Five historical innovations that have shaped modern urological surgery.

Throughout history, many innovations have contributed to the development of modern urological surgery, improving patient outcomes and expanding the range of treatment options available to patients. This article explores five key historical innovations that have shaped modern urological surgery: External shockwave lithotripsy, transurethral resection of prostate, cystoscope, perioperative prostate-specific antigen and robotic surgery. The selection of innovations for inclusion in this article was meticulously determined through expert consensus and an extensive literature review. We will review the development, impact and significance of each innovation, highlighting their contributions to the field of urological surgery and their ongoing relevance in contemporary and perioperative practice.

Five historical innovations that have shaped modern cardiothoracic surgery.

Throughout history, many innovations have contributed to the development of modern cardiothoracic surgery, improving patient outcomes and expanding the range of treatment options available to patients. This article explores five key historical innovations that have shaped modern cardiothoracic surgery: cardiopulmonary bypass, surgical pacemakers, video assisted thoracic surgery, robotic surgery and mechanical circulatory support. We will review the development, impact and significance of each innovation, highlighting their contributions to the field of cardiothoracic surgery and their ongoing relevance in contemporary and perioperative practice.

Understanding and leveraging phenotypic plasticity during metastasis formation.

Cancer metastasis is the process of detrimental systemic spread and the primary cause of cancer-related fatalities. Successful metastasis formation requires tumor cells to be proliferative and invasive; however, cells cannot be effective at both tasks simultaneously. Tumor cells compensate for this trade-off by changing their phenotype during metastasis formation through phenotypic plasticity. Given the changing selection pressures and competitive interactions that tumor cells face, it is poorly understood how plasticity shapes the process of metastasis formation. Here, we develop an ecology-inspired mathematical model with phenotypic plasticity and resource competition between phenotypes to address this knowledge gap. We find that phenotypically plastic tumor cell populations attain a stable phenotype equilibrium that maintains tumor cell heterogeneity. Considering treatment types inspired by chemo- and immunotherapy, we highlight that plasticity can protect tumors against interventions. Turning this strength into a weakness, we corroborate current clinical practices to use plasticity as a target for adjuvant therapy. We present a parsimonious view of tumor plasticity-driven metastasis that is quantitative and experimentally testable, and thus potentially improving the mechanistic understanding of metastasis at the cell population level, and its treatment consequences.

Phenotypic Correction of Murine Mucopolysaccharidosis Type II by Engraftment of Ex Vivo Lentiviral Vector-Transduced Hematopoietic Stem and Progenitor Cells.

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is an X-linked recessive lysosomal disease caused by deficiency of iduronate-2-sulfatase (IDS). The absence of IDS results in the accumulation of the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate. Currently, the only approved treatment option for MPS II is enzyme replacement therapy (ERT), Elaprase. However, ERT is demanding for the patient and does not ameliorate neurological manifestations of the disease. Using an IDS-deficient mouse model that phenocopies the human disease, we evaluated hematopoietic stem and progenitor cells (HSPCs) transduced with a lentiviral vector (LVV) carrying a codon-optimized human IDS coding sequence regulated by a ubiquitous MNDU3 promoter (MNDU3-IDS). Mice treated with MNDU3-IDS LVV-transduced cells showed supraphysiological levels of IDS enzyme activity in plasma, peripheral blood mononuclear cells, and in most analyzed tissues. These enzyme levels were sufficient to normalize GAG storage in analyzed tissues. Importantly, IDS levels in the brains of MNDU3-IDS-engrafted animals were restored to 10-20% than that of wild-type mice, sufficient to normalize GAG content and prevent emergence of cognitive deficit as evaluated by neurobehavioral testing. These results demonstrate the potential effectiveness of ex vivo MNDU3-IDS LVV-transduced HSPCs for treatment of MPS II.

A larger sized cup accelerates cartilage erosion of acetabulum after bipolar hemiarthroplasty in elderly with femur neck fracture.

ABSTRACT: Bipolar hemiarthroplasty (BHA) is one of the common procedures done for the treatment of femur neck fracture. One of the frequently encountered complication with this surgery is erosion of the acetabular cartilage. This study was conducted to investigate acetabular erosion after BHA according to the difference in diameter between femoral head and implanted cup at minimum 10-year follow-up.We retrospectively reviewed 117 patients (117 hips) undergoing BHA with fracture of neck of the femur. Their mean age was 77.8 years (range, 65-96 years) and male: female ratio was 32:85. Patients were divided into 3 groups; Group A - bipolar cup size > actual head size, Group B - cup size < head size, Group C - cup size = head size. The degree of both superior and medial acetabular cartilage erosion was identified and calculated on postoperative radiographs using line of acetabular margin and Kohler line.The mean superior and medial acetabular erosion were 1.62 ±â€Š1.6 mm (range, 0-4.4) and 4.15 ±â€Š2.7 mm (range, 0-8.2) in Group A, 1.30 ±â€Š1.3 mm (range, 0-3.8) and 4.11 ±â€Š2.7 mm (range, 0-7.8) in Group B, and 0.90 ±â€Š1.1 mm (range, 0-2.6) and 3.16 ±â€Š2.9 mm (range, 0-7.9) in Group C (P = .039 and P = .187, respectively). The superior acetabular erosion showed significant difference between the 3 groups. During mean follow-up period of 12.3 years, 5 patients (5/117, 4.3%) underwent conversion to total hip arthroplasty due to superior acetabular erosion. All of 3 patient underwent BHA with a larger bipolar cup than the actual femoral head.A lager sized cup accelerated superior cartilage erosion of acetabulum after BHA. An optimal cup size should be considered when undergoing BHA in elderly patients.

Safe Elective Surgical Practice During COVID-19 Pandemic - A Prospective Observational Study of 303 Elective Surgeries in the UK.

Aim During the COVID-19 pandemic, there has been worldwide cancellation of elective surgeries to protect patients from nosocomial viral transmission and peri-operative complications. With the unfolding situation, there is a definite need for an exit strategy to reinstate elective services. Therefore, more literature evidence supporting exit plans for elective surgical services is imperative to adopt a safe working principle. This study aims to provide evidence for safe elective surgical practice during the pandemic. Methodology This single centre, prospective, observational study included adult patients who were admitted and underwent elective surgical procedures in the trust's COVID-free environment at the Birmingham Treatment Centre between May 19 and July 14, 2020. Data were collected on demographic parameters, peri-operative variables, surgical specialities, COVID-19 reverse transcription polymerase chain reaction (RT-PCR) testing results, post-operative complications and mortality. The study also highlighted the protocols it followed for the elective services during the pandemic. Results A total of 303 patients were included with mean age of 49.9 years (SD 16.5) comprising of 59% (178) female and 41% (125) male. They were classified according to the American Society of Anaesthesiologist Grade, different surgical specialities and types of anaesthesia used. Ninety-six percent (96%) of patients were discharged on the same day. Hundred percent (100%) compliance with pre-operative COVID-19 RT-PCR testing was maintained. There was no 30-day mortality or major respiratory complications. Conclusion Careful patient selection, simultaneous involvement of the pre-assessment and anaesthetic team, strict adherence to peri-operative protocols and delivering vigilant post-operative care for COVID-19 infection can help provide safe elective surgical services if the community transmission is under reasonable control. However, it is particularly important to maintain COVID-free safe environment for such procedures.

Correlation of endoscopic findings with Doppler ultrasound in portal hypertension in children.

AIM OF THE STUDY: To determine the correlation of the endoscopic findings with portal Doppler and ultrasound (USG) in children with suspected portal hypertension (PHT). MATERIAL AND METHODS: Eighty children with extrahepatic portal vein obstruction (EHPVO) and chronic liver disease (CLD) were included in this retrospective study conducted over a period of 1 year. All patients underwent upper gastrointestinal (GI) endoscopy and Doppler. RESULTS: The etiology was EHPVO in 30 (37.5%) patients, biliary atresia in 12 (15%), Budd-Chiari syndrome in 11 (13.7%), Wilson's disease in 10 (12.5%), idiopathic CLD in 8 (10%), autoimmune hepatitis in 4 (5%), glycogen storage disease (GSD) in 3 (3.8%), non-alcoholic liver disease (NAFLD) in 1 (1.3%) and systemic lupus erythematosus (SLE) in 1 (1.3%) patient. Fifty-three (66.25%) patients had esophageal varices on endoscopy, of whom 3 (3.8%) had associated gastric varices. Portal hypertensive gastropathy (PHG) was present in 30 (37.5%) patients, of whom 10 (12.5%) had severe PHG. Forty-one (51.3%) patients had PHT on Doppler (κ correlation 0.43). Kappa correlation was 0.43 in patients with biliary atresia, 0.31 in Budd-Chiari syndrome, 0.23 in idiopathic CLD, 0.21 in CLD, and 0.05 in Wilson's disease. All (100%) EHPVO patients and 39 (78%) CLD patients had PHT on USG. Endoscopic findings of PHT were seen in 24 (80%) EHPVO patients and 29 (58%) CLD patients. All patients with EHPVO had cavernous transformation of the portal vein on Doppler. For patients with CLD, the common Doppler findings were collaterals seen in 35 patients and reversal of flow in 12 patients. CONCLUSIONS: Doppler ultrasound followed by endoscopy should be used to diagnose PHT in children. In children with biliary atresia, Doppler ultrasound may miss changes of PHT.

The impact of phenotypic heterogeneity of tumour cells on treatment and relapse dynamics.

Intratumour heterogeneity is increasingly recognized as a frequent problem for cancer treatment as it allows for the evolution of resistance against treatment. While cancer genotyping becomes more and more established and allows to determine the genetic heterogeneity, less is known about the phenotypic heterogeneity among cancer cells. We investigate how phenotypic differences can impact the efficiency of therapy options that select on this diversity, compared to therapy options that are independent of the phenotype. We employ the ecological concept of trait distributions and characterize the cancer cell population as a collection of subpopulations that differ in their growth rate. We show in a deterministic model that growth rate-dependent treatment types alter the trait distribution of the cell population, resulting in a delayed relapse compared to a growth rate-independent treatment. Whether the cancer cell population goes extinct or relapse occurs is determined by stochastic dynamics, which we investigate using a stochastic model. Again, we find that relapse is delayed for the growth rate-dependent treatment type, albeit an increased relapse probability, suggesting that slowly growing subpopulations are shielded from extinction. Sequential application of growth rate-dependent and growth rate-independent treatment types can largely increase treatment efficiency and delay relapse. Interestingly, even longer intervals between decisions to change the treatment type may achieve close-to-optimal efficiencies and relapse times. Monitoring patients at regular check-ups may thus provide the temporally resolved guidance to tailor treatments to the changing cancer cell trait distribution and allow clinicians to cope with this dynamic heterogeneity.

Hepatic Portal Venous Gas: An Ill Omen or a Misleading Sign.

Hepatic portal venous gas (HPVG), a rare radiological finding, is historically considered an ominous sign with 100% mortality rates. The dictum that HPVG warrants surgical intervention is challenged in the recent literature. This is because of the identification of various causes of HVPG other than bowel gangrene. Most of these newly identified causes can be managed conservatively. However, bowel gangrene, if missed, is fatal. Hence, sound clinical judgment and accurate diagnosis based on specific clinical parameters and imaging findings are important. We present a case of a young male with tumor lysis syndrome and neutropenic sepsis. He underwent treatment for a relapse of T-cell acute lymphocytic leukemia and presented with abdominal pain and distension. Computed tomography (CT) scan showed HPVG, and the differential diagnosis was neutropenic colitis or pseudomembranous colitis, with steroid use as the probable cause. The patient was managed conservatively. The case emphasizes that the evaluation for a specific cause of HPVG is important to reduce unnecessary surgery. A succinct literature review provides the reasons for the changing mortality rates.

The diagnosis and management of temporal arteritis.

Temporal arteritis (TA), or giant cell arteritis, is a systemic autoimmune vasculitis affecting patients over 50 years of age. It can cause rapid, irreversible bilateral vision loss in older adults and is therefore considered an ophthalmological emergency. Many of the symptoms and signs of TA can be vague, non-specific and gradual in onset, often leading to a delayed or inaccurate diagnosis. As such, it is important for a wide variety of primary optometrists and health practitioners to maintain a robust understanding of the clinical presentation, key investigations and time-sensitive management of this disease, as early initiation of treatment for TA can be vision- and life-saving.

Prognostic potential of markers of bone turnover in delayed-healing tibial diaphyseal fractures.

INTRODUCTION: Clinical and radiographic examinations detect delayed or nonunion only after the event has occurred. Biochemical markers of bone turnover (BTMs) are promising laboratory tools that offer an early insight into the likelihood of delayed union. We hypothesized that BTMs display temporal variations following fractures and the behavior of BTMs differ between normal and delayed union of fractures. METHODS: This was a prospective study of patients with closed fracture of tibia treated with intramedullary, interlocking nailing. BTM assays (NTX, BSAP, P1NP and osteocalcin) and clinical and radiographic assessments were obtained preoperatively and postoperatively at 8,12, 24, 36 and 72 weeks. Temporal trend of elevation of serum levels of BTMs post-fracture was the primary assessment criterion and radiographic and clinical assessment of fracture union were the secondary assessment criteria. RESULTS: The average time for fracture union was 15.24 weeks (range 15-19 weeks). The values of both bone formation and resorption markers peaked at the eighth week following the fracture. Resorption markers returned to baseline by 36 weeks. Among the formation markers, BSAP levels showed the smallest increase and returned to baseline earlier (36 weeks) than P1NP and osteocalcin (72 weeks). P1NP showed the most dramatic change, increasing to 2.5 times the mean baseline level at 8 weeks in normal union of fractures. The levels of bone formation markers (BSAP, OC, PINP) were significantly lower in patients with delayed union. There was no significant difference in the levels of the resorption marker (NTX) between normal and delayed union patients. CONCLUSION: Serial monitoring of biochemical markers of bone turnover can be used as an adjunct to clinical and radiological observations to predict delayed union LEVEL OF EVIDENCE: Level 2 (prospective observational study).

Postmortem ICD interrogation in mode of death classification.

BACKGROUND: The definition of sudden death due to arrhythmia relies on the time interval between onset of symptoms and death. However, not all sudden deaths are due to arrhythmia. In patients with an implantable cardioverter defibrillator (ICD), postmortem device interrogation may help better distinguish the mode of death compared to a time-based definition alone. OBJECTIVE: This study aims to assess the proportion of "sudden" cardiac deaths in patients with an ICD that have confirmed arrhythmia. METHODS: We conducted a literature search for studies using postmortem ICD interrogation and a time-based classification of the mode of death. A modified QUADAS-2 checklist was used to assess risk of bias in individual studies. Outcome data were pooled where sufficient data were available. RESULTS: Our search identified 22 studies undertaken between 1982 and 2015 with 23,600 participants. The pooled results (excluding studies with high risk of bias) suggest that ventricular arrhythmias are present at the time of death in 76% of "sudden" deaths (95% confidence interval [CI] 67-85; range 42-88). CONCLUSION: Postmortem ICD interrogation identifies 24% of "sudden" deaths to be nonarrhythmic. Postmortem device interrogation should be considered in all cases of unexplained sudden cardiac death.

Neuroradiological Endovascular Intervention for Diplopia in a Case of Aneurysmal Aberrant Regeneration of the Third Nerve.

Aberrant regeneration of the third nerve occurs as a result of synkinetic 'miswiring' of the third nerve following its injury, such as in third cranial nerve palsy due to tumor, trauma, or aneurysm. The case presented is an elderly woman with new vertical diplopia, which led to a diagnosis of a third cranial nerve palsy, thought to be caused by a 5 mm blister aneurysm of the posterior communicating artery. However, neuro-ophthalmological evaluation diagnosed aberrant regeneration of the third nerve, with the cause of her new vertical diplopia being an ipsilateral fourth nerve palsy. The patient underwent endovascular treatment of her aneurysm using stent-assisted coiling. This procedure was complicated by an episode of air embolism, from which the patient made a good recovery. This patient's presentation demonstrates that the cause of any diplopia must be established, and presents a novel, semi-schematic illustration of aberrant regeneration of the third nerve that should aid clinicians in its recognition.

Kinase Activities of RIPK1 and RIPK3 Can Direct IFN-ß Synthesis Induced by Lipopolysaccharide.

The innate immune response is a central element of the initial defense against bacterial and viral pathogens. Macrophages are key innate immune cells that upon encountering pathogen-associated molecular patterns respond by producing cytokines, including IFN-ß. In this study, we identify a novel role for RIPK1 and RIPK3, a pair of homologous serine/threonine kinases previously implicated in the regulation of necroptosis and pathologic tissue injury, in directing IFN-ß production in macrophages. Using genetic and pharmacologic tools, we show that catalytic activity of RIPK1 directs IFN-ß synthesis induced by LPS in mice. Additionally, we report that RIPK1 kinase-dependent IFN-ß production may be elicited in an analogous fashion using LPS in bone marrow-derived macrophages upon inhibition of caspases. Notably, this regulation requires kinase activities of both RIPK1 and RIPK3, but not the necroptosis effector protein, MLKL. Mechanistically, we provide evidence that necrosome-like RIPK1 and RIPK3 aggregates facilitate canonical TRIF-dependent IFN-ß production downstream of the LPS receptor TLR4. Intriguingly, we also show that RIPK1 and RIPK3 kinase-dependent synthesis of IFN-ß is markedly induced by avirulent strains of Gram-negative bacteria, Yersinia and Klebsiella, and less so by their wild-type counterparts. Overall, these observations identify unexpected roles for RIPK1 and RIPK3 kinases in the production of IFN-ß during the host inflammatory responses to bacterial infection and suggest that the axis in which these kinases operate may represent a target for bacterial virulence factors.

RIPK1 and RIPK3 Kinases Promote Cell-Death-Independent Inflammation by Toll-like Receptor 4.

Macrophages are a crucial component of the innate immune system in sensing pathogens and promoting local and systemic inflammation. RIPK1 and RIPK3 are homologous kinases, previously linked to activation of necroptotic death. In this study, we have described roles for these kinases as master regulators of pro-inflammatory gene expression induced by lipopolysaccharide, independent of their well-documented cell death functions. In primary macrophages, this regulation was elicited in the absence of caspase-8 activity, required the adaptor molecule TRIF, and proceeded in a cell autonomous manner. RIPK1 and RIPK3 kinases promoted sustained activation of Erk, cFos, and NF-κB, which were required for inflammatory changes. Utilizing genetic and pharmacologic tools, we showed that RIPK1 and RIPK3 account for acute inflammatory responses induced by lipopolysaccharide in vivo; notably, this regulation did not require exogenous manipulation of caspases. These findings identified a new pharmacologically accessible pathway that may be relevant to inflammatory pathologies.

Utilisation of a Novel Test to Measure Severity and Treatment Efficacy of Posterior Blepharitis.

Background. This study evaluated the effectiveness of managing posterior blepharitis (PB) using a novel Posterior Blepharitis Management Protocol (PBMP). Design. Prospective, consecutive case series with 100% followup to one month. Participants. 27 patients (54 eyes) with PB from an Ophthalmology practice in Sydney, Australia. Methods. Each patient's PB was assessed by grading the nature and expressibility of the central lower lid tarsal gland secretions on Compression Of The Eyelid (COTE). Patients were then instructed in detail to undertake daily PB management sessions at home using our modified PBMP. Main Outcome Measures. On a subjective scale, patients compared their symptoms at one month with baseline. COTE scores were reevaluated to assess the objective effectiveness of each individual's PBMP. COTE scoring was described as grades 1 (clear oil), 2 (pus, liquid), 3 (toothpaste-like secretions), and 4 (complete tarsal gland obstruction). Results. Patients reported a mean 77.8% ± 13.5% subjective improvement in symptoms. There was a trend towards improvement in COTE grading at one month compared with baseline: grades 1 (0 to 7.4%), 2a (22.2 to 16.6%), 2b (7.4 to 3.7%), 3 (18.5 to 27.7%), and 4 (51.8 to 44%). Conclusions. PBMP provided a rapid, inexpensive, simple, effective, and safe method of treating PB.

Structure guided design of potent and selective ponatinib-based hybrid inhibitors for RIPK1.

RIPK1 and RIPK3, two closely related RIPK family members, have emerged as important regulators of pathologic cell death and inflammation. In the current work, we report that the Bcr-Abl inhibitor and anti-leukemia agent ponatinib is also a first-in-class dual inhibitor of RIPK1 and RIPK3. Ponatinib potently inhibited multiple paradigms of RIPK1- and RIPK3-dependent cell death and inflammatory tumor necrosis factor alpha (TNF-α) gene transcription. We further describe design strategies that utilize the ponatinib scaffold to develop two classes of inhibitors (CS and PN series), each with greatly improved selectivity for RIPK1. In particular, we detail the development of PN10, a highly potent and selective "hybrid" RIPK1 inhibitor, capturing the best properties of two different allosteric RIPK1 inhibitors, ponatinib and necrostatin-1. Finally, we show that RIPK1 inhibitors from both classes are powerful blockers of TNF-induced injury in vivo. Altogether, these findings outline promising candidate molecules and design approaches for targeting RIPK1- and RIPK3-driven inflammatory pathologies.

Is SIRT2 required for necroptosis?

Sirtuins can promote deacetylation of a wide range of substrates in diverse cellular compartments and regulate many cellular processes¹,². Recently Narayan et al., reported that SIRT2 was required for necroptosis based on their findings that SIRT2 inhibition, knock-down or knock-out prevented necroptosis. We sought to confirm and explore the role of SIRT2 in necroptosis and tested four different sources of the SIRT2 inhibitor AGK2, three independent siRNAs against SIRT2, and cells from two independently generated Sirt2−/− mouse strains, however we were unable to show that inhibiting or depleting SIRT2 protected cells from necroptosis. Furthermore, Sirt2−/− mice succumbed to TNF induced Systemic Inflammatory Response Syndrome (SIRS) more rapidly than wild type mice while Ripk3−/− mice were resistant. Our results therefore question the importance of SIRT2 in the necroptosis cell death pathway.