ART appointment, participants will receive facility navigation by the same nurse and afterward access ART services.Participants who choose facility-based ART (re)initiation will be referred  by the HIV counsellor (lay cadre) to the nearest facility of their choice and receive facility navigation on a day and time that is convenient for them.Men who do not (re)initiate care will be offered biweekly follow-up counselling at times and intervals determined by participants’ preferences until they engage in care or inform the nurse that they no longer wish to be contacted.The stepped arm will build in intensity over time for those who have not (re)initiated care 14 days after study enrolment, or who do not return for their first ART follow-up appointment after (re)initiation see . IndividStep 1 includes the same components described in the low-intensity arm. Briefly, participants will be traced in the community and receive a one-time male-specific counselling session. Men who wish to (re)initiate care will be provided facility navigation and standard of care facility-based services.Men who do not (re)initiate care (either have not engaged ART within 14 days of enrolment or do (re)initiate ART but are >7 days late for a follow-up appointment) will move to the next ‘step’ of the intervention, which adds ongoing motivational interviewing to their package of activities. Motivational interviewing is a client-centred, client-led method for counselling that helps participants identify barriers to a desired outcome and develop personalised solutions.Men who are not engaged after step 2 (either have not (re)initiated ART <14 days after moving to step 2 or did (re)initiate but are >7 days late for a follow-up ART appointment) will be offered outside-facility ART by a male nurse certified in HIV counselling. Steps will follow those outlined in the high-intensity arm, with a brief counselling session, WHO staging, same-day ART reinitiation for those WHO stage 1 or 2, and facility navigation for their 4-week follow-up appointment.The study will take place in central and southern Malawi. Malawi has an HIV prevalence of 9.6%,39 40We will recruit men from 13 high-burden health facilities in Malawi, using medical chart reviews to identify men living with HIV who are not engaged in HIV care. Study facilities will vary by facility type , management (public/mission), location  and region .Eligibility criteria for men include: (1) ≥15 years of age; (2) live in facility catchment area; and (3) tested HIV positive and either (a) self-report having not yet initiated ART within 7 days of testing HIV positive, (b) initiated ART but are at risk of immediate default , or (c) initiated ART and attended their first refill appointment but later defaulted . For those who never initiated ART and do not have proof of a confirmatory HIV test, study staff will offer an HIV self-test kit prior to enrolment, to confirm a positive HIV status. Those who choose to initiate ART will receive the standard Determine and Unigold confirmatory tests prior to ART initiation, following routine care.The primary outcome is the proportion of men who are retained in ART care 6 months after (re-)engagement. Secondary outcomes include: (1) ART initiation; (2) adverse events experienced by men or their female partners  intervention acceptability and (4) cost-effectiveness. ART retention outcomes will be measured through medical chart reviews, while secondary outcomes will be measured through self-reports. Process outcomes include: (1) the proportion of men who were successfully traced; (2) the proportion of eligible men who consented to participate; (3) men’s experience with the intervention and (4) the quality of the intervention.We powered the study to detect differences in 6-month retention between stepped and low-intensity arms, and the stepped and high-intensity arms. Based on pilot data, we assumed that 40% of men in the low-intensity arm, 60% in the stepped arm and 80% in the high-intensity arm will engage in ART and be retained at 6 months. Any man lost to follow-up will be treated as a failure for the outcome evaluation. With 181 men per arm and 20% loss to follow-up from the study in all arms, the power for detecting the specified differences between stepped and low-intensity arms and between stepped and high-intensity arms will be 0.8, with test level 0.025 after Bonferroni adjustment for two comparisons. We will have 0.99 power to detect specified differences between low-intensity and high-intensity arms. The calculation is based on asymptotic normality of log OR.Study recruitment, enrolment and data collection will be conducted by male study staff, who are distinct from local HCWs implementing the interventions.Men will be identified through both medical register reviews and in-person recruitment at participating health facilities. Various medical charts will be reviewed to identify different types of eligible men: HIV testing and counselling and ART registers to identify men who tested HIV positive but never initiated ART; client follow-up registers to identify those who initiated but never returned for their first ART appointment or those who defaulted from care; and index counselling and testing registers to identify male partners of female ART clients . In-persStudy staff will trace potential participants identified through medical chart reviews via phone (if available) or home visits based on tracing data provided in medical documentation. All potential participants will be traced up to three times before being considered lost to follow-up. All screening and enrolment processes will take place in person.http://www.surveycto.com).Men who are eligible for the study will complete written informed consent and complete a baseline survey immediately following enrolment. The baseline survey will collect data on key demographic variables  and previous engagement with HIV and non-HIV health services. All surveys will be conducted in the local language (Chichewa) by trained study staff using electronic tablets. Surveys will be programmed using SurveyCTO software (Study staff will administer follow-up surveys at 2 and 4 months after enrolment. Follow-up surveys will measure exposure to (and acceptability of) the interventions, changes in key demographics since enrolment , any adverse events since enrolment  and use of ART services. The location and specific time of the follow-up survey will be based on participant preference.Medical chart reviews will be conducted to assess men’s engagement with ART services 6 months after study enrolment. Individuals without a medical chart outcome will be followed up in person and their health passport, a pocket medical record where providers record data during health visits, will be reviewed to collect the ART outcome. Men who cannot be reached or are lost to follow-up in any arm will be counted as failures for that specific ART outcome of interest: (re)initiation or 6-month retention.Extensive formative work informed the development of the study protocol including in-depth interviews, focus group discussions and a systematic literature review. The study protocol and tools were presented to Ministry of Health, national stakeholders and implementing partners see .10.1136/bmjopen-2022-070896.supp2Supplementary dataThe average cost per successful outcome (6-month retention) will be calculated and compared across arms incrementally. We will use micro-costing methods by creating an inventory of the resources used to achieve the observed study outcomes including: (1) standard counselling interactions ; (2) motivational interviewing interactions ; (3) provider interactions ; and (4) cost of reminder messages sent, when messages are delivered telephonically instead of in person. For each study patient, the quantity (number of units) of resources used will be determined. Costs will be measured from the healthcare provider perspective. Unit costs of resources, which are not human subject data, will be obtained from external suppliers and the health facilities’ finance and procurement records and multiplied by the resource usage data to provide an average cost per study patient in each study arm. A cost-effectiveness analysis will be conducted by dividing the incremental cost between two arms by the incremental effectiveness (number of people retained at 6 months) in the respective arms.Data analysis will be conducted in R: A Language and Environment for Statistical Computing . We will use the Consolidated Standards of Reporting Trials standards for reporting trial outcomes.A series of nested, mixed-methods studies will be conducted to identify factors associated with ART engagement within each intervention arm, and to explore the implementation and acceptability of interventions.Guided by Grounded Theory, we will conduct cross-sectional in-depth interviews with a random subset of 40 male participants per arm  throughout the study period. Clients will be randomly selected at various times of the study using computer-generated randomisation, stratifying the sample by arm and successful trial outcomes . Data will assess characteristics of men who fail to engage in care, contextualise decisions around ART initiation and retention, and identify additional strategies that may be needed for men to successfully engage and be retained in ART programmes see . Data co10.1136/bmjopen-2022-070896.supp3Supplementary dataInterviews will be conducted by a trained male interviewer in the local language. Interviews will be digitally recorded, transcribed and translated into English for analysis. Four investigators will pilot a codebook by independently reading and coding a randomly selected subset of transcripts. Through an iterative consultative process and using iterative and deductive coding strategies, each investigator will revise their respective codebook until there is high inter-rater reliability among the group. All transcripts will be coded in Atlas.ti V.8.3During the course of the intervention, HCWs will keep daily logs as one of the study monitoring and evaluation tools to assess the implementation of the intervention for each participant. Primary events to be recorded in the daily logs are: (1) unable to reach participant (and reason); (2) contacted participant; (3) intervention provided  and (4) other comments relevant to intervention implementation. Each event will be recorded with a corresponding date. Logs will be digitised in English. Findings may influence how similar interventions are implemented in the future.The IDEaL trial is registered with ClinicalTrials.gov as NCT05137210. The protocol was approved by the Institutional Review Board of the University of California, Los Angeles and the National Health Sciences Research Committee in Malawi. Study findings will be disseminated through peer-reviewed journal articles, national and international conference presentations, and meetings with Malawi Ministry of Health, facility and community stakeholders.Studies have reported poorer outcomes for HIV testing, treatment initiation and treatment adherence in men compared with womenIDEaL is different from other ART engagement and re-engagement interventions in several important ways. First, we will enrol men living with HIV across the treatment cascade, including those who have never initiated ART, those who are at risk of immediate default after initiation and those who have been in care but subsequently defaulted. Formative research suggests that barriers to ART initiation and reinitiation may be similar49Finally, we will test a stepped intervention that builds in intensity over time until men (re)initiate care. This approach allows men who are ready to (re)initiate to do so at minimal cost to the health system, while those who need additional support can receive more resource-intensive interventions to support their ART engagement.


A 51-year-old female was referred to the emergency department with a one-day history of severe right eye pain, blurry vision, and conjunctival injection. A review of past ocular history was notable for nanophthalmos and narrow angles with patent peripheral iridotomies. Anterior segment exam findings were consistent with aqueous misdirection and a review of medications indicated recent topiramate initiation for headaches and depression. The acute attack was initially controlled with medical management and plans for future surgical intervention were made. Although ocular screening prior to initiation of topiramate is not recommended, this case highlights the importance of pre-screening in a patient with a pre-existing condition such as nanophthalmos. Additionally, this case addresses the ocular side effects of anti-depressants and the emerging relationship between glaucoma and depression. Appropriately addressing these issues and coordinating care with behavioral health providers has the potential to prevent optic nerve damage and loss of vision. Topiramate is an anti-epileptic drug that has been used off-label for the treatment of migraines, as well as some mood disorders including biopolar disorder and depression. One of the known side effects of topiramate is acute angle-closure glaucoma thought to be caused by ciliochoroidal effusion with forward displacement of the lens-iris diaphragm and anterior chamber shallowing, resulting in acute myopia and angle-closure glaucoma . We presA 51-year-old female with a past medical history of depression and migraine presented to the emergency department with a one-day history of severe right eye pain, blurry vision, and conjunctival injection. Past ocular history was notable for nanophthalmia in both eyes with axial lengths of 17.29 right eye (OD) and 16.96 left eye (OS). On an earlier exam, the patient’s best-corrected visual acuity was 20/50 with a refractive error of +9.00 diopters in both eyes. The patient had narrow angles and had undergone prophylactic laser peripheral iridotomies (LPIs). She was seen in the neurology clinic one month prior to this presentation and was started on topiramate 25mg for her migraine headaches and depression.The patient’s best-corrected visual acuity was counting fingers in the right eye and 20/50 in the left eye. Her intraocular pressure (IOP) was 65 and 12 in the right and left eye, respectively. Anterior segment exam showed 3+ conjunctival injection and mild corneal edema with a severely narrow anterior chamber depth of 0.69 mm  can help eliminate the pupillary block before the occurrence of peripheral anterior synechiae develops . While tThough this case demonstrates the association between topiramate and aqueous misdirection, it also highlights the pressing relationship between glaucoma patients and clinical depression. Glaucoma can be a debilitating disease that significantly impacts the quality of life of an individual. Recent studies have consistently demonstrated the alarmingly high rate of depression in glaucoma patients -13. StudThis unfortunate reality needs to be recognized and care must be coordinated with the patient’s behavioral health provider. While topiramate is believed to induce ciliochoroidal swelling and anterior movement of the lens, other antidepressant medications can cause primary angle closure through alternative mechanisms. The current standard of treatment for clinical depression involves initiating a selective serotonin-reuptake inhibitor (SSRI). This class of medications can trigger iris dilation and induce pupillary block through anticholinergic properties. Patients with narrow angles should prophylactically receive LPIs prior to starting SSRI, and high-risk eyes such as nanophthalmic eyes should not be prescribed an angle-closure-provoking medication. A careful review of systemic medications and medical history by the ophthalmologist can help coordinate care with the patient’s neurologists and behavioral health providers . An openWe present the first reported case of topiramate-induced angle-closure glaucoma in a nanophthalmic eye. In addition to reviewing the management of aqueous misdirection, our case highlights the emerging relationship between glaucoma and clinical depression. As the preponderance of contemporary anti-depressive agents can induce angle closure glaucoma, careful attention must be placed on high-risk patients and treatment needs to be coordinated with the patient’s mental health provider.


Environmental stresses have a profound impact on the growth and productivity of plants . The preSarkar et al. on maize successfully mapped the QTLs for the growth- and yield-related traits under water availability scenarios. The genes underlying these QTLs have specific functions in maintaining the growth and senescence, and hormone signaling under water deficit conditions. The nucleotide polymorphism in the promoter elements in rice has been shown to modulate the salt-responsive attributes by Haque et al. The comparative sequence analysis of K+ salt-responsive transporters (OsTPKa and OsHAK) among two contrasting rice genotypes differed in salt-responsiveness revealing that both have unique TF-binding motifs. These modifications in the elements, played a key role in the coordinated expression of both transports, leading to an effective acclimation response in rice.The identification of hotspots in the genomic architecture of plant species by chromosome-scale genome assembly, comparative genomics, and multi-omics approach could assist in mapping stress-associated genes and quantitative trait loci (QTLs). The captured QTLs and SNPs markers in the genome not only provide information about the genomic architecture but could impart stress resilience in plants by marker-assisted selection and breeding. A study done by Camellia sinensis) genome by Wang et al. These potential targets in the tea genome could play an imperative role in the development of tea plants resistant to green leafhopper infestation. A similar approach was also applied to understand the genetic basis of cold adaptation in Asparagus beans by Liang et al. In the comparative genomics approach between contrasting bean accessions, a set of variable genes in two individual genomes was retrieved. A detailed analysis of these genes identified that in the genome of cold tolerant accession, Ningjiang 3 the presence of ABCC-type transports (a sub-gene family of ABC transporters) was linked with enhanced abiotic stress resilience.The candidate genes and proteins belonging to the flavonoid, phenylpropanoid, and α-linolenic acid metabolism were mapped on the tea  and WRKY transcription factors were due to alterations in the copy numbers, shifts in their location, and structural changes in the cis-element and exon-intron structure. These transcription factors (TFs) have a very specific role in the regulation of plants’ defense against environmental stress, hence suggesting the adaptive selection pressure leading to structural variation in the sesame genome. Similarly, the comparative analysis of the chloroplast genome of black pepper (Piper nigrum L.) with related piper species was studied by Gaikwad et al. The study provided key insights into the chloroplast genome evolution, which will assist in the development of molecular markers and accelerate ongoing black pepper improvement programs.A massive structural variation in the sesame pan-genome due to evolutionary adaptations was reported by in-silico genome-wide analysis of key gene families and their comparative analysis could decipher the biotic and abiotic stress adaptations in plant species. A similar strategy was further exploited by Nie et al., to explore the role of leucine-rich repeat receptor-like kinases (LRR-RLKs) during Bursaphelenchus xylophilus infestation in Pinus massoniana. The candidate RLK genes retrieved from the transcriptome datasets were subjected to structural and molecular characterization. The study revealed that an LRR XII subfamily gene PmRLKs32, having ROS-producing properties played an important role in providing nematode resistance in pine trees. An extensive structural, functional, molecular, and evolutionary study on the Caffeoyl-CoA O-methyltransferase (CCoAOMT) gene family was carried out in two jute species by Akhter et al. Despite both species showing high syntenic conservation among CCoAOMTs, the gene expression level was modulated among them under various abiotic stresses and hormonal treatment. Hence, the key gene from the CCoAOMT gene family could be used to genetically engineered jute plants that can withstand a wide range of environmental stresses. Though, it is also important to functionally characterize the candidate genes for the required traits. For example, Zhang et al., showed how an MYC TF plays a major role in regulating growth and fruit quality in tomato. Through molecular study, they reported that the interplay between MYC2 and jasmonic acid (JA) and TOR signaling pathways regulates the growth and development of tomato seedlings.Moreover, Papolu et al., focused on the dynamics of LTR retrotransposons and the associated mechanism of genome expression and adaptive evolution during high-temperature stress. The epigenetic changes are transgenerational and important for the stress memories in plants  and epigenetic (reversible changes) modifications in the genome leading to stress adaptations in plants. The retrotransposons are varied in copy number and activated by various biotic and abiotic stresses due to retrotransposition bursts. The review by n plants . The revOverall, the present research studies highlight the importance of genetic and genomic tools in the identification and development of stress-tolerant plants. The progress made towards understanding how structural changes in plant genomes could shape the unique response to environmental stresses will be critical for the improvement of crop plants.All authors have contributed in writing, editing, reading and agreed to the final version of the manuscript.


Lung ultrasound has been described for over a decade and international protocols exist for its application. It is a controversial area among pulmonologists and has had more uptake with emergency as well as intensive care physicians. We discuss the basics and evidence behind the use of lung ultrasound in respiratory failure, and what role we see it playing in the current 2019 novel coronavirus pandemic. At the time of writing, there have been 3 175 207 cases and 224 172 deaths.3A review of 16 749 hospitalised UK patients with COVID-19 using the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol found the most common symptoms to be cough (70%), fever (69%) and shortness of breath (65%), all part of a syndrome of acute respiratory distress.3 49% of patients were discharged alive, 33% had died and 17% were continuing to receive care at date of reporting; 17% required admission to high dependency or intensive care units for treatment of respiratory failure.4Many patients with COVID-19 present with relatively preserved lung compliance and a severely compromised pulmonary gas exchange which leads to severe hypoxaemia. By increasing their minute ventilation (compensatory ventilatory response to hypoxaemia), patients develop severe hypocapnia.5The pathophysiological explanation for respiratory failure in COVID-19 is still being studied but it is likely that diffuse alveolar damage with interstitial thickening, varying degrees of atelectasis and consolidation contributes.6Case series have described bilateral chest radiograph abnormalities such as diffuse interstitial changes in over 84% of patients with the detection of changes approaching 100% with the use of CT.The above respiratory symptoms require a full assessment, and the first step is normally a clinical examination of the respiratory system, in which the stethoscope plays a major role.7 Acquiring and wearing a stethoscope has become a rite of passage for doctors and has formed an integral part of the diagnostic pathway.8 9 The respiratory examination comprises four basic tenets: inspection, palpation, percussion and auscultation. Auscultation requires the stethoscope to be applied to the front and back of chest, as well as under the axillae.8 9 However, the signs are neither specific nor sensitive. The main sign in respiratory failure syndromes is crackles.In 1816, a French physician, René Laennec, invented the stethoscope and was also the first to describe the terms rales, rhonchi, crepitance, and egophony which are associated with specific respiratory conditions.10 Thus, their use in ruling pneumonia in or out is limited as their presence or absence only slightly changes the initial diagnosis .11 Lovrenski et al replicated similar findings in children with suspected pneumonia.12Crackles on auscultation have a sensitivity of 19–67% and a specificity of 36–96%, a positive likelihood ratio of 2.3 and a negative likelihood ration of 0.8.13Given the high incidence of interstitial changes and respiratory failure in COVID-19 and the risk of cross-infection when taking a stethoscope from patient to patient, should lung ultrasound have an increased and complementary role to play in the diagnostic pathway?14 The methods were standardised and reproducible and consensus guidance has since been produced.15 The BLUE protocol also comprises the assessment of the deep venous system, but the discussion of this aspect is beyond the scope of this article. The BLUE protocol has higher sensitivity, specificity and diagnostic accuracy for pleural effusions, alveolar consolidation and interstitial syndromes: this is described by Lichtenstein et al 16 and all the values for LUS are between 92% and 100%. We will concentrate on core LUS; the full BLUE protocol for LUS is beyond the scope of this article.Lung ultrasonography (LUS) in acute respiratory failure has been described for over a decade. A 2008 single centre study (Bedside Lung Ultrasound in Emergency [BLUE]) of LUS at the bedside showed an accuracy of 90.5% in diagnosing the cause of acute respiratory failure in critically ill patients.LUS requires the knowledge of the following signs:pleural line .Identification of the -ine . The sinusoid sign is an M-mode finding indicating respiratory movement of atelectatic lung in a sinusoidal pattern within surrounding pleural fluid. These two signs have a high sensitivity and specificity for pleural effusion. Signs of effusion include the 17; Focused Ultrasound in Intensive Care (FUSIC) is the POCUS standard for the Intensive Care Society.18 Both offer ultrasound training targeted to prompt assessment and diagnosis of the acutely unwell adult patient.In the UK, Focused Acute Medicine Ultrasound (FAMUS) is the point of care ultrasound (POCUS) standard endorsed by the Society of Acute Medicine for Acute Physicians as a specialist skill19 An initial negative result then requires a risk assessment as to whether the patient should be considered as high index clinical suspicion of COVID-19. Imaging can assist with further risk stratification. Chest radiography (CXR), using a template classification system produced by British Society of Thoracic Imaging (BSTI)20 21 groups patients into one of the four groups based on their CXR: COVID classic/probable, COVID indeterminate, COVID normal and Non-COVID. Classic CXR changes of COVID-19 are well described as showing bilateral multi-lobar consolidation or infiltrative changes, with multiple peripheral air space opacities.22 CT scans have been used as first-line investigation but this has significant challenges in terms of infection control and burden of work on radiology departments.19 23 CT scan findings typically show a combination of ground glass opacities and peripheral consolidations and are highly sensitive  although not completely specific.25 Hence, it has been suggested that CT not be used as a first-line diagnostic test, but is reserved for a patient with high clinical suspicion of COVID-19 and a negative swab result.19 25If a patient presents to hospital, the traditional pathway dictates a full history and examination, followed by targeted tests. In COVID-19, the gold standard for the diagnosis of COVID-19 is the positivity of a swab through reverse-transcription PCR (RT-PCR) but there can be a delay in that particular result.26 27COVID-19 causes clear and typical ultrasonographic patterns. B lines in COVID-19 occur in large numbers, both in separate and coalescent forms (light-beam patterns), and can give the appearance of a shining white lung. Irregularity of the pleural line, sub-pleural pulmonary consolidations and poor blood flow also occur in bilateral patchy clusters, and are mainly visible in the posterior and inferior areas.et al found strong correlation between similar ultrasound findings and concurrent CT scans.28 12 patients with COVID-19 underwent both LUS and CT scanning. All patients had diffuse B−lines with spared areas. Three had posterior subpleural consolidations and four had the appearance of organising pneumonias: bilateral patchy subpleural or peripheral consolidations. CT scans confirmed bilateral lung involvement with ground-glass opacities and consolidation changes in all patients.28Poggiali et al argue that there are ultrasonographic patterns that would suggest alternative diagnoses to COVID-19.29 A smooth pleural line with uniform and gravity-dependent B-lines suggests cardiogenic pulmonary oedema. Diffuse abnormalities of the pleural line and no patchy distribution are more likely in chronic diffuse interstitial pulmonary fibrosis. Isolated large lobar consolidation with or without effusion and with dynamic air bronchograms indicate bacterial pneumonias and large pleural effusion with atelectatic consolidations or echoic septations would suggest another infection as COVID-19 does not seem to be associated with complex pleural disease.30Volpicelli 31 60000 ultrasound frames from 30 patients were reviewed by an expert panel and then submitted to a biomedical engineer who then produced a grading system for LUS in COVID-19. In an attempt to achieve high inter-observer variability, the images produced by the engineer were re-submitted to the panel to evaluate and agree on the scoring system. A continuous pleural line with some A lines suggest moderate aeration and a score 0. An irregular pleural line with some B lines suggest some loss of aeration and a score of 1. Score 2 due to severe loss of aeration is suggested by a broken pleural line and small-to-large consolidated areas with associated areas of white below the consolidated area. Score 3 is attributed if the scanned area shows large dense consolidations which signify complete loss of aeration. The scores can be applied to every lung area scanned. Soldati et al propose a standardised process for the use of LUS in COVID-19 patients,32 It has also been suggested that pulmonary physiotherapists could help in expanding the use of LUS.32 Decontamination guidance has been produced for any machines used but the vast majority of (POCUS) machines are small, portable and routinely easily cleaned in between patients.33 A national service evaluation dataset has been created, and this uses the scoring system described by Soldati et al. 31 34In the UK, the Intensive Care Society (ICS) and the Society for Acute Medicine (SAM) have jointly proposed guidance for the role of ultrasound in patients with suspected or proven COVID-19.There are currently no data to show for any outcomes for LUS in COVID-19. The setting up of national datasets as well as governance pathways provide this opportunity to study this area longitudinally and hopefully provide real-time analysis and any outcomes that may influence patient care.Proposed potential uses of LUS are:29 35 A quick LUS  can help with this.At triage: patients presenting with acute respiratory failure require rapid triage and prompt isolation in settings where resources may have already been stretched.In patients who are swab PCR negative and have an indeterminate CXR: the presence of the above classical changes of COVID-19 would suggest a false negative of the swab result and allow a firm diagnosis to be established. It must be remembered that LUS is an adjunct in the diagnostic pathway and is to be interpreted in light of all clinical findings and diagnostic considerations.37 The resolution of pathological signs to an A line pattern also signifies disease improvement and may be used for monitoring.38 These two patterns were used by Italian and Chinese groups for day to day management of COVID-19 patients.39 40A Lung USS can also be useful at detecting, pneumothoraces in patients who are mechanically ventilated and guiding any ensuing procedures.41To determine ventilation strategies and post procedures in mechanically ventilated patients: In patients with bilateral and widespread multiple or coalescent B−line plus pleural irregularities, increased positive end-expiratory pressures may be beneficial; in patients with a relatively normal anterior lung, but posterior-lateral consolidation, prone ventilation may be tried.42 Some barriers to widespread use of POCUS are discussed below, and we expand on why those barriers should not exist.However, LUS is a controversial topic among pulmonologists and emergency physicians and uptake has been traditionally low, with pulmonologists focussing more on the pleura than the lung.The vast majority of physicians are also not trained at lung ultrasound and this might prove time consuming. We agree that there will be a learning curve with this, but with more physicians doing LUS and with physiotherapists weighing in with their specialised skills, more and more doctors will become adept at this.33 The availability of machines should not be a problem. We work in a large district general hospital in the North East of England, and we have six large machines and four handheld devices between the Emergency department, the Acute Medical Unit and the Respiratory unit. Locally, all non-urgent work has been stopped in line with national guidance2 and the ultra-sonographers and echocardiography technicians have all been offered training to perform lung ultrasound. This has had the effect of greatly increasing the number of people who can perform LUS and available machines. POCUS training and machines is already in place in low resource settings43 44 and there is no reason why LUS cannot be widely applied if and when COVID-19 reaches those settings.Cost of procurement of the POCUS machines: over time, the machines have become more efficient, smaller and less costly.45 Newer systems such as ones from the Butterfly Network46 can connect to existing picture archiving and communication systems (PACS) for storing and retrieving images on hospital networks.Governance and storage of images: images from POCUS examinations are very rarely stored on a central database and therefore are not readily available for review for any potential refuting or confirmation of findings. A study in the United States over 20 years found five lawsuits associated with the use of POCUS. All were related to failure to perform POCUS or failure to perform one in a timely manner and there were no missing diagnoses or harm reported.Locally, in a large district general hospital in the North East of the United Kingdom, we have set up an ultrasound steering committee with a view to devise a strategy regarding lung USS. The key points are to:Devise a local policy as to where lung USS might play a role.Produce a training programme for interested physicians and physiotherapists.Ensure that any learning plan is incorporated into the practitioners professional learning and development plan.Ensure that the trainers have time in their job plans and funding set aside to develop the aforementioned programme.Ensure that the correct ultrasound machines are bought for all the department and that a single business plan and bid is submitted.Ensure that images can be uploaded to the local radiological online archive (PACS).COVID-19 has required a paradigm shift in healthcare utilisation. Imaging has a key role to play in the diagnostic pathway and LUS might play an important role. Lung ultrasound is a non-invasive, rapid, repeatable, and sensitive bedside method to detect a range of pulmonary pathologies. Whilst there is currently no clear data to show improved patient outcomes, the COVID-19 era poses unprecedented challenges but also learning opportunities. The current enthusiasm for LUS must be directed into strong controlled studies and descriptive analyses towards determining patient outcomes. LUS findings must also be taken in context of all other clinical and radiological.COVID-19 patients have findings on lung USS which can be used to rule out COVID-19 alongside all other clinical and radiological parameters.There is a national drive in the UK to determine the role lung USS has in the diagnostic pathway of COVID-19.Lung USS needs wider uptake by healthcare practitioners and current pandemic provides a unique opportunity.What is the role of lung ultrasound in the triage of potential COVID-19 patients?What is the role of lung ultrasound in patients who are swab PCR negative and have an indeterminate CXR?What is the role of lung ultrasound in selecting ventilation strategies in the intensive care unit.Which one of the following statements about B-lines is TRUE?B-lines do not extend all the way to the edge of the field without fading.B-lines are reverberation artefacts arising from aerated and fluid parts of the lung.B-lines are diagnostic of COVID-19.B-lines show well-aerated lung.Which one of the following statements is FALSE?B-lines occur in COVID-19 patients.B-lines occur in pulmonary oedema.B-lines occur in acute respiratory distress syndromes.B-lines occur in exacerbations of chronic obstructive pulmonary disease.Which one of the following statements are TRUE?Coalescent B−lines can occur in COVID-19 patients.Irregularity of the pleural line can occur in COVID-19 patients.Sub-pleural pulmonary consolidations can occur in COVID-19 patients.Complex pleural disease is rare in the initial presentation of COVID-19 patients.Which one of the following statements are TRUE?CT scanning is not recommended as a first-line investigation in COVID-19.CT scan findings have very high sensitivity and specificity for infection with COVID-19.CT scanning of COVID-19 patients does not pose an infection control risk.A CXR showing classic signs of COVID-19 requires a CT scan for confirmation of the diagnosis.Which one of the following statements are TRUE?There is clear evidence for the benefit of lung USS in the triage in COVID-19 patients.There is clear evidence for the benefit of lung USS in COVID-19 patients who are swab PCR negative.Uptake of lung USS among pulmonologists in the UK has traditionally been poor.POCUS machines are large, bulky and difficult to treat.Chest 134(1):117–125, doi:10.1378/chest.07-2800.Lichtenstein D, Meziere G. Relevance of lung ultrasound in the diagnosis of acute respiratory failure*: The BLUE Protocol. https://www.ics.ac.uk/ICS/ICS/FUSIC/FUSIC_COVID-19.aspx (accessed 3.5.2020).Ultrasound J 2020;12(22), doi:10.1186/s13089-020-00171-w.Volpicelli, G, Gargani, L. Sonographic signs and patterns of COVID-19 pneumonia. et al. CT imaging changes of corona virus disease 2019 (COVID-19): a multi-center study in Southwest China. J Transl Med 2020;18:154, doi:10.1186/s12967-020-02324-w.Li X, Zeng W, Li X, et al. Proposal for international standardization of the use of lung ultrasound for patients with COVID-19. J Ultrasound Med 2020, doi:10.1002/jum.15285.Soldati, G., Smargiassi, A., Inchingolo, R, (A) False (B) True (C) False (D) False(A) True (B) True (C) True (D) False(A) True (B) True (C) True (D) True(A) True (B) False (C) False (D) False(A) False (B) False (C) True (D) False


Landfill Waste Directive and Circular Economy Action Plan will reduce the number of predictable anthropogenic food subsidies (PAFS), above all, by closing landfills to preclude negative effects on human health. Obligate avian scavengers, the most threatened group of birds worldwide, are the most likely group of species that will be forced to change their behaviour and use of space in response to landfill site closures. Here, we examine the possible consequences of these management decisions on the foraging patterns of Egyptian vultures (Neophron percnopterus) in an expanding population in the Iberian Peninsula.Changes in human-induced resource availability can alter the behaviour of free-living species and affect their foraging strategies. The future European We tracked 16 individuals in 2018–2021, including breeders and non-breeders, and, using a combination of spatial-use and spatial-network modelling, assessed landscape connectivity between key resources based on movement patterns. We then carried out simulations of future scenarios based on the loss of PAFS to predict likely changes in the movement patterns of both non-breeders and breeders.Our results show that foraging strategies in non-breeders and breeders differ significantly: non-breeders performed more dispersal movements than breeding birds across a spatial-use network. Non-breeding and breeding networks were found to be vulnerable to the removal of central foraging areas containing landfill sites, a highly predictable resource, while perturbation analysis showed dissimilar foraging responses to the gradual reduction of other predictable resources. Under a context of the non-availability of landfills for breeders and non-breeders, vultures will increase their use of extensive livestock as a trophic resource.Future environmental policies should thus extend the areas used by scavengers in which livestock carcasses are allowed to remain in the wild, a strategy that will also mitigate the lack of food caused by any reduction in available waste if landfills close. In general, our results emphasize the capabilities of a spatial network approaches to address questions on movement ecology. They can be used to infer the behavioural response of animal species and, also demonstrate the importance of applying such approaches to endangered species conservation within a context of changing humanized scenarios.The online version contains supplementary material available at 10.1186/s40462-023-00383-4. Many human activities result in modifications in both the spatial distribution and availability of trophic resources, thereby altering the behaviour of wildlife species –3. AlterLandfill Waste Directive (2008/98/EC) and the Circular Economy Action Plan [The term PAFS refers to resources of anthropic origin whose appearance is predictable over space and/or time . The mosion Plan , which cSeveral approaches have been developed to study movement behaviour including state-of-the-art animal tracking by telemetry that can explore movements by wild animals –30. The Neophron percnopterus) as responses to food availability. Firstly, we identified the key resources within home ranges and their connectivity at landscape scale . Secondly, we tested the effect of different types of perturbations  on resource prioritization and infer a population-level response.Here, we use spatial network analyses to investigate changes in movement behaviour in free-ranging Egyptian vultures  and eight birds with Ornitela (www.ornitela.com) digital telemetry devices using a Teflon ribbon harness. Captured birds were aged according to plumage  and 10 non-breeders (1 adult and 9 immatures)—with GPS-GSM devices during the summers of 2018 and 2019. All birds were captured at a landfill site in Osona . We equipped eight birds with 40-g solar-powered e-Obs satellite transmitters GPS-GSM  composed of nodes and links to determine how animals interconnect feeding areas along movement paths. The nodes—the areas most used by all individuals—were spatially delimitated as follows. First, we measured the home range of all tagged individuals using the 50% Dynamic Brownian Bridge Movement Model (dBBMM) for each individual and year to represent the core areas in which these birds spent the most time. The dBBMM algorithm allows us to estimate the spatial-use likelihood by taking into account the temporal dependency of GPS data. The outcome of the dBBMM algorithm is a probability layer with a 500-mtion (UD ), a probwww.land.copernicus.eu/) program  and two quantitative metrics at node level  have the same number (on average) of links per node, whereas heterogeneous networks  differ in the number of links per node [density illustrates whether the movement paths of birds are random or non-random [degree to identify which nodes were most heavily used by individuals. We used betweenness to measure the frequency of a node as an intermediate step between the path of two other nodes. Higher values of betweenness represent a more central position for nodes with large numbers of links to other nodes . The noal birds .degree and betweenness.Finally, we calculated two sets of parameters: first, the node fidelity was used to understand in detail the effects of node features on the use of space and was defined by (1) the number of revisits that individuals make to a specific node and (2) the accumulated residence time that focal birds spent at each node. Second, the spatial connectivity of non-breeders and breeders was represented by the diameter and density) in terms of reproductive status [degree and betweenness). To do this, we fitted separate models for each response variable  and each reproductive status because the spatial-use networks of non-breeders and breeders were completely different (see Results). For each model, we estimated the importance of each explanatory variable (node features described above) by removing it from the model and then performing an F-ratio test to derive P values for the variable of interest [We used the F-statistic of analysis of variance (ANOVA) to test differences between non-breeders and breeders in the metric parameters of their foraging behaviour at network level. We compared the number of elements (nodes and links) and the network quantitative metrics at network level  until there were no more nodes with a specific feature, and then recalculated the betweenness measures for each iteration. In both cases, each iteration refers to the gradual one-by-one removal of nodes. ‘Random removal’ of nodes allowed us to infer whether the foraging response to the limitation on PAFS is a stochastic process if compared to the ‘targeted removal’ of nodes, or whether it follows a deterministic process. Therefore, we ran each random and targeted removal iteration 1000 times to generate two different frequency histograms of the betweenness. Finally, we compared these histograms resulting from each random and targeted simulation using a paired T-test. In such a way, we identified which node feature drives the robustness of both the non-breeder and breeder spatial-use networks.Finally, we used a perturbation analysis to assess the foraging responses of individuals under future scenarios linked to the limitation of PAFS by environmental regulations. We simulated different perturbations on the network by removing nodes of different types and computing network robustness and the presence of key nodes according to available food resources. Network robustness refers to the ability of a network to maintain its features regardless of the degradation of the network itself . The strrecurse [move [igraph packages [All analytical procedures were carried out within the R environment  using threcurse , move [5se [move  and igrapackages .4,600 = 61.29, P < 0.001; links: F4,600 = 45.16, P < 0.001). Moreover, comparing the diameter and density at network level between non-breeders and breeders, we found two completely different patterns of movement. Compared to breeders, non-breeders had more dispersive movement paths  and made many more random and heterogeneous movements . Nevertheless, for both breeders and non-breeders landfills were central areas during their movements. Nodes in which landfills were present had the highest betweenness and acted as hubs connecting the other nodes with different space use and ecological features  and southern France , both factors having a positive effect on the degree. Likewise, the nodes considered as central areas were positively driven by the presence of landfills . On the other hand, for breeding individuals, node fidelity was positively explained by breeding territory  and extensive livestock  was related to the presence of roosting sites, extensive livestock and intensive farms and landfills  and, in turn, modify the foraging strategy of these two subsets of this vulture population .–57.55–57Larus occidentalis) [Morus bassanus) than in non-breeding birds, almost certainly imposed by their central foraging behaviour and habitat use [Non-breeding and breeding vultures have different foraging strategies, as illustrated by the differences in the spatial topology of their networks. Non-breeding individuals disperse more along a spatial-use network that has more nodes and links than the breeding bird networks. This could be related to the larger exploratory capacity of non-breeders as they have no nest attachments or functional constraints imposed by the demands of breeding. It is known that non-breeders have larger home ranges than breeders , 43 and entalis) . Conversitat use . The spaitat use . Althougitat use , it is kitat use . Accordiitat use , 65. Oveitat use –68 despiitat use ; white sitat use ; gulls [itat use ).Perturbation analysis demonstrates that both non-breeder and breeder foraging strategies are vulnerable to the removal of nodes with highly predictable food sources, especially if landfills are present. Our results show that the systematic removal of landfills (hub-nodes) changes patterns of population movements such that other nodes become key in the use-of-space strategies of focal birds. Therefore, when a node with a landfill is removed, another node with a different food resource becomes the new hub. In line with our prediction, we found that this is especially important for non-breeding birds whose movements mainly target local areas with landfills . A possThe studied Egyptian vulture population showed a great dependence on PAFS and our results indicate that the future closure of landfills (see 2008/98/EC ) will reAdditional file 1:Table S1. Egyptian vultures tagged with GPS-GMS devices during the summer period between 2018 and 2019 in Catalonia (NE Spain). Table S2. Total of nodes used by non-breeder and breeder Egyptian vultures. Table S3 Factor loadings after Principal Component Analysis for the nine categories assigned to land uses in the study area. Figure S1. Dynamic Brownian Bridge Models home ranges at 50% (dark grey) and 95% (light grey) of 10 non-breeders and 6 breeders of Egyptian vulture tagged in Catalonia (Northeast Spain) at the population level. Figure S2. Correlation between nodes’ features and the parameters related to node fidelity (number of revisits and accumulated residence time) and local network metrics (degree and betweenness) for the focal a) non-breeders and b) breeders. Figure S3. Boxplots of non-breeders node fidelity. Figure S4. Boxplot of breeders node fidelity.Additional file 2: Topology parameters of spatial networks.Additional file 3:Table S4. Results of the top-ranked models (lowest AIC) for non-breeder and breeder Egyptian vultures accounting for site fidelity (number of revisits and accumulated residence time) and spatial-use network topology (degree and betweenness).Additional file 4:Figure S5. Degree (K) and betweenness (B) distributions of spatial-use networks for breeding and non-breeding populations of Egyptian vultures.


Fluorescence-guided SLN biopsy using indocyanine green (ICG), a green fluorophore dye, was introduced in 2005 for breast cancer in an attempt to overcome drawbacks of BD and RI.3 There is a lack of data on a direct comparison between gold standard dual technique of BD-RI versus ICG combined with RI (ICG-RI).There is no consensus on how ICG will complement or potentially replace traditional methods of SLN mapping. This is due to the technique’s infancy and quality of current available data mostly consisting of comparative cohort studies.4 The number of SLNs identified, rate of failed mapping, identification of metastatic SLNs, and adverse reactions between the two techniques were found to be equivalent. Cost-minimization analysis showed that ICG-RI cost an additional AU $197 per case in addition to the imaging system cost, which could be a significant limiting factor in the adoption of ICG technology.Our study compared 150 prospective patients with early breast cancer undergoing SLN biopsy using ICG-RI with 150 prior patients using BD-RI.We found that novel tracer combination, ICG-RI, provided an effective and safe alternative to gold standard dual tracer. The proviso was the higher expense associated with ICG. Increased uptake of fluorescence technology in the future could potentially lower costs of the imaging system. The combination of ICG-RI could represent a transition phase with ICG used as a sole tracer in future. Future multicenter randomized controlled trials evaluating ICG as single or dual tracer are needed to provide definitive information for change in practice.


Drug synergy prediction is approached with machine learning techniques using molecular and pharmacological data. The published Cancer Drug Atlas (CDA) predicts a synergy outcome in cell-line models from drug target information, gene mutations and the models’ monotherapy drug sensitivity. We observed low performance of the CDA, 0.339, measured by Pearson correlation of predicted versus measured sensitivity on DrugComb datasets.We augmented the approach CDA by applying a random forest regression and optimization via cross-validation hyper-parameter tuning and named it Augmented CDA (ACDA). We benchmarked the ACDA’s performance, which is 68% higher than that of the CDA when trained and validated on the same dataset spanning 10 tissues. We compared the performance of ACDA to one of the winning methods of the DREAM Drug Combination Prediction Challenge, the performance of which was lower than ACDA in 16 out of 19 cases. We further trained the ACDA on Novartis Institutes for BioMedical Research PDX encyclopedia data and generated sensitivity predictions for PDX models. Finally, we developed a novel approach to visualize synergy-prediction data.https://github.com/TheJacksonLaboratory/drug-synergy and the software package at PyPI.The source code is available at Bioinformatics Advances online. Drug combination therapy is a promising approach to cancer treatment . HoweverMany computational methods for drug synergy prediction have recently been developed and applied -based model instead of linear regression. Further, we added training optimization and implemented the algorithm as a Python package called Augmented CDA (ACDA). We benchmarked the CDA and ACDA methods on a collection of datasets. Additionally, to support the conclusions of ACDA strengths, we implemented and tested the ACDA alongside a second-best method developed by M. Zaslavskiy (which we denote as EN) of the community-powered DREAM Drug Combination Prediction Challenge to develop and assess computational models for drug-synergy prediction  models from the Novartis Institutes for BioMedical Research PDX encyclopedia (NIBR PDXE) collection  of A, hierarchically cluster M with Ward linkage to make a dendrogram. Finally, calculate the cophenetic distance of the clustering.Step 1. To calculate the drug–drug distance (a drug-similarity measure based on monotherapy sensitivity in the models), first project drug response vectors  sensitivity measures (e.g. AUC) to cosine similarity, and construct matrix A. Then calculate Euclidean similarity M , and drug–drug distance (i.e. the cophenetic distance derived in Step 1).Step 3. Compute (predict) synergy values for new or validation data.Step 4. Visualize predicted and known synergy-pairs data using dendrograms and heatmaps (compare to Voronoi diagrams used in the CDA).The Augmented CDA model follows novel aspects compared to those employed by the CDA model  with CDA synergy pairs. The GDSC1 breast subset contains 119 drug pairs (54 with synergy and randomly chosen 65 unknown pairs assuming no synergy). The GDSC2 breast subset contains 163 pairs , and GDSC1&2 with 191 pairs . We tested 10 randomly chosen sets of ‘no synergy’ pairs for each scenario.The second data source was DrugComb which includes 650,909 harmonized drug sensitivity and synergy values from many in vitro studies and tissues  and, speAs an independent dataset for demonstrating the high benchmarking performance and utility of the ACDA to generate candidate drug–drug combinations in PDX models, we use the NIBR PDXE collection  and tumor mutation profiles of the PDX models from the NIBR PDXE collection  over 10 MCCV iterations for each case of the GDSC and DrugComb-AstraZeneca (DC-AZ) datasets are reported in We observed that the performance of the ACDA on a down-sampled DrugComb-AstraZeneca dataset decreased slightly with the smaller training set. In contrast, the performance of the CDA is much lower on the same set. However, the performance of the CDA did not significantly change with the training set size .We performed validation and benchmarking of our ACDA and CDA implementation using all datasets from DrugComb , which aWe additionally designed an experiment to split the GDSC1 data set into 3-1-1 folds, where fine-tuning is done on four folds and validated on the fifth fold while rotating the test fold to reuse data. The hyperparameter tuning gives an 8% performance increase in the tuned model compared to the base model.The hyperparameter tuning by training on the GDSC2 breast subset and testing on the GDSC1 breast subset led to the increased correlation of the predicted values with ground truth from 0.390 (base model) to 0.797. A similar test using GDSC1 and GDSC2 as a training and testing set suffered from overfitting and decreased correlation from 0.248 (base model) to 0.209.The results for visualization of the synergistic pairs are detailed in the Supplementary Results, and examples of the two visualization tools are shown in Using MCCV, we applied the ACDA method trained on a randomly selected two-third of measured dual-drug responses stratified to leave out drug combination to predict synergistic combinations (model-specific drug pairs) in NIBR PDXE models (P-value <Then we used all available drug-combinations data in the breast cancer subset of NIBR PDXE to train the methods and then generated sensitivity predictions for the cases where drug-combination tumor-volume measurements were unavailable, but the computational model predictors were available. The top 30 drug–drug-model synergy candidates with per-pair averaged synergy scores are listed in in vivo PDX tumor-volume data to predict drug–drug combinations that may synergistically affect specific models.The newly developed ACDA method is an open-source software package and includes the CDA, EN, and EN-ACDA implementations. Benchmarking the four methods demonstrated that ACDA and EN-ACDA were better at predicting synergistic drug combinations than CDA and EN. The ACDA approach can be used with cell-line drug screens and vbad051_Supplementary_DataClick here for additional data file.


The COVID-19 pandemic has led to over 760 million cases and 6.9 million deaths worldwide. To mitigate the loss of lives, emergency use authorization was given to several anti-SARS-CoV-2 monoclonal antibody (mAb) therapies for the treatment of mild-to-moderate COVID-19 in patients with a high risk of progressing to severe disease. Monoclonal antibodies used to treat SARS-CoV-2 target the spike protein of the virus and block its ability to enter and infect target cells. Monoclonal antibody therapy can thus accelerate the decline in viral load and lower hospitalization rates among high-risk patients with susceptible variants. However, viral resistance has been observed, in some cases leading to a transient viral rebound that can be as large as 3–4 orders of magnitude. As mAbs represent a proven treatment choice for SARS-CoV-2 and other viral infections, evaluation of treatment-emergent mAb resistance can help uncover underlying pathobiology of SARS-CoV-2 infection and may also help in the development of the next generation of mAb therapies. Although resistance can be expected, the large rebounds observed are much more difficult to explain. We hypothesize replenishment of target cells is necessary to generate the high transient viral rebound. Thus, we formulated two models with different mechanisms for target cell replenishment  and fit them to data from persons with SARS-CoV-2 treated with a mAb. We showed that both models can explain the emergence of resistant virus associated with high transient viral rebounds. We found that variations in the target cell supply rate and adaptive immunity parameters have a strong impact on the magnitude or observability of the viral rebound associated with the emergence of resistant virus. Both variations in target cell supply rate and adaptive immunity parameters may explain why only some individuals develop observable transient resistant viral rebound. Our study highlights the conditions that can lead to resistance and subsequent viral rebound in mAb treatments during acute infection. Monoclonal antibodies have been used as a treatment for SARS-CoV-2. However, viral evolution and development of variants has compromised the use of all currently authorized monoclonal antibodies for SARS-CoV-2. In some individuals treated with one such monoclonal antibody, bamlanivimab, transient nasal viral rebounds of 3–4 logs associated with resistant viral strains occur. To better understand the mechanisms underlying resistance emergence with high viral load rebounds, we developed two different models that incorporate drug sensitive and drug resistant virus as well as target cell replenishment and fit them to data. The models accurately capture the observed viral dynamics as well as the proportion of resistant virus for each studied individual with little variation in model parameters. In the models with best-fit parameters, bamlanivimab selects for resistance mutants that can expand to high levels due to target cell replenishment. The ultimate clearance of virus however depends on the development of adaptive immunity. As of September 2023, SARS-CoV-2 has caused over 6.9 million deaths worldwide . While vOne concerning observation during treatment of SARS-CoV-2 infection with mAbs is the emergence of viral resistance and concomitant viral rebound. In the case of BAM treatment, after the initial peak in the viral load, viral rebounds of up to 3–4 orders of magnitude consisting mostly of resistant virus have been observed in small subsets of patients in multiple studies . During Since mAbs are a treatment for SARS-CoV-2 and other viral infections such as respiratory syncytial virus and Ebola virus , understNCT04518410) of BAM  of BAM , BAM can) of BAM . As a si) of BAM . The selDrug resistance to antiviral treatments has been studied extensively for many viral pathogens . Rapid vMathematical models are well suited to study the phenomenon of drug resistance and viral rebound  described in detail previously . Viral lClassical target cell limited models with a single viral population have been used to study within-host dynamics of SARS-CoV-2  and otheWe classify SARS-CoV-2 viruses as either sensitive We define We explicitly incorporate the passive infusion and decay dynamics of BAM based on the model developed by Cardozo-Ojeda and Perelson (2021). We let For each study participant, we have the maximum antibody concentration infusion . Thus, aThe neutralizing effect of BAM is modeled as follows. Antibodies bind to sensitive and resistant viruses at rates Together, Our first intuition is perhaps to attribute the observed viral rebound solely to resistance to BAM as the majority of rebound viruses are resistant mutants. However, the timing of viral rebound suggests a greatly reduced pool of target cells at the time of BAM treatment, which was a median of 4.5 days post-symptom onset for the seven individuals analyzed. Thus, a mechanism for a supply of target cells is needed to support the rebound . We investigate two non-mutually exclusive mechanisms that may contribute to the availability of target cells after peak viral load, i.e., proliferation of target cells  and tranWe assume homeostatic mechanisms induce a logistic growth of target cells that attempts to restore the population size to its baseline level. This leads to the following modification of the target cell dynamics:impaired . Hence, The protective effect of the type-I and type III interferons (representative of the innate immune response) is modeled as in previous studies  to fit each model to the viral load and mutant frequency data for all individuals simultaneously. Specifically, besides fitting the total viral load, we fit n (BICc) , 2004 asSince we do not know the time of infection and estimating the time of infection without data during the early phase of infection is problematic due to model identifiability issues , we fixe7 cells (8 cells)  . For thenfection .As we do not know the number of viruses that initiate infection, we use a method suggested by 5 M−1s−1 and the dissociation constant −5 s−1 . This gives a dissociation constant We fixed the association constant for BAM binding to the SARS-CoV-2 spike protein  for BAM . Due to −6 per day , the AIC and BICc for both models . The innIn a target cell limited model , the constant depletion of target cells ultimately leads to the decline in viral load; however, both the logistic proliferation model and the innate immune response model contain mechanisms that can replenish the pool of target cells. In a logistic proliferation model without adaptive immunity, the production of target cells makes it possible for virus to oscillate or be sustained indefinitely . In the innate immune response model without adaptive immunity, the dynamics of target cells going in and out of the refractory state can also give rise to oscillations and the possibility of a slowly decreasing viral load . Thus, for these models to generate dynamics consistent with the observed data with rapid ultimate virus clearance, adaptive immunity must be included in both models.A previous study using a similar innate immune response model for SARS-CoV-2 infection but fit to a different set of data from untreated, unvaccinated individuals estimated studied) . Comparent virus .To study this further, we used the best fit parameters for B2–8 and simulated the effect of decreasing the supply rate of target cells, diminish , left. Rdiminish , right. diminish , etc. maThe emergence of BAM resistant viral mutants associated with transient viral rebounds of 3–4 viral logs has been observed in some individuals treated with BAM . While tIn an acute infection, target cells production is often assumed to be negligible due to the short duration of the infection—continued viral infection is then dependent upon the availability of target cells . HoweverUpon viral infection, infected cells as well as plasmacytoid dendritic cells (not modeled), release type-I and type-III interferons, which put neighboring target cells into an antiviral state, protecting them from viral infection . Thus, aSARS-CoV-2 may be able to antagonize the initial innate immune response by inducing lower production of type I and III interferons as compared to other respiratory viruses, which has been linked to the severity of SARS-CoV-2 disease . HoweverTwo SARS-CoV-2 studies using a murine model , 2021 suThe supply rate of target cells should have a strong impact on the magnitude of the transient viral rebound of resistant virus, or whether the emergence of resistant virus is observable clinically. We examined this effect by varying the target cell supply rate in both models. In addition to the above two mechanisms, we also examined the possibility of antibody-dependent enhancement (ADE) extending the range of cells that are targets of infection (not shown). Recent studies provide evidence that SARS-CoV-2 -antibody immune complexes can infect and replicate in macrophages via interactions with FcγRIIA and FcγRIIIA receptors, or even via the complement component C1q receptor (Junqueira et al., 2020; In this study, we tested the hypothesis that the generation of drug resistant variants coupled with an additional supply of target cells can lead to the observed transient viral rebound in some persons with acute SARS-CoV-2 infection following treatment with BAM. Two models were formulated with different mechanisms that allow for the replenishment of target cells during the infection. By fitting the models to patient data, we showed that both models can explain the emergence of resistant virus associated with large transient viral rebounds of 3–4 logs. Comparison between the two models showed that the logistic proliferation model was slightly preferred based on BICc due to having fewer parameters to fit. Nevertheless, both mechanisms may be operational. We also found that variations in the target cell supply rate parameters have a strong impact on the magnitude of the viral rebound, which may explain why only some individuals develop observable transient resistant viral rebound. Finally, we highlighted the role of adaptive immunity in viral clearance in our models.