Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH.

BACKGROUND AND AIMS: Advanced fibrosis attributable to NASH is a leading cause of end-stage liver disease. APPROACH AND RESULTS: In this phase 2b trial, 392 patients with bridging fibrosis or compensated cirrhosis (F3-F4) were randomized to receive placebo, selonsertib 18 mg, cilofexor 30 mg, or firsocostat 20 mg, alone or in two-drug combinations, once-daily for 48 weeks. The primary endpoint was a ≥1-stage improvement in fibrosis without worsening of NASH between baseline and 48 weeks based on central pathologist review. Exploratory endpoints included changes in NAFLD Activity Score (NAS), liver histology assessed using a machine learning (ML) approach, liver biochemistry, and noninvasive markers. The majority had cirrhosis (56%) and NAS ≥5 (83%). The primary endpoint was achieved in 11% of placebo-treated patients versus cilofexor/firsocostat (21%; P = 0.17), cilofexor/selonsertib (19%; P = 0.26), firsocostat/selonsertib (15%; P = 0.62), firsocostat (12%; P = 0.94), and cilofexor (12%; P = 0.96). Changes in hepatic collagen by morphometry were not significant, but cilofexor/firsocostat led to a significant decrease in ML NASH CRN fibrosis score (P = 0.040) and a shift in biopsy area from F3-F4 to ≤F2 fibrosis patterns. Compared to placebo, significantly higher proportions of cilofexor/firsocostat patients had a ≥2-point NAS reduction; reductions in steatosis, lobular inflammation, and ballooning; and significant improvements in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, cytokeratin-18, insulin, estimated glomerular filtration rate, ELF score, and liver stiffness by transient elastography (all P ≤ 0.05). Pruritus occurred in 20%-29% of cilofexor versus 15% of placebo-treated patients. CONCLUSIONS: In patients with bridging fibrosis and cirrhosis, 48 weeks of cilofexor/firsocostat was well tolerated, led to improvements in NASH activity, and may have an antifibrotic effect. This combination offers potential for fibrosis regression with longer-term therapy in patients with advanced fibrosis attributable to NASH.

Clinical Features Associated With Need for Mechanical Ventilation in Children With Guillain-Barré Syndrome: Retrospective Cohort From India.

OBJECTIVES: To analyze the clinical features associated with the need for mechanical ventilation (MV) in children with Guillain-Barré syndrome (GBS). DESIGN: Retrospective cohort study, 2010-2019. SETTING: PICU. PATIENTS: All children, 1 month to 12 years old, diagnosed with GBS in our single-center PICU. INTERVENTION: Retrospective chart and data review. MEASUREMENTS AND MAIN RESULTS: Out of 189 children identified with a diagnosis of GBS, 130 were boys (69%). The median (interquartile range [IQR]) age was 6 years (3-9 yr). At admission, the Hughes disability score was 5 (4-5), and cranial nerve palsies were present in 81 children (42%). Autonomic instability subsequently occurred in a total of 97 children (51%). In the 159 children with nerve conduction studies, the axonal variant of GBS (102/159; 64%) predominated, followed by the demyelinating variant (38/189; 24%). All children received IV immunoglobulins as first-line therapy at the time of admission. The median (IQR) length of PICU stay was 12 days (3-30.5 d). Ninety-nine children (52%) underwent invasive MV, and median duration of MV was 25 days (19-37 d). At admission, upper limb power less than or equal to 3 (p = 0.037; odds ratio (OR), 3.5 [1.1-11.5]), lower limb power less than or equal to 2 (p = 0.008; OR, 3.5 [1.4-8.9]), and cranial nerve palsy (p = 0.001; OR, 3.2 [1.6-6.1]) were associated with subsequent need for MV. Prolonged (> 21 d) MV was associated with more severe examination findings at admission: upper limb power less than or equal to 2 (p < 0.0001; OR, 4.2 [2.5-6.9]) and lower limb power less than or equal to 1 (p < 0.0001; OR, 4.5 [2.6-7.9]). CONCLUSIONS: In children with GBS, referred to our center in North India, severe neuromuscular weakness at admission was associated with the need for MV. Furthermore, greater severity of this examination was associated with need for prolonged (> 21 d) MV. Identification of these signs may help in prioritizing critical care needs and early PICU transfer.

User experience study of an affordable manual standing wheelchair.

PURPOSE: The manual user-operated Arise Standing Wheelchair (SWC) is the end-result of multiple design iterations based on comments from user trials. The Arise SWC provides standing functionality, outdoor mobility, affordability, and customizability. This paper describes a user experience study of the Arise SWC's pre-commercial version. METHODS: Thirty participants (N = 30, 25 Male, 5 Female) were recruited for the study. All the participants were people with spinal cord injury. The study was conducted over a period of six weeks (five participants per week) within the hospital premises under the supervision of clinical personnel. A 30 min interactive training session involved thirteen activities. During the trial period, the participants were trained to perform twenty-two activities to familiarize themselves with the SWC. The participants were also trained to perform four functional usage activities with the SWC. At the end of the study, participant responses to ten outcome measures were captured using a smiley-based Likert-scale questionnaire. RESULTS: A majority of the participants (93.3%) felt happy when they stood in the SWC. The majority participants (83.3%) preferred the Arise SWC over their current wheelchair. Also, 80% participants anticipated that they could get more work done at home using the standing function of the wheelchair. CONCLUSIONS: A one-time fitting and training ensured optimal effort for the SWC operation, correct posture, and comfortable user experience. With proper dissemination and awareness, it is believed that the Arise SWC will benefit eligible users and improve their quality of life.IMPLICATIONS FOR REHABILITATIONThe Arise wheelchair provides standing functionality, outdoor mobility, affordability, and customizability.Study confirms that incorporating standing functionality can improve the quality of life for wheelchair users.The majority of users were happy, felt safe and expected to do more with the standing functionality.Study results support further testing in real world conditions beyond the hospital setting.

Utility of modified Mann assessment of swallowing ability (MMASA) in predicting aspiration risk and safe swallow in stroke patients.

Introduction: Aspiration pneumonia is one of the commonest causes of post-stroke mortality. We may be able to reduce this morbidity and mortality by assessing the risk of aspiration in stroke patients. Assessment of this risk can be done using a physician-administered screening protocol to assess dysphagia. A score of ≥95 is a good cut off to detect patients who can take oral feeds safely. Objectives: The primary objective was to predict aspiration risk using the Modified Mann Assessment Swallowing Ability (mMASA) scale. The secondary objective was to predict the safety of oral feeds using the same scale. Materials and Methods: An analytical cross-sectional study was conducted at a tertiary care rehabilitation centre in South India. A total of 100 stroke patients who underwent stroke rehabilitation in the study institution were divided into patients who were able to eat orally or not based on the mMASA scale. Demographic and stroke characteristics were recorded. The mMASA score was calculated and those with a score of ≥95 were given oral feeds. Those who scored <95 were given swallow therapy and re-evaluated in 2 weeks. Also, the mMASA score below which the patient was likely to develop aspiration pneumonia was detected using the receiver operating characteristic curve (ROC). Results: Out of the 100 patients, 37 patients had a score of ≥95 and were started on oral feeds and had no complications; the rest were started on 2 weeks of swallow therapy. On re-evaluation after swallow therapy, 12 more were started on oral feeds. The remaining 51 patients did not reach the cut-off score of ≥95 and were continued on nasogastric tube feeding. A total of 11 patients developed features of aspiration pneumonia; all of them belonged to the group of 51 patients who consistently had a mMASA score <95. The ROC curve determined that a score of <89 was a good cut off to predict patients who are at high risk of aspiration. Conclusion: The scale can be used to predict the likelihood of aspiration and readiness to start oral feeds in sub-acute stroke patients.

What do we know about optimal nutritional strategies in children with pediatric acute respiratory distress syndrome?

Nutrition in pediatric acute respiratory distress syndrome (PARDS) is an essential aspect of therapy, with potential to modify outcomes. The gut is slowly establishing its place as the motor of critical illness, and the 'gut-lung' axis has been shown to be in play in the systemic inflammatory response. Thus, utilizing the gut to modify outcomes in PARDS is an exciting prospect. PARDS is associated with high mortality in low- and middle-income countries (LMIC), where malnutrition is also prevalent and may worsen during hospital stay. Mortality may be higher in this subgroup of patients. At present, the gold standard to estimate resting energy expenditure (REE) in critically ill children is indirect calorimetry. However, it is a cumbersome and expensive procedure, as a result of which its routine practice is limited to very few units across the world. Therefore, predictive equations, which may under- or over-estimate REE, are relied upon to approximate calorie and protein needs of children with PARDS. Despite having target calorie and protein requirements, studies have found that a large proportion of critically ill children do not achieve these levels even at the end of a week in pediatric intensive care unit (PICU). The preferred mode of nutrition delivery is enteral, and if possible, early enteral nutrition (EEN). Immunonutrition has been a lucrative subject of research, and while there have been some strides, no therapy has yet conclusively demonstrated benefit in terms of mortality or reduced length of stay in PICU or the hospital. Probable immunonutrients in PARDS include omega-3 fatty acids, arginine, glutamine and vitamin D, though none are a part of any recommendations yet.

Fluid Therapy For Pediatric Patients With Diabetic Ketoacidosis: Current Perspectives.

Diabetic ketoacidosis (DKA) is a preventable life-threatening complication of type 1 diabetes. Fluids form a crucial component of DKA therapy, goals being the restoration of intravascular, interstitial and intracellular compartments. Hydration reduces hyperglycemia by decreased counter-regulatory hormones, enhanced renal glucose clearance and augmented insulin sensitivity. However, for the last several decades, fluids in DKA have been subject of intense debate owing to their possible role in causation of cerebral edema (CE). Rehydration protocols have been modified to prevent major osmotic shifts, correct electrolyte imbalances and avoid cerebral or pulmonary edema. In DKA, a conservative deficit assumption ranging from 6.5% to 8.5% is preferred. Normal saline (0.9%) has been the traditional fluid of choice, for both, volume resuscitation and deficit replacement in DKA. However, the risk of AKI with its liberal chloride content remains a contentious issue. On the other hand, balanced crystalloids with restricted chloride content need more exploration in children with DKA, both with respect to DKA resolution and AKI. Although fluids are an integral part of DKA management, a fine balance is needed to avoid under-hydration or over-hydration during DKA management. In this narrative review, we discuss the current perspectives on fluids in pediatric DKA.

Frontal pyomucocoele as forehead swelling in a five-year-old girl.

Mucocoeles are slow-growing, locally aggressive, mucus-containing cysts, lined by epithelium, which, when infected, are called pyomucocoeles. We present the case of a five-year-old girl who presented with a frontal pyomucocoele requiring decompression and adequate antibiotics.

Severe Dengue and Associated Hemophagocytic Lymphohistiocytosis in PICU.

OBJECTIVES: To study the clinico-laboratory profile and outcome of children with severe dengue and dengue-associated hemophagocytic lymphohistiocytosis (HLH). METHODS: In this retrospective study, 22 children with laboratory confirmed severe dengue admitted to pediatric intensive care unit (PICU) were enrolled. Clinical features, laboratory parameters, and outcome were noted and compared between cases fulfilling HLH-2004 criteria and those without HLH. RESULTS: Median (IQR) age was 8 (5-10.3) y. Fever was present for mean (SD) duration of 5.3 (2.1) d. Vomiting, respiratory distress, pain abdomen and hepatomegaly were other clinical features. Thrombocytopenia, anemia and elevated serum transaminases were noted in 91%, 41% and 30% respectively; coagulopathy and hypoalbuminemia were seen in 36% each. Half (n = 11, 50%) had dengue shock syndrome. Acute respiratory distress syndrome (ARDS) (n = 7, 32%) and acute kidney injury (AKI) (n = 6, 28%) were other major organ dysfunctions. Mean (SD) duration of PICU stay was 3.6 (1.5) d with 13.6% mortality. HLH was noted in 7 (32%) cases at a median (IQR) hospital stay of 5 (2-8) d. Children with HLH had significantly higher Pediatric Index of Mortality 2 (PIM 2) score at admission and higher frequency of pain abdomen, anemia, hypoalbuminemia, elevated alanine aminotransferase (ALT) and ARDS. Length of PICU stay (5.1 vs. 2.9 d) and mortality (28.6% vs. 6.7%) were higher in HLH group, however the difference was not statistically significant. Steroids were used in 4 cases with HLH and all survived, whereas among 3 who did not receive steroids, 2 died (p = 0.23). CONCLUSIONS: Severe dengue presents with life-threatening organ dysfunctions. HLH is increasingly recognized in dengue infection and maybe considered as a differential diagnosis in children with lower hemoglobin, hypoalbuminemia, elevated ALT and severe organ dysfunction.

Child with Abdominal Pain.

Abdominal pain is one of the common symptoms reported by children in urgent care clinics. While most children tend to have self-limiting conditions, the treating pediatrician should watch out for underlying serious causes like intestinal obstruction and perforation peritonitis, which require immediate referral to an emergency department (ED). Abdominal pain may be secondary to surgical or non-surgical causes, and will differ as per the age of the child. The common etiologies for abdominal pain presenting to an urgent care clinic are acute gastro-enteritis, constipation and functional abdominal pain; however, a variety of extra-abdominal conditions may also present as abdominal pain. Meticulous history taking and physical examination are the best tools for diagnosis, while investigations have a limited role in treating benign etiologies.

Transient renal dysfunction with Raynaud's phenomenon: is there a connection?

We describe a patient with an episode of severe Raynaud's phenomenon and early or mild scleroderma who presented with a transient elevation of her serum creatinine that resolved spontaneously after 2 days. Vascular response to cold temperatures has been described in vascular beds other than the extremities, and a similar phenomenon in the kidney might have been responsible for the transient renal dysfunction. Possible mechanisms to explain this phenomenon are discussed. Vasospasm merits consideration as an uncommon but largely reversible cause of elevated creatinine in patients with Raynaud's phenomenon.