Sanford USD Medical Center

PURPOSE: To update the ASCO guideline on the recommended prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathy (CIPN) in adult cancer survivors. METHODS: An Expert Panel conducted targeted systematic literature reviews to identify new studies. RESULTS: The search strategy identified 257 new references, which led to a full-text review of 87 manuscripts. A total of 3 systematic reviews, 2 with meta-analyses, and 28 primary trials for prevention of CIPN in addition to 14 primary trials related to treatment of established CIPN, are included in this update. RECOMMENDATIONS: The identified data reconfirmed that no agents are recommended for the prevention of CIPN. The use of acetyl-l-carnitine for the prevention of CIPN in patients with cancer should be discouraged. Furthermore, clinicians should assess the appropriateness of dose delaying, dose reduction, substitutions, or stopping chemotherapy in patients who develop intolerable neuropathy and/or functional impairment. Duloxetine is the only agent that has appropriate evidence to support its use for patients with established painful CIPN. Nonetheless, the amount of benefit from duloxetine is limited.Additional information is available at www.asco.org/survivorship-guidelines.

Enteral nutrition (EN) is a valuable clinical intervention for patients of all ages in a variety of care settings. Along with its many outcome benefits come the potential for adverse effects. These safety issues are the result of clinical complications and of process-related errors. The latter can occur at any step from patient assessment, prescribing, and order review, to product selection, labeling, and administration. To maximize the benefits of EN while minimizing adverse events requires that a systematic approach of care be in place. This includes open communication, standardization, and incorporation of best practices into the EN process. This document provides recommendations based on the available evidence and expert consensus for safe practices, across each step of the process, for all those involved in caring for patients receiving EN.

Regular participation in organized youth sports does not ensure adequate exposure to skill- and health-related fitness activities, and sport training without preparatory conditioning does not appear to reduce risk of injury in young athletes. Current trends indicate that widespread participation in organized youth sports is occurring at a younger age, especially in girls. Current public health recommendations developed to promote muscle strengthening and bone building activities for youth aged 6 yr and older, along with increased involvement in competitive sport activities at younger ages, has increased interest and concern from parents, clinicians, coaches, and teachers regarding the optimal age to encourage and integrate more specialized physical training into youth development programs. This review synthesizes the latest literature and expert opinion regarding when to initiate neuromuscular conditioning in youth and presents a how-to integrative training conceptual model that could maximize the potential health-related benefits for children by reducing sports-related injury risk and encouraging lifelong, regular physical activity.

We herein summarise the evidence concerning the impact of sperm DNA fragmentation in various clinical infertility scenarios and the advances on sperm DNA fragmentation tests. The collected evidence was used to formulate 41 recommendations. Of these, 13 recommendations concern technical aspects of sperm DNA fragmentation testing, including pre-analytical information, clinical thresholds and interpretation of results. The remaining 28 recommendations relate to indications for sperm DNA fragmentation testing and clinical management. Clinical scenarios like varicocele, unexplained infertility, idiopathic infertility, recurrent pregnancy loss, intrauterine insemination, in vitro fertilisation/intracytoplasmic sperm injection, fertility counselling for men with infertility risk factors and sperm cryopreservation have been contemplated. The bulk evidence supporting the recommendations has increased in recent years, but it is still of moderate to low quality. This guideline provides clinicians with advice on best practices in sperm DNA fragmentation testing. Also, recommendations are provided on possible management strategies to overcome infertility related to sperm DNA fragmentation, based on the best available evidence. Lastly, we identified gaps in knowledge and opportunities for research and elaborated a list of recommendations to stimulate further investigation.

NBIA characterizes a class of neurodegenerative diseases that feature a prominent extrapyramidal movement disorder, intellectual deterioration, and a characteristic deposition of iron in the basal ganglia. The diagnosis of NBIA is made on the basis of the combination of representative clinical features along with MR imaging evidence of iron accumulation. In many cases, confirmatory molecular genetic testing is now available as well. A number of new subtypes of NBIA have recently been described, with distinct neuroradiologic and clinical features. This article outlines the known subtypes of NBIA, delineates their clinical and radiographic features, and suggests an algorithm for evaluation.

Background: Ambulatory hemodynamic monitoring with an implantable pulmonary artery (PA) sensor is approved for patients with New York Heart Association Class III heart failure (HF) and a prior HF hospitalization (HFH) within 12 months. The objective of this study was to assess the efficacy and safety of PA pressure-guided therapy in routine clinical practice with special focus on subgroups defined by sex, race, and ejection fraction. Methods: This multi-center, prospective, open-label, observational, single-arm trial of 1200 patients across 104 centers within the United States with New York Heart Association class III HF and a prior HFH within 12 months evaluated patients undergoing PA pressure sensor implantation between September 1, 2014, and October 11, 2017. The primary efficacy outcome was the difference between rates of adjudicated HFH 1 year after compared with the 1 year before sensor implantation. Safety end points were freedom from device- or system-related complications at 2 years and freedom from pressure sensor failure at 2 years. Results: Mean age for the population was 69 years, 37.7% were women, 17.2% were non-White, and 46.8% had preserved ejection fraction. During the year after sensor implantation, the mean rate of daily pressure transmission was 76±24% and PA pressures declined significantly. The rate of HFH was significantly lower at 1 year compared with the year before implantation (0.54 versus 1.25 events/patient-years, hazard ratio 0.43 [95% CI, 0.39–0.47], P <0.0001). The rate of all-cause hospitalization was also lower following sensor implantation (1.67 versus 2.28 events/patient-years, hazard ratio 0.73 [95% CI, 0.68–0.78], P <0.0001). Results were consistent across subgroups defined by ejection fraction, sex, race, cause of cardiomyopathy, presence/absence of implantable cardiac defibrillator or cardiac resynchronization therapy and ejection fraction. Freedom from device- or system-related complications was 99.6%, and freedom from pressure sensor failure was 99.9% at 1 year. Conclusions: In routine clinical practice as in clinical trials, PA pressure-guided therapy for HF was associated with lower PA pressures, lower rates of HFH and all-cause hospitalization, and low rates of adverse events across a broad range of patients with symptomatic HF and prior HFH. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02279888.

A potential emerging problem associated with increasingly popularized extreme conditioning programs (ECPs) has been identified by the military and civilian communities. That is, there is an apparent disproportionate musculoskeletal injury risk from these demanding programs, particularly for novice participants, resulting in lost duty time, medical treatment, and extensive rehabilitation. This is a significant and costly concern for the military with regard to effectively maintaining operational readiness of the Force. While there are certain recognized positive aspects of ECPs that address a perceived and/or actual unfulfilled conditioning need for many individuals and military units, these programs have limitations and should be considered carefully. Moreover, certain distinctive characteristics of ECPs appear to violate recognized accepted standards for safely and appropriately developing muscular fitness and are not uniformly aligned with established and accepted training doctrine. Accordingly, practical solutions to improve ECP prescription and implementation and reduce injury risk are of paramount importance.

OBJECTIVE: In the presurgical workup of magnetic resonance imaging (MRI)-negative (MRI(-) or "nonlesional") pharmacoresistant focal epilepsy (PFE) patients, discovering a previously undetected lesion can drastically change the evaluation and likely improve surgical outcome. Our study utilizes a voxel-based MRI postprocessing technique, implemented in a morphometric analysis program (MAP), to facilitate detection of subtle abnormalities in a consecutive cohort of MRI(-) surgical candidates. METHODS: Included in this retrospective study was a consecutive cohort of 150 MRI(-) surgical patients. MAP was performed on T1-weighted MRI, with comparison to a scanner-specific normal database. Review and analysis of MAP were performed blinded to patients' clinical information. The pertinence of MAP(+) areas was confirmed by surgical outcome and pathology. RESULTS: MAP showed a 43% positive rate, sensitivity of 0.9, and specificity of 0.67. Overall, patients with the MAP(+) region completely resected had the best seizure outcomes, followed by the MAP(-) patients, and patients who had no/partial resection of the MAP(+) region had the worst outcome (p < 0.001). Subgroup analysis revealed that visually identified subtle findings are more likely correct if also MAP(+) . False-positive rate in 52 normal controls was 2%. Surgical pathology of the resected MAP(+) areas contained mainly non-balloon-cell focal cortical dysplasia (FCD). Multiple MAP(+) regions were present in 7% of patients. INTERPRETATION: MAP can be a practical and valuable tool to: (1) guide the search for subtle MRI abnormalities and (2) confirm visually identified questionable abnormalities in patients with PFE due to suspected FCD. A MAP(+) region, when concordant with the patient's electroclinical presentation, should provide a legitimate target for surgical exploration.

Post hepatectomy liver failure (PHLF) remains a significant cause of morbidity and mortality after major liver resection. Although the etiology of PHLF is multifactorial, an inadequate functional liver remnant (FLR) is felt to be the most important modifiable predictor of PHLF. Pre-operative evaluation of FLR function and volume is of paramount importance before proceeding with any major liver resection. Patients with inadequate or borderline FLR volume must be considered for volume optimization strategies such as portal vein embolization (PVE), two stage hepatectomy with portal vein ligation (PVL), Yttrium-90 radioembolization, and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). This paper provides an overview of assessing FLR volume and function, and discusses indications and outcomes of commonly used volume optimization strategies.

BACKGROUND: In alpha1-AR knockout (alpha1ABKO) mice that lacked cardiac myocyte alpha1-adrenergic receptor (alpha1-AR) binding, aortic constriction induced apoptosis, dilated cardiomyopathy, and death. However, it was unclear whether these effects were attributable to a lack of cardiac myocyte alpha1-ARs and whether the alpha1A, alpha1B, or both subtypes mediated protection. Therefore, we investigated alpha1A and alpha1B subtype-specific survival signaling in cultured cardiac myocytes to test for a direct protective effect of alpha1-ARs in cardiac myocytes. METHODS AND RESULTS: We cultured alpha1ABKO myocytes and reconstituted alpha1-AR signaling with adenoviruses expressing alpha1-GFP fusion proteins. Myocyte death was induced by norepinephrine, doxorubicin, or H2O2 and was measured by annexin V/propidium iodide staining. In alpha1ABKO myocytes, all 3 stimuli significantly increased apoptosis and necrosis. Reconstitution of the alpha1A subtype, but not the alpha1B, rescued alpha1ABKO myocytes from cell death induced by each stimulus. To address the mechanism, we examined alpha1-AR activation of extracellular signal-regulated kinase (ERK). In alpha1ABKO hearts, aortic constriction failed to activate ERK, and in alpha1ABKO myocytes, expression of a constitutively active MEK1 rescued alpha1ABKO myocytes from norepinephrine-induced death. In addition, only the alpha1A-AR activated ERK in alpha1ABKO myocytes, and expression of a dominant-negative MEK1 completely blocked alpha1A survival signaling in alpha1ABKO myocytes. CONCLUSIONS: Our results demonstrate a direct protective effect of the alpha1A subtype in cardiac myocytes and define an alpha1A-ERK signaling pathway that is required for myocyte survival. Absence of the alpha1A-ERK pathway can explain the failure to activate ERK after aortic constriction in alpha1ABKO mice and can contribute to the development of apoptosis, dilated cardiomyopathy, and death.

OBJECTIVE: To review pharmacokinetic and pharmacodynamic drug-drug interactions (DDIs) involving new oral anticoagulants for atrial fibrillation. DATA SOURCES: A literature search was conducted via PubMed and the Cochrane database to identify DDI studies using the terms drug interactions, dabigatran, rivaroxaban, and apixaban. Prescribing information and Food and Drug Administration briefing documents were used to supplement published data. STUDY SELECTION AND DATA EXTRACTION: English publications identified on Medline from 2005 up to August 2013 and US prescribing information for approved oral anticoagulants. DATA SYNTHESIS: Articles reviewed focused on drugs affecting the permeability glycoprotein (P-gp) efflux transporter protein and/or cytochrome P (CYP) 450 3A4 enzymes, and pharmacodynamic DDIs when drugs are administered concomitantly. Phase I DDI studies have reported pharmacokinetic DDIs mediated by P-gp alone (dabigatran etexilate) or in combination with CYP3A4 enzymes (rivaroxaban and apixaban). Dabigatran etexilate should not be administered with any P-gp inhibitor in patients with severe renal impairment. Briefing documents indicate that rivaroxaban and apixaban should not be used with drugs that are strong inhibitors of both P-gp and CYP3A4. DDI studies involving rifampicin suggest that rivaroxaban and apixaban should be avoided when strong inducers of P-gp and CYP3A4 are used concurrently. Concomitant use of apixaban and strong dual inhibitors of P-gp and CYP3A4 should be avoided or the dose reduced. Five randomized clinical trials report additive effects with rivaroxaban, dabigatran, and apixaban when used concomitantly with antiplatelet agents; bleeding rates have been found to be higher, especially with dual antiplatelet therapy. CONCLUSIONS: Awareness of drugs that alter the function of the P-gp efflux transporter protein and CYP3A4 enzymes and provide additive effects should enable prescribers to anticipate and avoid potential DDIs involving the new oral anticoagulants. To this end, briefing documents and prescribing information have applied cautionary measures for individuals treated with these newer anticoagulants.

Skeletal muscle cramps during exercise are a common affliction, even in highly fit athletes. And as empirical evidence grows, it is becoming increasingly clear that there are two distinct and dissimilar general categories of exercise-associated muscle cramps. Skeletal muscle overload and fatigue can prompt muscle cramping locally in the overworked muscle fibers, and these cramps can be treated effectively with passive stretching and massage or by modifying the exercise intensity and load. In contrast, extensive sweating and a consequent significant whole-body exchangeable sodium deficit caused by insufficient dietary sodium intake to offset sweat sodium losses can lead to a contracted interstitial fluid compartment and more widespread skeletal muscle cramping, even when there is minimal or no muscle overload and fatigue. Signs of hyperexcitable neuromuscular junctions may appear first as fasciculations during breaks in activity, which eventually progress to more severe and debilitating muscle spasms. Notably, affected athletes often present with normal or somewhat elevated serum electrolyte levels, even if they are "salty sweaters," because of hypotonic sweat loss and a fall in intravascular volume. However, recovery and maintenance of water and sodium balance with oral or intravenous salt solutions is the proven effective strategy for resolving and averting exercise-associated muscle cramps that are prompted by extensive sweating and a sodium deficit.

CONTEXT: Evolving concussion diagnosis/management tools and guidelines make Knowledge Transfer and Exchange (KTE) to practitioners challenging. OBJECTIVE: Identify sports concussion knowledge base and practise patterns in two family physician populations; explore current/preferred methods of KTE. DESIGN: A cross-sectional study. SETTING: Family physicians in Alberta, Canada (CAN) and North/South Dakota, USA. PARTICIPANTS: CAN physicians were recruited by mail: 2.5% response rate (80/3154); US physicians through a database: 20% response rate (109/545). INTERVENTION/INSTRUMENT: Online survey. MAIN AND SECONDARY OUTCOME MEASURES: Diagnosis/management strategies for concussions, and current/preferred KTE. RESULTS: Main reported aetiologies: sports/recreation (52.5% CAN); organised sports (76.5% US). Most physicians used clinical examination (93.8% CAN, 88.1% US); far fewer used the Sport Concussion Assessment Tool (SCAT1/SCAT2) and balance testing. More US physicians initially used concussion-grading scales (26.7% vs 8.8% CAN, p=0.002); computerised neurocognitive testing (19.8% vs 1.3% CAN; p<0.001) and Standardised Assessment of Concussion (SAC) (21.8% vs 7.5% CAN; p=0.008). Most prescribed physical rest (83.8% CAN, 75.5% US), while fewer recommended cognitive rest (47.5% CAN, 28.4% US; p=0.008). Return-to-play decisions were based primarily on clinical examination (89.1% US, 73.8% CAN; p=0.007); US physicians relied more on neurocognitive testing (29.7% vs 5.0% CAN; p<0.001) and recognised guidelines (63.4% vs 23.8% CAN; p<0.001). One-third of Canadian physicians received KTE from colleagues, websites and medical school training. Leading KTE preferences included Continuing Medical Education (CME) courses and online CME. CONCLUSIONS: Existing published recommendations regarding diagnosis/management of concussion are not always translated into practise, particularly the recommendation for cognitive rest; predicating enhanced, innovative CME initiatives.

Prevention of musculoskeletal injuries (MSKI) is critical in both civilian and military populations to enhance physical performance, optimize health, and minimize health care expenses. Developing a more unified approach through addressing identified movement impairments could result in improved dynamic balance, trunk stability, and functional movement quality while potentially minimizing the risk of incurring such injuries. Although the evidence supporting the utility of injury prediction and return-to-activity readiness screening tools is encouraging, considerable additional research is needed regarding improving sensitivity, specificity, and outcomes, and especially the implementation challenges and barriers in a military setting. If selected current functional movement assessments can be administered in an efficient and cost-effective manner, utilization of the existing tools may be a beneficial first step in decreasing the burden of MSKI, with a subsequent focus on secondary and tertiary prevention via further assessments on those with prior injury history.

BACKGROUND: Two-stage reimplantation arthroplasty is a commonly used approach for treating chronic periprosthetic joint infections. A prereimplantation threshold value of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) to determine infection eradication and the proper timing of reimplantation remains ill defined. We theorized that rather than a specific numeric threshold, a percentage of improvement in these serology markers might improve diagnostic accuracy in determining the timing of reimplantation. QUESTION/PURPOSES: We investigated if (1) the percent, or delta, change in ESR and CRP values from preresection to prereimplantation ([INCREMENT]ESR, [INCREMENT]CRP) is a useful marker of infection eradication and (2) whether the initial PJI causative organism (resistant, nonresistant, or culture-negative) is associated with serum ESR and CRP values before and after treatment with an antibiotic spacer and parenteral antibiotic therapy. METHODS: We retrospectively reviewed 300 patients, nine of whom were lost to followup, treated with a two-stage revision THA or TKA protocol between 2005 and 2014 from two separate institutional arthroplasty registries. Serum ESR and CRP values were recorded at two designated points: (1) preresection and (2) after 6 weeks of intravenous antibiotic therapy with a drug-eluting spacer and completion of an organism-specific intravenous antibiotic regimen. Patient records were reviewed electronically for causative species of infection, revision surgeries, and recurrent/persistent infection based on Musculoskeletal Infection Society criteria for a minimum of 2 years. Forty-eight of 291 patients (16%) underwent a revision procedure for recurrent or persistent infection, whereas 31 patients (10%) were revised for noninfectious reasons. The [INCREMENT]ESR, [INCREMENT]CRP, culture results, and patient demographics were recorded and analyzed with receiver operator curves controlling for American Society of Anesthesiologists (ASA) class. RESULTS: Receiver operator characteristic area under the curves (AUC) demonstrated that both the [INCREMENT]ESR (AUC = 0.581) and [INCREMENT]CRP (AUC = 0.539) percentages were poor markers of recurrent or persistent infection. When comparing preresection with prereimplantation values, the median percent [INCREMENT]ESR was 50% (interquartile range [IQR], 17%-77%) for those patients who remained infection-free versus 59% (IQR, 29%-78%) for those who developed reinfection (p = 0.540). The median percent [INCREMENT]CRP was 77% (IQR, 47%-92%) for those patients who remained infection-free versus 79% (IQR, 46%-95%) for those who experienced reinfection (p = 0.634). Although no significant differences were found between organism type and CRP values at the two time points, the preresection ESR level was higher in patients infected with resistant bacteria (median, 69; IQR, 60%-85%) compared with nonresistant organisms (median, 55; IQR, 33%-83%; p = 0.020). CONCLUSIONS: The percent change in serum ESR and CRP inflammatory markers before and after two-stage reimplantation for PJI was not associated with reinfection risk when controlling for ASA class. Although a return to normal serology infrequently occurs before reimplantation, [INCREMENT]ESR and [INCREMENT]CRP provide no additional diagnostic accuracy to determine the timing of reimplantation. Furthermore, the pre- and postresection serology values have no meaningful relationship to resistant or nonresistant pathogens. Decisions for reimplantation must take into account multiple variables rather than a specific threshold change in serum inflammatory markers. LEVEL OF EVIDENCE: Level III, diagnostic study.

Neutrophil-to-lymphocyte ratio is a strong predictor for overall survival and disease free survival in many cancers. Our study is the first investigation aiming to determine the predictive value of neutrophil-to-lymphocyte ratio on prognosis of patients with stage III melanoma. This retrospective study utilized a cohort of 107 patients with stage III melanoma treated at Huntsman Cancer Institute, University of Utah, from May 2002 to March 2016. The optimal cutoff of neutrophil-to-lymphocyte ratio was determined by the significance of log-rank tests. A total of 97 log-rank tests were conducted to find the optimal cutoff. Disease free survival was assessed using the Kaplan-Meier method, and univariable and multivariable Cox models were applied to evaluate the predictive value of neutrophil-to-lymphocyte ratio. 2.5 was identified as the optimal cutoff. Kaplan-Meier curve showed that the disease free survival rate of the low value group was significantly higher compared to that of high value group. After adjusting for confounders and other prognostic factors, the neutrophil-to-lymphocyte ratio ≥ 2.5 remained a strong predictor for disease recurrence in patients with stage III melanoma.

Dysphagia affects a multitude of people worldwide with tremendous impact on the affected individual, families, and caregivers. Understanding dysphagia, as well as the status of screening, evaluation, and treatment, aids in the knowledge required by a interprofessional team to holistically care for patients with dysphagia and their caregivers. The impact of dysphagia includes potential associated risk and a cascade of effects. Conversations regarding meeting nutrition and fluid needs with consideration for quality of life need to be integrated into the plan of care for individuals with dysphagia.

Gut microbiome plays an important role in adult human health and diseases. However, how nutritional factors shape the initial colonization of gut bacteria in infants, especially in preterm infants, is still not completely known. In this study, we compared the effects of feeding with mothers’ own breast milk (MBM) and formula on the initial composition and gene expression of gut bacteria in moderate-late preterm infants. Fecal samples were collected from ten formula-fed and ten MBM healthy infants born between 32 to 37 weeks’ gestation after they reached full volume enteral feedings. Total DNAs were extracted from fecal samples for amplicon sequencing of 16S ribosomal RNA (rRNA) gene and total RNA with rRNA depletion for metatranscriptome RNA-Seq. 16S rRNA gene amplicon sequencing results showed that the alpha-diversity was similar between the MBM and formula fed preterm infants, but the beta-diversity showed a significant difference in composition (p = 0.002). The most abundant taxa were Veillonella (18.4%) and Escherichia/Shigella (15.2%) in MBM infants, whereas the most abundant taxa of formula fed infants were Streptococcus (18.6%) and Klebsiella (17.4%). Propionibacterium, Streptococcus, and Finegoldia had significantly higher relative abundance in the MBM group than the formula group, whereas operational taxonomic units (OTUs) under family Enterobacteriaceae, genera Enterococcus and Veillonella, and class Bacilli were more abundant in formula group. In general, microbiomes from both diet groups exhibited high functional levels of catalytic activity and metabolic processing when analyzed for gene ontology using a comparative metatranscriptome approach. Statistically, the microbial genes in MBM group had an upregulation in expression related to glycine reductase, periplasmic acid stress response in Enterobacteria, acid resistance mechanisms and L-fucose utilization. In contrast, the formula fed group had upregulations in genes associated with methionine and valine degradation functions. Our data suggest that the nutritional source plays a role in shaping the moderate-late preterm gut microbiome as evidenced by the differences in bacterial composition and gene expression profiles in the fecal samples. The MBM group enriched Propionibacterium. Glycine reductase was highly upregulated in the microbiota from MBM along with the upregulated acid stress tolerance genes, suggesting the intensity of fermentation process was enhanced.

OBJECTIVE: Predictors of long-term functional impairment in acute respiratory failure of all causes are poorly understood. Our objective was to assess the frequency and predictors of long-term functional impairment or death after invasive mechanical ventilation for acute respiratory failure of all causes. DESIGN: Population-based, observational cohort study. SETTING: Eight adult ICUs of a single center. PATIENTS: All adult patients from Olmsted County, Minnesota, without baseline functional impairment who received mechanical ventilation in ICUs for acute respiratory failure of all causes from 2005 through 2009. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In total, 743 patients without baseline functional impairment received mechanical ventilation in the ICU. At 1- and 5-year follow-up, the rates of survival with return to baseline functional ability were 61% (366/597) and 53% (356/669). Among 71 patients with new functional impairment at 1 year, 55% (39/71) had recovered and were alive without functional impairment at 5 years. Factors predictive of new functional impairment or death at 1 year were age, comorbidities, discharge to other than home, mechanical ventilation of 7 days or longer, and stroke. Of factors known at the time of intubation, the following are predictive of new functional impairment or death: age, comorbidities, nonsurgical condition, Acute Physiology and Chronic Health Evaluation III score, stroke, and sepsis. Post hoc sensitivity analyses revealed no significant change in predictor variables in patient populations when stroke was excluded or who received more than 48 hours of mechanical ventilation. CONCLUSIONS: At 1- and 5-year follow-up, many patients who received mechanical ventilation for acute respiratory failure from all causes are no longer alive or have new moderate-to-severe functional impairment. Functional recovery between year 1 and year 5 is possible and common. Sepsis, stroke, illness severity, age, and comorbidities predict long-term functional outcome at intubation.

Background Management of patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC) when cisplatin is contraindicated is controversial. We aimed to assess whether radiotherapy with concurrent and adjuvant durvalumab would improve outcomes compared with radiotherapy with cetuximab. Methods NRG-HN004 was designed as an open-label, multicentre, parallel-group, randomised, phase 2/3 trial with safety lead-in conducted at 89 academic and community medical centres in North America. Eligible patients were aged 18 years or older with American Joint Committee on Cancer 8th edition stage III–IVB p16-negative HNSCC or unfavourable stage I–III p16-positive oropharyngeal or unknown primary carcinoma, who had a contraindication to cisplatin (Eastern Cooperative Oncology Group [ECOG] performance status 2, renal or hearing impairment, peripheral neuropathy, aged at least 70 years with moderate or severe comorbidity, or aged younger than 70 years with severe comorbidity). Patients were randomly assigned (2:1) by permuted block randomisation (multiples of 6) to intravenous durvalumab 1500 mg starting 2 weeks before radiotherapy then every 4 weeks starting week 2 of radiotherapy (seven cycles) or intravenous cetuximab 400 mg/m 2 1 week before radiotherapy then 250 mg/m 2 weekly beginning week 1 of radiotherapy (eight cycles), with intensity-modulated radiotherapy (70 Gy in 35 fractions over 7 weeks). Stratification factors were tumour and nodal stage, ECOG performance status and comorbidity, and primary site and p16 status. The phase 2 primary endpoint was progression-free survival in the intention-to-treat population. There was one prespecified interim futility analysis at 50% of progression-free survival information. If the observed hazard ratio was 1·0 or more, favouring cetuximab, early stopping would be considered. Extended follow-up analysis was post hoc. This trial is registered with ClinicalTrials.gov, NCT03258554, and is closed to enrolment. Findings Following a ten-patient safety lead-in, the phase 2 trial enrolled 190 patients from March 12, 2019, to July 30, 2021, 186 of whom were randomly assigned (123 to durvalumab and 63 to cetuximab). Median age was 72 years (IQR 64–77), 30 (16%) patients were women and 156 (84%) were men. Phase 2 accrual was suspended in July 30, 2021, following an interim futility analysis, and permanently closed in Sept 1, 2022. The phase 3 part of the trial was not conducted. At a median follow-up of 2·3 years (IQR 1·9–3·1) for the extended follow-up (data cutoff July 31, 2023; post-hoc analysis), 2-year progression-free survival was 50·6% (95% CI 41·5–59·8) in the durvalumab group versus 63·7% (51·3–76·1) in the cetuximab group (hazard ratio 1·33 [95% CI 0·84–2·12]; p=0·89). Adverse events were similar in both groups. The most common grade 3–4 adverse events were dysphagia (26 [22%] of 119 patients in the durvalumab group vs 18 [30%] of 61 patients in the cetuximab group), lymphopenia (33 [28%] vs 20 [33%]), and oral mucositis (13 [11%] vs 11 [18%]). Four (3%) patients in the durvalumab group and one (2%) in the cetuximab group died from treatment-related adverse events (death not otherwise specified, laryngeal oedema, lung infection, and respiratory failure in the durvalumab group and sudden death not otherwise specified in the cetuximab group). Interpretation Our findings suggest that durvalumab did not improve outcomes compared with cetuximab in patients with HNSCC with contraindications to cisplatin. Further trials are needed to define the standard of care for this population. Funding US National Cancer Institute and AstraZeneca.