There are strong incentives for human populations to develop antiviral systems. Similarly, genomes that encode antiviral systems have had strong selective advantages. Protein-guided immune systems, which have been well studied in mammals, are necessary for survival in our virus-laden environments. Small RNA–directed antiviral immune systems suppress invasion of cells by non-self genetic material via complementary base pairing with target sequences. These RNA silencing-dependent systems operate in diverse organisms. In mammals, there is strong evidence that microRNAs (miRNAs) regulate endogenous genes important for antiviral immunity, and emerging evidence that virus-derived nucleic acids can be directly targeted by small interfering RNAs (siRNAs), PIWI-interacting RNAs (piRNAs), and transfer RNAs (tRNAs) for protection in some contexts. In this review, we summarize current knowledge of the antiviral functions of each of these small RNA types and consider their conceptual and mechanistic overlap with innate and adaptive protein-guided immunity, including mammalian antiviral cytokines, as well as the prokaryotic RNA-guided immune system, CRISPR. In light of recent successes in delivery of RNA for antiviral purposes, most notably for vaccination, we discuss the potential for development of small noncoding RNA–directed antiviral therapeutics and prophylactics. Viruses are all around us and are likely inside some of the reader’s cells at this moment. Organisms are accommodated to this reality and encode various immune systems to limit virus replication. In mammals, the best studied immune systems are directed by proteins that specifically recognize viruses. These include diverse antibodies and T cell receptors, which recognize viral proteins, and pattern recognition receptors, some of which can recognize viral nucleic acids. In other organisms, including bacteria, immune systems directed by small RNAs are also well known; spacer-derived guide RNAs in CRISPR/Cas immune systems are one prominent example. The small RNAs directing these systems derive their specificity via complementary base pairing with their targets, which include both host and viral nucleic acids. Rather than having “traded in” these systems for more advanced protein-directed systems, increasing evidence supports the perspective that small RNA–directed immune systems remain active in mammalian antiviral immunity in some contexts. Here, we review what is known so far about the emerging roles of mammalian siRNAs, miRNAs, piRNAs, and tRNAs in directing immunity to viruses. Viruses are the most abundant and genetically diverse entity in our biosphere and exist wherever life is found . VirusesComponents of mammalian immune systems are often categorized as belonging to innate or adaptive arms based on generalizably distinct functional and evolutionary features. When a virus infects human cells, innate immunity is activated first, followed by adaptive immunity. Innate immunity is activated by features common to invading pathogens, termed pathogen-associated molecular patterns (PAMPs). PAMPs are recognized by sensor proteins such as Toll-like receptors (TLRs) and RIG-I like receptors (RLRs) –9. Upon Recent studies have suggested that antiviral immune systems directed by small RNAs are active in mammals  13–18].–18.13–18The best studied example of small RNA–directed immunity is that guided by viral siRNAs . When RNTwo types of mechanisms, those enabled by viral suppressors of RNAi (VSRs) and IFN signaling, reportedly limit the effectiveness of viral siRNAs in mammalian immunity. Several viral genes are reported as VSRs. The deletion or mutation of VSRs such as B2 protein of NoV  or nonstAntagonism between IFN and RNAi pathways may also limit the effectiveness of the latter. Deletion of either MAVS , an essential adaptor protein in IFN signaling triggered by RIG-I or MDA5, or IFNAR1, an IFN receptor on the cell surface, enables dsRNA-induced RNAi in MEF . dsRNA-iSeveral observations may harmonize the apparently discordant observations in this field. Whereas in general differentiated cells produce IFN upon viral infection or poly(I:C) treatment, some pluripotent or multipotent stem cells do not  and showmiRNAs direct posttranscriptional gene regulation and, in so doing, often regulate antiviral responses in a manner consistent with this being among their evolved functions . miRNAs Some miRNAs target endogenous mRNAs in a manner that promotes antiviral responses, while the others target viral RNAs directly  79–87].–87.79–87As for siRNA, mutual regulation with the IFN system has also been reported for miRNA. IFN stimulation leads to distinct regulation of miRNA pools, with some increased and some decreased ,87. For Both global regulation of miRNAs and regulation of specific populations of miRNAs may enhance virus elimination or link the innate and adaptive immune systems. Global decrease of miRNAs induces proinflammatory cytokine production . SpecifipiRNAs are small RNAs that have been experimentally demonstrated to interact with Piwi proteins. piRNAs are often 24 to 31 nt, and most are transcribed from regions known as piRNA clusters. The biogenesis, nucleotide composition, and modification pattern of many piRNAs is distinct from other small RNAs . piRNAs The evolutionary origins and replication strategies of some viruses and TEs overlap; viruses and TEs can be considered together as mobile genetic elements, and recent reports in nonmammalian organisms suggest that both can be repressed by the piRNA system ,99. SourIn many somatic or cancer cells, epigenetic manipulations that result in ERV expression also induce IFN signaling in an RLR-dependent manner ,105. In tRNAs regulate virus infections and TEs in addition to, or connected with, their canonical role in protein synthesis. Viruses generally do not encode tRNAs, while in humans, tRNAs are among the most abundant RNAs . There aEndogenous and exogenous retroviruses, as well as the TEs derived from them, use tRNAs as primers to initiate reverse transcription. IAP is an active mouse TE in the family of lysine tRNA-primed ERVs, and at least one IAP locus encodes functional membrane fusion machinery and can produce infectious particles . tRFs weSome tRFs are reported to be loaded into Ago or Piwi proteins. tRF-5s and tRF-3s associate with all Ago paralogues in humans as tRNA-derived miRNAs (td-miRNA) . SeveralSmall RNAs have favorable characteristics as antiviral therapeutics. Various types of 18 to 30 nt length RNAs have been approved by the FDA as nucleic acid medicines as of April 2021: 9 antisense oligonucleotides (ASOs), 1 aptamer, 4 siRNAs, and 1 CpG oligonucleotide. The specific sequences and modifications of these nucleic acid medicines are not present in nature, but each harnesses an endogenous system directed by small RNAs. As powerfully demonstrated in development of mRNA vaccines against COVID-19, which took only 45 days from the publication of the SARS-CoV-2 draft genome sequence to shipment of a product for clinical trials, nucleic acid medicines can be chemically synthesized in large amounts quickly. Target and off-target recognition of small RNAs can be rationally designed and screened in silico against databases of nucleic acids present in uninfected human cells. This stands as an advantage over existing platforms for designing protein-based therapeutics, notably monoclonal antibodies, despite advances in structure prediction and molecular dynamic simulations. Among the approved small RNA medicines, ASO and siRNA were rationally designed based on predicted complementarity to the target RNA, whereas the sequence of the approved aptamer was experimentally screened using SELEX . Among tUncovering the mechanisms that enable human immunity to viruses has led to many success stories in development of antiviral therapies, from plant-derived compounds to IFN therapy to CCR5 antagonists to monoclonal antibodies. Clarifying the role of small RNA–directed antiviral immune systems in mammals will likely provide additional successes; the recently described antiviral actions of miRNAs, piRNAs, and tRNAs are especially promising. In parallel to advances in the basic science, mRNA-based therapies and prophylactics have seen accelerated development since the SARS-CoV-2 pandemic, seemingly overcoming previous barriers to nucleic acid medicines. Small RNAs have big potential for the future therapeutic applications.


We are presenting the imaging findings of COVID-19-related leukoencephalopathy associated with bilateral reticular formation diffusion restriction in brain magnetic resonance imaging. To the best of our knowledge, this is the first reported case of bilateral reticular formation affection in a COVID-19 patient. A 44-year-old male, with history of diabetes mellitus and hypertension, presented to the emergency department with a progressive course of shortness of breath, cough and fever for 5 days. On examination, the patient was fully conscious and oriented, with a Glasgow Coma Scale of 15. He was tachypneic with a respiratory rate of 40–45 breaths/min and oxygen saturation that only improved from 54 to 80% with non-re-breather mask. The decision was made to intubate the patient considering his hypoxaemia and tachypnea. The patient then tested positive for COVID-19 polymerase chain reaction (PCR) from oropharyngeal and nasopharyngeal swabs.The chest radiograph displayed bilateral pulmonary airspace opacities with no evidence of pleural effusion. Initial laboratory studies revealed elevated c-reactive protein, fibrinogen, lactate, liver enzymes and glucose level. However, complete blood count was unremarkable.The patient received multiple medications including azithromycin, enoxaparin, esomeprazole, hydroxychloroquine, lopinavir/ritonavir, methylprednisolone, oseltamivir, piperacillin-tazobactam and paracetamol. He was maintaining oxygen saturation of 98% on mechanical ventilation.Three weeks later, trials to wean sedations failed, and the patient had persistent low GCS. A brain CT was done which was unremarkable. Three days later, brain MRI study showed bilateral symmetric cerebral deep white matter confluent hyperintensities in T2W and FLAIR images , with coThe patient gradually improved and was extubated one week after the brain MRI scan. Two weeks after being extubated and continuously improving, he was transferred to a rehabilitation facility due to generalized muscle weakness and poor balance. One month later, he was discharged from rehabilitation with residual impairment in walking ability.1Following the emergence and global spread of the highly pathogenic coronavirus named SARS‐CoV‐2, different neurological manifestations were encountered in addition to the respiratory involvement in acute pneumonia coronavirus disease 2019 (COVID‐19). Reported neurological manifestations included encephalitis, epileptic seizures, ischaemic/haemorrhagic stroke, delirium, headache and ataxia as well as gustatory and olfactory dysfunction.1 However, two hypotheses proposed that coronaviruses may utilize the neuronal-axonal route or the bloodstream to reach the CNS cells.1,2While human-to-human transmission of coronaviruses was reported to be by respiratory droplets, the virus also demonstrated tropism for neuronal cells. The mechanisms by which the virus can reach cerebral tissue remain incompletely clear.3,4 The proinflammatory state in COVID-19 and potentially disrupted blood–brain barrier are speculated to allow the passage of inflammatory and neurotoxic factors into the brain and result in leukoencephalopathy.3 Reported intracerebral microhaemorrhages associated with COVID-19 infection can be possibly related to hypoxaemia, disrupted blood–brain barrier or small vessel vasculitis.4,5 However, in patients with COVID-19, consumption coagulopathy with increased D-dimer can result in small medullary venous thrombosis with consequent cerebral microbleeds.6 High D-dimer was found in our case.Various neuroimaging features were described in association with COVID-19 infection including MRI findings of different patterns of leukoencephalopathy. The reported patterns of leukoencephalopathy include discrete multifocal white matter hyperintense lesions in FLAIR and DWI with variable enhancement, extensive confluent supratentorial white matter FLAIR hyperintensities, FLAIR hyperintense lesions involving both middle cerebellar peduncles and FLAIR hyperintensities affecting both internal capsules. Patient can have more than one pattern as evident in our case. This leukoencephalopathy was considered non-specific and might represent a hypoxaemia-related late complication in critically ill COVID-19 patients; in a similar fashion to delayed post-hypoxic leukoencephalopathy. However, diffuse leukoencephalopathy in critically ill patients might be seen in direct cerebral infection, sepsis-associated encephalopathy, post-infectious demyelinating or haemorrhagic encephalitis, or toxic encephalopathy.7 The lateral zone is mainly related to cranial nerve reflexes and visceral functions. Reticular neurons exhibit extensive and complex axonal projections, reaching various levels in the spinal cord, brainstem, diencephalon and even the cerebral cortex, which contributes to the complexity of the evaluation of this region.7The reticular formation (RF) forms the central core of the brainstem and it contains different interconnected nuclei that help in organizing different functions. At most brainstem levels, the RF can be divided, from medial to lateral, into three longitudinal regions; the raphe nuclei, the medial zone (gigantocellular nuclei) and the lateral zone (parvocellular nuclei). The medial zone represents a source of most of the long ascending and descending projections of the RF.7The RF is involved in various functions like taking part in controlling motor responses through reticulospinal tracts, which receive projections from various areas, like basal nuclei, substantia nigra and cerebral cortex.5 This reticulothalamic pathway in collaboration with monoamine-containing reticular projections are vital for maintaining a normal conscious status. Interestingly, bilateral damage of the brainstem reticular formation neurons and fibers travelling through will end up with prolonged coma. This physiologic input from reticular formation to the cerebrum to sustain a conscious state is named the ascending reticular activating system (ARAS).5 Different studies reported an association between consciousness impairment and damaged ARAS parts due to hypoxic ischaemic brain injury.8,9 Also, recovery of damaged ARAS with change of related neural connectivity was reported in the recovery of patients with impaired consciousness.10,11 Jang et al suggested that thalamocortical projections might be more linked to awareness affection than lower dorsal ARAS.8 Injured lower ARAS, connecting the pontine reticular formation and the thalamus, was associated with impaired arousal following hypoxic ischaemic brain injury.12The RF also participates in modulating information transmission in pain pathways, programming autonomic reflex circuits, and in the control of arousal state and consciousness. Information about different sensory modalities, like pain, are collected into the RF neurons in the midbrain and rostral pons, which are then projected to the thalamic intralaminar nuclei. The latter will project to different regions in the cortex, resulting in heightened arousal after sensory stimuli.13 In addition, coma causing lesions were reported to be centred in the upper pontine region, including RF nuclei, and that these lesions can result in coma even without a midbrain damage. Involved nuclei include nucleus pontis oralis that projects to intralaminar nuclei in the thalamus, which in turn projects to cortical regions. Locus coeruleus and raphe complex are other potential pontine nuclei that were also related to maintaining conscious state. Lesions in these nuclei are more likely to result in coma when they are bilateral.13 It was suggested that these lesions might either impair the nuclei modulation function on cerebral activity or involve ascending projections from these nuclei or descending fibres from rostral structures that target the upper pons.13The upper pontine tegmentum role was identified in sustaining consciousness, in comparison with other midbrain structures.We postulate that the BRF hyperintensities encountered in our case probably contributed to the initial refractory impaired consciousness and difficult extubation. This disturbed consciousness might be due to the affection of RF nuclei bilaterally, or ascending or descending projections passing through the region, with consequent impairment on ARAS system. Also, the recovery of the patient might have coincided with healing of these lesions. More neuropathological studies are recommended for radiologic-pathologic correlation and elucidation of the molecular mechanisms of the injuries noted in such patients.14 The specificity and significance of the radiologic findings of CTT lesions and their clinical correlation are not clearly defined. The pathogenesis of CTT lesions in the different clinical conditions was suggested to be related to intramyelination oedema, gliosis or white matter secondary degeneration.14Given the proximity of reticular formation to central tegmental tracts (CTT) fibers , which tThe reticular formation is a part of the brainstem that is involved in various functions like taking part in the control of arousal state and consciousness.Bilateral damage of the reticular formation neurons and fibers travelling through will affect the arousal state and may end up with prolonged coma.We postulate that the bilateral affection of the reticular formation, evidenced by bilateral reticular formation hyperintensities in MRI, can be a potential consequence in critically ill COVID-19 patients, especially those with refractory impaired consciousness and difficult extubation.


Volatile organic compounds (VOCs) were originally identified as communication compounds between plants and insects. Today, we know that VOCs are released by organisms of all kingdoms, including bacteria and fungi, and mediate diverse intra- and interspecific interactions both above- and below-ground. Following recent trends in this research field, the majority of reviews and research papers in this special issue focus on possible biological and ecological functions and various other aspects of microbial VOCs (mVOCs). Additional reviews and research papers highlight connections between microbe-induced plant VOCs, and their possible application in future sustainable crop protection strategies.Pistacia trees  and the gall-forming aphid Baizongia pistaciae. The authors identified that the aphid is able to reprogram the terpene pathways of the host tree, leading to the characteristic, aphid-protecting high terpene emission from the galls. This is just one example of the diverse functions of VOCs in plant–insect interactions, as reviewed in Biogenic VOCs were detected as herbivore-induced plant signaling cues for the first time in the early 1980s . The disBacillus amyloliquefaciens. These mVOCs inhibit growth of Arabidopsis thaliana plants, potentially as a result of the growth–defense trade-off following activation of salicylic acid (SA)-associated immunity in the same plants -associated defense gene expression in above-ground plant tissues depended on root NO accumulation. This is one of the first demonstrations of a molecular mechanism underlying ISR. Whereas the VOC or the VOC mixture behind the altered resistance remains unknown, previous studies have shown that Trichoderma spp. release a high diversity of various VOCs, among others various terpenoids and typical fungal eight-carbon (C8) VOCs (in vitro study (The various functions of mVOCs as cues mediating microbe–microbe and microbe–plant interactions are highlighted by several contributions in this special issue. Whereas much is known about the chemical nature of plant-derived VOCs, or of those derived from plants and plant organs in interaction with their microbiomes, our knowledge of mVOCs has been significantly improving only recently. In this special issue, e plants . While te plants . The autPseudomonas simiae, in Arabidopsis thaliana (Trichoderma-induced ISR reported on in this issue by P. simiae without physical contact between A. thaliana roots and bacteria (P. simiae or Trichoderma spp. VOCs depends on the A. thaliana root-expressed transcription factor MYB72 (Trichoderma VOCs is shown to additionally depend on root NO accumulation acting upstream of MYB72 (Bacillus amyloliquefaciens both promote and inhibit A. thaliana growth depending on VOC intensity/concentration at the root surface. Future research is required to further unravel the molecular mechanisms downstream of ISR-inducing mVOCs and the complex, in part antagonistic, responses that are triggered by different VOC concentrations and probably also composition, especially if we also take into account further possible ‘interference’ by microbiome-derived mVOCs.Interactions between plant roots and beneficial microorganisms in the rhizosphere can prime defense responses in above-ground plant parts in a process termed induced systemic resistance (ISR; Serratia plymuthica volatiles, including ammonia, on membrane integrity of pathogenic fungi. In this interaction, bacterial volatile compounds might thus influence fungistasis in the rhizosphere and by this means potentially in turn also plant homeostasis.Microbes release not only VOCs but also more simple, inorganic volatiles (Accumulating evidence points to a prominent role for plant VOCs in plant–plant propagation of, for example, defense reactions. When we consider VOC detection in biological systems, insects are known to perceive odors in their peripheral nervous system . It remaIn addition to acting as signaling intermediates in different biological processes, VOCs are well known for their more ‘direct’ repellant and attractant properties, which have already found use in sustainable agriculture. A prominent example is the use of VOCs in so-called push–pull systems . Here, cThe last 40 years of VOC research have been fascinating, but the coming decades do not seem likely to become less exciting. Combining the information from the articles in this special issue, it becomes evident that intra- and interspecific interactions are driven to a large extent by volatile compounds, and can influence the fitness of both microbes and plants. At the same time, many intriguing questions remain. For example, the evolutionary advantages of the distinct, species-specific VOC patterns remain unclear. In future, the roles of VOCs and full VOC bouquets should be deciphered as near to natural environments as possible . Such ap


Hodgkin lymphoma (HL) is a non-AIDS defining neoplasm, but people living with HIV (PLWH) have between a 5- and 26-fold higher risk of developing it than the general population. Epstein-Barr virus is present in almost all HIV-related HL cases, and plays an important role in its etiopathogenesis. Despite the aggressive characteristics, the prognosis of HL affecting PLWH is similar to that of the general population if patients are treated following the same recommendations. Administration of cART concomitantly with chemotherapy is highly recommended. However, this combination may be challenging due to drug–drug interactions and overlapping toxicity. Thus, interdisciplinary collaboration between hemato-oncologists and HIV specialists is crucial for the optimal treatment of both lymphoma and HIV infection.Despite widespread use of combined antiretroviral therapy (cART) and increased life expectancy in people living with HIV (PLWH), HIV-related lymphomas (HRL) remain a leading cause of cancer morbidity and mortality for PLWH, even in patients optimally treated with cART. While the incidence of aggressive forms of non-Hodgkin lymphoma decreased after the advent of cART, incidence of Hodgkin lymphoma (HL) has increased among PLWH in recent decades. The coinfection of Epstein–Barr virus plays a crucial role in the pathogenesis of HL in the HIV setting. Currently, PLWH with HRL, including HL, are treated similarly to HIV-negative patients and, importantly, the prognosis of HL in PLWH is approaching that of the general population. In this regard, effective cART during chemotherapy is strongly recommended since it has been shown to improve survival rates in all lymphoma subtypes, including HL. As a consequence, interdisciplinary collaboration between HIV specialists and hemato-oncologists for the management of potential drug–drug interactions and overlapping toxicities between antiretroviral and antineoplastic drugs is crucial for the optimal treatment of PLWH with HL. In this article the authors review and update the epidemiological, clinical and biological aspects of HL presenting in PLWH with special emphasis on advances in prognosis and the factors that have contributed to it. Since the introduction of combination antiretroviral therapy (cART) the incidence of opportunistic infections and AIDS defining cancers, such as Kaposi sarcoma (KS), aggressive B-cell non-Hodgkin lymphomas (NHL) and invasive cervical cancer, has decreased in people living with HIV (PLWH) ,2. HowevClassical HL (cHL) is the type that has been linked to PLWH. The most common histologic subtype is mixed cellularity followed by nodular sclerosis and lymphocyte-depleted ,7,8,9. UAlthough presenting with more aggressive characteristics, PLWH with cHL have similar response rates and survival to HIV-negative patients when they are treated with the same standard therapies ,14. EarlIn this article the authors review and update the epidemiological, clinical, and biological aspects of cHL presenting in PLWH with special emphasis on the improvement of prognosis and the factors that have contributed to it.9/L who have a similar risk than the general population Pneumocystis jirovecii should be given to all PLWH who receive chemotherapy or radiotherapy as these treatments have been demonstrated to decrease CD4+ lymphocyte counts [Mycobacterium avium complex should also be prevented in patients with CD4+ lymphocytes lower than 50/µL, using oral azithromycin [In addition to specific lymphoma treatment, there are other issues to take into account in the management of HIV-related lymphomas. Antimicrobial systematic prophylaxis is a matter of controversy. Some groups are in favor of using fluoroquinolones, but this practice is not generally recommended, because of the concern of generating bacterial resistances to antibiotics and side effects ,87. Howee counts ,90,91. Thromycin ,92.Whether combining cART with chemotherapy outweighs potential risk of increased toxicity has remained controversial. The risk of overlapping toxicities and the potential for difficult-to-manage drug–drug interactions have been reasons to justify postponement or interruption of cART during chemotherapy by some authors ,93. HoweCurrently approved antiretroviral drugs include nucleos(t)ide and non-nucleoside reverse-transcriptase inhibitors , protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), and entry inhibitors . ManagemDespite the lack of controlled studies, clinically significant interactions between chemotherapy regimens and cART have been reported. The risk for interactions is highest with antiretroviral regimens that include ritonavir or cobicistat (commonly known as “boosters”). The use of boosters aims to increase concentrations in plasma of other antiretrovirals including PIs or the INSTI elvitegravir to attain therapeutic concentrations over 24 h. However, ritonavir and cobicistat are potent inhibitors of cytochrome P450 enzymes and drug transporters which are involved in the disposition of numerous drugs, leading to marked increases in drug exposure ,104. SpeIn patients with lymphoma unboosted INSTIs may be particularly recommended due to their favorable interaction profile with antineoplastic drugs. Raltegravir, dolutegravir or bictegravir do not exert inducer or inhibitor effects on P450 enzymes or drug transporters, minimizing their potential for drug interactions ,111,112.On the contrary to ritonavir or cobicistat, some NNRTIs  are moderate to potent inducers of cytochrome P450 enzymes, and could potentially reduce exposure, and thus efficacy, of certain chemotherapy drugs . RilpiviNucleoside analogues reverse-transcriptase inhibitors are still considered the backbone of cART . AlthougBeside causing drug interactions, antiretroviral drugs may also be victims of interactions caused by co-medications commonly used in patients with lymphoma. For example, omeprazole and other proton pump inhibitors may reduce oral bioavailability of rilpivirine, and coadministration may result in the loss of the therapeutic effect of rilpivirine . Antiaciwww.hiv-druginteractions.org (accessed on 30 May 2021) [www.hivclinic.ca/main/drugs_interact.html (accessed on 30 May 2021) [Since standard dosing algorithms do not exist for managing interactions between cART and chemotherapy, increased monitoring for safety and efficacy is strongly recommended in PLWH undergoing chemotherapy for cHL. In addition, the risk of specific drug–drug interactions between antiretroviral and antineoplastic or supportive drugs should be addressed. In this regard, we recommend consulting specific web pages on this topic, such as ay 2021)  or www.hay 2021)  (Table 2A stable antiretroviral regimen can be modified before chemotherapy to avoid drug–drug interactions, reduce toxicity, and improve adherence and tolerability. As abovementioned, discontinuation of ritonavir or cobicistat-containing regimens in favor of unboosted INSTIs should be encouraged. However, the discontinuation of a single drug in the antiretroviral regimen thought to interact with chemotherapy must be avoided, as this may decrease the efficacy of cART and promote the development of viral resistance to the other antiretrovirals that are to be continued. Changes in cART should be made in consultation with an HIV specialist, since knowledge of the patient’s complete treatment history, including resistance data is crucial when designing alternative cART options. Therefore, interdisciplinary collaboration for the optimal treatment of the oncologic process and HIV infection is mandatory ,121,122,The widespread use of cART initially produced an increase in the incidence of cHL in PLWH. The etiopathogenesis of this lymphoma in the HIV-setting has some differential characteristics due to HIV and EBV cooperation and the different composition of the microenvironment compared to non-HIV patients. Although more aggressive clinical features are still present in cHL affected PLWH, the prognosis has improved and is currently similar to that of HIV-negative patients. The therapeutic approach for HIV-related cHL should not differ from that for the general population. The standard strategies used in the general population to treat cHL have been shown to be equally effective among PLWH. Patients with HIV-related cHL should be placed or maintained on cART during treatment. However, the concomitant administration of chemotherapy with cART may be challenging due to drug–drug interactions and overlapping toxicity. Thus, interdisciplinary collaboration between hemato-oncologists and HIV specialists is crucial for the optimal treatment of both lymphoma and HIV infection while minimizing the risk of adverse outcomes for the patient.


The COVID-19 pandemic has highlighted the inability of health systems to leverage existing system infrastructure in order to rapidly develop and apply broad analytical tools that could inform state- and national-level policymaking, as well as patient care delivery in hospital settings. The COVID-19 pandemic has also led to highlighted systemic disparities in health outcomes and access to care based on race or ethnicity, gender, income-level, and urban-rural divide. Although the United States seems to be recovering from the COVID-19 pandemic owing to widespread vaccination efforts and increased public awareness, there is an urgent need to address the aforementioned challenges.This study aims to inform the feasibility of leveraging broad, statewide datasets for population health–driven decision-making by developing robust analytical models that predict COVID-19–related health care resource utilization across patients served by Indiana’s statewide Health Information Exchange.We leveraged comprehensive datasets obtained from the Indiana Network for Patient Care to train decision forest-based models that can predict patient-level need of health care resource utilization. To assess these models for potential biases, we tested model performance against subpopulations stratified by age, race or ethnicity, gender, and residence .For model development, we identified a cohort of 96,026 patients from across 957 zip codes in Indiana, United States. We trained the decision models that predicted health care resource utilization by using approximately 100 of the most impactful features from a total of 1172 features created. Each model and stratified subpopulation under test reported precision scores >70%, accuracy and area under the receiver operating curve scores >80%, and sensitivity scores approximately >90%. We noted statistically significant variations in model performance across stratified subpopulations identified by age, race or ethnicity, gender, and residence .This study presents the possibility of developing decision models capable of predicting patient-level health care resource utilization across a broad, statewide region with considerable predictive performance. However, our models present statistically significant variations in performance across stratified subpopulations of interest. Further efforts are necessary to identify root causes of these biases and to rectify them. The COVID-19 pandemic has impacted the health and well-being of individuals, communities, and economies worldwide at an unprecedented scale . As of JIn the United States, the COVID-19 pandemic has highlighted (1) the inability of health systems to leverage existing system infrastructure in order to rapidly develop and apply broad analytical tools that could inform state- and national-level policymaking and patient care delivery in hospital settings and 2) systemic disparities in COVID-19–related outcomes and access to care based on race or ethnicity , gender  systemicAlthough the United States seems to be recovering from the COVID-19 pandemic owing to widespread vaccination efforts and increased public awareness, there is still a need to address the aforementioned limitations. Overcoming these limitations will ensure better disaster preparedness and response in anticipation of any future outbreaks caused by either COVID-19 variants or other diseases and to manage the care of vaccine-hesitant populations. The United States boasts significant health information system infrastructure, resulting in the active collection of a wide variety of patient-level clinical, medication, and visit history data. However, such datasets are often siloed across different health systems. As a result, analytical model development is often spearheaded at the health system level. Although such models may be useful in caring for a specific health system, they may not generalize across broader populations and cannot contribute to large-scale public health responses delivered across broad geographies, such as at the county, metropolitan area, or state level.In this study, we sought to inform the feasibility of leveraging broad, statewide datasets for population health–driven decision-making by developing robust analytical models that predicted COVID-19–related health care resource utilization at the patient level among those served by Indiana’s statewide Health Information Exchange (HIE).We leveraged the COVID-19 Research Data Commons (CoRDaCo) , a rich,We extracted and vectorized a wide variety of patient-level features representing their demographics; diagnoses; past encounter history; medications; and social determinants of health, defined as conditions in which people are born, grow, live, work and age  Table 1Table 1.Creation of feature vectors for model development was performed by the authors using the python programming language.We parsed past encounter history data on each patient to identify those who had been hospitalized (defined as patients who had been admitted to either inpatient or intensive care) within either of the following:The first week of receiving a diagnosis of COVID-19 , including a measure of which patients were in need of urgent care at the time of, or soon after, diagnosis.The first 6 weeks of receiving a diagnosis of COVID-19 . A metric of which patients would need inpatient care during the course of their illness ), mostly urban , and had a larger representation of females . A total of 18,694 (19.47%) of these patients were hospitalized during the first week of being diagnosed with COVID-19, whereas 22,678 (23.62%) were hospitalized during the first 6 weeks of receiving a COVID-19 diagnosis.The CoRDaCo dataset consisted of 230,981 patients with a positive COVID-19 diagnosis. However, we noted that a considerable number of these patients were out-of-state residents who visited health systems that were part of the INPC only to obtain COVID-19 tests or were Indiana residents whose only interaction with INPC-affiliated health systems were to undergo COVID-19 testing. As such, we had no clinical data beyond COVID-19 status on these patients. To enrich the quality of datasets used for model building, we excluded such patients by identifying and removing any patient whose only INPC record was a positive COVID-19 test result. This resulted in a total of 96,115 patients. We excluded an additional 89 patients owing to errors in their medical records, resulting in a total of 96,026 The feature preparation process  resultedBoth models delivered strong performance metrics. However, the model for the 1-week cohort reported significantly greater specificity, accuracy, and AUC-ROC scores than the 6-week cohort model.To assess model performance across different subpopulations of interest, we stratified the holdout test dataset by age, race or ethnicity, gender, and residence , and we then evaluated their performance using each performance metric. As presented in Our results demonstrate the ability to train decision models capable of predicting the need of COVID-19–related hospitalization across a broad, statewide patient population with considerable performance accuracy. The 1-week model for predicting the need of COVID-19–related hospitalization reported specificity, accuracy, and AUC-ROC scores that were significantly larger than the 6-week model. The findings are intuitive given that hospitalization risk is more predictable over shorter time frames. Such utilization prediction models may be used for population health management programs in health systems, to identify high-risk populations to monitor or screen, as well as predicting resource need in crisis situations, such as future spikes in pandemic activity or outbreaks.Stratification of model performance across age, race or ethnicity, gender, and urban versus rural divide identified statistically significant variations in model performance across subpopulations. Each model and stratified subpopulation under test reported precision scores >70%, accuracy and AUC-ROC scores >80%, and sensitivity scores approximately >90%. We note that recall scores for each model (approximately 50%-54%) were lower than ideal, implying that a considerable proportion of patients in need of health care services were being ignored. However, model precision, which is indicative of what percentage of patients identified by the model actually needed care was high (>70%), suggesting that it was pragmatic for use in clinical settings. Additionally, model specificity scores were very high (approximately >90%). This finding indicated that the models were able to correctly identify patients who were not in need of care with very high accuracy, which is very valuable in making clinical decisions on which patients to prioritize.Features that influenced the prediction of health care resource utilization included patient age , chronicEach model exhibited significant variations in predictive performance across subpopulations. Overall, male gender or living in an urban area was associated with stronger predictive performance. These differences may be influenced by variations in access to health care services or health care delivery prevalent in the datasets, and the models could learn them during the training process. We cannot make further assumptions on the causes of varying model predictions without a proper assessment of underlying causes of this behavior.legacy patients, who were participants of the INPC system prior to March 1, 2020. It is unclear how the models will perform against other patients who do not regularly interact with the health system and sought care only for COVID-19 testing purposes. This is concerning given that such patients may suffer from a higher disease burden. Our modelling efforts covered a broad time period spanning several waves of the COVID-19 pandemic, as well as the enforcement and relaxation of various mandates aimed at controlling COVID-19 infection rates. These changes may have influenced the capacity of hospital systems resulting in changes in how many patients were provided inpatient care. Alternatively, hospital admission and emergency management protocols may have also changed throughout this period, further impacting which patients received care. Our current effort did not consider how these variations influence the training datasets, and as such, how our models would generalize across future outbreaks and mandates, as COVID-19 infection rates continue to change. Future research will systematically investigate and calibrate model performance across different stages of the pandemic.We noted several limitations to this study. We leveraged statewide datasets from the INPC HIE system to ensure that our models could be operationalized across a broad geographic region. As such, our modeling did not include data elements that were collected by health systems but not shared with the INPC. Since the collection of such datasets and their availability at the HIE level may vary based on the health system, the inclusion of such elements may impact the generalizability of our models across different health systems. Our use cases assessed the need of hospitalization during the first 6 weeks of diagnosis. This excludes the needs of patients suffering long-COVID, where patients may not fully recover for several months . Models We sought to demonstrate the ability to develop broad, state-level models for COVID-19–related research. As such, the biases in analytical models detected in this study highlight significant concerns that researchers must protect against. These biases in analytical model performance will be addressed during the next phase of our work. Further, although the generalizability of our models across other states is untested, they can influence other emerging COVID-19 analytical efforts. In particular, these models can influence data collection, curation, and modeling activities undertaken by the National COVID Cohort Collaborative (N3C) , which iThis study presents the possibility of developing decision models capable of predicting patient-level health care resource utilization across a broad, statewide region with considerable predictive performance. However, the analytical models present statistically significant variations in performance across stratified subpopulations of interest. Further efforts are necessary to identify root causes of these biases and to rectify them.


Langerhans cell histiocytosis (LCH) is a rare inflammatory neoplasia in which somatic mutations in components of the MAPK/ERK pathway have been identified. Osseous involvement is evident in approximately 80% of all patients and may present as a single osteolytic lesion, as a multi-ostotic single system disease or as part of multisystem disease. Both exogenous, such as treatment with glucocorticoids, and endogenous parameters, such as anterior pituitary hormone deficiencies and inflammatory cytokines, may severely affect bone metabolism in LCH. Computed tomography (CT) or magnetic resonance imaging (MRI) are usually required to precisely assess the degree of bone involvement; 18F-fluorodeoxyglucose (FDG) positron emission tomography—CT can both detect otherwise undetectable LCH lesions and differentiate metabolically active from inactive or resolved disease, while concomitantly being useful in the assessment of treatment response. Treatment of skeletal involvement may vary depending on location, extent, size, and symptoms of the disease from close observation and follow-up in unifocal single-system disease to chemotherapy and gene-targeted treatment in cases with multisystem involvement. In any case of osseous involvement, bisphosphonates might be considered as a treatment option especially if pain relief is urgently needed. Finally, a patient-specific approach is suggested to avoid unnecessary extensive surgical interventions and/or medical overtreatment. Langerhans cell histiocytosis (LCH) is an orphan disease characterized by clonal proliferation of abnormal CD1a+/CD207+ myeloid precursors cells. The abnormal cells in LCH are actually derived from myeloid dendritic cells that exhibit the same antigens  and the same unique intracytoplasmic organelles (Birbeck granules) with the normal Langerhans cells found in the skin and mucosa ,2928,29]Vertebral lesions with intraspinal projection or craniofacial bone lesions with soft tissue extensions are considered “special site lesions” because of the risk of developing spinal cord compression and CNS infiltration, respectively. In particular, patients with craniofacial bone lytic lesions are at increased risk of developing HP axis damage, space-occupying CNS lesions, and neurodegenerative disease ,18. MoreOral cavity involvement, with or without mandibular infiltration, occurs early in LCH, but it is frequently misdiagnosed as the initial symptoms may be non-specific . InvolveRadiographs during the active phase typically show lytic lesions without marginal sclerosis or periosteal reaction . As lesiThe changes in the management of LCH with bone involvement over the years reflect the changing concepts regarding the disease pathogenesis. Unlike pediatric LCH treatment, a standard first-line chemotherapy treatment has not been established for adult LCH patients. Glucocorticoids, immunosuppressive agents, chemotherapy, and antiresorptives may be used in different regimens and doses depending on the age, the number and location of the lesions and the symptoms of the patient . RadiatiIn case of unifocal bone involvement of “non-CNS-risk facial bones” in SS LCH, treatment may vary depending on location, size, and symptoms of the disease from close observation and follow-up (after biopsy or curettage), to radiation therapy, or intralesional injection of glucocorticoids  ,40. BiopFor patients with multifocal bone LCH, bisphosphonates can be used as the initial treatment approach  and in cA retrospective international study that included both children and adults concluded that bisphosphonates  are effective in active bone lesions, especially in pain resolution, with less adverse effects than other systemic treatments; zoledronate was the most frequently used regimen in this study and almost half of the cases received a single infusion . The resAs detailed above, denosumab, a human antibody against RANKL, could be a rational treatment option in LCH, even in extraosseous disease, in order to contribute and further support the endogenous OPG action and control the lesional immunological process ,45. A phFor patients with bone disease within an MS symptomatic setting, first-line treatment options include chemotherapy with cytarabine, cladribine (2-CdA), methotrexate or methotrexate plus cytarabine, or hydroxyurea given that LCH shares both features of an inflammatory and neoplastic disease . The comRecent studies suggest 2-CdA monotherapy as an effective treatment option with a high overall response rate of around 80–90% ,49. ImpoAmong patients with BRAF V600E-mutated LCH, targeted therapy with BRAF inhibitors  represents a novel therapeutic approach. These agents may be preferably considered in patients with critical organ involvement or severe symptomatic disease where a quick response is needed. Their use is limited by toxicities, including a higher risk for primary malignancies .As noted above, histiocytic neoplasms are collectively characterized by dependence on MAPK pathway signaling and, consequently, responsiveness to MEK1/2 inhibition. Cobimetinib, a selective inhibitor of MEK1/2, had marked and durable activity in adults with histiocytic neoplasms regardless of the tumor genotype , implyinThe skeleton is a frequently involved organ in LCH and severe disability and discomfort can be induced in a patient harboring such lesions. Although the symptoms and signs can be impressive in some cases a careful, patient-specific approach is suggested to avoid unnecessary extensive surgical interventions and/or medical treatment. Both gene-targeted treatment, as well as therapeutic modalities focusing on the specific cytokine environment of the LCH osseous lesion, seem to be the therapeutic approaches that would probably predominate in the future although further research and prospective control studies are urgently needed.


It is unusual for a de novo eating disorder to emerge in late adulthood. Across a number of years, a number of patients were identified who experienced severe and unexpected weight loss post curative management of an upper abdominal cancer . Each of the patients was readmitted to the tertiary surgical hospital due to complications of severe malnutrition. Each presentation was initially considered to have a major physical health problem (such as cancer recurrence). Each required extensive investigations and multidisciplinary team involvement and were later conceptualised as a new-onset (in later adulthood) eating disorder that emerged post curative cancer treatment. The team wished to better understand this group and/or characterise and/or inform the scientific community of this phenomena if not already well described.The review identified that the re-emergence of pre-existing eating disorders at the time of cancer treatment was described; however, there was no identification of similar new-onset in later adulthood cases of eating disorders in cancer survivors in the medical literature.Once ethics and consent was obtained, then the clinical course of four complex individuals were reviewed, including the use of a multidisciplinary Delphi review process, to understand commonalities and then plot a common care pathway with potential intervention points.Common factors identified among the four patients included the lack of a physical health (organic) cause to the weight loss and ongoing weight loss despite intense multidisciplinary care. All had abnormal attitudes and behaviours relating to food, nutritional rehabilitation and/or recovery. None returned to a healthy weight and/or healthy eating despite extensive team input. The presentations were ultimately conceptualised as having severe disordered eating behaviours and in at least three cases met criteria for a formal eating disorder. The cohort had similar psychosocial characteristics including low socioeconomic status and complex family dynamics. None had prior formal psychiatric care. The outcomes were poor; one patient died, another required admission to a specialist eating disorder admission with a subsequent relapsing remitting course, and the remaining two had complicated chronic courses.Similar cases may be underreported. If identified earlier, there may be a role for intervention to prevent high morbidity and mortality and to support clinical teams managing similar complex patients. Feeding and eating disorders (FEDs) have at their core entrenched disordered eating behaviours (DEBs). Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 outlines criteria for six specific FEDs, namely anorexia nervosa (AN), Bulimia Nervosa, Binge-Eating Disorder, Avoidant/Restrictive Food Intake Disorder (ARFID), Pica and Rumination Disorder . Whilst Firstly, we wished to clarify whether such a cohort was previously identified in the scientific literature. Secondly, we wished to investigate whether commonalities to their presentation and/or clinical characteristics existed. Lastly, we supposed that similar presentations occur in other hospitals and so wished to raise awareness.The authors identified a group of older adult patients who were readmitted to a surgical ward in a general hospital due to complications of severe malnutrition. The patients were unable to maintain their expected weight and the malnutrition occurred many months, and in one case years, post treatment for cancer . The weight loss was not attributable to cancer recurrence, surgical complications, anatomical anomalies, or other physiological explanations. Over time the patients required intensive multi-disciplinary support  with subsequent consultation to psychiatry for opinion and management advice, given their complexities. New  onset in later adulthood (> 40 years old),Severe  feeding and eating disorders (FEDs) of psychiatric origin,In cancer survivors post-surgery.Firstly, a literature review was completed in late 2019 looking to identify reports that had all three of the following characteristics:Secondly, a case-based review of the identified suitable patient charts was undertaken with completion of a summary of common characteristics/ factors to better characterise the cohort.Lastly, several rounds of consultation between the authors, utilising a Delphi method , occurreThe literature review did not identify similar case reports meeting all three of the criteria of (a), (b) and (c) as outlined above in methods.There is however scientific literature showing case series of “Synopsis of reported cases of anorexia nervosa associated to cancer” in children and young people . There aSimilarly single  articles in this area discuss how common body image disorders are in the cancer setting . Other p, FED post bariatric surgery (commonly known as weight loss surgery), with some authorship groups proposing the need to formally recognise a new FED for patients who develop an AN-like illness post bariatric surgery, Post-Surgical Eating Avoidance Disorder [Lastly, there are case series of later adult onset FEDs post-surgery; however not in cancer survivors. Within the late-onset subset of patients with eating disorders, case reports emerged in the literature over 20 years ago of a possible new-onset, or de novoDisorder .Hence, overall there was no identified scientific literature identifying all three key aspects of the cases i.e., (a) new-onset in late adult hood, (b) eating disorder  and, (c) occurring in cancer survivors.Due to the lack of similar case reports in the scientific community, it was deemed appropriate to consider reporting the cases. Appropriate correspondence with the hospital ethics board occurred. For the purpose of this case series, five patients were identified over the course of two years (2018 and 2019). When approached retrospectively only four consented for the study. Written consents were obtained (from three patients and in the fourth case from the deceased’s next-of-kin).A sixty-seven year-old, unemployed female living with her ex-partner was diagnosed with early stage oesophageal cancer upon investigation for dysphagia. She underwent preoperative combined chemo-radiotherapy to shrink the tumour and subsequently had upper abdominal surgery (Ivor-Lewis oesophagectomy). She had early post-surgical weight loss and was discharged from hospital with nutrition via a feeding tube. On community dietician follow-up she admitted to non-adherence to the feed schedule and reported stress and anxiety associated with feeding. She became upset when the option of increasing feed rates was raised. She had repeat presentations to the emergency department with dislodged feeding tube. Due to concerns about a possible physical problem (stricture) impacting on her oral intake, a preventative dilatation was performed. Despite this, she continued to lose weight in the community, became increasingly fussy about food textures and flavours and justified her minimal intake to family and dieticians. Eight months post initial surgery she was admitted with severe bradycardia and hypotension secondary to malnutrition. A nasogastric tube was then inserted for the purpose of refeeding.She was initially referred to the consultation liaison (CL) psychiatry team due to concerns around stress/anxiety. She was initially diagnosed with major depressive disorder with anxious features. Though her difficulties swallowing had some structural basis, they were exacerbated by anticipatory anxiety about choking. Conflict at home over her oral intake led to heated arguments, increased stress and subsequent loss of appetite. Aside from pre-existing moderate obsessive tendencies, she had no known psychiatric or substance use history, nor pertinent family history. Subsequent reviews revealed full remission of the major depressive features and acknowledgement of typical anorexic cognitions including a fear of weight gain. In time, she was noted to tamper with nutrition given via tube feeding and over-exercise. Later, a formal diagnosis of Anorexia Nervosa was made. Over the next two years she required multiple admissions for complications of malnutrition including ultimately an admission to a Specialist Eating Disorder Unit. Further medical admissions have occurred due to medical complications of severe malnutrition.A sixty-nine year-old retired woman, living with her husband and acting as his career as he had a dementia illness, was diagnosed with early stage oesophageal cancer. She underwent preoperative chemotherapy, followed by upper abdominal surgery . She had a complicated post-operative course with multiple admissions to intensive care owing to wound infection. She was commenced on total parenteral nutrition , which was later transferred to nutrition via a feeding tube. She was discharged four months post-operatively, not yet meeting her nutritional needs orally. On community dietician follow-up, she admitted to non-adherence to feeds and reported simply being unable to eat on most days. She had multiple presentations to the emergency department (ED), complaining of uncontrollable dry-retching, preventing her from complying with feeds via the feeding tube. The dry-retching was not observed during any ED assessments but further weight loss was noted. Eight months post-surgery, she warranted readmission for nutritional rehabilitation.She was initially referred to CL psychiatry on account of the disparity between her stated intentions to recover and her refusal to comply with advice regarding feeding. No formal psychiatric diagnosis was given at the time, nor suggestion made about personality vulnerabilities. She had no previous formal psychiatric diagnoses, bar a solitary depressive episode in her twenties, nor history of substance use. She attributed her inability to eat as being secondary to a reported alteration in taste (dysgeusia), early satiety and anorexia. Over time she had an increasingly narrow repertoire of foods she would agree to eat, became increasingly non-compliant with nursing and dietician advice and refused all nutritional supplements. More than a year post surgery, she was given a diagnosis of an Atypical Anorexia Nervosa. Despite attempts at ongoing care, she remains severely underweight and has now disengaged with all follow-up.A sixty-two year-old married man, living with his ageing mother and second wife was diagnosed with oesophageal cancer. He underwent an upper abdominal surgery (Ivor Lewis oesophagectomy). Though he had expected post-surgical weight loss, he ultimately made a good recovery. Nine years later however, he presented with complications of severe, rapid weight loss attributed to nausea. After the possibility of cancer recurrence was excluded, he was discharged with advice to take nutritional supplements, use anti-emetics and follow-up with a community-based dietician. Over the following six weeks, he had multiple presentations to ED with various unrelated somatic complaints. Further weight loss was noted on each occasion. He was eventually re-admitted for delivery of nutrition via a feeding tube and re-establishment of normal oral intake. Again, physical health problems such as motility gut problems and strictures were excluded.He was referred to psychiatric services for assessment of atypical eating behaviours and related cognitions; extreme anxiety around consumption, narrowing of food repertoire, avoidance of particular food groups and cutting food into minute pieces. Though he had no formal psychiatric history, there was evidence to suggest he had developed features of an Illness Anxiety Disorder after his cancer surgery many years prior. He had no drug and alcohol use, nor history of the same. At the time of first psychiatric assessment, he was given a diagnosis of Somatic Symptom Disorder and was seen on a regular basis by a CL clinical psychologist, for cognitive behavioural therapy. He went on to total refusal of all oral intake and anti-emetics (despite his chronic complaint of nausea). There was marked cognitive dissonance between his DEB and an enduring wish to live. He appeared to understand the outcome of chronic food refusal  and repeatedly reported wanting to recover. He later had a revised diagnosis of Avoidant Restrictive Food Intake Disorder. He made little effort to engage with psychological/psychiatric services and made no improvement in his oral intake. He ultimately died from infection superimposed on extreme frailty.A 61-year-old partnered male, living alone, presented with a diagnoses of stomach cancer (gastric adenocarcinoma). He underwent upper abdominal surgery . Post-operatively, he was unable to tolerate any oral intake and was discharged with a feeding tube in place. The feeds provided less than fifty percent of his nutritional needs. As an outpatient, he was non-compliant with the prescribed feed schedule and did not adhere to the recommended post-gastrectomy diet. He restricted his oral intake to sugar-packed carbonated beverages and did not take the pancreatic enzyme replacement (Creon®), nor the prescribed dietary supplements. At community-based dietician review, he was noted to have lost more weight. There were numerous incidences of unexplained feeding tube dislodgement. He had three emergency department presentations due to nausea, with further weight loss noted on each occasion. He was eventually admitted due to extreme frailty and uncontrollable nausea. Repeat investigations were all unremarkable.Referral to CL psychiatry for concern around dietary non-compliance was made eight months post initial surgery. Though no formal diagnosis was made initially, he was noted to have an anxious preoccupation with food planning, to the extent that he developed total food avoidance.There was an obvious discrepancy between his stated fears of further weight loss as a precursor to death and his wish to recover. His therapy-interfering behaviours persisted despite traumatic memories of his mother’s cachexia secondary to cancer resulting in her death. He demonstrated limited insight into the contradictory nature between his cognitions and behaviours thought to reflect very poor health literacy. He had a prolonged in-patient admission for nutritional rehabilitation which was unsuccessful. Later in that admission a diagnosis of an Atypical Anorexia Nervosa was made. Despite not recovering, he was discharged due to limited benefit of ongoing inpatient care. Clinical acumen deemed that he was unlikely to engage with any further service and had poor prognostic indicators.expected body weight loss of 15–17% at postoperative 1-year [Table e 1-year  for an oe 1-year . PremorbThere was some variation in the type of DEBs. All presented with a disparity between their stated wish to recover  and their observed actions of further restriction, resulting in malnutrition. In contrast to anorexia nervosa, there were no classic body image concerns expressed; however, like anorexia nervosa, each patient downplayed, or were unable to appreciate, the concerns of their clinicians and family. Some patients were in keeping with “classic” anorexia nervosa with therapy interfering behaviours such as tampering with nasogastric feeding; however, other patients were simply non-compliant with all basic dietary advice and refusal of all supplements despite obvious life-threatening malnutrition. There were confirmed cases of a compensatory behaviour . To our knowledge there was no laxative abuse.From a psychiatric viewpoint, two had pre-existing formal psychiatric diagnoses . There were no past or present psychotic or cognitive disorders. Early life adversity and premorbid personality vulnerabilities were identifiable in all four patients. None were taking psychotropic medications at time of initial psychiatric referral.The outcome for the patients were one dying, one proceeding to an admission to the public specialist eating disorder unit, and then as per the remaining two, continuing to have ongoing malnutrition and intermittent general medical-surgical admissions with general disengagement from mental health/ dietitian/ support services.. Potential points of intervention for either education, earlier detection and/or interventions for patients who develop FED post-surgery for upper-abdominal cancer are shown.A pathway outlining the shared features in the treatment trajectory of the four patients is presented in Fig. 1These four cases demonstrate new-onset disordered eating behaviours (DEB) after the surgical management of upper abdominal  cancer. The current nomenclature for eating disorders does not account for these patients; nor are they normal findings in upper abdominal cancer survivors. The cohort differs from the usual or expected weight loss trajectory that most upper abdominal surgical (oesophagectomy/gastrectomy) patients experience.One of the most common sequelae of total and partial removal of the stomach (gastrectomy) is weight loss, with a number of previous studies showing that percentage body weight loss after gastrectomy ranges from 10 to 20% of the preoperative body weight , includipersistent disturbance of eating, or eating related behaviour, that result in the altered consumption or absorption of food and that significantly impair physical health or psychosocial functioning” [DSM-5 considers feeding and eating disorders (FED) to be “tioning” . Whilst tioning” .Prevailing assumptions of the psychosocial aetiologies of FED have been found less applicable amongst the older age-of-onset subgroup. In contrast to those with a typical age-of-onset, there is a lesser predominance of extreme personality traits, or the cardinal features of anorexia, namely body dysmorphia and an aesthetically driven pursuit of thinness . PhysicaThere is some evidence that earlier intervention for AN may improve outcomes ; suggestClinicians  on the primary team could look for similar patients post-operatively  and then individualise care pathways according to the setting. If failure to restore weight at pre-determined points are identified, then a system to flag concerns could be of help . Similarly, hospital based mental health services need to be available and accessible to assist the primary team members to understand and conceptualise the abnormal behaviours, and be prepared to undertake longitudinal assessments if unclear pathology is present on first review. Finally, the broader team may wish to seek specialist eating disorder advice if needed and available.In this case series, we chose to focus on the psychosocial factors and have therefore not closely examined the details of each patient’s treatment course, which may have contributed to their clinical presentation. Notably, we did not examine the role of specific surgeries, differences in postoperative commencement of oral intake, pre-existing medical comorbidities, or timing of chemotherapy. Nor did the treating multidisciplinary teams specifically, systematically, considered each of the potential biological drivers of post-operative weight loss for each patient. Though surgical investigation and imaging ruled out major anatomical/functional contributors, there was little, if any mention, of the hormonal and neurological factors which may have been affecting the patients’ presentations.This case series is limited to a very small number of patients, affecting generalizability. Moreover, the largely qualitative nature of the data limits the reliability and validity of the data, as it is subject to reporter sensitivity and bias.The retrospective nature of the case studies means that our data pool was limited to the information recorded at the time of each patient’s care, with potentially key pieces of data, (with respect to our hypothesis), not having been thought to be of import at the time.Similarly, a detailed psychodynamic approach to their case formulations, including addressing any existential themes relating to their initial cancer diagnosis is not presented.We propose that a small subset of upper GI cancer patients exist that have (a) severe, excessive, weight loss and (b) psychologically mediated disordered eating behaviours, and that this may lead to very poor clinical outcomes. No similar case series was found in the literature at this time and the clinical significance is uncertain. These findings require further validation and/or similar findings in other settings.


Tenodesis of the long head of the biceps tendon can be performed through arthroscopic and open techniques with various fixation methods and at different locations on the humerus. Many techniques have been described, with controversy surrounding the advantages and disadvantages of each. In this Technical Note, we describe an all-arthroscopic, intra-articular, single-portal, suprapectoral biceps tenodesis with an all-suture anchor. This technique also allows for suture passage through the biceps tendon before tenotomy to ensure proper maintenance of the length–tension relationship of the biceps musculotendinous unit. Video presentation of the surgical technique for arthroscopic single-portal suprapectoral biceps tenodesis with an all-suture anchor. This is an effective treatment for some patients with isolated biceps pathology, but failure of conservative management or concomitant pathology can necessitate operative intervention. Despite LHB tendon pathology being so common, the current literature on treatment of this pathology remains controversial, as some advocate tenotomy of the tendon, whereas others support tenodesis.The surgical technique is shown in An anterior portal is placed centrally in the rotator interval under visualization and an 8-mm × 7-mm disposable cannula  is inserted. Establishing the portal in the central or slightly medial aspect of the rotator interval will ensure appropriate trajectory later on for the penetrator through the biceps tendon. Concomitant intra-articular pathology can be addressed through the anterior working portal as needed before biceps tenodesis. The arm is then positioned in approximately 60° of forward flexion with the elbow flexed to 90°. While viewing through the posterior portal, a straight drill guide is introduced percutaneously and placed at the proximal aspect of the bicipital groove . The driThrough the anterior working portal, the LHB tendon is pierced using a 70° Champion Slingshot  suture passing device  A and B.After retrieval of the corresponding limb of each passed suture through the anterior working cannula , arthrosOnce the biceps tenodesis is confirmed to be structurally sound with a probe, the residual intra-articular portion of tendon is released from a site proximal to the anchor using arthroscopic scissors  and the We present an all-arthroscopic biceps tenodesis technique that places the tenodesis site proximal to the bicipital groove in the suprapectoral region that can be performed from the glenohumeral joint. The majority of studies comparing arthroscopic with open tenodesis have demonstrated no significant differences regarding postoperative pain, patient satisfaction, or outcomes scores.18Complications associated with all forms of biceps tenodesis include length–tension mismatch, loss of fixation, persistent pain, shoulder stiffness, infection, hematoma, neurologic injuries, vascular injuries, and reflex sympathetic dystrophy.24,,,The literature remains inconclusive regarding optimal site of tenodesis, that is, above  or below  the insertion of the pectoralis major tendon. Described suprapectoral arthroscopic techniques have included tenodesis sites proximal, within, or distal to the bicipital groove.,Fixation options described include, but are not limited to, sutures, suture anchors, interference screws, and cortical buttons.,,,Arthroscopic suprapectoral biceps tenodesis has been described with use of various fixation methods and alternative exposures and preparation.We present a technique for arthroscopic, suprapectoral, intra-articular biceps tenodesis through a single anterior portal with an all-suture anchor. This technique allows for suture passage through the biceps tendon before tenotomy to ensure proper maintenance of the length-tension relationship of the biceps musculotendinous unit and offers the benefits of arthroscopic procedures, including an overall less invasive procedure, better cosmesis, and decreased blood loss.


Noncoding RNAs (ncRNAs) defy the central dogma by representing a family of RNA molecules that are not translated into protein but can convey information encoded in their DNA. Elucidating the exact function of ncRNA has been a focus of discovery in the last decade and remains challenging. Nevertheless, the importance of understanding ncRNA is apparent since these molecules regulate gene expression at the transcriptional and post-transcriptional level exerting pleiotropic effects critical in development, oncogenesis, and immunity. NcRNAs have been referred to as “the dark matter of the nucleus”, and unraveling their role in physiologic and pathologic processes will provide vast opportunities for basic and translational research with the potential for significant therapeutic progress. Consequently, strong efforts are underway to exploit the therapeutic utility of ncRNA, some of which have been approved by the US Food and Drug Administration and the European Medicines Agency. The use of ncRNA therapeutics (or “vaccines” if defined as anti-disease agents) may result in improved curative strategies when used alone or in combination with existing treatments. This review will focus on the role of ncRNA therapeutics in prostatic carcinoma while exploring basic biological aspects of these molecules that represent about 97% of the transcriptome in humans. Noncoding RNAs (ncRNAs) represent a family of RNA molecules that are not translated into protein but execute a multitude of biological functions informing significant therapeutic potential. It is possible that some ncRNAs are nonfunctional products of spurious transcription, sometimes referred to as “junk RNA”. However, the exact number and function of ncRNAs are still a matter of debate and the focus of active research. It has been estimated that ncRNAs represent approximately 97% of the transcriptome, widely surpassing the amount of coding messenger RNAs (mRNAs). Approximately 30,000 molecules of ncRNAs have been identified, which may be functionally as important as proteins. Interestingly, it has been recognized that approximately 22% of ncRNAs have been misclassified and do encode small polypeptides, which may muddle translational research ,2. OveraIn contrast, the smaller ncRNA transcripts are usually about 20 nucleotides in length and represent about 2000 to 5000 molecules with evolutionarily well-conserved sequences that are processed by endonucleases. In common with lncRNAs, the location of smaller ncRNAs can be intergenic or intronic.Functionally, ncRNAs are divided into homeostatic/housekeeping and regulatory types, although some molecules defy categorization. For example, circular RNAs , which are usually lncRNAs that can, on occasion, encode proteins and be structurally shorter than 200 nucleotides long .Well-known homeostatic ncRNAs include transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs). tRNAs are short (~80 nucleotides) ncRNAs that ferry individual amino acids to ribosomes allowing protein translation. In contrast, rRNAs represent a specialized type of long ncRNAs (1500 to 3000 nucleotides in length) that constitute ~60% of the mass of the ribosomes and bind to riboproteins, contributing to the formation of the catalytic sites necessary for protein translation from mRNAs.Regulatory ncRNAs have been functionally grouped into at least four main categories, sometimes displaying overlapping features: (1) splicing RNAs, (2) self-modifying RNAs, (3) transcriptional regulatory/gene silencing RNAs , and (4) multifunctional gene-regulatory long RNAs, exemplified by lncRNAs. Splicing RNAs comprise small nuclear RNAs (snRNAs) that bind proteins in the spliceosome. Self-modifying RNAs represent small nucleolar RNAs (snoRNAs), which form part of the ribonuclear protein complex of the nucleolus and have functional similarity to guiding RNAs, serving to chemically modify other RNA molecules. The transcriptional regulatory/gene-silencing RNAs denote at least three types of molecules—namely, (a) small interfering RNAs (siRNAs), involved in gene silencing; (b) microRNAs (miRNAs), which represses mRNA translation by binding to the 3′ untranslated regions of mRNA, promoting its degradation; (c) PIWI-interacting RNAs (piRNAs), which interact with the piwi-subfamily of Argonaute proteins (a highly conserved family of RNA-binding proteins abbreviated as PIWI for the “P-element induced wimpy testis in Drosophila”), which predominantly silence transposable elements through both epigenetic, transcriptional and post-transcriptional mechanisms.This overwhelming variety of ncRNA species, together with their abundance and rich overlapping functionality, suggests regulatory effects on almost every gene. For example, it has been estimated that in humans, one molecule of miRNA is able to bind with perfect or imperfect complementary base pairing to hundreds 100 to 500) of different mRNA molecules. Therefore, because more than 2000 mature miRNAs have been deposited in the miRNABase V22 00 of dif. In this regard, ncRNA agents could act as immunomodulators or even therapeutic “vaccines”, when defined as medicines that contribute to eliminating or controlling disease, recognizing that so far the immunogenic potential of ncRNAs has not been exploited. Therefore, ncRNA therapeutics cannot be currently considered bona fide vaccines, and quotation marks will be used for clarification in the following sections. ncRNA “vaccines” can be mechanistically diverse, acting directly at a genetic or epigenetic level, or indirectly by modulating innate and adaptive immune responses to find and destroy harmful infectious agents and cancer cells. Modulating ncRNA represents an attractive strategy in oncologic therapy, as well as many other disciplines, and although RNA-based therapeutics have experienced significant prominence in the last 20 years, employing predominantly antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), important hurdles need to be overcome. Several products have gained regulatory approval by the US Food and Drug Administration (FDA) or the European Medicines Agencies (EMA). However, trial results have been disappointing so far due to a combination of factors that include limited efficacy or significant toxicity. Alternative RNA products, such as lncRNAs and anti-miRNAs, are currently undergoing clinical evaluation, but importantly, other ncRNA species have not been extensively targeted to develop therapeutics yet.In this review, we explore the potential for ncRNAs as therapeutics/“vaccines” in prostatic carcinoma (PC), since this disease remains a significant public health burden. Prostate cancer is the most frequently diagnosed nonskin cancer in the United States, representing approximately 6% of all cancer deaths (disproportionately affecting black men) and the second-most-common malignancy worldwide ,8. Even Several excellent reviews have recently covered a variety of strategies to manipulate the medicinal potential of ncRNAs by using small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), short hairpin RNAs (shRNAs), anti-microRNAs (anti-miRNAs), miRNA mimics, miRNA sponges, therapeutic circular RNAs (cirRNAs), and CRISPR-Cas9-based gene editing ,20,21. TDespite the rapidly evolving refinements in precision medicine, ncRNA “vaccine” development remains daunting. Many different ncRNA therapeutic products are in the pipeline, but only a few have been approved by the FDA and/or the EMA. Most of them were designed to treat monogenic inherited diseases by using siRNAs or ASOs that would specifically downregulate wild-type genes or alter pathological splicing of mutated genes restoring functionality. However, none of these tools have been approved to treat carcinomas due, in part, to the complex multigenic nature of malignancy. Nevertheless, several ncRNA therapeutics are in phase II or III clinical development, which include different molecules such as miRNA mimics and anti-miRNAs . Of thesNotably, three products have been deployed in clinical trials for advanced PC . ApatorsOther genes have also been targeted by ncRNA therapeutics in clinical trials for advanced PC. The AFFINITY phase III trial employed the ASO custirsen  to downregulate Clusterin, a heat shock protein that regulates apoptosis. Interestingly, the results contradicted previous clinical trials since no significant survival benefits could be demonstrated in patients with metastatic castration-resistant PC . The triThe immense therapeutic potential of ncRNA “vaccines” remains still unrealized, partly due to toxicity and delivery issues, which could be tackled with evolving innovation in the field . As alluAn alternative method to decrease the unwanted immunogenicity of ncRNA “vaccines” is exemplified by third-generation modifications, such as phosphoramidate morpholino oligomers (PMOs or simply morpholinos) that should not activate TLR signaling . PMOs arSeveral additional strategies are being explored to overcome excessive immunogenic effects of ncRNA agents, including screening for possible TLR activation before deployment, and using “tiny” antisense RNA, metronomic miRNA therapy, and combinatorial RNA therapeutics, as has been thoroughly reviewed recently . InteresAnother prominent obstacle for optimal efficacy of ncRNA products is controlling their specific delivery.The most common cause of termination of ncRNA “vaccine” clinical trials has been the lack of efficacy, which may be multifactorial including stability and delivery issues. Efforts to improve the delivery of ncRNA therapeutics must consider both the delivery of these agents into the targeted organ, as well as access to the cytoplasm of the appropriate cell type . VariousThird-generation antisense oligonucleotides  utilized modifications of the furanose ring and the phosphodiester bonds to improve resistance to RNAses but also to target affinity and pharmacokinetic profiles , as descInterestingly, local delivery schemes using lipid nanoparticle-like systems have shown success in PC cell lines  and in dIn conclusion, we reviewed exciting and growing applications of ncRNA therapeutics, focusing on clinical trials and future prospects for PC. The results of the trials in PC have been so far contradictory and plagued with issues related to toxicity and suboptimal delivery. However, substantial scientific advances reaffirm the potential of ncRNA therapeutics for the treatment of a multitude of diseases, including PC. The fact that one ncRNA molecule controls numerous different genes in an amplifying effect reinforces the therapeutic value of these agents.Third-generation chemical modification of ncRNA “vaccines” has achieved a level of sophistication that ensures acceptable tolerability and pharmacokinetic profiles. New delivery systems, including conjugates with nanopolymers and/or specific antibodies, highlight the promise of precise targeting. To date, most of the clinical trials have used anti-miRNA ASO (antagomiRs) and siRNA, which leaves the field wide open for development and experimentation with other ncRNA therapeutics in the future. Ample opportunities to explore ncRNA species exist that have not been used in the clinic, such as miRNA sponges  ,70 or miIn summary, the field of ncRNA therapeutics is reaching maturity and offers tremendous hope to deliver a revolutionary change in the treatment of carcinoma and many other maladies.