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Aging is a complex biological process with multifactorial nature underlined by genetic, environmental, and social factors. In the present paper, we review several mechanisms of aging and the pre-clinically and clinically studied anti-aging therapies. Variability characterizes biological processes from the genome to cellular organelles, biochemical processes, and whole organs’ function. Aging is associated with alterations in the degrees of variability and complexity of systems. The constrained disorder principle defines living organisms based on their inherent disorder within arbitrary boundaries and defines aging as having a lower variability or moving outside the boundaries of variability. We focus on associations between variability and hallmarks of aging and discuss the roles of disorder and variability of systems in the pathogenesis of aging. The paper presents the concept of implementing the constrained disease principle-based second-generation artificial intelligence systems for improving anti-aging modalities. The platform uses constrained noise to enhance systems’ efficiency and slow the aging process. Described is the potential use of second-generation artificial intelligence systems in patients with chronic disease and its implications for the aged population.

Viral-mediated liver injury can result from infections with the classic hepatotropic viruses, hepatitis A through E, or by other viruses. In the present chapter, we review the immune-based pathogenesis and liver-related manifestations of hepatitis A virus as well as several additional viruses that affect the liver including Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV), varicella-zoster virus (VZV), human herpesviruses (HHV 6, 7, and 8), human parvovirus B19, adenoviruses, and influenza virus. The clinical presentations range from mild and transient elevation of aminotransferases to severe chronic liver disease and liver failure. These viruses should be considered as possible etiologic agents in patients who manifest liver injury and whose serologic markers for the classic hepatotropic viruses are negative.

Henny Azmanov,* Areej Bayatra,* Yaron Ilan Hebrew University, Faculty of Medicine, Hadassah Medical Center, Jerusalem, Israel*These authors contributed equally to this workCorrespondence: Yaron Ilan, Department of Medicine, Hebrew University, Faculty of Medicine, Hadassah Medical Center, Ein-Kerem, POB 1200, Jerusalem, IL91120, Israel, Tel +972-2-6778511, Email ilan@hadassah.org.ilAbstract: Opioids remain an essential part of the treatment of chronic pain. However, their use and increasing rates of misuse are associated with high morbidity and mortality. The development of tolerance to opioids and analgesics further complicates dosing and the need to reduce side effects. First-generation digital systems were developed to improve analgesics but are not always capable of making clinically relevant associations and do not necessarily lead to better clinical efficacy. A lack of improved clinical outcomes makes these systems less applicable for adoption by clinicians and patients. There is a need to enhance the therapeutic regimens of opioids. In the present paper, we present the use of a digital analgesic that consists of an analgesic administered under the control of a second-generation artificial intelligence system. Second-generation systems focus on improved patient outcomes measured based on clinical response and reduced side effects in a single subject. The algorithm regulates the administration of analgesics in a personalized manner. The digital analgesic provides advantages for both users and providers. The system enables dose optimization, improving effectiveness, and minimizing side effects while increasing adherence to beneficial therapeutic regimens. The algorithm improves the clinicians’ experience and assists them in managing chronic pain. The system reduces the financial burden on healthcare providers by lowering opioid-related morbidity and provides a market disruptor for pharma companies.Keywords: digital health, algorithm, opioids, tolerance, analgesics

Background and Objective: OPRX-106 is an orally administered BY2 plant cell-expressing recombinant TNF fusion protein (TNFR). Oral administration of OPRX-106 was shown to be safe and effective in inducing favorable anti-inflammatory immune modulation in humans. The current study was aimed at determining the safety and efficacy of OPRX-106 in patients with ulcerative colitis (UC). Methods: Twenty-five patients with active mild-to-moderate UC were enrolled in an open-label trial. Patients were randomized to receive 2 or 8 mg of OPRX-106 administered orally once daily, for 8 weeks. Patients were monitored for safety and efficacy including clinical response or clinical remission, based on the Mayo score. The histopathological improvement in Geboes score, calprotectin level and hs-CRP, and exploratory immune parameters by means of fluorescence-activated cell sorting and cytokine levels were monitored. Results: Oral administration of OPRX-106 was found to be safe and well tolerated without absorption into the circulation. Out of 24 patients, 18 completed the trial. The analysis of the patients completing treatment demonstrated clinical efficacy as measured by clinical response or remission in 67% and 28%, respectively. Reduction in calprotectin levels and improved Geboes score were noted in the majority of the treated patients. The beneficial clinical effect was associated with an increase in a CD4+CD25+FoxP3 subset of suppressor lymphocytes and a reduction in interleukin 6 and interferon gamma serum levels. Conclusions: Oral administration of the nonabsorbable OPRX-106 is safe and effective in mild-to-moderate UC, and not associated with immune suppression, while inducing favorable anti-inflammatory immune modulation.

Irritable bowel syndrome (IBS) is a common functional disorder. The syndrome’s multifactorial pathophysiology makes it challenging to design effective therapies. The present paper reviews several therapeutic approaches to treating IBS, highlighting the challenges of losing response over time to therapies. Here, we present the relevance of chronobiology in biological systems focusing on the potential of chronotherapy for IBS. Artificial intelligence- (AI-) based approaches have been developed over the last few years to improve the diagnosis, therapeutic approaches, and monitoring of patients with various diseases. We discuss the use of first-generation AI platforms and their limitations in clinical practice and present the establishment of a second-generation system designed to overcome obstacles in managing these patients. The system identifies costly patients and those who do not respond to therapies and may benefit from algorithm-based therapies. We present a patient-tailored approach for improving the response to therapy in IBS using an AI-based algorithm. This system provides a tool for a patient-tailored monitoring system. The second-generation AI system can provide a comprehensive tool for improving the diagnosis and therapy and monitoring of patients with IBS.

Biological adjuvants that target the gut immune system are being developed for modulating the immune system. Hyperimmune bovine colostrum (HBC), produced by harvesting the bovine colostrum of dairy cows immunized to exogenous antigens, has been shown to modulate the immune responses and alleviate immune‐mediated organ damages. The aim of the present study was to determine the ability of HBC to promote antiviral interferonγ (IFNγ) T cell responses. In a preclinical study, mice were orally administered with HBC for 5 days and tested for the number of T cell clones secreting IFNγ in response to viral antigens of the swine flu, New Caledonia influenza, and cytomegalovirus. In a phase I/IIa clinical trial, five healthy volunteers were treated for 5 days with HBC followed by testing the anti‐coronavirus disease (COVID‐19) immunity. In the preclinical study, oral administration of HBC augmented the number of T cell clones secreting IFNγ in response to viral antigens. In the clinical trial, oral administration of HBC to healthy males significantly increased the number of anti‐COVID‐19 spike protein IFNγ positive T cell clones. Oral administration of HBC provides a novel method for augmenting antiviral responses. Its high‐safety profile makes it ideal for all disease stages and for pre‐emptive therapy among medical personnel and other workers who are at a high risk of exposure to infections. The relatively low cost of HBC is expected to minimize care provider burdens, costs, and enable its global application.

The microbiome is explored as a potential target for therapy of bowel and systemic diseases. Fecal microbiota transplantation (FMT) has demonstrated efficacy in Clostridium difficile infection. However, clinical results regarding other diseases are modest, despite the abundant research on the microbiome over the last decade. Both high rate variability of the microbiome and adaptation to gut manipulations may underlie the lack of ultimate effects of FMT, probiotics, prebiotics, synbiotics, and antibiotics, which are aimed at restoring a healthier microbiome. The present review discusses the inherent variability of the microbiome and multiple factors that affect its diversity, as possible causes of the adaptation of the gut microbiome to chronic manipulation. The potential use of randomness is proposed, as a means of overcoming the adaptation and of restoring some of the inherent variability, with the goal of improving the long-term efficacy of these therapies.

Yaron Ilan Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, IsraelAbstract: The microbiome is explored as a potential target for therapy of bowel and systemic diseases. Fecal microbiota transplantation (FMT) has demonstrated efficacy in Clostridium difficile infection. However, clinical results regarding other diseases are modest, despite the abundant research on the microbiome over the last decade. Both high rate variability of the microbiome and adaptation to gut manipulations may underlie the lack of ultimate effects of FMT, probiotics, prebiotics, synbiotics, and antibiotics, which are aimed at restoring a healthier microbiome. The present review discusses the inherent variability of the microbiome and multiple factors that affect its diversity, as possible causes of the adaptation of the gut microbiome to chronic manipulation. The potential use of randomness is proposed, as a means of overcoming the adaptation and of restoring some of the inherent variability, with the goal of improving the long-term efficacy of these therapies.Keywords: microbiome, randomness, gut, fecal transplantation

The term acute liver failure (ALF) is frequently applied as a generic expression to describe patients presenting with or developing an acute episode of liver dysfunction. In the context of hepatological practice, however, ALF refers to a highly specific and rare syndrome, characterised by an acute abnormality of liver blood tests in an individual without underlying chronic liver disease. The disease process is associated with development of a coagulopathy of liver aetiology, and clinically apparent altered level of consciousness due to hepatic encephalopathy. Several important measures are immediately necessary when the patient presents for medical attention. These, as well as additional clinical procedures will be the subject of these clinical practice guidelines.

Viruses other than the classic hepatotropic viruses, hepatitis A through E, may cause hepatic injury [1]. Among these are Epstein–Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV), varicella zoster virus (VZV), human herpes viruses (HHV) 6, 7, and 8, human parvovirus B19, and adenoviruses (Table 11.1). The clinical presentation of infections with these viruses may be indistinguishable from that associated with infection with classic hepatotropic viruses. The presentation ranges from mild and transient elevation of aminotransferases to acute hepatitis and can also lead to acute liver failure [1]. These viruses should be considered as possible etiologic agents in patients who have acute liver injury and whose serologic markers for the classic hepatotropic viruses are not indicative of an active infection [1]. In the present chapter, we review the clinical manifestations and the potential for immune-mediated liver injury associated with several of these viruses (see summary Table 11.2).

Summary Pneumonia complicates as many as 2.7 in every 1000 pregnancies putting both mother and fetus at increased risk. Parapneumonic pleural effusion is generally managed by thoracocentesis and, if “complicated”, by tube thoracostomy. If conservative management is unsuccessful, surgical decortication may be necessary. We report the case of a 24 year old gravida, who at 33 weeks of gestation presented to the emergency department with right sided pneumonia complicated by empyema. Blood and pleural fluid cultures were positive for Streptococcus pneumonia. Treatment with antibiotics, tube thoracsotomy and interpleural streptokinase led to resolution of the pneumonia and empyema without the need for surgical intervention. The patient carried her pregnancy to term and delivered a healthy baby after 39 weeks and 5 days of gestation. To our knowledge this is the first report of empyema treated with streptokinase in advanced pregnancy.