Indian consensus on the management of CRE infection in critically ill patients (ICONIC) — India

Background: The increasing burden of carbapenem-resistant Enterobacteriaceae (CRE) carriage and infection in different patient settings in India has created an acute need for guidance for clinicians regarding optimal strategies for the management of CRE infection in critically ill patients.

Research design and methods: A multidisciplinary panel of 11 Indian experts in CRE infection assembled for comprehensive discussion and consensus development. The experts developed clinical statements through a systematic review of key literature.

Main outcome measures: The panel voted anonymously on 60 clinically relevant questions, through a modified Delphi process.

Results: Forty-six key clinical consensus statements (CCS) were proposed. The panel reached a consensus on several important issues, providing recommendations on surveillance, diagnosis, prevention, pharmacokinetic challenges, combination therapy, and cornerstone molecules in CRE infections. The panel also proposed a treatment algorithm for NDM-prevalent settings.

Conclusion: These consensus statements may offer clinicians expert guidance on the management of CRE infections. There is a dearth of high-/moderate-level evidence on managing CRE infections; the recommendations presented herein are based on expert opinion.     

Reliability and validity of measurements of cervical retraction strength obtained with a hand-held dynamometer

Objectives: The purpose of this study was to describe the reliability and validity of measurements of cervical retraction strength obtained with a hand held dynamometer (HHD) from healthy adults.

Background: Impaired neck muscle strength is related to neck pain, abnormal posture, and various cervical pathologies. While sophisticated devices to objectively measure neck strength exist, many are not practicable in typical orthopedic practices or have questionable validity and reliability.

Methods: Forty participants were included in the analysis of neck strength using isometric testing with an HHD fixed in a cradle on a table top. The highest neck retraction force recorded in Newtons (N) for each participant, was used for data analysis.

Results: Both intratester and intertester reliability were excellent as judged by intraclass correlation coefficients (ICCs) (.885 – .974) and minimal detectable change (MDC) (21.1 to 47.6 N). Validity was confirmed on the basis of expected gender and age differences (ie, men were stronger than women and younger participants were stronger than older participants).

Conclusion: Fixed HHD is a reliable and valid tool for measuring isometric neck retraction strength in ostensibly healthy adults. Its value in the assessment of individuals with neck pathology awaits further examination.     

Do prognostic variables predict a set of outcomes for patients with chronic low back pain: a long-term follow-up secondary analysis of a randomized control trial

Objective: The objective was to explore for universal prognostic variables, or predictors, across three different outcome measures in patients with chronic low back pain (LBP). We hypothesized that selected prognostic variables would be ‘universal’ prognostic variables, regardless of the outcome measures used.

Methods: This study was a secondary analysis of data from a previous randomized controlled trial comparing the McKenzie treatment approach with placebo in patients with chronic LBP. Ten baseline prognostic variables were explored in predictive models for three outcomes: pain intensity, disability, and global perceived effect, at 6 and 12 months. Predictive models were created using backward stepwise logistic and linear multivariate regression analyses.

Results: Several predictors were present including age, expectancy of improvement, global perceived effect; however, we only identified baseline disability as a universal predictor of outcomes at 6 months. The second most represented universal predictor was baseline pain intensity for outcomes at 12 months.

Discussion: Only two predictors demonstrated an association with more than one outcome measure. High baseline disability predicts multidimensional outcome measures at 6 months in patients with chronic LBP while baseline pain intensity can best predict the outcome at 12 months. Nevertheless, other predictors seem to be unique to the outcome used.

Level of evidence: 2c.     

The immediate effects of cervical spine manipulation on pain and biochemical markers in females with acute non-specific mechanical neck pain: a randomized clinical trial

Study Design: Randomized clinical trial with pre-test, post-test control group design.

Objectives: To examine the immediate effects of cervical spinal manipulation (CSM) on serum concentration of biochemical markers (oxytocin, neurotensin, orexin A, and cortisol).

Background: Several studies have found an association between spinal manipulation (SM) and pain perception. However, the mechanism by which SM modulates pain remains undefined.

Methods: Twenty-eight female subjects with non-specific mechanical neck pain were randomly assigned to one of two interventions (CSM versus sham CSM). Blood samples were drawn before and immediately after the respective interventions. Oxytocin, neurotensin, orexin A, and cortisol were measured from the blood and serum using the Milliplex Map Magnetic Bead Panel Immunoassay on the Luminex 200 Platform.

Results: In the CSM group, there were significant increases in pre- versus post-manipulation mean oxytocin (154.5 ± 60.1 vs. 185.1 ± 75.6, p = .012); neurotensin (116.0 ± 26.5 vs.136.4 ± 34.1, p < . 001); orexin A (52.2 ± 31.1 vs. 73.8 ± 38.8, p < .01) serum concentration; but no significant differences in mean cortisol (p = .052) serum concentration. In the sham group, there were no significant differences in any of the biomarkers (p > .05).

Conclusion: The results of the current study suggest that the mechanical stimuli provided through a CSM may modify neuropeptide expression by immediately increasing the serum concentration of nociception-related biomarkers (oxytocin, neurotensin, orexin A, but not cortisol) in the blood of female subjects with non-specific mechanical neck pain.     

Directional preference constructs for patients’ neck pain in the absence of centralization

Objectives: We conducted a secondary analysis of a prospective, observational cohort study to (1) report the prevalence of Directional Preference (DP) constructs at first examination for patients with cervical spine challenges, and (2) determine the association between DP constructs and clinical outcomes at discharge from physical therapy.

Methods: We analyzed data collected from 718 consecutive patients who presented to outpatient, private practice clinics with primary complaints of non-specific neck pain; 200 patients met the inclusion criteria and completed first examination and discharge data. Statistical analysis determined the association between DP constructs at first examination and clinical outcomes at discharge.

Results: The findings in this investigation were that (1) the most prevalent DP constructs at first examination were related to ROM and pain intensity including Patient Reported Improvement in ROM (79.5%), Increase in Spine ROM (32.5%), and Pain Intensity Change (15.0%), (2) all DP groups improved and met the MCID for disability and pain intensity change at discharge except for the group that did not exhibit Increase in Spine ROM for pain intensity, (3) no clinically significant differences in pain intensity or disability existed between DP groups at discharge, and (4) 28.5% and 6.5% of patients exhibited a relative increase in cervical spine extension and flexion ROM, respectively, post-repeated movement testing on the first examination.

Discussion: The most prevalent DP constructs at first examination were related to ROM and pain intensity, and each was associated with a comparable clinical trajectory in terms of pain and disability outcomes at discharge. The findings of this study help Mechanical Diagnosis and Therapy (MDT) providers understand the common DP constructs encountered in routine clinical practice and their relation to pain and disability outcomes for patients with cervical spine challenges.

Level of Evidence: 2b     

Immunotherapy for renal cell carcinoma

Introduction: Advanced renal cell cancers (aRCC) has historically been responsive to immune system manipulation. A better understanding of the anti-tumor immune response has fueled the emergence of immunotherapy-based regimens, including combinations with vascular endothelial growth factor (VEGF) inhibitors.

Areas covered: In this review, we will describe the historic use of immunotherapies and their integration with newer agents, specifically in clear cell aRCC.

Expert opinion: Novel immunotherapeutic agents, as well as combinations with VEGF/TKI therapy, will become the standard of care initial therapy in the management of aRCC. Further studies in the sequencing of drug administration, managing treatment-related adverse events (TRAE), and exploring innovative approaches are warranted.     

Abnormal performance of cervical stabilizer muscles in individuals with low back pain

Objectives: To compare the performance of cervical stabilizer muscles using the craniocervical flexion test (CCFT) among individuals with subacute, chronic, and asymptomatic low back pain (LBP) conditions.

Methods: Individuals with subacute (N = 23) and chronic LBP (N = 23) with their age- and gender-matched controls (N = 30) participated in this study. All recruited participants were required to perform the CCFT. The activation score (AS) and the performance index (PI) were recorded by an assessor who was blinded to the group of participants.

Results: Approximately, 74% of subacute LBP participants and 60–65% of chronic LBP participants obtained abnormal AS and PI. AS was significantly lower in participants with subacute (P = 0.0002) and chronic LBP (P = 0.0009) than the control group. Likewise, the PI was significantly lower in participants with subacute (P = 0.0002) and chronic LBP (P = 0.0036) than the control group. Participants in the subacute LBP group showed significantly greater percentages of abnormal responses on the AS (P < 0.0001) and the PI (P = 0.0001) than the control.

Discussion: Abnormal performance of cervical stabilizer muscles using the CCFT was demonstrated in a high proportion of participants with LBP. The findings highlight the plausible association in muscle control between cervical and lumbar stabilizers.

Level of Evidence: 2b.     

Pembrolizumab for the treatment of cervical cancer

Introduction: The prognosis of patients with recurrent and/or metastatic cervical cancer remains poor, with a 5-year survival rate of 17%. Most of cervical cancers are associated with the human papillomavirus (HPV) infection that leads to viral antigens production, supporting the development of immunotherapy in cervical cancer.

Areas covered: Here we report the pharmacologic properties, clinical efficacy, and safety profile of pembrolizumab, an IgG4-kappa humanized monoclonal antibody against the programmed cell death protein 1 (PD-1) receptor, for the treatment of cervical cancer.

Expert opinion: Single agent pembrolizumab has limited efficacy in the recurrent and/or metastatic setting in an unselected patient population. However, durable responses in PD-L1-expressing cervical cancer patients led the U.S. Food and Drug Administration to grant accelerated approval of pembrolizumab in this patient population. Outside this patient population, further development involves combinations with other treatment options including chemotherapy, radiotherapy and other immunotherapeutic agents. The identification of biomarkers of efficacy beyond PD-L1 expression will be essential in order to identify patients who will most likely benefit from pembrolizumab.     

Why do we need to improve monitoring of patients with inflammatory bowel disease (IBD) on biologic treatment?

Introduction: Treatment goals for IBD patients traditionally focused on symptom control. It is increasingly recognized that many patients have continued disease activity without symptoms. Subclinical inflammation increases the risk of disease flares and long-term complications. A consensus is therefore emerging on the need to treat beyond symptoms and to define clear treatment targets for IBD patients receiving biologic medicines.

Areas covered: We review validated tools used in IBD for monitoring clinical and endoscopic response to therapy. We discuss the value of using non-invasive tests in assessing disease activity. We summarise the latest guidelines in IBD treatment and review recommendations regarding therapeutic drug monitoring. We examine the role of monitoring for and prevention of avoidable complications of treatment.

Expert Opinion: The goals of treatment in IBD are to achieve both clinical remission and mucosal healing. Whether we adopt a top-down or more conventional treatment strategy there is now an imperative to monitor patients using a combination of endoscopic and biochemical markers to assess the degree of continuing inflammation and establish early disease control. TDM has facilitated huge improvement in the ability to personalize delivery of biologics. This has allowed for early detection and prevention of loss of response.     

Self-reported sinus headaches are associated with neck pain and cervical musculoskeletal dysfunction: a preliminary observational case control study

Objectives: Headaches can be associated with rhinosinusitis and may present a diagnostic challenge because of symptomatic overlap with other recurring headaches. Neck pain has received extensive attention in migraine, tension-type and cervicogenic headache but not as a comorbid feature of headache in those with rhinosinusitis. This study investigated the occurrence of neck pain and cervical musculoskeletal dysfunction in individuals with self-reported sinus headaches (SRSH).

Methods: Participants with and without SRSH attended a single data collection session. Participants completed the Headache Impact Test (HIT)-6 and the Sino-Nasal Outcome Test (SNOT)-22. Cervical range of motion (ROM), segmental examination, muscle endurance and pressure-pain threshold (PPT) were measured .

Results: Participants included 31 with SRSH (77.4% female; age 43.7 (9.9) years) and 30 without headache. Average symptom duration was 89.7 (±85.6) months. Mean SNOT-22 and HIT-6 scores were 36.2 (15.3) and 56.7 (7.1), respectively. In the SRSH group, 83.9% (n = 26) reported neck pain. There was a significant difference between groups for cervical sagittal (14.3° [5.3°, 23.3°], p = 0.002) and transverse plane ROM (21.5° [12.4°, 30.6°], p < 0.001), but no difference in frontal plane motion (p = 0.017). There were significant between groups difference in neck flexor endurance (19.5 s [10.1 s, 28.9 s], <0.001), segmental dysfunction O-C4 (p < 0.001) but not in PPT (p = 0.04).

Discussion: Neck pain and cervical musculoskeletal dysfunction are common among persons with SRSH and may be a comorbid feature or contributing factor to headaches attributed to rhinosinusitis. Further research is needed to understand these associations.     

Pragmatic neural tissue management improves short-term pain and disability in patients with sciatica: a single-arm clinical trial

Objectives: To evaluate the clinical effect of sciatic neural mobilization in combination with the treatment of surrounding structures for sciatica patients. Secondly, we were also interested in identifying possible baseline characteristics that may be associated with improvements in pain and disability for sciatica patients.

Methods: Twenty-eight patients with a clinical diagnosis of sciatica were treated with neural mobilization, joint mobilization and soft tissue techniques. Pain intensity and lumbar disability were assessed at baseline and after treatment using a Numerical Rating Scale (0–10) and the Oswestry Disability Index (0–100), respectively. The pre- and post-intervention data were compared. The research protocol was registered under the number NCT03663842.

Results: Participants attended an average of 16 (SD±5.6) treatment?sessions over an average of 12 weeks. Decrease in pain scores (before median = 8, after median = 2; p < 0.001) and improvement in lumbar disability scores (before median = 33.3%, after median = 15.6%; p < 0.001) were observed. A multiple linear regression analysis showed that duration of pain and age of the patient predicted the disability improvement: F (2, 24) = 4.084, p < 0.030, R² = 0.254.

Discussion: Patients with sciatica may benefit from neural mobilization in combination with manual therapy for pain and lumbar disability. Longer pain duration and younger age had a negative influence on lumbar disability improvement.     

Predictors of adverse outcomes after transcatheter mitral valve replacement

Introduction: Transcatheter mitral valve replacement (TMVR) is still a recent technology with numerous unknowns but also great promises. The risk of complications reported in observational studies have limited its adoption by interventional cardiology and surgical communities.

Areas covered: Some of the major setbacks of TMVR are complications related to the devices and those related to the pathway. Device-related complications include left ventricle outflow tract (LVOT) obstruction, transcatheter heart valve (THV) dislocation or embolization, thrombosis, and stroke. The transapical approach currently remains the main pathway for TMVR but is associated with high risk of major bleeding and residual apical myocardial scarring. Complication prediction and prevention seem possible. Device-related complication prediction is based on pre-operative imaging including multi-slice computed tomography with 3-dimensional reconstructions and echocardiography which allow LVOT obstruction prediction and appropriate sizing aiming at avoiding dislocation. Industry should aim at the development of transfemoral delivery systems. Nevertheless, several recent feasibility observational studies suggested acceptable safety and efficacy of transcatheter mitral valve replacement.

Expert opinion: TMVR complications and transapical delivery are some of the main setbacks which need to be addressed for TMVR to be adopted for broad clinical use.     

Challenges in the management of HIV infection: update on the role of probiotic supplementation as a possible complementary therapeutic strategy for cART treated people living with HIV/AIDS

Introduction: Recent insights show that gut-mucosal immunity and intestinal microbiota play a key role in the pathogenesis of HIV infection. Alterations in the composition of intestinal flora (dysbiosis) could be associated with an impaired intestinal epithelium barrier activity and an impaired mucosal immunity function, significantly contributing to microbial translocation which is considered a major driver of chronic immune activation.

Areas covered: This article provides an overview on the novel trends in probiotic therapy application. A particular emphasis is addressed to the importance of probiotics as a novel strategy to attenuate or prevent gastrointestinal involvement and to improve gut-mucosal immunity in HIV-infected subjects. Therefore, opportunities, limits and methodological criticalities of supplementation with probiotic therapy are considered and analyzed.

Expert opinion: Use of probiotics is emerging as a novel strategy to manage dysbiosis and gut-mucosal impairment, to reduce immune activation and to limit a number of non-AIDS-related disorders. However, despite the growing use of probiotic therapy, mechanisms by which oral bacteria intake exhibits its effects are strain-related and disease-specific, hence clinicians need to take these two factors into consideration when suggesting probiotic supplementation to HIV-infected patients.     

Management and prevention of drug resistant infections in burn patients

Introduction: Despite modern advances, the primary cause of death after burns remains infection and sepsis. A key factor in determining outcomes is colonization with multi-drug resistant (MDR) organisms. Infections secondary to MDR organisms are challenging due to lack of adequate antibiotic treatment, subsequently prolonging hospital stay and increasing risk of adverse outcomes.

Areas covered: This review highlights the most frequent organisms colonizing burn wounds as well as the most common MDR bacterial infections. Additionally, we discuss different treatment modalities and MDR infection prevention strategies as their appropriate management would minimize morbidity and mortality in this population. We conducted a search for articles on PubMed, Web of Science, Embase, Cochrane, Scopus and UpToDate with applied search strategies including a combination of: “burns, ‘thermal injury,’ ‘infections,’ ‘sepsis,’ ‘drug resistance,’ and ‘antimicrobials.’

Expert opinion: Management and prevention of MDR infections in burns is an ongoing challenge. We highlight the importance of preventative over therapeutic strategies, which are easy to implement and cost-effective. Additionally, targeted, limited use of antimicrobials can be beneficial in burn patients. A promising future area of investigation within this field is post-trauma microbiome profiling. Currently, the best treatment strategy for MDR in burn patients is prevention.     

Controversies in classification of peritoneal tuberculosis and a proposal for clinico-radiological classification

Introduction: Peritoneal tuberculosis is a common type of abdominal tuberculosis. The most commonly used classification divides peritoneal tuberculosis into wet-ascitic type, dry-plastic type, and fixed-fibrotic type.

Areas covered: We performed a systematic literature search on the definitions of existing classification of peritoneal tuberculosis. The literature search identified confusion in the classification of peritoneal tuberculosis. The classification system also fails to classify some patterns of peritoneal tuberculosis like an abdominal cocoon and a substantial overlap in various categories was found. The impact of the present classification on clinical management is unclear. Lack of prospective studies and the presence of heterogeneity in reporting add to the confusion.

Expert opinion: We suggest that a uniform system which better classifies peritoneal tuberculosis and helps in clinical management should be used in future studies. We propose a simple, clinico-radiological classification of peritoneal tuberculosis into two types: distension-dominant and/or pain-obstruction dominant based on the clinical presentation. This approach will be relevant to clinicians as patients with the pain-obstruction dominant presentation are more likely to receive surgical interventions and may benefit from additional measures aimed to reduce fibrosis-like addition of steroids to ATT. Future studies should aim to validate the proposed clinico-radiological classification in patients with peritoneal tuberculosis.     

Immunotherapy and biologicals for the treatment of allergy to Hymenoptera stings

Introduction: Venom immunotherapy (VIT) is an effective treatment for Hymenoptera venom allergy. The occurrence of severe reactions (SRs) to VIT, although infrequent, hampers the achievement of tolerance to insect stings. Risk factors for such reactions include allergy to honeybee venom, concomitant mast cell disorders, and the build-up phase of VIT. A role for omalizumab has come forward in recent years.

Areas covered: This article reviews the available literature on the efficacy of omalizumab in preventing SRs and allowing the attainment of VIT maintenance doses. Pre- and co-treatments with omalizumab were evaluated, with positive overall results. Adding omalizumab to VIT in patients with SRs generally results in tolerance to VIT, thus restoring its precious preventive value.

Expert opinion: VIT is effective for patients with Hymenoptera venom allergy and is recommended to prevent further (possibly fatal) reactions to stings. Omalizumab has shown efficacy in protecting patients from VIT-related SRs, particularly in those at high risk of SRs because of mast cell disorders and/or honeybee venom allergy. Notwithstanding, the accepted dose and time course of omalizumab for achieving tolerability and ensuring safety during VIT are not yet defined. In the future, other biologicals may play a role in preventing SRs during VIT.     

Prevalence of comorbidities in heart failure patients and those treated with cellular therapeutics

Introduction: Changes in our daily living, particularly in work routines, diet, and physical exercise, have influenced a worldwide crisis for life-threatening comorbidities and the likelihood of cardiovascular disease diagnosis. Cardiovascular regenerative medicine researchers continue to investigate new therapeutic approaches and reexamine completed clinical trials to design more effective future studies. As the frequency of cardiovascular disease diagnosis continues to rise, investigations of how to repair and regenerate the failing myocardium remains an essential mission for human health.

Areas covered: This review first examines the aging process, the rising rate of comorbidities, and the likelihood of developing heart disease. In the ongoing efforts to recapitulate human health needs in clinical trials, a review of clinical trials involving cellular therapeutics for cardiac repair, with a focus on the patient population and patients’ complex medical records, is presented.

Expert opinion: The expert opinion first draws attention to the changing demographics of patients diagnosed with diseases that lead to heart failure and focusing on obesity as a primary driver for increased cardiovascular disease. The opinion focuses on the importance of designing preclinical models and experimentation that better mimic the patient population and clinical situations to evaluate the effectiveness of potential future therapeutic interventions.     

Coronary no-reflow in the modern era: a review of advances in diagnostic techniques and contemporary management

Introduction: Atherosclerotic coronary artery disease, in particular acute myocardial infarction (AMI), is a leading cause of morbidity and mortality globally. Percutaneous coronary intervention (PCI) is the mainstay of treatment for obstructive coronary artery disease and AMI through the restoration of TIMI III flow. Despite good macrovascular flow, the myocardium can remain hypoperfusion due to poor microvascular perfusion, and this is referred to as ‘no-reflow’. Various treatments have been studied with variable success in both prevention and treatment of no-reflow.

Areas covered: This review outlines the cutting-edge diagnostic investigations which have been explored in no-reflow, allowing a deeper understanding of mechanism and microvascular pathological processes involved in its genesis. These include utility of novel MRI techniques and perfusion echo in conjunction with traditional approaches. Detailed review has been undertaken of both pharmacological and non-pharmacological techniques to prevent and manage microvascular dysfunction associated with no-reflow. Particular attention was paid to the evolution and successes of various mechanical protection devices.

Expert opinion: Most promising innovations in the diagnosis and management of no-reflow are evaluated, and future outlook is explored. Emerging advances in acute coronary syndrome have their findings applied a role in modifying the pathophysiology of no-reflow.     

Pembrolizumab for the treatment of head and neck squamous cell cancer

Introduction: Groundbreaking progress in cancer immunotherapy in the recent years has revolutionized the field of oncology with unprecedented survival rates in multiple cancer types. Head and neck cancers comprise the sixth most common cancer type in the United States with estimated 14,620 deaths in 2019. Two checkpoint inhibitors, e.g. antibodies against programmed cell death protein 1 (PD-1), are currently FDA approved for second-line therapy of recurrent and/or metastatic head and neck squamous cell carcinomas (HNSCC). Pembrolizumab is one of the two approved anti-PD-1 antibodies and under active investigation of its role in managing HNSCCs.

Areas covered: This review provides an in-depth discussion of pembrolizumab’s structural features, pharmacokinetics, pharmacodynamics, efficacy data, toxicity profile, ongoing studies, and competing agents including the standard of care options in the context of treating HNSCCs.

Expert opinion: Immune checkpoint inhibitor therapy is already an integral part of HNSCC management, especially in the recurrent and/or metastatic stage, and is preferable to conventional cytotoxic therapies due to a generally more favorable toxicity profile. Pembrolizumab’s role in treating HNSCC is highly anticipated to expand over to other contexts such as definitive combination therapy and neoadjuvant therapy for locally advanced HNSCC.