Expanding Clinical Spectrum of Female X-linked Lymphoproliferative Syndrome 2Shruthi Suryaprakash, MD1, Mohammad El-Baba2, MD, Kelly J. Walkovich, MD3, Süreyya Savaşan, MD41Children’s Hospital of Michigan2Division of Gastroenterology, Children’s Hospital of Michigan3Division of Hematology/Oncology, Immuno-Hematology Comprehensive Program, C.S. Mott Children’s Hospital, University of Michigan4Division of Hematology/Oncology and Blood and Marrow Transplant Program, Children’s Hospital of Michigan, Carman and Ann Adams Department of Pediatrics, Barbara Ann Karmanos Cancer Center, Central Michigan University College of MedicineCorrespondence: Süreyya Savaşan, MD3901 Beaubien Blvd.Division of Hematology/OncologyBlood and Marrow Transplant ProgramChildren’s Hospital of MichiganDetroit, Michigan 48201E-mail: firstname.lastname@example.orgPhone: 313-745-5516 Fax: 313-745-5237Text word count: 495Reference count: 4Tables and figures: 1Short running title: Spectrum of Symptomatic Female XLP2Key words: Female XLP2, EBV reactivation, Vitamin B12 deficiency, B-cell lymphopenia, clonal T-LGL proliferationDear Editor:X-linked lymphoproliferative syndrome type 2 (XLP2) due to pathogenic variants in the X-linked inhibitor of apoptosis (XIAP) gene is a rare cause of primary immunodeficiency. Symptomatic patients, primarily males, present with hemophagocytic lymphohistiocytosis (HLH), inflammatory bowel disease (IBD) and/or transient hypogammaglobinaemia.1 However, XLP2 in female patients is complicated with the rarity of symptomatic cases and clinical heterogeneity.2 We report a female affected by XLP2 with previously unreported findings.A currently 18-year-old female presented with fever, abdominal pain, diffuse lymphadenopathy, splenomegaly, and pancytopenia three years ago. She was diagnosed with HLH, treated with steroids and found to have low B-cells and borderline hypogammaglobinemia. Additionally, a single pathogenic variant in XIAP (c.389_392delACAG [p.Asp130Glyfs*11]) was identified. Further workup showed presence of EBV IgG, and normal expression of XIAP protein in only 8-19% of various white blood cell types by flow cytometry indicating skewed X chromosome inactivation. She had intermittent infections, one resulting in an additional HLH flare with elevated IL-18 and CXCL9 levels that was treated with steroids and intravenous immunoglobulin (IVIG). Repeated EBV PCR testing had been negative.However, she was found to have EBV reactivation with positive EBV VCA-IgM, high titer VCA-IgG and EA-IgG levels while EBV-PCR was negative when she presented to our clinic with diarrhea. There was ongoing history of headaches, abdominal pain, joint pain, and ADHD at that time. Later, she underwent work up for recurrent abdominal pain, diarrhea, urgency and elevated fecal calprotectin. MRI-enterography and capsule endoscopy were negative. Endoscopy was remarkable for chronic active proctitis. She was prescribed mesalamine with significant improvement in abdominal pain and resolution of mucuosy stools.Due to persistent knee/ankle pain, she was investigated for peripheral neuropathy and was found to have low vitamin B12 levels (112-145pg/mL; N:180-914) without dietary restrictions, absent anti-intrinsic factor antibodies and negative family history. Her pain improved significantly on vitamin B12 injections and gabapentin with normalization of vitamin B12 levels.She continued to have fluctuating and borderline low levels of serum immunoglobulins with persistently low B-cells. She was given IVIG supplementation when serum IgG levels were low. No additional HLH flares have occurred. Mild increase in CD5-dim T-cells (9%) representing T-large granular lymphocytes (T-LGL) and clonal T-cell receptor (TCR) rearrangement pattern were identified in peripheral blood. She continues to have migraine episodes and very high EA-IgG at >150U/mL (N <9).Female carriers are at risk for extra hematopoietic manifestations, if they have an extremely skewed X chromosome inactivation.3 She was EBV-PCR negative, but EBV VCA-IgM positive repeatedly suggesting a recent reactivation at presentation to our institution. Persistent high EBV EA-IgG titers is suggestive of ongoing EBV challenge due to immune deficiency and emphasizes the significance of EBV serology testing. Clonal T-LGL expansion may be related to EBV and/or immune deficiency.4 Low vitamin B12 raises the possibility of impairment in absorption; the presence of proctitis raises possible subclinical inflammation in the distal ileum. Observed conditions in this case add to the spectrum of this rare entity (Table1).
The Coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is overwhelming healthcare resources and infrastructure worldwide. Cardiac surgical operating capacity during the COVID-19 pandemic is dramatically lower due to postponement or cancellation of elective or semi-urgent procedures. Earlier reports have demonstrated complicated post-operative courses and high fatality rates in patients undergoing emergent cardiothoracic surgery who were diagnosed post-operatively with COVID-19. These reports raise the possibility that active COVID-19 might precipitate a catastrophic pathophysiogical response to infection in the post-operative period and lead to unfavorable surgical outcomes. Hence, it is imperative to screen patients with SARS-CoV-2 infection prior to surgery and to carefully monitor them in the post-operative period to identify any early signs of active COVID-19. In this report, we present the successful outcome of coronary artery bypass grafting (CABG) operation in a patient with asymptomatic SARS-CoV-2 infection presenting with an acute coronary syndrome and requiring urgent surgical intervention. We employed a meticulous strategy to identify subclinical COVID-19 disease, and after confirming the absence of active disease, proceeded with the CABG operation. The patient outcome was successful with the absence of any overt COVID-19 manifestations in the post-operative period.
This is a response to the Letter to Editor received regarding the article “The effect of patient obesity on extracorporeal membrane oxygenator outcomes and ventilator dependency.” We aim to address the authors’ comments regarding the relationship between BMI and survival after venoarterial extracorporeal membrane oxygenation (VA-ECMO).
The authors share their experience of managing the cardiac surgery services across London during the challenging Covid-19 pandemic. The Pan London Emergency Cardiac Surgery Service model could serve as a blueprint to design policies applicable to other surgical specialities and parts of the UK and worldwide.
COVID-19 PANDEMIC: A CHALLENGE TO A CHILD WITH CANCER Dear Editor,People of all ages can be infected by the new coronavirus (2019-nCoV). Older people, and people with pre-existing medical conditions (such as asthma, diabetes, heart disease) are more vulnerable to becoming severely ill with the virus. There is a widespread anxiety among families of children with cancer due to risk of exposure to SARS-CoV-2, either in the hospital or community setting. Recently Ogimi et al  reported that infants and younger children (i.e., ≤5 years) are more likely to develop severe clinical manifestations than older children, maybe due to immaturity of the immune system. Sullivan et al  reported that the COVID-19 pandemic was one of the most serious global challenge to delivering affordable and equitable treatment to children with cancer. They have provided some practical advice for adapting diagnostic and treatment protocols for children with cancer during the pandemic, the measures to be taken to contain it (e.g. extreme social distancing) and how to prepare for the anticipated recovery period.The Government and administrative measures such as lockdown has further compounded these challenges. Lack of state transport, closure of district borders, non-availability of medications has put these children at risk of rapid growth of disease, delay in treatment and poor outcome. A four and half year-old child, a known case of synchronous bilateral Wilms tumour, having undergone bilateral nephron sparing surgery was on adjuvant chemotherapy. The COVID-19 pandemic brought about an interruption in his chemotherapy schedule in January 2020. When he presented in early May, he had a small swelling of 1.5 cm diameter below the left subcostal margin (Figure 1a). Ultra sonography revealed a hypoechoic lesion below the skin measuring 1.5 cm in diameter (Figure 1b). Fine needle aspiration cytology was done which revealed sheets of cells with high nuclear/cytoplasm ratio (Figure 1c). The features were highly suspicious of a malignant lesion. The lesion was excised and histo-pathological examination revealed a metastasis from WILMS tumour (Figure 1d). The child has been resumed on further chemotherapy.Most childhood cancers behave aggressively and need immediate treatment, often requiring prolonged periods of intensive multiagent chemotherapy. Postponement of treatment such as surgery, radiation and chemotherapy is not a safe option in children. There is an urgent need amongst health professionals and families for informed guidance on the range of reasonable and safe adaptations to their services and cancer treatment during the pandemic.Conflict of Interest: None.Compliance with Ethical Standards.
Large osteochondroma arising from chest wall and sternum is uncommon and presentation with airway compression is further uncommon. Here we present a case of large chest wall osteochondroma as a part of Hereditary multiple exostoses in a 9 years old boy presented with a history of stridor and shortness of breath. The bony mass of the right chest wall was extending up to a suprasternal notch and compressing the trachea. The case was successfully managed by initial femoro-femoral cardiopulmonary bypass under local anesthesia prior to the induction of anesthesia to prevent respiratory collapse, followed by debulking surgery was done.
In December 2019, China reported the first cases of the coronavirus disease 2019 (COVID-19). This disease, caused by the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), has developed into a pandemic. To date it has resulted in ~5.6 million confirmed cases and caused 353,334 related deaths worldwide. Unequivocally, the COVID-19 pandemic is the gravest health and socio-economic crisis of our time. In this context, numerous questions have emerged in demand of basic scientific information and evidence-based medical advice on SARS-CoV-2 and COVID-19. Although the majority of the patients show a very mild, self-limiting viral respiratory disease, many clinical manifestations in severe patients are unique to COVID-19, such as severe lymphopenia and eosinopenia, extensive pneumonia, a “cytokine storm” leading to acute respiratory distress syndrome, endothelitis, thrombo-embolic complications and multiorgan failure. The epidemiologic features of COVID-19 are distinctive and have changed throughout the pandemic. Vaccine and drug development studies and clinical trials are rapidly growing at an unprecedented speed. However, basic and clinical research on COVID-19-related topics should be based on more coordinated high-quality studies. This paper answers pressing questions, formulated by young clinicians and scientists, on SARS-CoV-2, COVID-19 and allergy, focusing on the following topics: virology, immunology, diagnosis, management of patients with allergic disease and asthma, treatment, clinical trials, drug discovery, vaccine development and epidemiology. Over 140 questions were answered by experts in the field providing a comprehensive and practical overview of COVID-19 and allergic disease.
Adolescent and young adult (AYA) patients need additional support while they experience the challenges associated with their age. They need specific training to learn the knowledge and skills required to confidently self-manage their allergies and/or asthma. Transitional care is a complex process which should address the psychological, medical, educational and vocational needs of AYA in the developmentally appropriate way. The European Academy of Allergy and Clinical Immunology has developed a clinical practice guideline to provide evidence-based recommendations for healthcare professionals to support the transitional care of AYA with allergy and/or asthma. This guideline was developed by a multi-disciplinary working panel of experts and patient representatives based on two recent systematic reviews. It sets out a series of general recommendations on operating a clinical service for AYA, which include: (i) starting transition early (11-13 years), (ii) using a structured, multidisciplinary approach, (iii) ensuring AYA fully understand their condition and have resources they can access, (iv) active monitoring of adherence and (v) discussing any implications for further education and work. Specific allergy and asthma transition recommendations include (i) simplifying medication regimes and using reminders; (ii) focusing on areas where AYA are not confident and involving peers in training AYA patients; (iii) identifying and managing psychological and socioeconomic issues impacting disease control and quality of life; (iv) enrolling the family in assisting AYA to undertake self-management and (v) encouraging AYA to let their friends know about their allergies and asthma. These recommendations may need to be adapted to fit into national healthcare systems.
Metabolic pathways have emerged as cornerstones in carcinogenic deregulation providing new therapeutic strategies for cancer management. This is illustrated by the recent discovery of a cholesterol metabolic branch involving the biochemical transformation of 5,6-epoxycholesterol (5,6-ECs). 5,6-ECs have been shown to be differentially metabolized in breast cancers (BC) compared to normal breast tissue. 5,6-ECs are metabolized into the tumour promoter oncosterone in BC, while they are transformed into the tumour suppressor metabolite dendrogenin A (DDA) in normal breast tissue. Blocking oncosterone’s mitogenic and invasive potential will represent new opportunities for BC treatment. The reactivation of DDA biosynthesis, or its use as a drug, represents promising therapeutic approaches such as DDA-deficiency complementation, activation of BC cell re-differentiation and BC chemoprevention. This review presents current knowledge as to the 5,6-EC metabolic pathway in BC focusing on the 5,6-EC metabolic enzymes ChEH and HSD11B2, and on 5,6-EC metabolite targets LXRβ and GR.
B-LINES IN COVID-19: “UNSPECIFICITY” IS NOT “MEANINGLESS”Luigi Vetrugno1,2 MD, Prof, Tiziana Bove1,2 MD, Prof, Daniele Orso1 MD, Federico Barbariol2 MD, Flavio Bassi2 MD, Enrico Boero3 MD, Giovanni Ferrari4 MD, Robert Kong5MD, FRCA, EDIC,1Department of Medicine, University of Udine, ItalyAnesthesia and Intensive Care ClinicVia Colugna n° 50, 33100 Udine, Italy2University-Hospital of Udine, ItalyDepartment of Anesthesia and Intensive CareP.le S. Maria della. Misericordia n° 15, 33100 Udine, Italy3Anesthesia and Intensive Care, San Giovanni Bosco Hospital, Torino, Italy4SC Pneumologia ad Indirizzo Semi Intensivo, Azienda Ospedaliera Ordine Mauriziano. Largo Turati 62 – Torino, Italy5 Cardiac Anaesthesia & Intensive Care, Brighton & Sussex University Hospital, Brighton BN2 5BE United KingdomShort title: lung ultrasound and B-lines*Corresponding author:Prof. Luigi Vetrugno, MDDepartment of Medicine, University of Udine, ItalyAnesthesia and Intensive Care ClinicVia Colugna n° 50, 33100 Udine, ItalyPhone: +39 0432 559509Fax: +39 0432 559502Financial Support and Sponsorship: None.Conflict of Interest: Luigi Vetrugno received travel support for Congress Lecture by Cook Medical.The other authors declare no conflict of interest.Key works: Lung Ultrasound; interstitial syndrome, COVID-19, B-lines.Authors’ contributions LV and DO concept, design and drafting the manuscript. TB, FB, EB, FB, GF critical revision of the manuscript for important intellectual content. RK critical review and editing the manuscript. All authors read and approved the final manuscript.We thank Prof. Trovato and Dr Sperandeo for commenting on our article.1 We agree with them that lung ultrasound (LU) imaging is useful and our aim was to provide readers with a succinct overview of how LU was used in the care of COVID-19 patients at two centres in Italy.2 The frequent finding in COVID-19 patients of lung consolidation at the inferior and basal regions means that one of the limitations of LU, which is to perform a complete assessment of the periphery of the lungs, is mitigated, as affected regions are not obscured by the scapula. Other authors have shown that in COVID-19 patients, LU provided results similar to those of computed tomography (CT) of the lung and superior to those of standard chest x-rays.3-5 Therefore, LU provides clinicians with another mode of lung imaging that can be performed non-invasively and without the logistic challenges of obtaining CT lung scan in these patients, as is well-known to centers who have been faced with a large caseload.6 As stated in our article, we have not identified an LU finding that is pathognomonic of COVID-19.1-7 However, the presence of B lines in several different clinical situations does not decrease their significance. In medicine, many signs are frequent in various diseases, like fever, but this is not a good reason to underestimate or not consider them at all. Furthermore, emerging ultrasound image analysis based on artificial intelligence and deep learning has the potential to further enhance the utility of LU.8-9 Although caution is needed in terms of exaggerating the power of LU, we hope it will continue to be used widely after the pandemic.ReferencesSperandeo M, Trovato G. Usefulness of lung ultrasound imaging in Covid-19 pneumonia: the persisting need of safety and evidences. Echocardiography. in press (ECHO-2020-0386)Vetrugno L, Bove T, Orso D, et al. Our Italian experience using lung ultrasound for identification, grading and serial follow-up of severity of lung involvement for management of patients with COVID-19. Echocardiography. 2020;37:625‐627. doi:10.1111/echo.14664Huang Y, Wang S, Liu Y. A Preliminary Study on the Ultrasonic Manifestations of Peripulmonary Lesions of Non-Critical Novel Coronavirus Pneumonia (COVID-19). SSRN. 2020. doi: 10.21203/rs.2.24369/v1Jin YH, Cai L, Cheng ZS, et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Mil Med Res. 2020;7:4. doi: 10.1186/s40779-020-0233-6Convissar D, Gibson LE, Berra L, Bittner EA, Chang MG. Application of Lung Ultrasound during the COVID-19 Pandemic: A Narrative Review [published online ahead of print, 2020 Apr 30]. Anesth Analg. 2020;10.1213/ANE.0000000000004929. doi:10.1213/ANE.0000000000004929Wang E, Mei W, Shang Y, et al. Chinese Association of Anesthesiologists Expert Consensus on the Use of Perioperative Ultrasound in Coronavirus Disease 2019 Patients [published online ahead of print, 2020 Apr 10]. J Cardiothorac Vasc Anesth. 2020;S1053-0770(20)30325-6. doi:10.1053/j.jvca.2020.04.002Vetrugno L, Bove T, Orso D, Bassi F, Boero E, Ferrari G. Lung Ultrasound and the COVID-19 ”Pattern”: Not All That Glitters Today Is Gold Tomorrow [published online ahead of print, 2020 May 8]. J Ultrasound Med. 2020;10.1002/jum.15327. doi:10.1002/jum.15327Corradi F, Brusasco C, Vezzani A, et al. Computer-aided quantitative ultrasonography for detection of pulmonary edema in mechanically ventilated cardiac surgery patients. Chest 150:640‐651, 2016 doi:10.1016/j.chest.2016.04.013Gullett J, Donnelly JP, Sinert R, et al. Interobserver agreement in the evaluation of B-lines using bedside ultrasound. J Crit Care. 2015;30:1395-1399 doi:10.1016/j.jcrc.2015.08.021
Since the beginning of the 21st century, three coronaviruses have crossed the species barrier and caused serious human disease: severe acute respiratory syndrome coronavirus (SARS-CoV) in November 2002 [1, 2], Middle-East respiratory syndrome coronavirus (MERS-CoV) in 2012 [3, 4], and SARS-CoV-2 in 2019 [5, 6]. SARS-CoV-2 , initially called 2019-nCoV, is the etiological agent of COVID-19, a highly contagious infectious illness that was first reported in December 2019 in Wuhan, China and subsequently spread globally . As of May 24, 2020, COVID-19 has caused >5,370,000 infections and >343,000 deaths worldwide .Unfortunately, nearly 20 years after the SARS outbreak, and despite many attempts for vaccines and therapeutic agents directed against SARS and MERS, no approved prophylactics or therapeutics exist. As a result, the management of COVID-19 largely relies on supportive care [10, 11] and on hopes surrounding compounds that appeared promising against previous coronaviruses [12, 13]. This lost opportunity, in itself, offers a valuable lesson for current and future outbreaks, and the need for new experimental rationales to accelerate discovery.The cellular entry of coronaviruses is fairly conserved across members of the Coronaviridae family and is mediated by the transmembrane spike (S) glycoprotein , a homotrimer [15, 16] that is often heavily glycosylated  and protrudes from the viral surface. Each of the three monomers of the spike glycoprotein consists of two functional subunits, S1, involved in membrane attachment, and S2, required for membrane fusion [15, 18]. In many coronaviruses, the spike glycoprotein is cleaved at the S1/S2 interface by host cell proteases . Within the S1 domain, the receptor binding domain (RBD) attaches to the cellular receptor, which in the case of both SARS-CoV and SARS-CoV-2 is the angiotensin-converting enzyme 2 (ACE2) [19-21]. Another cleavage site, S2’, is located within S2 [17, 19]. The spike glycoproteins of SARS-CoV and SARS-CoV-2 share 76% identity at the amino acid level [22, 23], although biophysical assays indicate that SARS-CoV-2 binds their common receptor, ACE2, with a 10-20 fold higher affinity than SARS–CoV .As we contemplate the dynamics of COVID-19 and the development of prophylactic and therapeutic interventions, one of the key considerations is the emergence and potential relevance of viral mutations. In the short time since the pandemic started, several missense mutations have been observed in various SARS-CoV-2 isolates . One of these, the 23403A>G variant, substitutes the aspartic acid at position 614 of the viral spike glycoprotein with glycine (D614G), and is frequently documented in European countries but rarely observed in China .In the current issue of the IJCP , Becerra-Flores and Cardozo interrogate the impact of this mutation on pathogenicity and offer a structural correlate for their findings . Their analysis includes confirmed COVID-19 cases and deaths as reported by the European CDC during the first week of April 2020 and examines the viral spike genomic sequences deposited in the GISAID database over that period, correlating the prevalence of the D614G mutation with fatality rates in the same regions. The authors then use cryo-electron microscopy data andin silico mutagenesis of this key residue to predict conformational preferences of the two variants of the spike protein.The analysis indicates that viruses isolated from European patients predominantly expressed a glycine at position 614 of the spike glycoprotein, while a high percentage of the isolates collected from Far East patients favored aspartic acid at the same position. The proportion of viral isolates having a glycine at this position significantly correlated with higher average and median case fatality rates across geographic areas. Interestingly, their data also imply a rationale for divergence in the behavior of the disease between the East and West coasts of the United States, based upon the provenance of the viral ‘founders’ in these regions, from the European and Asian variants, respectively.Surprisingly, the authors’ molecular modeling indicates that the presence of a glycine at position 614 diminishes binding to the cellular receptor when replacing the aspartic acid at that residue, mainly by reducing the spike protein’s occupancy of the “up” or liganded state, when it is most amenable to receptor interaction. While seemingly counterintuitive, this finding opens at least two fascinating scenarios. As the authors hypothesize, a spike glycoprotein that harbors glycine at this position might be better protected from immune recognition, elicit the production of harmful antibodies, flood the host with ineffective antibodies, or some combination of all three. A delay in immune recognition may impact viral transmission by delaying symptomatic presentation or allowing unfettered infection without effective immune response. An aberrant response, suited to the viral conformation at large but not the infective conformation, could equally allow for an increased—but poorly targeted—inflammatory cascade. The possibility of a harmful immune response is particularly thought provoking, as antibody-dependent enhancement, the phenomenon by which antibodies facilitate viral entry into host cells that do not necessarily have viral receptors [27, 28], has been reported for many viruses, including coronaviruses [27, 29], dengue virus [30, 31], feline infectious peritonitis virus  , Ebola virus , and HIV . Another possibility, not mutually exclusive, is that the D614G mutation creates or exposes a novel cleavage site in the spike glycoprotein.Delving into these molecular mechanisms with confirmatory in vitro studies will hopefully reap the benefits of decades of scientific strides while simultaneously highlighting deficiencies in key areas that can guide our approach to the current pandemic. One of the immediate questions involves the impact of this and other mutations on vaccine efficiency and the potential need to develop multiple candidate vaccines that cover a range of epitopes and their variants. In all likelihood, there is a lengthy and tortuous road ahead, but characterizing significant variants will allow us to better understand many elusive aspects of this virus’ success – the latent/incubation period, immune evasion and hyper-response, variable receptor binding, replication dynamics, and organ-specific pathogenesis—and discover host vulnerabilities that mutations such as D614G seem to exploit.The D614G mutation appears to become more common as the pandemic unfolds . That this phenomenon is simply the result of a founder effect is possible but unlikely, and rather may be explained by this variant’s selective advantage allowing more efficient spread. Whether this advantage is conferred by infectivity, immune evasion, or pathogenicity—or some combination of these—is yet to be understood. Interestingly, this mutation is now known to travel simultaneously with other mutations, including one that affects the RNA-dependent RNA polymerase, with implications for proofreading, replication efficiency (and thus viral titer), and the emergence of drug-resistant viral phenotypes .Addressing these molecular questions relies heavily on widespread efforts to assemble accurate and comprehensive data on population infection rates and mortality, and frequent sampling of the genotypes of circulating isolates on a global basis. So far, this feat has been challenging and continued deficiencies will translate into missed singular opportunities to link molecular findings with population-level consequences, ultimately leaving us less prepared to address both this and future pandemics.The valuable and timely experimental strategy used by Becerra-Flores and Cardozo serves as an important analytic model that should be employed routinely to understand the ‘molecular strategy’ of this virus in the context of the evolving pandemic. This approach will also prove to be an indispensable instrument if also employed routinely at the onset of future outbreaks, which are all but guaranteed in the coming years, given the only recently appreciated ease of global spread of viruses in the modern world. In summary, this set of tools allows us to perform active surveillance, monitor the emergence of deleterious mutations prior to their widespread distribution, and use informed in silico and structural data to make informed decisions guiding molecular research and epidemic preparedness.
Many Western countries have been affected by the outbreak of COVID-19. Italy has been particularly hit at the beginning of the pandemic, immediately after China. In Italy and elsewhere women seem to be less affected then men by severe/fatal COVID-19 infection, regardless of their age. Despite the evidence that women and men are different fort this infection, very few studies consider different therapeutic approaches for the two sexes. Undoubtedly, understanding the mechanisms at the bases of these differences may help to find appropriate and sex specific therapies. Here we consider that other mechanisms but estrogen protection are involved. Several X-linked genes (such as ACE2) and Y-linked genes (SRY, SOX9) may explain sex differences. Cardiovascular comorbidities are among the major enhancers of virus lethality. In addition, the number of sex-independent non-genetic factors that can change susceptibility and mortality is enormous, and many other factors are likely to be considered, including gender and cultural habits in different countries.
Abstract Rationale: Our current global healthcare system is not sustainable. It is structured based on the principles of reductionist science which was discovered and developed over the past 400 – 600 years. Because of increasing pace of change and increasing complexity in our world we have increased fragmentation in our healthcare system leading to more harm and waste. Over 100 years ago, the principles of systems, or complexity, science were discovered, first in the discipline of physics. These principles accommodate the constant change and biologic variability in our world. While reductionist principles would be applicable in a static, mechanical world where parts of the system could be isolated, this does not exist in the real biologic world. Method: For the past decade, our abdominal wall hernia team has been applying the principles of systems science to real patient care. Some of the tools we have applied include continuous quality improvement for whole hernia patient processes and non-linear analytical tools to gain insight to improve value-based outcomes. Until we learn to apply and scale these principles across our whole global healthcare system, we will continue to suffer the consequences of our current unsustainable system. Results: We have learned that the application of systems and complexity science to real patient care can lead to lower costs and better outcomes in the context of patients with complex hernia problems. However, these concepts have not yet been adopted in our global healthcare system. Conclusion: Applying the principles of systems and complexity science to our global healthcare system has the potential to lower costs and improve patient outcomes for any patient care process to which it is applied.