Patellofemoral stability is maintained through a complex network of static and dynamic soft-tissue stabilizers, the osseous structure of the patella and trochlea, and overall limb alignment. Thus, ...determining the risk of recurrent patellar instability must account for as many of these factors as possible in the clinical decision-making process. The tibial tubercle–trochlear groove distance is the most common parameter used for this evaluation but may be limited because of methodologic issues and because this distance is an absolute value. Indices that incorporate other predisposing factors, including trochlear dysplasia, increase the accuracy of predicting recurrent patellar instability and can be used to generate a patient-specific treatment plan.
Patient-reported outcome measures (PROMs) have been developed and used as the primary determinant of successful patient-centered results. The patient acceptable symptomatic state delineates an ...absolute value for PROMs indicating that patients are satisfied with their outcome. When this metric is used for anterior cruciate ligament reconstruction, patients reach a satisfactory outcome at between 6 and 8 months postoperatively, and more than 90% reach a satisfactory outcome at 12 months. Preoperative variables such as preoperative exercise, Workers' Compensation, and diabetes impact patient outcomes, whereas preoperative PROMs and use of the anteromedial portal technique for femoral tunnel drilling have a limited impact on satisfaction. Iliotibial band tenodesis shows a large impact on satisfactory outcomes; however, this result may be affected by patient demographic issues (selection bias). Ultimately, a "satisfactory" outcome is a very general term and may not necessarily apply to active athletes desiring a return to competitive sport. Thus, the patient acceptable symptomatic state should be interpreted in combination with a surgeon's experience. Ultimately, the success of a surgical procedure could be determined, in large part, based on the patient's individual preoperative expectations.
There has been a notable increase in the number of neonates born 28 weeks gestational age or younger in the United States. Many of these patients require tracheostomy early in life and subsequent ...laryngotracheal reconstruction (LTR). Although extremely premature infants often undergo LTR, there is no known study to date examining their post-surgical outcomes.
To compare decannulation rates, time to decannulation and complication rates between LTR patients born extremely premature to those born preterm and term.
We identified 179 patients treated at a stand-alone tertiary children's hospital who underwent open airway reconstruction from 2008 to 2021. A Chi Squared test was used to detect differences in categorical clinical data between the groups of patients. A Mann-Whitney test was used to analyze continuous data within these same groups. Time to decannulation analysis was performed using Kaplan Meier analysis and evaluated with log-rank and Cox proportional hazards regression.
Children born extremely premature were more likely to incur complications following LTR (OR = 2.363, p = 0.005, CI 1.295-4.247). There was no difference in time to decannulation (p = 0.0543, Log-rank) or rate of decannulation (OR = 0.4985, p = 0.05, CI 0.2511-1.008). Extremely premature infants were more likely to be treated with an anterior and posterior grafts (OR = 2.471, p = 0.004, CI 1.297-4.535) and/or an airway stent (OR = 3.112, p < 0.001, CI 1.539-5.987).
Compared with all other patients, extremely premature infants have equivalent decannulation success, but are at an increased risk for complications following LTR.
3 Laryngoscope, 133:3608-3614, 2023.
The management of tyrosinaemia type 1 (HT1, fumarylacetoacetase deficiency) has been revolutionised by the introduction of nitisinone but dietary treatment remains essential and the management is not ...easy. In this review detailed recommendations for the management are made based on expert opinion, published case reports and investigational studies as the evidence base is limited and there are no prospective controlled studies.The added value of this paper is that it summarises in detail current clinical knowledge about HT1 and makes recommendations for the management.
Most patients with anaplastic lymphoma kinase (ALK)-rearranged or ROS proto-oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC) are sensitive to tyrosine kinase inhibitor (TKI) therapy, ...but resistance invariably develops, commonly within the CNS. This study aimed to analyse the safety, efficacy, and pharmacokinetic properties of lorlatinib, a novel, highly potent, selective, and brain-penetrant ALK and ROS1 TKI with preclinical activity against most known resistance mutations, in patients with advanced ALK-positive or ROS1-positive NSCLC.
In this international multicentre, open-label, single-arm, first-in-man phase 1 dose-escalation study, eligible patients had advanced ALK-positive or ROS1-positive NSCLC and were older than 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate end-organ function. Lorlatinib was administered orally to patients at doses ranging from 10 mg to 200 mg once daily or 35 mg to 100 mg twice daily, with a minimum of three patients receiving each dose. For some patients, tumour biopsy was done before lorlatinib treatment to identify ALK resistance mutations. Safety was assessed in patients who received at least one dose of lorlatinib; efficacy was assessed in the intention-to-treat population (patients who received at least one dose of study treatment and had either ALK or ROS1 rearrangement). The primary endpoint was dose-limiting toxicities during cycle 1 according to investigator assessment; secondary endpoints included safety, pharmacokinetics, and overall response. This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865.
Between Jan 22, 2014, and July 10, 2015, 54 patients received at least one dose of lorlatinib, including 41 (77%) with ALK-positive and 12 (23%) with ROS1-positive NSCLC; one patient had unconfirmed ALK and ROS1 status. 28 (52%) patients had received two or more TKIs, and 39 (72%) patients had CNS metastases. The most common treatment-related adverse events among the 54 patients were hypercholesterolaemia (39 72% of 54 patients), hypertriglyceridaemia (21 39% of 54 patients), peripheral neuropathy (21 39% of 54 patients), and peripheral oedema (21 39% of 54 patients). One dose-limiting toxicity occurred at 200 mg (the patient did not take at least 16 of 21 prescribed total daily doses in cycle 1 because of toxicities attributable to study drug, which were grade 2 neurocognitive adverse events comprising slowed speech and mentation and word-finding difficulty). No maximum tolerated dose was identified. The recommended phase 2 dose was selected as 100 mg once daily. For ALK-positive patients, the proportion of patients who achieved an objective response was 19 (46%) of 41 patients (95% CI 31–63); for those who had received two or more TKIs, the proportion of patients with an objective response was 11 (42%) of 26 patients (23–63). In ROS1-positive patients, including seven crizotinib-pretreated patients, an objective response was achieved by six (50%) of 12 patients (95% CI 21–79).
In this phase 1, dose-escalation study, lorlatinib showed both systemic and intracranial activity in patients with advanced ALK-positive or ROS1-positive NSCLC, most of whom had CNS metastases and had previously had two or more TKI treatments fail. Therefore, lorlatinib might be an effective therapeutic strategy for patients with ALK-positive NSCLC who have become resistant to currently available TKIs, including second-generation ALK TKIs, and is being investigated in a phase 3 randomised controlled trial comparing lorlatinib to crizotinib (ClinicalTrials.gov, NCT03052608).
Pfizer.
A harvested hamstring autograft that is too small is a technical challenge for an effective anterior cruciate ligament reconstruction. One potential solution is to assemble the graft differently to ...maximize the diameter and length of the graft. Compared with the traditional, all-inside, 4-strand graft preparation, alternative graft constructs could be further explored and evaluated.
Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a phase 1 study, activity was seen in patients with ...ALK-positive non-small-cell lung cancer, most of whom had CNS metastases and progression after ALK-directed therapy. We aimed to analyse the overall and intracranial antitumour activity of lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer.
In this phase 2 study, patients with histologically or cytologically ALK-positive or ROS1-positive, advanced, non-small-cell lung cancer, with or without CNS metastases, with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and adequate end-organ function were eligible. Patients were enrolled into six different expansion cohorts (EXP1–6) on the basis of ALK and ROS1 status and previous therapy, and were given lorlatinib 100 mg orally once daily continuously in 21-day cycles. The primary endpoint was overall and intracranial tumour response by independent central review, assessed in pooled subgroups of ALK-positive patients. Analyses of activity and safety were based on the safety analysis set (ie, all patients who received at least one dose of lorlatinib) as assessed by independent central review. Patients with measurable CNS metastases at baseline by independent central review were included in the intracranial activity analyses. In this report, we present lorlatinib activity data for the ALK-positive patients (EXP1–5 only), and safety data for all treated patients (EXP1–6). This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865.
Between Sept 15, 2015, and Oct 3, 2016, 276 patients were enrolled: 30 who were ALK positive and treatment naive (EXP1); 59 who were ALK positive and received previous crizotinib without (n=27; EXP2) or with (n=32; EXP3A) previous chemotherapy; 28 who were ALK positive and received one previous non-crizotinib ALK tyrosine kinase inhibitor, with or without chemotherapy (EXP3B); 112 who were ALK positive with two (n=66; EXP4) or three (n=46; EXP5) previous ALK tyrosine kinase inhibitors with or without chemotherapy; and 47 who were ROS1 positive with any previous treatment (EXP6). One patient in EXP4 died before receiving lorlatinib and was excluded from the safety analysis set. In treatment-naive patients (EXP1), an objective response was achieved in 27 (90·0%; 95% CI 73·5–97·9) of 30 patients. Three patients in EXP1 had measurable baseline CNS lesions per independent central review, and objective intracranial responses were observed in two (66·7%; 95% CI 9·4–99·2). In ALK-positive patients with at least one previous ALK tyrosine kinase inhibitor (EXP2–5), objective responses were achieved in 93 (47·0%; 39·9–54·2) of 198 patients and objective intracranial response in those with measurable baseline CNS lesions in 51 (63·0%; 51·5–73·4) of 81 patients. Objective response was achieved in 41 (69·5%; 95% CI 56·1–80·8) of 59 patients who had only received previous crizotinib (EXP2–3A), nine (32·1%; 15·9–52·4) of 28 patients with one previous non-crizotinib ALK tyrosine kinase inhibitor (EXP3B), and 43 (38·7%; 29·6–48·5) of 111 patients with two or more previous ALK tyrosine kinase inhibitors (EXP4–5). Objective intracranial response was achieved in 20 (87·0%; 95% CI 66·4–97·2) of 23 patients with measurable baseline CNS lesions in EXP2–3A, five (55·6%; 21·2–86·3) of nine patients in EXP3B, and 26 (53·1%; 38·3–67·5) of 49 patients in EXP4–5. The most common treatment-related adverse events across all patients were hypercholesterolaemia (224 81% of 275 patients overall and 43 16% grade 3–4) and hypertriglyceridaemia (166 60% overall and 43 16% grade 3–4). Serious treatment-related adverse events occurred in 19 (7%) of 275 patients and seven patients (3%) permanently discontinued treatment because of treatment-related adverse events. No treatment-related deaths were reported.
Consistent with its broad ALK mutational coverage and CNS penetration, lorlatinib showed substantial overall and intracranial activity both in treatment-naive patients with ALK-positive non-small-cell lung cancer, and in those who had progressed on crizotinib, second-generation ALK tyrosine kinase inhibitors, or after up to three previous ALK tyrosine kinase inhibitors. Thus, lorlatinib could represent an effective treatment option for patients with ALK-positive non-small-cell lung cancer in first-line or subsequent therapy.
Pfizer.
Background:
Lysergic acid diethylamide (LSD) and psilocybin are serotonergic hallucinogens that are used primarily for recreational abuse. Small studies evaluated the efficacy of LSD and psilocybin ...for several psychiatric conditions. There are limited safety or toxicity data for either of these substances, especially in large populations.
Methods:
This was a retrospective analysis of single-substance exposures of LSD or psilocybin-containing mushrooms (PcMs) reported to United States poison centers from 1 January 2000 to 31 December 2016. The study describes the most frequent toxicities, management sites, and medical outcomes.
Results:
A total of 5883 PcM and 3554 LSD exposures were included. Most patients were between 13 and 29 years of age (83.9% PcM, 88.9% LSD) and primarily male (77.9% PcM, 74.1% LSD). Most common clinical effects were hallucinations (45.8% PcM, 37.4% LSD), agitation (24.1% PcM, 42.4% LSD), and tachycardia (18.0% PcM, 38.6% LSD). Serious clinical effects were infrequent, but included hyperthermia, seizures, coma, increased serum creatinine, and cardiac arrest. Most patients were treated and released from the emergency department. More LSD patients were admitted to critical care and non-critical care units than PcM patients. Moderate effect was the most frequent outcome for both substances (61.0% PcM, 62.3% LSD).
Conclusion:
These data find that LSD and PcM use occurs primarily in adolescents and young adults, who experience mild to moderate adverse effects. Serious effects are infrequent but can occur. While most LSD and PcM users require only emergency department management, LSD use is more likely to require medical admission.
Cannabis exposures in children have risen sharply in recent years, resulting in increased hospital visits and admission to pediatric intensive care units (PICUs). The intent of this study was to ...describe the proportion of pediatric patients admitted to the PICU after unintentional cannabis ingestion that received critical care interventions (CCIs) along with describing trends over time in hospitalization, admission to the PICU, and clinical effects and treatments outside of the PICU.
This was a retrospective database study utilizing the National Poison Data System (NPDS) from 1/1/2000 to 12/31/2020. Children 6 months to 12 years of age with single substance cannabis exposures were included.
A total of 12,882 cases were included. There was an increase in the proportion of cases seen in a hospital over time from 43.8% in 2000 to 54.6% in 2020 (range 29.1-62.6%). In patients seen in a HCF, the proportion admitted to the PICU was 9.5% in 2000 and 14% in 2020 (range: 5.6-29.0%). The 875 (6.8%) children admitted to the PICU were analyzed for the primary outcome. CCIs were performed in 69/875 (7.9%) cases that were admitted to the PICU. The most common CCIs in the PICU were intubation and sedation, 4.9 and 3.7%, respectively.
Unintentional pediatric cannabis exposures are associated with clinically significant effects, including respiratory depression, hypotension, and bradycardia, but fewer than 5% of exposures were treated with CCIs, like intubation or vasopressors, in patients admitted to the PICU. Further work should assess specific reasons for admission to the PICU.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The diagnosis of toxic alcohol poisoning is often based on clinical presentation and nonspecific surrogate laboratory studies due to limited testing availability. Fomepizole is the recommended ...antidote and often administered empirically. The objective of this study is to identify substances that mimic toxic alcohols and compare key clinical factors between toxic alcohol and non-toxic alcohol exposures when fomepizole was administered.
This study was a retrospective evaluation using the National Poison Data System from January 1, 2010 through December 31, 2021. Exposures were included if fomepizole was administered. Toxic alcohol exposures had ethylene glycol or methanol as a coded substance. For exposures not coded as a toxic alcohol, the first substance was described. Paracetamol (acetaminophen) exposures from 2020 and 2021 were excluded.
Fomepizole was reportedly used 25,110 times over 12 years. Use increased from 1,955 in 2010 to 2,710 in 2021. Most administrations were for reported toxic alcohol poisoning (60 percent) but use in reported non-toxic alcohol poisoning was greater starting in 2020. Toxic alcohol exposures were older (43.3 versus 39.8 years;
< 0.001) and more likely male (65.7 percent versus 58.2 percent). Level of care was mostly a critical care unit (67.7 percent), which was less common in toxic alcohol (63.3 percent) than non-toxic alcohol exposures (74.2 percent). The most common non-toxic alcohol substances were ethanol (24.9 percent) or an unknown drug (17.5 percent). Acidosis, increased creatinine concentration, anion gap, and osmolal gap, and kidney failure were coded in a lower proportion of toxic alcohol exposures than non-toxic alcohol exposures (
< 0.001).
The inability to provide rapid clinical confirmation of toxic alcohol poisoning results in the empiric administration of fomepizole to many patients who will ultimately have other diagnoses. Although fomepizole is relative well tolerated we estimated that this practice costs between $1.5 to $2.5 million. The major limitations of this work include the biases associated with retrospective record review, and the inability to confirm the exposures which may have resulted in allocation error.
Most fomepizole use was for a presumed toxic alcohol. This recently shifted to greater use in likely non-toxic alcohol poisoning. Key difference between the groups suggest fomepizole administration was likely due to the difficulty in diagnosis of toxic alcohol poisoning along with the efficacy and safety of fomepizole. Increased toxic alcohol laboratory testing availability could improve timely diagnosis, reserving fomepizole use for toxic alcohol poisoning.
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