Combination chemotherapy in rodents: a model for chemotherapy-induced neuropathic pain and pharmacological screening.

Chemotherapy-induced neuropathic pain (CINP) remains a therapeutic challenge, with no US-FDA approved drugs or effective treatments available. Despite significant progress in unravelling the pathophysiology of CINP, the clinical translation of this knowledge into tangible outcome remains elusive. Here, we employed behavioural and pharmacological approaches to establish and validate a novel combination-based chemotherapeutic model of peripheral neuropathy. Male Sprague Dawley rats were subjected to chemotherapy administration followed by assessment of pain behaviour at different time-points post-chemotherapy. Paclitaxel-treated animals displayed an enhanced thermal and mechanical hypersensitivity from day four onwards which continued till day thirty-five post last paclitaxel injection. Notably, rats subjected to combination chemotherapy, displayed prolonged hypersensitivity that emerged on day four and persisted until day fifty-six. RT-PCR analysis revealed significant upregulation in DRG and spinal mRNA expressions of TRP channels (TRPA1, TRPV1, & TRPM8), pro-inflammatory cytokines (TNF-α & IL-1ß) and neuropeptides, Substance P and CGRP in both the pain models. Interestingly, the combination chemotherapy model demonstrated a significant increase in DRG and spinal NR2B expressions compared to rats solely treated with paclitaxel. Pharmacological investigations revealed that gabapentin treatment substantially mitigates pain hypersensitivity in both the combined chemotherapy and paclitaxel-administered groups, with the simultaneous reversal of cellular and molecular changes observed in the lumbar DRG and spinal cord of rats. The findings from this study suggests that combination chemotherapy model exhibits heightened and prolonged hypersensitivity in comparison to the conventional paclitaxel-induced neuropathic pain model. This model not only recapitulates clinical biomarkers of neuropathy but also presents a potential alternative platform for screening analgesic drugs targeted at CINP.

Healthcare Trajectories and Outcomes in the First Year After Tracheostomy Based on Patient Characteristics.

OBJECTIVES: To define healthcare trajectories after tracheostomy to inform shared decision-making efforts for critically ill patients. DESIGN: Retrospective epidemiologic cohort study. SETTING: California Patient Discharge Database 2018-2019. PATIENTS: Patients who received a tracheostomy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We tracked 1-year outcomes after tracheostomy, including survival and time alive in and out of a healthcare facility (HCF. Patients were stratified based on surgical status (did the patient require a major operating room procedure or not), age (65 yr old or older and less than 65 yr), pre-ICU comorbid states (frailty, chronic organ dysfunction, cancer, and robustness), and the need for dialysis during the tracheostomy admission. We identified 4,274 nonsurgical adults who received a tracheostomy during the study period with 50.9% being 65 years old or older. Among adults 65 years old or older, median survival after tracheostomy was less than 3 months for individuals with frailty, chronic organ dysfunction, cancer, or dialysis. Median survival was 3 months for adults younger than 65 years with cancer or dialysis. Most patients spent the majority of days alive after a tracheostomy in an HCF in the first 3 months. Older adults had very few days alive and out of an HCF in the first 3 months after tracheostomy. Most patients who ultimately died in the first year after tracheostomy spent almost all days alive in an HCF. CONCLUSIONS: Cumulative mortality and median survival after a tracheostomy were very poor across most ages and groups. Older adults and several subgroups of younger adults experienced high rates of prolonged hospitalization with few days alive and out of an HCF. This information may aid some patients, surrogates, and providers in decision-making.

Association of Hospital Mortality With Initiation of Mechanical Ventilation on a Weekend: A Retrospective Cohort Study.

RATIONALE: Increased mortality in patients admitted to hospitals on weekends is a well-described phenomenon labeled the "weekend effect." Studies evaluating the weekend effect in intensive care units (ICUs) have arrived at conflicting results. Identifying a weekend effect for critically-ill patients may inform clinical care pathways and resource allocation. OBJECTIVES: Determine the association of initiation of mechanical ventilation (MV) upon admission on a weekend versus weekday with hospital mortality. METHODS: We conducted a retrospective cohort study of non-surgical adult patients using the California Patient Discharge Database from 2018 to 2019. We identified MV initiated on the day of admission and diagnoses using discharge billing codes. The primary exposure was admission and initiation of MV on a weekend versus weekday and the primary outcome was hospital mortality. Hierarchical logistic regression was used to determine the association between hospital mortality and MV initiation timing, adjusting for case-mix. RESULTS: Among 90 288 admissions in 2018 and 2019 meeting inclusion criteria, 24 771 (27.5%) had MV initiated on weekends, while 65 517 (72.6%) had MV initiated on weekdays. Patient demographics and comorbidities were similar between groups. Chronic alcohol and substance use disorders, and acute intoxications and traumas were more prevalent among patients with MV initiated on weekends. No difference in hospital mortality was observed with initiation of MV on weekends versus weekdays (23.1% vs 22.8%, ARD = 0.3%, aOR = 1.02, 95% CI 0.98, 1.07). CONCLUSIONS: Contrary to prior studies, no increased mortality was observed among newly admitted patients initiated on MV on weekends compared to weekdays. While weekend effects may exist in other settings, newly admitted patients likely have MV initiated in the emergency department or ICU, which tend to have more consistent staffing levels. Further research is needed to determine if care patterns in these units could be used as a model for units where weekend effects continue to impact outcomes.

Battling the emerging epidemic of rhino-orbital-cerebral mucormycosis (ROCM) in COVID-19 pandemic: an interventional study.

PURPOSE: The most recent challenge being faced by the healthcare system during the worldwide COVID-19 pandemic is increase in the incidence rate of coinfection or superinfection; one of the most fatal being mucormycosis. This study aimed to estimate the risk factors, symptoms and signs, treatment outcome and prognosis of COVID-19-associated mucormycosis (CAM) patients. METHODS: This is an interventional study of 35 patients diagnosed and managed as CAM at a tertiary care centre in New Delhi, India. RESULTS: The mean age of patients was 40.45 ± 6 years with a male preponderance. CAM did not affect healthy individuals; the major risk factors included diabetes in 65.7% and injudicious steroid use in 51.4% patients. Orbital/facial edema was the most common presenting symptom (25.7%) as well as sign (28.57%). 68.5% patients were stage 3 (involvement of orbit) at presentation; 33.3% showed medial wall involvement. Treatment included intravenous Amphotericin and oral Posaconazole in all patients, paranasal sinus (PNS) debridement in 94.2%, orbital exenteration was done in 8 patients. Adjuvant retrobulbar Amphotericin B injection was administered in 12 patients with radiological resolution seen in 50% after 1 cycle. In patients with Stage 4 disease who underwent exenteration along with PNS debridement, survival rate was 100% at 30 days, and disease reduction occurred in 87.5% patients (P < 0.01). Overall, 68.5% responded to therapy, 8.5% showed progression and mortality rate was 22.85%, at a mean follow up period of 59.5 days. CONCLUSION: A multidisciplinary and aggressive approach is essential in the management of CAM patients.

Endolysosomal N-glycan processing is critical to attain the most active form of the enzyme acid alpha-glucosidase.

Acid alpha-glucosidase (GAA) is a lysosomal glycogen-catabolizing enzyme, the deficiency of which leads to Pompe disease. Pompe disease can be treated with systemic recombinant human GAA (rhGAA) enzyme replacement therapy (ERT), but the current standard of care exhibits poor uptake in skeletal muscles, limiting its clinical efficacy. Furthermore, it is unclear how the specific cellular processing steps of GAA after delivery to lysosomes impact its efficacy. GAA undergoes both proteolytic cleavage and glycan trimming within the endolysosomal pathway, yielding an enzyme that is more efficient in hydrolyzing its natural substrate, glycogen. Here, we developed a tool kit of modified rhGAAs that allowed us to dissect the individual contributions of glycan trimming and proteolysis on maturation-associated increases in glycogen hydrolysis using in vitro and in cellulo enzyme processing, glycopeptide analysis by MS, and high-pH anion-exchange chromatography with pulsed amperometric detection for enzyme kinetics. Chemical modifications of terminal sialic acids on N-glycans blocked sialidase activity in vitro and in cellulo, thereby preventing downstream glycan trimming without affecting proteolysis. This sialidase-resistant rhGAA displayed only partial activation after endolysosomal processing, as evidenced by reduced catalytic efficiency. We also generated enzymatically deglycosylated rhGAA that was shown to be partially activated despite not undergoing proteolytic processing. Taken together, these data suggest that an optimal rhGAA ERT would require both N-glycan and proteolytic processing to attain the most efficient enzyme for glycogen hydrolysis and treatment of Pompe disease. Future studies should examine the amenability of next-generation ERTs to both types of cellular processing.

Association of Proximity to a Long-Term Acute Care Hospital With Hospital Tracheostomy Practices.

OBJECTIVES: Availability of long-term acute care hospitals has been associated with hospital discharge practices. It is unclear if long-term acute care hospital availability can influence patient care decisions. We sought to determine the association of long-term acute care hospital availability at different hospitals with the likelihood of tracheostomy. DESIGN: Retrospective cohort study. SETTING: California Patient Discharge Database, 2016-2018. PATIENTS: Adult patients receiving mechanical ventilation for respiratory failure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Using the California Patient Discharge Database 2016-2018, we identified all mechanically ventilated patients and those who received tracheostomy. We determine the association between tracheostomy and the distance between each hospital and the nearest long-term acute care hospital and the number of long-term acute care hospital beds within 20 miles of each hospital. Among 281,502 hospitalizations where a patient received mechanical ventilation, 22,899 (8.1%) received a tracheostomy. Patients admitted to a hospital closer to a long-term acute care hospital compared with those furthest from a long-term acute care hospital had 38.9% (95% CI, 33.3-44.6%) higher odds of tracheostomy (closest hospitals 8.7% vs furthest hospitals 6.3%, adjusted odds ratio = 1.65; 95% CI, 1.40-1.95). Patients had a 32.4% (95% CI, 27.6-37.3%) higher risk of tracheostomy when admitted to a hospital with more long-term acute care hospital beds in the immediate vicinity (most long-term acute care hospital beds within 20 miles 8.9% vs fewest long-term acute care hospital beds 6.7%, adjusted odds ratio = 1.54; 95% CI, 1.31-1.80). Distance to the nearest long-term acute care hospital was inversely correlated with hospital risk-adjusted tracheostomy rates (ρ = -0.25; p < 0.0001). The number of long-term acute care hospital beds within 20 miles was positively correlated with hospital risk-adjusted tracheostomy rates (ρ = 0.22; p < 0.0001). CONCLUSIONS: Proximity and availability of long-term acute care hospital beds were associated with patient odds of tracheostomy and hospital tracheostomy practices. These findings suggest a hospital effect on tracheostomy decision-making over and above patient case-mix. Future studies focusing on shared decision-making for tracheostomy are needed to ensure goal-concordant care for prolonged mechanical ventilation.

Research Needs for Inpatient Management of Severe Alcohol Withdrawal Syndrome: An Official American Thoracic Society Research Statement.

Background: Severe alcohol withdrawal syndrome (SAWS) is highly morbid, costly, and common among hospitalized patients, yet minimal evidence exists to guide inpatient management. Research needs in this field are broad, spanning the translational science spectrum. Goals: This research statement aims to describe what is known about SAWS, identify knowledge gaps, and offer recommendations for research in each domain of the Institute of Medicine T0-T4 continuum to advance the care of hospitalized patients who experience SAWS. Methods: Clinicians and researchers with unique and complementary expertise in basic, clinical, and implementation research related to unhealthy alcohol consumption and alcohol withdrawal were invited to participate in a workshop at the American Thoracic Society 2019 International Conference. The committee was subdivided into four groups on the basis of interest and expertise: T0-T1 (basic science research with translation to humans), T2 (research translating to patients), T3 (research translating to clinical practice), and T4 (research translating to communities). A medical librarian conducted a pragmatic literature search to facilitate this work, and committee members reviewed and supplemented the resulting evidence, identifying key knowledge gaps. Results: The committee identified several investigative opportunities to advance the care of patients with SAWS in each domain of the translational science spectrum. Major themes included 1) the need to investigate non-γ-aminobutyric acid pathways for alcohol withdrawal syndrome treatment; 2) harnessing retrospective and electronic health record data to identify risk factors and create objective severity scoring systems, particularly for acutely ill patients with SAWS; 3) the need for more robust comparative-effectiveness data to identify optimal SAWS treatment strategies; and 4) recommendations to accelerate implementation of effective treatments into practice. Conclusions: The dearth of evidence supporting management decisions for hospitalized patients with SAWS, many of whom require critical care, represents both a call to action and an opportunity for the American Thoracic Society and larger scientific communities to improve care for a vulnerable patient population. This report highlights basic, clinical, and implementation research that diverse experts agree will have the greatest impact on improving care for hospitalized patients with SAWS.

Informing Healthcare Decisions with Observational Research Assessing Causal Effect. An Official American Thoracic Society Research Statement.

Rationale: Decisions in medicine are made on the basis of knowledge and reasoning, often in shared conversations with patients and families in consideration of clinical practice guideline recommendations, individual preferences, and individual goals. Observational studies can provide valuable knowledge to inform guidelines, decisions, and policy.Objectives: The American Thoracic Society (ATS) created a multidisciplinary ad hoc committee to develop a research statement to clarify the role of observational studies-alongside randomized controlled trials (RCTs)-in informing clinical decisions in pulmonary, critical care, and sleep medicine.Methods: The committee examined the strengths of observational studies assessing causal effects, how they complement RCTs, factors that impact observational study quality, perceptions of observational research, and, finally, the practicalities of incorporating observational research into ATS clinical practice guidelines.Measurements and Main Results: There are strengths and weakness of observational studies as well as RCTs. Observational studies can provide evidence in representative and diverse patient populations. Quality observational studies should be sought in the development of ATS clinical practice guidelines, and medical decision-making in general, when 1) no RCTs are identified or RCTs are appraised as being of low- or very low-quality (replacement); 2) RCTs are of moderate quality because of indirectness, imprecision, or inconsistency, and observational studies mitigate the reason that RCT evidence was downgraded (complementary); or 3) RCTs do not provide evidence for outcomes that a guideline committee considers essential for decision-making (e.g., rare or long-term outcomes; "sequential").Conclusions: Observational studies should be considered in developing clinical practice guidelines and in making clinical decisions.

Rhino-orbital mucormycosis in a patient with no susceptibility following P.vivax malaria infection-a case report.

BACKGROUND: Mucormycosis is a potentially lethal, angioinvasive fungal infection caused by the Mucoracea family comprising Mucor, Rhizopus, and Absidia species. It is commonly associated with uncontrolled diabetes mellitus, the use of corticosteroids, immunosuppressive drugs, and Covid-19 infection. The occurrence of mucormycosis in an immunocompetent patient is rare. Also, only a few case reports have been published where patients developed mucormycosis with associated malarial infection. CASE PRESENTATION: A young female presented with a 3-weeks history of painful swelling and outward protrusion of the right eye with complete loss of vision. She had a history of P.vivax malaria two weeks before her ocular symptoms. On ocular examination, there was proptosis and total ophthalmoplegia with loss of corneal sensations in the right eye. Hematological examination revealed normocytic normochromic anemia and thrombocytopenia. MRI was suggestive of right-sided pansinusitis and orbital cellulitis with right superior ophthalmic vein thrombosis and bulky cavernous sinus. Nasal biopsy was negative for fungal culture. An emergency surgical debridement of all the sinuses was done with right orbital exenteration. Histopathology confirmed the diagnosis of mucormycosis and the patient improved post-operatively on systemic antifungals. CONCLUSION: Such an association of mucormycosis with malaria infection is rarely reported in the literature and is hypothesized to be a result of immunosuppression caused by malaria. Also, emphasis is laid upon having a high index of suspicion for fungal infection in the setting of pansinusitis even if the risk factors are absent. We hereby report a case of rhino-orbital mucormycosis following P.vivax malaria in a 20-year-old female with anemia and thrombocytopenia.

Stability of Do-Not-Resuscitate Orders in Hospitalized Adults: A Population-Based Cohort Study.

OBJECTIVES: Prior work has shown substantial between-hospital variation in do-not-resuscitate orders, but stability of do-not-resuscitate preferences between hospitalizations and the institutional influence on do-not-resuscitate reversals are unclear. We determined the extent of do-not-resuscitate reversals between hospitalizations and the association of the readmission hospital with do-not-resuscitate reversal. DESIGN: Retrospective cohort study. SETTING: California Patient Discharge Database, 2016-2018. PATIENTS: Nonsurgical patients admitted to an acute care hospital with an early do-not-resuscitate order (within 24 hr of admission). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified nonsurgical adult patients who survived an initial hospitalization with an early-do-not-resuscitate order and were readmitted within 30 days. The primary outcome was the association of do-not-resuscitate reversal with readmission to the same or different hospital from the initial hospital. Secondary outcomes included association of readmission to a low versus high do-not-resuscitate-rate hospital with do-not-resuscitate reversal. Among 49,336 patients readmitted within 30 days following a first do-not-resuscitate hospitalization, 22,251 (45.1%) experienced do-not-resuscitate reversal upon readmission. Patients readmitted to a different hospital versus the same hospital were at higher risk of do-not-resuscitate reversal (59.5% vs 38.5%; p < 0.001; adjusted odds ratio = 2.4; 95% CI, 2.3-2.5). Patients readmitted to low versus high do-not-resuscitate-rate hospitals were more likely to have do-not-resuscitate reversals (do-not-resuscitate-rate quartile 1 77.0% vs quartile 4 27.2%; p < 0.001; adjusted odds ratio = 11.9; 95% CI, 10.7-13.2). When readmitted to a different versus the same hospital, patients with do-not-resuscitate reversal had higher rates of mechanical ventilation (adjusted odds ratio = 1.9; 95% CI, 1.6-2.1) and hospital death (adjusted odds ratio = 1.2; 95% CI, 1.1-1.3). CONCLUSIONS: Do-not-resuscitate reversals at the time of readmission are more common than previously reported. Although changes in patient preferences may partially explain between-hospital differences, we observed a strong hospital effect contributing to high do-not-resuscitate-reversal rates with significant implications for patient outcomes and resource.

Safety and Outcomes of Prolonged Usual Care Prone Position Mechanical Ventilation to Treat Acute Coronavirus Disease 2019 Hypoxemic Respiratory Failure.

OBJECTIVES: Prone position ventilation is a potentially life-saving ancillary intervention but is not widely adopted for coronavirus disease 2019 or acute respiratory distress syndrome from other causes. Implementation of lung-protective ventilation including prone positioning for coronavirus disease 2019 acute respiratory distress syndrome is limited by isolation precautions and personal protective equipment scarcity. We sought to determine the safety and associated clinical outcomes for coronavirus disease 2019 acute respiratory distress syndrome treated with prolonged prone position ventilation without daily repositioning. DESIGN: Retrospective single-center study. SETTING: Community academic medical ICU. PATIENTS: Sequential mechanically ventilated patients with coronavirus disease 2019 acute respiratory distress syndrome. INTERVENTIONS: Lung-protective ventilation and prolonged protocolized prone position ventilation without daily supine repositioning. Supine repositioning was performed only when Fio2 less than 60% with positive end-expiratory pressure less than 10 cm H2O for greater than or equal to 4 hours. MEASUREMENTS AND MAIN RESULTS: Primary safety outcome: proportion with pressure wounds by Grades (0-4). Secondary outcomes: hospital survival, length of stay, rates of facial and limb edema, hospital-acquired infections, device displacement, and measures of lung mechanics and oxygenation. Eighty-seven coronavirus disease 2019 patients were mechanically ventilated. Sixty-one were treated with prone position ventilation, whereas 26 did not meet criteria. Forty-two survived (68.9%). Median (interquartile range) time from intubation to prone position ventilation was 0.28 d (0.11-0.80 d). Total prone position ventilation duration was 4.87 d (2.08-9.97 d). Prone position ventilation was applied for 30.3% (18.2-42.2%) of the first 28 days. Pao2:Fio2 diverged significantly by day 3 between survivors 147 (108-164) and nonsurvivors 107 (85-146), mean difference -9.632 (95% CI, -48.3 to 0.0; p = 0·05). Age, driving pressure, day 1, and day 3 Pao2:Fio2 were predictive of time to death. Thirty-eight (71.7%) developed ventral pressure wounds that were associated with prone position ventilation duration and day 3 Sequential Organ Failure Assessment. Limb weakness occurred in 58 (95.1%) with brachial plexus palsies in five (8.2%). Hospital-acquired infections other than central line-associated blood stream infections were infrequent. CONCLUSIONS: Prolonged prone position ventilation was feasible and relatively safe with implications for wider adoption in treating critically ill coronavirus disease 2019 patients and acute respiratory distress syndrome of other etiologies.

One-Year Outcomes Following Tracheostomy for Acute Respiratory Failure.

OBJECTIVES: Tracheostomy utilization has dramatically increased recently. Large gaps exist between expected and actual outcomes resulting in significant decisional conflict and regret. We determined 1-year patient outcomes and healthcare utilization following tracheostomy to aid in decision-making and resource allocation. DESIGN: Retrospective cohort study. SETTING: All California hospital discharges from 2012 to 2013 with follow-up through 2014. PATIENTS: Nonsurgical patients who received a tracheostomy for acute respiratory failure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Our primary outcome was 30-day, 90-day, and 1-year mortality. We also determined hospitals readmissions rates and healthcare utilization in the first year following tracheostomy. We identified 8,343 tracheostomies during the study period. One-year mortality following tracheostomy was high, 46.5%. Older adults (≥ 65 yr) had significantly higher mortality compared with younger patients (< 65 yr) (54.7% vs 36.5%; p < 0.0001). Median survival for older adults was 175 days (95% CI, 150-202 d) compared with greater than 1 year for younger adults (adjusted hazard ratio, 1.25; 95% CI, 1.14-1.36). Within 1 year of tracheostomy, 60.3% of patients required hospital readmission. Older adults were more likely to be readmitted in the first year after tracheostomy compared with younger adults (66.1% vs 55.2%; adjusted hazard ratio, 1.19; 95% CI, 1.09-1.29). Total short-term acute care hospital costs (index and readmissions) in the first year after tracheostomy were high (mean, $215,369; SD, $160,874). CONCLUSIONS: Long-term outcomes following tracheostomy are extremely poor with high mortality, morbidity, and healthcare resource utilization especially among older patients. Some subsets of younger patients may have better outcomes compared with the general tracheostomy population. Short-term acute care costs were extremely high in the first year following tracheostomy. If extended to the entire U.S. population, total short-term acute care hospital costs approach $11 billion dollars per year for tracheostomy-related to acute respiratory failure. These findings may aid families and surrogates in the decision-making process.

Hospital Mechanical Ventilation Volume and Patient Outcomes: Too Much of a Good Thing?

OBJECTIVES: Prior studies investigating hospital mechanical ventilation volume-outcome associations have had conflicting findings. Volume-outcome relationships within contemporary mechanical ventilation practices are unclear. We sought to determine associations between hospital mechanical ventilation volume and patient outcomes. DESIGN: Retrospective cohort study. SETTING: The California Patient Discharge Database 2016. PATIENTS: Adult nonsurgical patients receiving mechanical ventilation. INTERVENTIONS: The primary outcome was hospital death with secondary outcomes of tracheostomy and 30-day readmission. We used multivariable generalized estimating equations to determine the association between patient outcomes and hospital mechanical ventilation volume quartile. MEASUREMENTS AND MAIN RESULTS: We identified 51,689 patients across 274 hospitals who required mechanical ventilation in California in 2016. 38.2% of patients died in the hospital with 4.4% receiving a tracheostomy. Among survivors, 29.5% required readmission within 30 days of discharge. Patients admitted to high versus low volume hospitals had higher odds of death (quartile 4 vs quartile 1 adjusted odds ratio, 1.40; 95% CI, 1.17-1.68) and tracheostomy (quartile 4 vs quartile 1 adjusted odds ratio, 1.58; 95% CI, 1.21-2.06). However, odds of 30-day readmission among survivors was lower at high versus low volume hospitals (quartile 4 vs quartile 1 adjusted odds ratio, 0.77; 95% CI, 0.67-0.89). Higher hospital mechanical ventilation volume was weakly correlated with higher hospital risk-adjusted mortality rates (ρ = 0.16; p = 0.008). These moderately strong observations were supported by multiple sensitivity analyses. CONCLUSIONS: Contrary to previous studies, we observed worse patient outcomes at higher mechanical ventilation volume hospitals. In the setting of increasing use of mechanical ventilation and changes in mechanical ventilation practices, multiple mechanisms of worse outcomes including resource strain are possible. Future studies investigating differences in processes of care between high and low volume hospitals are necessary.

Practice Patterns and Outcomes Associated With Procalcitonin Use in Critically Ill Patients With Sepsis.

BACKGROUND.: Randomized trials support use of procalcitonin (PCT)-based algorithms to decrease duration of antibiotics for critically ill patients with sepsis. However, current use of PCT and associated outcomes in real-world clinical settings is unclear. We sought to determine PCT use in critically ill patients with sepsis in the United States and to examine associations between PCT use and clinical outcomes. METHODS.: This was a retrospective cohort study of approximately 20% of patients with sepsis hospitalized in US intensive care units. Hierarchical regression models were used to determine associations of PCT use with outcomes (antibiotic-days, incidence of Clostridium difficile infection, and in-hospital mortality). Sensitivity analyses were conducted to assess robustness of findings to different methods used to address unmeasured confounding (eg, instrumental variable, difference-in-differences analyses). RESULTS.: Among 20750 critically ill patients with sepsis in 107 hospitals with PCT available, 3769 (18%) patients had PCT levels checked; 1119 (29.7%) had serial PCT measurements. PCT use was associated with increased antibiotic-days (adjusted relative risk, 1.1; 95% confidence interval [CI], 1.15-1.18) and incidence of C. difficile (adjusted odds ratio, 1.42; 95% CI, 1.09-1.85) without a change in mortality (adjusted hazard ratio, 1.05; 95% CI, 0.93-1.19). Analysis of PCT use by instrumental variable and difference-in-difference analyses showed similar lack of antibiotic or outcome improvements associated with PCT use. CONCLUSIONS.: PCT use was not associated with improved antibiotic use or other clinical outcomes in real-world settings. Programs to improve implementation of PCT-based strategies are warranted prior to widespread adoption.

Granuloma after sling surgery: an attempt to answer the 'why' and 'what to do next'.

PURPOSE: To review cases of granuloma formation after sling surgery with a view to find out possible aetiological factors and propose a further plan of management MATERIALS AND METHODS: A retrospective analysis of 120 eyes of 108 patients who underwent frontalis sling surgery with silicone rod from Jan 2008 to Dec 2015 was conducted. All patients with severe ptosis and poor levator function who underwent frontalis sling surgery with silicone rod were included in the study irrespective of the cause of ptosis and method of passing the sling. A complete ophthalmic and ptosis examination was done. In all the cases, the prolene suture was tied over the sleeve to tighten it and it was buried along with the silicone rod in forehead pocket. All the cases with granuloma formation were first subjected to a microbiological examination including culture and sensitivity to antibiotics. All the patients were given a trial of antibiotics. RESULTS: We encountered 10 cases of granuloma in 120 eyes of 108 patients operated during this period. The duration between time of surgery and presentation varied from 2 weeks to 4 months. The microbiological examination revealed positive culture in 5 cases. None of the cases responded to the course of antibiotics given for 10 days. The histopathological examination done in 5 cases (2 of them culture positive and 3 of them culture negative) revealed granulomatous inflammation of non-specific type. The sling was explanted in all cases which resulted in prompt resolution of granuloma in 7-10 days. CONCLUSIONS: The granuloma is primarily due to exposure of the sling itself or the sleeve enveloping the sling or the suture tied around the sleeve thereby. They do not respond to antibiotics but respond very well to explantation. These patients can be taken up for re-sling surgery after a waiting period of 3 months.

Hospital Variation in Early Tracheostomy in the United States: A Population-Based Study.

OBJECTIVE: Controversy exists regarding perceived benefits of early tracheostomy to facilitate weaning among mechanically ventilated patients, potentially leading to significant practice-pattern variation with implications for outcomes and resource utilization. We sought to determine practice-pattern variation and outcomes associated with tracheostomy timing in the United States. DESIGN: In a retrospective cohort study, we identified mechanically ventilated patients with the most common causes of respiratory failure leading to tracheostomy: pneumonia/sepsis and trauma. "Early tracheostomy" was performed within the first week of mechanical ventilation. We determined between-hospital variation in early tracheostomy utilization and the association of early tracheostomy with patient outcomes using hierarchical regression. SETTING: 2012 National Inpatient Sample. PATIENTS: A total of 6,075 pneumonia/sepsis patients and 12,030 trauma patients with tracheostomy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Trauma patients were twice as likely as pneumonia/sepsis patients to receive early tracheostomy (44.5% vs 21.7%; p < 0.001). Admission to hospitals with higher early tracheostomy-to-total-tracheostomy ratios was associated with increased risk for tracheostomy among mechanically ventilated trauma patients (adjusted odds ratio = 1.04; 95% CI, 1.01-1.07) but not pneumonia/sepsis (adjusted odds ratio =1.00; 95% CI, 0.98-1.02). We observed greater between-hospital variation in early tracheostomy rates among trauma patients (21.9-81.9%) compared with pneumonia/sepsis (14.9-38.3%; p < 0.0001). We found no evidence of improved hospital mortality. Pneumonia/sepsis patients with early tracheostomy had fewer feeding tube procedures and higher odds of discharge home. CONCLUSION: Early tracheostomy is potentially overused among mechanically ventilated trauma patients, with nearly half of tracheostomies performed within the first week of mechanical ventilation and large unexplained hospital variation, without clear benefits. Future studies are needed to characterize potentially differential benefits for early tracheostomy between disease subgroups and to investigate factors driving hospital variation in tracheostomy timing.

Trends in Tracheostomy for Mechanically Ventilated Patients in the United States, 1993-2012.

RATIONALE: National trends in tracheostomy for mechanical ventilation (MV) patients are not well characterized. OBJECTIVES: To investigate trends in tracheostomy use, timing, and outcomes in the United States. METHODS: We calculated estimates of tracheostomy use and outcomes from the National Inpatient Sample from 1993 to 2012. We used hierarchical models to determine factors associated with tracheostomy use among MV patients. MEASUREMENTS AND MAIN RESULTS: We identified 1,352,432 adults who received tracheostomy from 1993 to 2012 (9.1% of MV patients). Tracheostomy was more common in surgical patients, men, and racial/ethnic minorities. Age-adjusted incidence of tracheostomy increased by 106%, rising disproportionately to MV use. Among MV patients, tracheostomy rose from 6.9% in 1993 to 9.8% in 2008, and then it declined to 8.7% in 2012 (P < 0.0001). Increases in tracheostomy use were driven by surgical patients (9.5% in 1993; 15.0% in 2012; P < 0.0001), with little change among nonsurgical patients (5.8% in 1993; 5.9% in 2012; P < 0.0001). Over time, tracheostomies were performed earlier (median, 11 d in 1998; 10 d in 2012; P < 0.0001), whereas hospital length of stay declined (median, 39 d in 1993; 26 d in 2012; P < 0.0001), discharges to long-term facilities increased (40.1% vs. 71.9%; P < 0.0001), and hospital mortality declined (38.1% vs. 14.7%; P < 0.0001). CONCLUSIONS: Over the past two decades, tracheostomy use rose substantially in the United States until 2008, when use began to decline. The observed dramatic increase in discharge of tracheostomy patients to long-term care facilities may have significant implications for clinical care, healthcare costs, policy, and research. Future studies should include long-term facilities when analyzing outcomes of tracheostomy.