Ventral hernia repair in India: a Delphi consensus.

PURPOSE: While research on inguinal hernias is well-documented, ventral/incisional hernias still require investigation. In India, opinions on laparoscopic ventral hernia repair (LVHR) techniques are contested. The current consensus aims to standardize LVHR practice and identify gaps and unfulfilled demands that compromise patient safety and therapeutic outcomes. METHODS: Using the modified Delphi technique, panel of 14 experts (general surgeons) came to a consensus. Two rounds of consensus were conducted online. An advisory board meeting was held for the third round, wherein survey results were discussed and the final statements were decided with supporting clinical evidence. RESULTS: Experts recommended intraperitoneal onlay mesh (IPOM) plus/trans-abdominal retromuscular/extended totally extraperitoneal/mini- or less-open sublay operation/transabdominal preperitoneal/trans-abdominal partial extra-peritoneal/subcutaneous onlay laparoscopic approach/laparoscopic intracorporeal rectus aponeuroplasty as valid minimal access surgery (MAS) options for ventral hernia (VH). Intraperitoneal repair technique is the preferred MAS procedure for primary umbilical hernia < 4 cm without diastasis; incisional hernia in the presence of a vertical single midline incision; symptomatic hernia, BMI > 40 kg/m2, and defect up to 4 cm; and for MAS VH surgery with grade 3/4 American Society of Anaesthesiologists. IPOM plus is the preferred MAS procedure for midline incisional hernia of width < 4 cm in patients with a previous laparotomy. Extraperitoneal repair technique is the preferred MAS procedure for L3 hernia < 4 cm; midline hernias < 4 cm with diastasis; and M5 hernia. CONCLUSION: The consensus statements will help standardize LVHR practices, improve decision-making, and provide guidance on MAS in VHR in the Indian scenario.

Peritoneal flap technique for abdominal wall expansion in the management of complex ventral hernias: a multicentre study from India.

INTRODUCTION: Large abdominal wall hernias often require techniques for wall expansion to improve surgical outcomes. The peritoneal flap hernioplasty (PF) is one such technique that utilizes the hernia sac to reconstruct the abdominal wall, however, with limited published data. It is a modification of the Rives-Stoppa mesh repair where a part of the bisected hernia sac is utilized to reconstruct the anterior fascia and the other part for the posterior fascia. We present a collated retrospective analysis of the outcomes from three centers performing PF with or without transverse abdominis release (TAR) in patients with complex ventral hernias. METHODS: The PF was performed in patients with incisional hernias, both midline and lateral. The primary outcome measured was hernia recurrence. The secondary outcomes were to evaluate pain, surgical site infection, seroma, hematoma, wound dehiscence, pseudo-recurrence, Clavien-Dindo score for complications, and the patient's reported quality of life. The quality of life was assessed by oral questionnaires in the follow-up period. RESULTS: We analyzed 63 patients (38 female, 25 male) with a mean width of hernia defect of 11 cm SD 4. Based on the European Hernia Society (EHS) classification 42 patients were W3 and 21 were W2 hernias. Fifty patients had a midline hernia, while the rest of the patients included transverse, subcostal, and rooftop incision hernias. The classical peritoneal flap procedure was done in 29 (46%) patients, while the peritoneal flap with TAR was done in 34 (54%) patients. Four patients had symptomatic seroma (6%), seven superficial surgical site infection (SSI) (11%), one deep SSI (1.5%), one skin necrosis (1.5%), and one anterior peritoneal flap necrosis (1.5%). No patient required postoperative ventilatory support. The mean pain score on day one was 3/10. There was no recurrence in the mean follow-up of 17 months (range 5 to 49 months). Overall, 58 of 63 (92%) patients reported being satisfied with their surgery. CONCLUSION: In our multicentre study, we found the PF technique with or without TAR for midline and non-midline ventral hernia leads to satisfactory outcomes in terms of low recurrence, low rate of complications, and a good quality of life in the medium to long term. It appears to be a useful technique in the surgeon's armamentarium to repair W2 and W3 hernias needing expansion of abdominal domain.

Delphi consensus statement for understanding and managing the subcostal hernia: subcostal hernias collaborative report (scholar study).

INTRODUCTION: Subcostal hernias are categorized as L1 based on the European Hernia Society (EHS) classification and frequently involve M1, M2, and L2 sites. These are common after hepatopancreatic and biliary surgeries. The literature on subcostal hernias mostly comprises of retrospective reviews of small heterogenous cohorts, unsurprisingly leading to no consensus or guidelines. Given the limited literature and lack of consensus or guidelines for dealing with these hernias, we planned for a Delphi consensus to aid in decision making to repair subcostal hernias. METHODS: We adopted a modified Delphi technique to establish consensus regarding the definition, characteristics, and surgical aspects of managing subcostal hernias (SCH). It was a four-phase Delphi study reflecting the widely accepted model, consisting of: 1. Creating a query. 2. Building an expert panel. 3. Executing the Delphi rounds. 4. Analysing, presenting, and reporting the Delphi results. More than 70% of agreement was defined as a consensus statement. RESULTS: The 22 experts who agreed to participate in this Delphi process for Subcostal Hernias (SCH) comprised 7 UK surgeons, 6 mainland European surgeons, 4 Indians, 3 from the USA, and 2 from Southeast Asia. This Delphi study on subcostal hernias achieved consensus on the following areas-use of mesh in elective cases; the retromuscular position with strong discouragement for onlay mesh; use of macroporous medium-weight polypropylene mesh; use of the subcostal incision over midline incision if there is no previous midline incision; TAR over ACST; defect closure where MAS is used; transverse suturing over vertical suturing for closure of circular defects; and use of peritoneal flap when necessary. CONCLUSION: This Delphi consensus defines subcostal hernias and gives insight into the consensus for incision, dissection plane, mesh placement, mesh type, and mesh fixation for these hernias.

An international survey of 1014 hernia surgeons: outcome of GLACIER (global practice of inguinal hernia repair) study.

INTRODUCTION: The practice of inguinal hernia repair varies internationally. The global practice of inguinal hernia repair study (GLACIER) aimed to capture these variations in open, laparoscopic, and robotic inguinal hernia repair. METHODS: A questionnaire-based survey was created on a web-based platform, and the link was shared on various social media platforms, personal e-mail network of authors, and e-mails to members of the endorsed organisations, which include British Hernia Society (BHS), The Upper Gastrointestinal Surgical Society (TUGSS), and Abdominal Core Health Quality Collaborative (ACHQC). RESULTS: A total of 1014 surgeons from 81 countries completed the survey. Open and laparoscopic approaches were preferred by 43% and 47% of participants, respectively. Transabdominal pre-peritoneal repair (TAPP) was the favoured minimally invasive approach. Bilateral and recurrent hernia following previous open repair were the most common indications for a minimally invasive procedure. Ninety-eight percent of the surgeons preferred repair with a mesh, and synthetic monofilament lightweight mesh with large pores was the most common choice. Lichtenstein repair was the most favoured open mesh repair technique (90%), while Shouldice repair was the favoured non-mesh repair technique. The risk of chronic groin pain was quoted as 5% after open repair and 1% after minimally invasive repair. Only 10% of surgeons preferred to perform an open repair using local anaesthesia. CONCLUSION: This survey identified similarities and variations in practice internationally and some discrepancies in inguinal hernia repair compared to best practice guidelines, such as low rates of repair using local anaesthesia and the use of lightweight mesh for minimally invasive repair. It also identifies several key areas for future research, such as incidence, risk factors, and management of chronic groin pain after hernia surgery and the clinical and cost-effectiveness of robotic hernia surgery.

Characterisation of patients referred to a tertiary-level inherited cardiac condition clinic with suspected arrhythmogenic right ventricular cardiomyopathy (ARVC).

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) or arrhythmogenic cardiomyopathy is a rare inherited disease with incomplete penetrance and an environmental component. Although a rare disease, ARVC is a common cause of sudden cardiac death in young adults. Data on the different stages of ARVC remains scarce. The purpose of this study is to describe the initial presentation and cardiac phenotype of definite and non-definite ARVC for patients seen at a tertiary service. METHODS: This is a single centre, observational cohort study of patients with definite and non-definite ARVC seen at the Inherited Cardiac Conditions services at University Hospital Birmingham (UHB) in the period 2010-2021. Patients were identified by interrogation of digital health records, medical history, imaging and by examining 12-lead electrocardiograms (ECG). RESULT: The records of 1451 patients were reviewed; of those, 165 patients were at risk of ARVC (mean age 41 ± 17 years, 56% male). 60 patients fulfilled task force criteria for definite ARVC diagnosis (n = 40, 67% males), and 38 (72%) of them carried a known pathogenic variant. The remaining 105 patients (50% males) were non-definite, and of these 45 (62%) carried a known pathogenic variant. Patients in the definite group were more symptomatic, with palpitations (57% vs. 17%), syncope (35% vs. 6%) and shortness of breath (28% vs. 5%, p < 0.001). T-wave inversion in V1-V3 and epsilon waves were observed only in the definite group. Both PR interval and QRS duration were longer in the definite (170 ± 34 ms and 100 ± 19 ms, p < 0.001) compared to (149 ± 25 and 91 ± 14 ms, p = 0.005). Patients with definite ARVC had significantly larger RV end diastolic areas and significantly reduced biventricular function (RVEDA = 27 ± 10 cm2, RVFAC = 37 ± 11% and EF = 56 ± 12%) compared to the non-definite group (RVEDA = 18 ± 4 cm2, RVFAC 49 ± 6% and LVEF 64 ± 7%, p < 0.001). Sustained ventricular tachycardia (VT) occurred more frequently in the definite group compared to the non-definite group (27% vs. 2%, p < 0.001). Ventricular fibrillation was observed in the definite group only (8 of 60 patients, 13%). CONCLUSION: Our study showed differences between definite and non-definite ARVC patients in terms of clinical, electrophysiological and imaging features. Major adverse cardiac events occurred more commonly in the definite group, but also were observed in non-definite ARVC. This single centre observational cohort study forms a basis for further prospective multicentre interventional studies.

Community- vs. hospital-based management of multidrug-resistant TB in Pakistan.

BACKGROUND Multidrug-resistant TB (MDR-TB) treatment takes 18-24 months and is complex, costly and isolating. We provide trial evidence on the WHO Pakistan recommendation for community-based care rather than hospital-based care.METHODS Two-arm, parallel-group, superiority trial was conducted in three programmatic management of drug-resistant TB hospitals in Punjab and Sindh Provinces, Pakistan. We enrolled 425 patients with MDR-TB aged >15 years through block randomisation in community-based care (1-week hospitalisation) or hospital-based care (2 months hospitalisation). Primary outcome was treatment success.RESULTS Among 425 patients with MDR-TB, 217 were allocated to community-based care and 208 to hospital-based care. Baseline characteristics were similar between the community and hospitalised arms, as well as in selected sites. Treatment success was 74.2% (161/217) under community-based care and 67.8% (141/208) under hospital-based care, giving a covariate-adjusted risk difference (community vs. hospital model) of 0.06 (95% CI -0.02 to 0.15; P = 0.144).CONCLUSIONS We found no clear evidence that community-based care was more or less effective than hospital-based care model. Given the other substantial advantages of community-based care over hospital based (e.g., more patient-friendly and accessible, with lower treatment costs), this supports the adoption of the community-based care model, as recommended by the WHO.

Practice and short-term outcomes in ventral hernia repair: a prospective multicenter data audit of Indian Association of Gastrointestinal Endo Surgeons Research Collaborative.

INTRODUCTION: There is considerable variation in the practice of ventral hernia repair (VHR). Consequently, both short- and long-term outcomes are different. We report the first multicenter data from India on the variations in procedures and short-term outcomes after ventral hernia repair. METHODS: A prospective study was planned under the aegis of the Indian Association of Gastrointestinal Endo Surgeons (IAGES). Participating surgeons prospectively recorded the data of patients who underwent VHR from January 21, 2021, to April 20, 2021. Patients were followed for 3-6 months. RESULTS: Data from 648 patients were analyzed for demographics, hernia characteristics, technical variations, and outcomes. 375 (57.8%) were primary hernias (PH) and 273 (42.15%) were incisional hernias (IH), of which 63 (9.7%) were recurrent hernias. In the PH group, there were 171 minimal access (MAS) and 170 open repair. In descending order of frequency, there were 111 (32.6%) open onlay, 83 (24.3%) intraperitoneal onlay meshplasty (IPOM) Plus, 36 (10.6%) IPOM, 35 (10.3%) suture repair, 22 (6.5%) endoscopic Rives Stoppa (eRS), 11 (3.2%) open RS, 11 (3.2%) TAPP, 7 (2%) hybrid, 6 (1.8%) open preperitoneal, 19 (5.6%) others. There were 3.73% seroma, 3.2% SSI, 0% 90-day readmission, 0% recurrence, and 0.3% mortality. In the IH group, 164 patients underwent open repair and 104 MAS repair. In descending order of frequency, there were 90 (33.6%) open onlay, 47 (17.5%) IPOM Plus, 38 (14.1%) open sublay, 28 (10.4%) IPOM, 12 (4.5%) Transversus Abdominis Release (TAR), 11 (4.1%) suture repair, 9 (3.4%) open preperitoneal, 7 (2.6%) hybrid, 6 (2.2%) TAPP, 5 (1.9%) eRS, 4 (1.5%) TARM, 3 (1.1%) endoscopic TAR (eTAR), and 8 (3%) others. There were 13.92% seroma, 4.4% hematoma, 9.5% SSI, 1.1% mesh explantation, 0.4% wound sinus, 2.2% 90-day readmission, 0% recurrence, and 1.1% mortality. CONCLUSION: Onlay meshplasty is the commonest procedure in India both in PH and IH. IPOM/IPOM plus is the second commonest procedure. TAR is the preferred component separation technique. Complication rates were comparable to published literature. TRIAL REGISTRATION: The study was registered with Clinical Trial Registry of India. CTRI number-CTRI/2021/01/030435.

Management of ventral hernia in patients with BMI > 30 Kg/m2: outcomes based on an institutional algorithm.

INTRODUCTION: Management of ventral hernia in obese is a complex problem. The methods of weight loss, alternatives if the patient cannot undergo bariatric surgery, timing, and type of hernia surgery lacks clarity and are dependent on resources and expertise. There is a need for algorithms based on local population and expertise. In this paper, we present the outcomes of our institutional algorithm. METHODS: It was a retrospective analysis of prospectively collected data. Patients with body mass index (BMI) > 30Kg/m2 were included to undergo surgery as per algorithm taking into account (a) presentation (symptomatic vs asymptomatic), (b) hernia characteristics (defect width, site, reducibility), and (c) obesity characteristics (BMI, subcutaneous fat, android vs gynecoid). Data on age, BMI, comorbidities, tobacco consumption, hernia width, location, contents, previous surgery, intraoperative parameters (the type of surgery, mesh, drain, fixation), and outcomes (seroma, hematoma, infection, recurrence) were collected. RESULTS: A total of 50 patients underwent treatment as per the algorithm. Mean BMI was 36.6 ± 7.3 kg/m2. The mean follow-up was 17.6 ± 7.2 months. The mean defect width was 4.8 ± 2.9 cm. There were two (4%) recurrences in patients who underwent an anatomical repair under emergency conditions. None of the patients who underwent an elective repair had a recurrence. Total surgical site occurrence was 12% and surgical site occurrence requiring procedural intervention was 8%. There was one (2%) mortality on postoperative day 7 due to myocardial infarction. CONCLUSION: The algorithm has shown encouraging results in the short-to-medium term. Long-term evaluation with a higher number of patients is needed to confirm its usefulness.

A randomised clinical trial of methotrexate points to possible efficacy and adaptive immune dysfunction in psychosis.

NMDA autoantibody encephalitis presenting as schizophrenia suggests the possible role of adaptive cell-mediated immunity in idiopathic schizophrenia. However, to our knowledge there have been no trials of the immune-suppressant methotrexate in schizophrenia. We tested if low-dose methotrexate as used in the treatment of systemic autoimmune disorders would be tolerable and effective in people with schizophrenia in a feasibility study. Ninety-two participants within 5 years of schizophrenia diagnosis were recruited from inpatient and outpatient facilities in Karachi, Pakistan. They were randomised to receive once weekly 10-mg oral methotrexate (n = 45) or matching placebo (n = 47) both with daily 5-mg folic acid, in addition to treatment as usual for 12 weeks. There were eight dropouts per group. Side effects were non-significantly more common in those on methotrexate and were not severe. One person developed leukopenia. Positive symptom scores improved more in those receiving methotrexate than placebo (ß = -2.5; [95% CI -4.7 to -0.4]), whereas negative symptoms were unaffected by treatment (ß = -0.39; [95% CI -2.01 to 1.23]). There were no immune biomarkers but methotrexate did not affect group mean leucocyte counts or C-reactive protein. We conclude that further studies are feasible but should be focussed on subgroups identified by advances in neuroimmune profiling. Methotrexate is thought to work in autoimmune disorders by resetting systemic regulatory T-cell control of immune signalling; we show that a similar action in the CNS would account for otherwise puzzling features of the immuno-pathogenesis of schizophrenia.

OSSI (Obesity and Metabolic Surgery Society of India) Guidelines for Patient and Procedure Selection for Bariatric and Metabolic Surgery.

BACKGROUND: India is the largest hub for bariatric and metabolic surgery in Asia. OSSI is committed to improve the quality of care and set the standards for its practice in India. METHODS: The first draft of OSSI guidelines was prepared by the secretary, Dr. Praveen Raj under the guidance of current President, Dr. Arun Prasad. All executive council members were given voting privileges, and the proposed guidelines were circulated on email for approval of the executive council. Guidelines were finalized after 100% agreement from all voting members and were also circulated among all OSSI members for their suggestions. RESULTS: OSSI upholds the BMI criteria for bariatric and metabolic surgery of 2011 IFSO-APC guidelines. In addition to this, we recognize that waist circumference of ≥ 80 cm in females and ≥ 90 cm in males along with obesity related co-morbidities may be considered for surgery. In addition to standard procedures as recommended by IFSO, OSSI acknowledges the additional procedures, and a review of literature for these procedures is presented in the discussion. CONCLUSION: The burden of obesity in India is one of the highest in the world and with numbers of bariatric and metabolic procedures rising rapidly; there is a need for country specific guidelines. The Indian population is unique in its phenotype, genotype and nutritional make up. This document enlists guidelines for surgeons and allied health practitioners as also multiple other stake-holders like primary health physicians, policy makers, insurance companies and the Indian government.

Vitamin D and bisphosphonate therapy in systemic lupus erythematosus patients who receive glucocorticoids: are we offering the best care?

OBJECTIVE: This study aimed to evaluate management practices for glucocorticoid (GC)-induced osteoporosis (GIOP) in systemic lupus erythematosus (SLE) patients using 2017 American College of Rheumatology guidelines as a gold standard. METHODS: We conducted a retrospective cohort study using a clinical database from the years 2011 to 2016. SLE cases with >90 days continuous prednisone use at doses of ≥7.51 mg daily were identified. Osteoporosis risk factors were assessed via chart review. The Fracture Risk Assessment (FRAX) score was estimated for patients > 40 years of age. Vitamin D, bisphosphonate prescriptions, and osteoporotic (OP) fractures were ascertained through chart review. A classification tree was used to identify the key patient-related predictors of bisphosphonate prescription. RESULTS: A total of 203 SLE patients met the inclusion criteria. The recommended dose of vitamin D supplement was prescribed to 58.9% of patients < 40 years of age and 61.5% of patients ≥ 40 years of age. Among patients aged ≥ 40 years, 25% were prescribed bisphosphonates compared to 36% who met indications for bisphosphonates per the ACR guidelines. Another 10% were prescribed a bisphosphonate, despite not having indication per the ACR guidelines, which was considered as overtreatment. Among patients aged ≥ 40 years, older age and a higher FRAX score for major OP fracture and hip fracture predicted bisphosphonate prescription. In a classification tree analysis, patients with FRAX scores (for major OP fracture) of ≥ 23.5% predicted bisphosphonate prescription in this SLE population. Among patients who had OP fractures in the follow-up period, nine (6.50%) were inpatients receiving appropriate GIOP care versus 12 (13.6%) who were inpatients not receiving ACR-appropriate care (p = 0.098). CONCLUSIONS: In clinical practice, fewer SLE patients with or at risk for GIOP are prescribed vitamin D and bisphosphonates than recommended by the 2017 ACR guidelines. Also, in this study, another 10% were prescribed a bisphosphonate, despite not having an indication per the ACR guidelines. Patients were most likely to receive a bisphosphonate prescription if they had a major OP FRAX score of > 23.5%.

Diagnosis and treatment of the cardiovascular consequences of Fabry disease.

Fabry disease (FD) has been a diagnostic challenge since it was first recognized in 1898, with patients traditionally suffering from considerable delay before a diagnosis is made. Cardiac involvement is the current leading cause of death in FD. A combination of improved enzyme assays, availability of genetic profiling, together with more organized clinical services for rare diseases, has led to a rapid growth in the prevalence of FD. The earlier and more frequent diagnosis of asymptomatic individuals before development of the phenotype has focussed attention on early detection of organ involvement and closer monitoring of disease progression. The high cost of enzyme replacement therapy at a time of constraint within many health economies, moreover, has challenged clinicians to target treatment effectively. This article provides an outline of FD for the general physician and summarizes the aetiology and pathology of FD, the cardiovascular consequences thereof, modalities used in diagnosis and then discusses current indications for treatment, including pharmacotherapy and device implantation.

Homozygosity for a missense variant in COMP gene associated with severe pseudoachondroplasia.

The phenotypic spectrum associated with heterozygous mutations in cartilage oligomeric matrix protein gene (COMP) range from a mild form of multiple epiphyseal dysplasia (MED) to pseudoachondroplasia (PSACH). However, the phenotypic effect from biallelic COMP variants is unclear. We investigated a large consanguineous Pakistani family with a severe form of PSACH in 2 individuals. Another 14 family members presented with a mild PSACH phenotype similar to MED. Using exome sequencing and subsequent segregation analysis, we identified homozygosity for a COMP missense variant [c.1423G>A; p.(D475N)] in the 2 severely affected individuals, whereas family members with the mild PSACH phenotype were heterozygous. Our observations show for the first time that a biallelic COMP variant may be associated with pronounced and widespread skeletal malformations suggesting an additive effect of the 2 mutated alleles.

Genetic heterogeneity in Pakistani microcephaly families revisited.

Autosomal recessive primary microcephaly (MCPH) is a rare and heterogeneous genetic disorder characterized by reduced head circumference, low cognitive prowess and, in general, architecturally normal brains. As many as 14 different loci have already been mapped. We recruited 35 MCPH families in Pakistan and could identify the genetic cause of the disease in 31 of them. Using homozygosity mapping complemented with whole-exome, gene panel or Sanger sequencing, we identified 12 novel mutations in 3 known MCPH-associated genes - 9 in ASPM, 2 in MCPH1 and 1 in CDK5RAP2. The 2 MCPH1 mutations were homozygous microdeletions of 164,250 and 577,594 bp, respectively, for which we were able to map the exact breakpoints. We also identified four known mutations - three in ASPM and one in WDR62. The latter was initially deemed to be a missense mutation but we demonstrate here that it affects splicing. As to ASPM, as many as 17 out of 27 MCPH5 families that we ascertained in our sample were found to carry the previously reported founder mutation p.Trp1326*. This study adds to the mutational spectra of four known MCPH-associated genes and updates our knowledge about the genetic heterogeneity of MCPH in the Pakistani population considering its ethnic diversity.

Potential of apoptotic pathway-targeted cancer therapeutic research: Where do we stand?

Underneath the intricacy of every cancer lies mysterious events that impel the tumour cell and its posterity into abnormal growth and tissue invasion. Oncogenic mutations disturb the regulatory circuits responsible for the governance of versatile cellular functions, permitting tumour cells to endure deregulated proliferation, resist to proapoptotic insults, invade and erode normal tissues and above all escape apoptosis. This disruption of apoptosis has been highly implicated in various malignancies and has been exploited as an anticancer strategy. Owing to the fact that apoptosis causes minimal inflammation and damage to the tissue, apoptotic cell death-based therapy has been the centre of attraction for the development of anticancer drugs. Increased understanding of the molecular pathways underlying apoptosis has enabled scientists to establish unique approaches targeting apoptosis pathways in cancer therapeutics. In this review, we reconnoitre the two major pathways (intrinsic and extrinsic) targeted cancer therapeutics, steering toward chief modulators of these pathways, such as B-cell lymphoma 2 protein family members (pro- and antiapoptotic), inhibitor of apoptosis proteins, and the foremost thespian of extrinsic pathway regulator, tumour necrosis factor-related apoptosis-inducing agent. Together, we also will have a look from clinical perspective to address the agents (drugs) and therapeutic strategies adopted to target these specific proteins/pathways that have entered clinical trials.