Renal relapse in children and adolescents with childhood-onset lupus nephritis: a 20-year study.

OBJECTIVES: There is little data on renal relapse in childhood-onset LN (cLN). We investigate the incidence, predictive factors and outcomes related to renal relapse. METHODS: We conducted a retrospective cohort study of all cLN diagnosed at ≤18 years between 2001-2021 to investigate the incidence and outcomes related to renal relapse. RESULTS: Ninety-five Chinese cLN patients (91% proliferative LN) were included. Induction immunosuppression was prednisolone and CYC [n = 36 (38%)] or MMF [n = 33 (35%)]. Maintenance immunosuppression was prednisolone and MMF [n = 53 (54%)] or AZA [n = 29 (31%)]. The rates of complete remission/partial remission (CR/PR) at 12 months were 78.9%/7.4%. Seventy renal relapses occurred in 39 patients over a follow-up of 10.2 years (s.d. 5.9) (0.07 episode/patient-year). Relapse-free survival was 94.7, 86.0, 80.1, 71.2, 68.3, 50.3 and 44.5% at 1, 2, 3, 4, 5, 10 and 20 years, respectively. Multivariate analysis showed that LN diagnosis <13.1 years [adjusted hazard ratio (HRadj) 2.59 995% CI 1.27, 5.29), P = 0.01], AZA maintenance [HRadj 2.20 (95% CI 1.01, 4.79), P = 0.05], PR [HRadj 3.9 (95% CI 1.03, 9.19), P = 0.01] and non-remission [HRadj 3.08 (95% CI 1.35, 11.3), P = 0.04] at 12 months were predictive of renal relapse. Renal relapse was significantly associated with advanced chronic kidney disease (stages 3-5) and end-stage kidney disease (17.9% vs 1.8%, P < 0.01). Furthermore, patients with renal relapse showed an increased incidence of infections (30.8% vs 10.7%, P = 0.02), osteopenia (38.5% vs 17.9%, P = 0.04) and hypertension (30.8% vs 7.1%, P < 0.01). CONCLUSION: Renal relapse is common among cLN, especially among young patients, and is associated with an increased incidence of morbidity and mortality. Attaining CR and the use of MMF appear to decrease the incidence of renal relapse.

Timely Completion of Direct Access Colonoscopy Is Noninferior to Office Scheduled for Screening and Surveillance.

GOALS: We aimed to evaluate whether direct access colonoscopy (DAC) is noninferior to office-scheduled colonoscopy (OSC) for achieving successful colonoscopy. BACKGROUND: DAC may improve access to colonoscopy. We developed an algorithm assessing eligibility, risk for inadequate preparation, and need for nursing/navigator assistance. STUDY: This was a retrospective, single-center study of DAC and OSC patients from June 5, 2018, to July 31, 2019. Patients were 45 to 75 years old with an indication of screening or surveillance. A successful colonoscopy met 3 criteria: complete colonoscopy (cecum, anastomosis, or ileum), adequate preparation (Boston Score ≥2/segment), and performed <90 days from initial patient contact. Unsuccessful colonoscopy did not meet ≥1 criteria. Secondary end points included days to successful colonoscopy, preparation quality, polyp detection, and 10-year recall rate. Noninferiority against risk ratio value of 0.85 was tested using 1-sided alpha of 0.05. RESULTS: A total of 1823 DAC and 828 OSC patients were eligible. DAC patients were younger, with a greater proportion of black patients and screening indications. For the outcome of successful colonoscopy, DAC was noninferior to OSC (DAC vs. OSC: 62.7% vs. 57.1%, RR 1.16, 95% LCL 1.09, P=0.001). For DAC, days to colonoscopy were fewer, and likelihood of 10-year recall after negative screening greater. Boston Score and polyp detection were similar for groups. Black patients were less likely to achieve successful colonoscopy; otherwise, groups were similar. For unsuccessful colonoscopies, proportionally more DAC patients canceled or no-showed while more OSC patients scheduled >90 days. DAC remained noninferior to OSC at 180 days. CONCLUSIONS: DAC was noninferior to OSC for achieving successful colonoscopy, comparing similarly in quality and efficiency outcomes.

Environmental-relevant bisphenol A exposure promotes ovarian cancer stemness by regulating microRNA biogenesis.

Bisphenol A (BPA) is a ubiquitous environmental xenobiotic impacting millions of people worldwide. BPA has long been proposed to promote ovarian carcinogenesis, but the detrimental mechanistic target remains unclear. Cancer stem cells (CSCs) are considered as the trigger of tumour initiation and progression. Here, we show for the first time that nanomolar (environmentally relevant) concentration of BPA can markedly increase the formation and expansion of ovarian CSCs concomitant. This effect is observed in both oestrogen receptor (ER)-positive and ER-defective ovarian cancer cells, suggesting that is independent of the classical ERs. Rather, the signal is mediated through alternative ER G-protein-coupled receptor 30 (GPR30), but not oestrogen-related receptor α and γ. Moreover, we report a novel role of BPA in the regulation of Exportin-5 that led to dysregulation of microRNA biogenesis through miR-21. The use of GPR30 siRNA or antagonist to inhibit GPR30 expression or activity, respectively, resulted in significant inhibition of ovarian CSCs. Similarly, the CSCs phenotype can be reversed by expression of Exportin-5 siRNA. These results identify for the first time non-classical ER and microRNA dysregulation as novel mediators of low, physiological levels of BPA function in CSCs that may underlie its significant tumour-promoting properties in ovarian cancer.

A Comparison of Temperature Thresholds to Begin Laboratory Evaluation of Well-Appearing Febrile Infants.

OBJECTIVE: Young infants who develop fever are at an increased risk for serious infection. It is unclear, however, what temperature cutoff would be optimal to begin evaluating these infants because some criteria use different thresholds. We sought to determine the percentage of infants presenting to the Emergency Department (ED) with a temperature less than 38.2°C who develop serious infection compared with those with higher temperatures. METHODS: We used a publicly available dataset from the Pediatric Emergency Care Applied Research Network. Patients were included if they were aged 60 days or younger, had a documented rectal temperature of 38.0°C or higher in the ED or a history of fever within 24 hours before presentation to the ED, and were being evaluated for serious infection. We used the same exclusion criteria as the original Pediatric Emergency Care Applied Research Network study but further excluded those who were ill-appearing (Yale Observation Score > 10). Serious infections included any of the following: urinary tract infection, bacteremia, bacterial or herpes meningitis, bacterial pneumonia, or bacterial enteritis. Data were described using frequencies (percentages) and compared between groups using χ 2 test. RESULTS: Of the 4619 eligible infants, 1311 (28.4%) had a temperature lower than 38.2°C. Infants with temperatures lower than 38.2°C were significantly less likely to have a serious infection compared with those with higher temperatures (97 [7.5%] vs 365 [11.2%], P < 0.001). Of the infants with temperatures lower than 38.2°C who were tested, 67 (5.8%) had a urinary tract infection, 10 (0.8%) had bacteremia, 3 (0.4%) had bacterial meningitis, 3 (2.9%) had herpes meningitis, 17 (4.5%) had bacterial pneumonia, and 2 (4.8%) had bacterial enteritis. CONCLUSIONS: In this study, we found that infants with temperatures lower than 38.2°C were significantly less likely to have a serious infection than those with higher temperatures. Using an evaluation cutoff of 38.2°C, however, would likely miss a clinically important number of well-appearing infants with serious infections.

Targeting estrogen-related receptor alpha inhibits epithelial-to-mesenchymal transition and stem cell properties of ovarian cancer cells.

Epithelial-mesenchymal transition represents a key event in cancer progression and has emerged as a promising anticancer target. Estrogen-related receptor alpha (ERRα) is frequently elevated in advanced-stage ovarian cancer, but its potential role in tumor progression is not known. Here we show that ERRα functions in epithelial-mesenchymal transition and in subsequent stem cell traits responsible for the acquisition of high degree of aggressiveness and potential for metastasis that are characteristic of ovarian cancer. Importantly, targeted inhibition of ERRα also inhibited the expression of Snail, a repressor of E-cadherin and an inducer of epithelial-mesenchymal transition. Interestingly, induction of Snail resulted from not only changes in mRNA transcription rate but also mRNA stability. We thus identified the miR-200 family as a new player in the ERRα-mediated posttranscriptional regulation of Snail, and antagonism of miR-200a/b could revert the decreased expression of Snail and reversal of epithelial-mesenchymal transition and stem cell characteristics due to ERRα depletion. Finally, we showed that RNA interference-mediated inhibition of ERRα significantly reduced tumor burden, ascites formation, and metastatic peritoneal nodules in vivo in an orthotopic model of ovarian cancer. These results suggest ERRα activation as a mechanism of tumor aggressiveness and imply that targeting ERRα may be a promising approach in ovarian cancer treatment.

Early Postoperative Aqueous Suppression Therapy and Surgical Outcomes of Ahmed Tube Shunts in Refractory Glaucoma.

PURPOSE: To compare early vs. delayed use of aqueous suppressants on Ahmed glaucoma valve (AGV) outcomes. DESIGN: Single-center retrospective comparative case series. PARTICIPANTS: Patients who underwent AGV surgery at Wills Eye Hospital in the period between 2016 and 2021. METHODS: Retrospective review of AGV surgery at Wills Eye Hospital 2016 to 2021 for refractory glaucoma. Two groups were created: group 1 or those who received early aqueous suppressant therapy in the first 2 weeks postoperatively whenever the intraocular pressure (IOP) was > 10 mmHg, and group 2 or those who received delayed treatment after 2 weeks whenever the IOP exceeded the target pressure. Aqueous suppressant therapy included topical beta blockers, carbonic anhydrase inhibitors, and/or alpha agonists. MAIN OUTCOME MEASURES: The primary outcome measures were the frequency of hypertensive phase (HP) defined as IOP > 21 mmHg in first 3 months after an initial reduction to 21 mmHg or less in the first postoperative week not caused by tube obstruction or retraction, and month-12 surgical failure defined as 5 ≥ IOP > 21 mmHg on 2 consecutive visits, vision decline to no light perception (NLP), or glaucoma reoperation. Secondary outcome measures included changes in visual acuity (VA), IOP, and glaucoma medications at 12 months. Predictive factors for surgical failure were also identified. RESULTS: A total of 407 eyes of 391 patients (260 in group 1, 147 in group 2) with similar baseline characteristics were included. Hypertensive phase was more common in group 2 than 1 (41.5% vs. 18.5%; P < 0.001). At month 12 (N = 303 eyes), group 1 was less likely to fail than group 2 (21.2% vs. 36.8%, P = 0.003). Multivariate regression analysis showed that HP (odds ratio [OR] = 10.47, P < 0.001), delayed aqueous suppression use (OR = 2.17, P = 0.003), and lower baseline VA (OR = 1.56, P = 0.015) were the strongest predictors of month-12 failure. CONCLUSIONS: Early use of aqueous suppressants may lower the risk of HP and improve AGV outcomes. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Fluid resuscitation of adults with severe falciparum malaria: effects on Acid-base status, renal function, and extravascular lung water.

OBJECTIVE: To evaluate the efficacy and safety of liberal fluid resuscitation of adults with severe malaria. DESIGN, SETTING, PATIENTS, AND METHODS: Twenty-eight Bangladeshi and Indian adults with severe falciparum malaria received crystalloid resuscitation guided by transpulmonary thermodilution (PiCCO) in an intensive care setting. Systemic hemodynamics, microvascular indices and measures of acidosis, renal function, and pulmonary edema were followed prospectively. RESULTS: All patients were hypovolemic (global end-diastolic volume index<680 mL/m) on enrollment. Patients received a median (range) 3230 mL (390-7300) of isotonic saline in the first 6 hours and 5450 mL (710-13,720) in the first 24 hours. With resuscitation, acid-base status deteriorated in 19 of 28 (68%), and there was no significant improvement in renal function. Extravascular lung water increased in 17 of 22 liberally resuscitated patients (77%); eight of these patients developed pulmonary edema, five of whom died. All other patients survived. All patients with pulmonary edema during the study were hypovolemic or euvolemic at the time pulmonary edema developed. Plasma lactate was lower in hypovolemic patients before (rs=0.38; p=0.05) and after (rs=0.49; p=0.01) resuscitation but was the strongest predictor of mortality before (chi-square=9.9; p=0.002) and after resuscitation (chi-square=11.1; p<0.001) and correlated with the degree of visualized microvascular sequestration of parasitized erythrocytes at both time points (rs=0.55; p=0.003 and rs=0.43; p=0.03, respectively). Persisting sequestration was evident in 7 of 15 patients (47%) 48 hours after enrollment. CONCLUSIONS: Lactic acidosis--the strongest prognostic indicator in adults with severe falciparum malaria--results from sequestration of parasitized erythrocytes in the microcirculation, not from hypovolemia. Liberal fluid resuscitation has little effect on this sequestration and does not improve acid-base status or renal function. Pulmonary edema--secondary to increased pulmonary vascular permeability--is common, unpredictable, and exacerbated by fluid loading. Liberal fluid replacement of adults with severe malaria should be avoided.

The reliability of the physical examination to guide fluid therapy in adults with severe falciparum malaria: an observational study.

BACKGROUND: Adults with severe malaria frequently require intravenous fluid therapy to restore their circulating volume. However, fluid must be delivered judiciously as both under- and over-hydration increase the risk of complications and, potentially, death. As most patients will be cared for in a resource-poor setting, management guidelines necessarily recommend that physical examination should guide fluid resuscitation. However, the reliability of this strategy is uncertain. METHODS: To determine the ability of physical examination to identify hypovolaemia, volume responsiveness, and pulmonary oedema, clinical signs and invasive measures of volume status were collected independently during an observational study of 28 adults with severe malaria. RESULTS: The physical examination defined volume status poorly. Jugular venous pressure (JVP) did not correlate with intravascular volume as determined by global end diastolic volume index (GEDVI; r(s) = 0.07, p = 0.19), neither did dry mucous membranes (p = 0.85), or dry axillae (p = 0.09). GEDVI was actually higher in patients with decreased tissue turgor (p < 0.001). Poor capillary return correlated with GEDVI, but was present infrequently (7% of observations) and, therefore, insensitive. Mean arterial pressure (MAP) correlated with GEDVI (rs = 0.16, p = 0.002), but even before resuscitation patients with a low GEDVI had a preserved MAP. Anuria on admission was unrelated to GEDVI and although liberal fluid resuscitation led to a median hourly urine output of 100 ml in 19 patients who were not anuric on admission, four (21%) developed clinical pulmonary oedema subsequently. MAP was unrelated to volume responsiveness (p = 0.71), while a low JVP, dry mucous membranes, dry axillae, increased tissue turgor, prolonged capillary refill, and tachycardia all had a positive predictive value for volume responsiveness of ≤50%. Extravascular lung water ≥11 ml/kg indicating pulmonary oedema was present on 99 of the 353 times that it was assessed during the study, but was identified on less than half these occasions by tachypnoea, chest auscultation, or an elevated JVP. A clear chest on auscultation and a respiratory rate <30 breaths/minute could exclude pulmonary oedema on 82% and 72% of occasions respectively. CONCLUSIONS: Findings on physical examination correlate poorly with true volume status in adults with severe malaria and must be used with caution to guide fluid therapy. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00692627.

Relative contributions of macrovascular and microvascular dysfunction to disease severity in falciparum malaria.

BACKGROUND: Sequestration of parasitized erythrocytes in the microcirculation is considered the central pathophysiological process in severe falciparum malaria. Hypovolemia with reduced oxygen delivery and microvascular obstruction have different implications for patient management; however, their relative contributions to disease severity are uncertain. METHODS: Adult patients (n = 28) with severe Plasmodium falciparum malaria were enrolled in a prospective hemodynamic study. Volume status and oxygen delivery were assessed using transpulmonary thermodilution. Microvascular sequestration was measured using orthogonal polarized spectroscopy. FINDINGS: Duration of therapy before study enrollment was correlated with the amount of directly visualized and quantitated microvascular sequestration (P = .03). The amount of sequestration correlated with plasma lactate (r(s )= 0.55; P = .003) and disease severity (r(s )= 0.41; P = .04). In patients who had received artesunate for <10 hours, sequestration was higher in fatal cases than in survivors: median (range) 45% (32-50) vs 15% (0-40); P = .03). Parasite biomass estimated from plasma P. falciparum histidine-rich protein 2 correlated positively with disease severity (r(s )= 0.48; P = .01) and was significantly higher in patients who died (P = .046). There was no relationship between oxygen delivery and disease severity (P = .64) or outcome (P = .74). INTERPRETATION: Vital organ dysfunction in severe malaria results primarily from sequestration of parasitized erythrocytes in the microvasculature rather than reduction in circulating blood volume and oxygen delivery.

Chronic angle closure glaucoma with an atypical iris-pupillary membrane.

PURPOSE: To report the presentation and management of a 65-year-old female who presented with chronic angle closure glaucoma and an atypical iris membrane. CASE REPORT: A 65-year-old healthy female with no significant past medical history presented to the emergency room with a 2-day history of headache, blurry vision, and right ocular pain. She denied any such prior episodes, any prior ocular history including ocular trauma, or a family history of glaucoma. She was diagnosed with bilateral, severe chronic angle closure glaucoma with an atypical, pigmented iris-pupillary membrane in the right eye. Given the appearance of the membrane, ocular oncology consultation and anterior segment imaging were unremarkable. Surgical management included complex cataract extraction, limited pars plana anterior vitrectomy, iris membrane removal, and placement of a sulcus tube shunt. CONCLUSIONS: This complex case of chronic angle closure glaucoma with an atypical pupillary membrane highlights the importance of maintaining a broad differential and ruling out secondary pathologies such as iris melanoma. Additionally, it highlights the complexities of cataract extraction with a shallow anterior chamber.

Severe ocular alkali injury managed with an externally sutured amniotic membrane and customized symblepharon ring.

Alkali injuries are ocular emergencies that require immediate evaluation and therapy to preserve vision. Severe alkali injuries can result in long-term vision-threatening sequelae including symblepharon, corneal ulceration, corneal scarring, limbal stem cell deficiency, xerophthalmia, cicatricial changes of the eyelid and adnexa, glaucoma, uveitis, and permanent vision loss. Treatment is aimed at neutralizing the pH, controlling inflammation, and restoring the ocular surface. Here, we present the case of a 35-year-old male who sustained direct ocular exposure to sodium hydroxide, resulting in significant corneal and conjunctival epithelial defects despite aggressive initial medical therapy. The patient subsequently received a large, externally sutured amniotic membrane (AM) with a customized symblepharon ring to promote healing. The corneal and conjunctival defects resolved, and at 4 months after the initial injury, the patient's visual acuity had improved to 20/25. Clinicians should be aware of the various surgical techniques to place an AM transplantation and identify the best strategy based on clinical findings and the extent and severity of the injury.

Clinical Outcomes of Retinal Arterial Macroaneurysms With Vitreous Hemorrhage Treated With Observation, Antivascular Endothelial Growth Factor Intravitreal Injections, or Pars Plana Vitrectomy.

Purpose: To evaluate the clinical outcomes of different types of treatment of retinal arterial macroaneurysm with vitreous hemorrhage. Methods: This retrospective cohort study comprised patients with retinal arterial macroaneurysm and vitreous hemorrhage who were examined at a single retina clinic between 2013 and 2021. Results: Treatment arms included observation (n = 33), intravitreal injections (IVIs) of antivascular endothelial growth factor agents (n = 5), and pars plana vitrectomy (PPV; n = 12). Baseline characteristics and final best-corrected visual acuity (BCVA) were similar in a combined analysis of all treatment groups (P > .05). The BCVA improved in all eyes, but the IVI and PPV arms had worse presenting BCVA. The mean number of injections was 3.6 ± 2.8. The incidence of subretinal hemorrhage was 18.2% in the observation arm, 25.0% in the PPV group (8.3% had subretinal tissue plasminogen activator), and 60.0% in the IVI group. The mean time to intervention was 13 ± 15.3 days for PPV and 38 ± 69.9 days for IVI. There was no correlation between the number of injections and the final BCVA (r = 0.13, P = .830). The IVI and PPV arms were more frequently on anticoagulants (P = .011). There was no difference in final BCVA between those using anticoagulants (0.52 ± 0.53) vs not using anticoagulants (0.55 ± 0.65) (P = .870). Conclusions: Most patients, regardless of treatment modality, demonstrated significantly improved BCVA and similar final visual outcomes. Patients with worse presenting BCVA were more likely to undergo PPV or IVI whereas those with better presenting BCVA had excellent outcomes with observation alone. Improved BCVA was not associated with the number of IVIs or anticoagulant use.

Hemorrhagic Complications Following Trabecular Bypass Microstent Surgery in the Setting of Antithrombotic Therapy.

PRCIS: In this retrospective study, the use of chronic antithrombotic therapy (ATT) did not increase the risk of hemorrhagic complications after trabecular bypass microstent surgery and phacoemulsification. Stent type and female sex were associated with hyphema. PURPOSE: To report the incidence of hemorrhagic complications after trabecular bypass microstent surgery and phacoemulsification with and without (ATT). METHODS: Retrospective case series on glaucoma patients on chronic ATT who underwent trabecular bypass microstent surgery (iStent, iStent inject, and Hydrus) combined with phacoemulsification between 2013 and 2019 with ≥3-month follow-up. The primary outcome measure was the incidence of hemorrhagic complications within a 3-month postoperative period. Generalized estimating equations were created to account for inter-eye correlation and logistic regression analysis was performed to identify factors predictive of hemorrhagic complications. RESULTS: Of 333 patients (435 eyes), 161 patients (211 eyes) were on ATT and 172 patients (224 eyes) were not on ATT; both groups were similar in age and baseline ocular characteristics. The only hemorrhagic complication was hyphema, which occurred in 84 (19.3%) eyes (41 ATT, 43 non-ATT eyes; P = 1.00). Onset was at postoperative day 1 in 98.8% of eyes, with a duration of 1 week in 73.8% of eyes, without difference between ATT and non-ATT groups. Hyphema was most common with Hydrus microstent (36.4%) versus iStent (19.9%) and iStent inject (8.5%) ( P = 0.003). In the multivariate model, the female sex was a predictor of hyphema [hazard ratio (HR) = 2.062; P = 0.009], iStent inject was protective against hyphema (HR = 0.379; P = 0.033), whereas Hydrus did not reach statistical significance (HR = 2.007; P = 0.081). Age, systemic comorbidities, ATT use, and baseline ocular characteristics were not significant predictors. CONCLUSIONS: Hemorrhagic complications after trabecular bypass microstent surgery were limited to transient hyphema and were not associated with chronic ATT use. Stent type and female sex were associated with hyphema.

Effect of Phacoemulsification on Intraocular Pressure in Eyes with Functioning Tube Shunts.

Purpose: To evaluate the effect of phacoemulsification on intraocular pressure (IOP) in eyes with functioning tube shunts. Methods: This was a retrospective chart review of primary open-angle glaucoma (POAG) patients with a functioning tube who underwent phacoemulsification and had ≥24 months of follow-up. The primary end point was defined as surgical failure (IOP > 21 mmHg) at month 24, progression to no light perception (NLP) vision, glaucoma reoperation, or implant removal. Surgical failure defined as IOP >18 and >15 mmHg, changes in visual acuity (VA), IOP, and number of medications were assessed. Results: Twenty-seven eyes of 27 patients with moderate or severe POAG were included. The mean age of the patients was 64.2 ± 10.8 years. The interval between the tube shunt and phacoemulsification was 28.8 ± 25.0 months. At the end of the study, four (14.8%) eyes met the failure criteria; the average time to failure was 9.3 ± 3.8 months. The causes of failure were high IOP in two (50.0%) and glaucoma reoperation in two (50.0%) eyes; however, no eyes progressed to NLP vision. Surgical failure defined as IOP >18 and >15 mmHg showed an increasing failure rate (18.5% and 48.5%, respectively).Themean IOP and medications number remained stable at month 24 compared to baseline (P = 0.131 and P = 0.302, respectively). Initially, VA showed improvement, with the greatest improvement at 6 months (P = 0.001), but at 24 months the improvement was no longer significant (P = 0.430). Conclusion: Phacoemulsification in patients with functioning tubes did not change the mean IOP in most of the patients (86.2%); the number of medications also did not increase.

Association of Pancreatic Adenocarcinoma Location With DNA Damage Response Status and Response to Platinum-Based Therapy.

PURPOSE: Pancreatic adenocarcinoma is an aggressive disease with poor clinical outcomes. Primary pancreatic tumors originating from the head of the pancreas (H) have different prognostic implications than tumors arising from the body and tail (BT). This is thought to be largely due to anatomic differences, as molecular underpinnings of survival have not been fully explored. We hypothesized that differences in the primary site of H and BT tumors might account for differential molecular outcomes and response to chemotherapy. METHODS: Retrospective data from a single high-volume academic center were analyzed for hypothesis generation. A large-scale, real-world retrospective cohort of 2015 patients with next-generation sequencing (NGS) results were analyzed from a Real-World Evidence database. Progression-free survival (PFS) was evaluated from the initiation of first line of therapy for advanced disease until discontinuation because of progression. HR and P values were computed via Cox regression between first-line FOLFIRINOX and gemcitabine/nanoparticle albumin-bound (gem/nab) paclitaxel. Differences in frequencies of genomic alterations between H and BT were analyzed by Fisher's exact test. RESULTS: Genomic alterations in the DNA damage response (DDR) pathway (such as BRCA1, BRCA2, and PALB2) were enriched (unadjusted P value = .00244) in BT tumors (21.7% of 618) relative to H tumors (15.6% of 942) where BRCA2 was a top contributor within this pathway. Median PFS in BT tumors on first-line FOLFIRINOX was longer than first line gem/nab-paclitaxel (P = .006393); this difference was not identified in H tumors (P = .5546). CONCLUSION: DDR pathway alterations including BRCA1/BRCA2/PALB2 are known predictors of increased benefit from platinum-based chemotherapy. NGS testing for germline and somatic mutations remains important in pancreatic ductal adenocarcinoma, especially in BT tumors where DDR pathway alterations may be more common than in H tumors.

Long-Term Outcomes of Children and Adolescents With Biopsy-Proven Childhood-Onset Lupus Nephritis.

Introduction: Long-term data pertaining to childhood-onset lupus nephritis (cLN) remain extremely scarce. Methods: We conducted a retrospective cohort study of biopsy-proven cLN with onset age <18 years diagnosed from 2001 to 2020 to ascertain the long-term patient and kidney survival rates, and the incidence of advanced chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] <60 ml/min per 1.73 m2). Results: A total of 92 subjects (78 female; age 13.7 ± 3.3 years; all Chinese) were included, with follow-up duration of 10.3 years (interquartile range, 5.8-15.9). Of these, 83 children (90%) had proliferative lupus nephritis (LN) (Class III/IV ± V). Mycophenolate was used for induction in 36%, whereas 34% received cyclophosphamide (CYC); 55% received mycophenolate as maintenance immunosuppression. The rates of complete remission (CR) and partial remission (PR) at 6 months and 12 months, respectively, were 65% and 20% and 78% and 8%. Two patients died (mortality rate 2.1/1000 patient-years), with a standardized mortality ratio of 22.3. Three patients (3.2%) developed end-stage kidney disease (ESKD), and advanced CKD occurred in 5 patients (5.4%). Survival rates without advanced CKD, ESKD, or death were 96.7%, 94.2%, 92.7%, 83.2% and 83.2% at 1 year, 5 years, 10 years, 15 years, and 20 years, respectively. Multivariate analysis revealed that severe kidney failure necessitating dialysis at presentation (adjusted hazard ratio 37.7, 95% confidence interval [CI] 4.0-355.6, P = 0.002), nonresponse (NR) after 12 months of treatment (adjusted hazard ratio 11.2, 95% CI 2.3-54.9, P = 0.003), and multiple nephritis flares (adjusted hazard ratio 2.6, 95% CI 1.1-6.2, P = 0.03) were predictive of advanced CKD, ESKD, or death. Other adverse outcomes included infections (2.9 episodes/100 patient-years), osteopenia (32%), hypertension (17%), short stature (14%), and avascular necrosis (7%). Conclusion: The long-term outcomes of cLN appeared to have improved in the present era with effective immunosuppression, cautious drug tapering, and assurance of medication adherence. There is still an unacceptably high prevalence of adverse outcomes.

Descriptive analysis of cornea and anterior segment fellowship program directors in 2020.

PURPOSE: To investigate demographic characteristics, educational backgrounds, and academic achievements among program directors (PDs) of cornea and external disease and anterior segment fellowships in the United States in 2020. SETTING: Database study of U.S. fellowship programs. DESIGN: Cross-sectional study. METHODS: PDs of cornea and external disease and anterior segment fellowships were identified using the San Francisco Match website. Fellowship program features reviewed included academic or private practice type, number of cornea faculty, and sex of chairperson. PD demographic characteristics, educational and training background, and academic productivity were analyzed using publicly available profiles and databases. RESULTS: 76 cornea and external disease and 10 anterior segment fellowships were reviewed. Of 86 reviewed programs, 55 (64.0%) were considered academic, 30 (34.9%) were private practice, and 1 (1.2%) was hybrid. 76 cornea and external disease PDs and 12 anterior segment PDs were identified. Overall, 21 (23.9%) of PDs were women, and the mean age for all PDs was 52.6 ± 11.5 years. Of the 88 PDs, the average number of publications was 45.1 ± 55.9. The mean h-index was 16.7 ± 15.4 and was higher among cornea and external disease than anterior segment PDs (18.2 ± 15.5 vs 7.1 ± 11.4, P = .008) and also higher among academic than private practice PDs (19.9 ± 15.1 vs 11.2 ± 14.7, P = .011). More female PDs were in departments with a female chairperson compared with male PDs (6 [28.6%] vs 4 [6.0%], P = .011). CONCLUSIONS: Cornea and external disease and anterior segment fellowship PDs represent a wide array of backgrounds and scholarly achievements. Female PDs remain in the minority and are more common in departments with female chairpersons.

Central venous catheter use in severe malaria: time to reconsider the World Health Organization guidelines?

BACKGROUND: To optimize the fluid status of adult patients with severe malaria, World Health Organization (WHO) guidelines recommend the insertion of a central venous catheter (CVC) and a target central venous pressure (CVP) of 0-5 cmH2O. However there are few data from clinical trials to support this recommendation. METHODS: Twenty-eight adult Indian and Bangladeshi patients admitted to the intensive care unit with severe falciparum malaria were enrolled in the study. All patients had a CVC inserted and had regular CVP measurements recorded. The CVP measurements were compared with markers of disease severity, clinical endpoints and volumetric measures derived from transpulmonary thermodilution. RESULTS: There was no correlation between the admission CVP and patient outcome (p = 0.67) or disease severity (p = 0.33). There was no correlation between the baseline CVP and the concomitant extravascular lung water (p = 0.62), global end diastolic volume (p = 0.88) or cardiac index (p = 0.44). There was no correlation between the baseline CVP and the likelihood of a patient being fluid responsive (p = 0.37). On the occasions when the CVP was in the WHO target range patients were usually hypovolaemic and often had pulmonary oedema by volumetric measures. Seven of 28 patients suffered a complication of the CVC insertion, although none were fatal. CONCLUSION: The WHO recommendation for the routine insertion of a CVC, and the maintenance of a CVP of 0-5 cmH2O in adults with severe malaria, should be reconsidered.

Trends in Female Authorship in Cornea From 2007 to 2019.

PURPOSE: To identify female authorship trends in first author and last author positions in Cornea from 2007 to 2019. METHODS: First and last authors of all Clinical Science and Basic Investigation publications in Cornea over 13 years were sorted by sex. Identification of sex was based on the author's institutional profile or a Google-based name identifier in cases of equivocal names. The proportion of female board-certified ophthalmologists between 2007 and 2019 was collected from the American Board of Ophthalmology total roster of certified diplomats. RESULTS: First and last author sexes were collected from 2313 publications (1837 Clinical Science and 476 Basic Investigation). Between 2007 and 2019, the percentage of female first authors increased from 30.5% to 41.5%, although this change was not significant (P = 0.240). Female last author percentage increased significantly from 14.9% to 26.6% (P = 0.016). The percentage of female American Board of Ophthalmology-certified diplomats also increased significantly from 17.4% to 24.5% (P < 0.001). Similarly, when comparing 2007 and 2008 with 2018 and 2019, we noted a significant increase in the proportion of women in the last author (P < 0.001) but not in the first author (P = 0.208) position. We also identified a significantly higher proportion of female first authors than that of female board-certified ophthalmologists (P < 0.001). Finally, there was a strong association between first author sex and last author sex (P < 0.001) across manuscripts. CONCLUSIONS: The proportion of women in last author positions increased over 13 years among manuscripts in Cornea. Despite these advances in academic female representation within the cornea subspecialty, a gender gap in authorship persists.

iStent versus iStent inject implantation combined with phacoemulsification in open angle glaucoma.

PURPOSE: To compare the outcomes of iStent vs. iStent inject implantation combined with phacoemulsification. METHODS: This single center retrospective comparative case series included subjects with open angle glaucoma who underwent iStent or iStent inject implantation combined with phacoemulsification with ≥1 year follow-up. The main outcome measures were in-group and between-group changes in intraocular pressure (IOP) and medication number, proportion of eyes that achieved IOP ≤15 mmHg, and surgical success defined as 20% IOP reduction from baseline at 6/12 months. Univariate/multivariate regression analyses were done to identify predictors of surgical failure. RESULTS: One hundred ninety-seven eyes of 148 patients were included (122 iStent, 75 iStent inject). Both groups achieved significant IOP and medication reduction at months 6/12 (P < 0.05). At month 6, IOP was significantly lower in iStent inject vs. iStent eyes (P = 0.003), but the difference was insignificant by month 12 (P = 0.172). Medication number was comparable in both groups at months 6/12 (P > 0.05). More iStent inject eyes achieved IOP ≤15 mmHg at month 6 (P = 0.003) and 12 (P = 0.047). Surgical success was comparable in both groups at months 6/12 (P > 0.05). Kaplan-Meier survival analysis showed similar cumulative rate of surgical failure at year-1 in both groups (P = 0.644). The multivariate model identified older age (P = 0.017) and lower baseline IOP (P = 0.002) as the strongest predictors of surgical failure. CONCLUSION: Compared to iStent, iStent inject achieved lower IOP at month 6 and higher proportion of eyes achieved IOP ≤15 mmHg at month 6/12. However, surgical success was similar in both groups. Predictors of surgical failure were older age and lower baseline IOP rather than the stent type.