Exploring Inner Ear and Brain Connectivity through Perilymph Sampling for Early Detection of Neurological Diseases: A Provocative Proposal.

Recent evidence shows that it is possible to identify the elements responsible for sensorineural hearing loss, such as pro-inflammatory cytokines and macrophages, by performing perilymph sampling. However, current studies have only focused on the diagnosis of such as otologic conditions. Hearing loss is a feature of certain neuroinflammatory disorders such as multiple sclerosis, and sensorineural hearing loss (SNHL) is widely detected in Alzheimer's disease. Although the environment of the inner ear is highly regulated, there are several communication pathways between the perilymph of the inner ear and cerebrospinal fluid (CSF). Thus, examination of the perilymph may help understand the mechanism behind the hearing loss observed in certain neuroinflammatory and neurodegenerative diseases. Herein, we review the constituents of CSF and perilymph, the anatomy of the inner ear and its connection with the brain. Then, we discuss the relevance of perilymph sampling in neurology. Currently, perilymph sampling is only performed during surgical procedures, but we hypothesize a simplified and low-invasive technique that could allow sampling in a clinical setting with the same ease as performing an intratympanic injection under direct visual check. The use of this modified technique could allow for perilymph sampling in people with hearing loss and neuroinflammatory/neurodegenerative disorders and clarify the relationship between these conditions; in fact, by measuring the concentration of neuroinflammatory and/or neurodegenerative biomarkers and those typically expressed in the inner ear in aging SNHL, it could be possible to understand if SNHL is caused by aging or neuroinflammation.

Functional phenotypes in schizophrenia spectrum disorders: defining the constructs and identifying biopsychosocial correlates using data-driven methods.

Functional impairments contribute to poor quality of life in schizophrenia spectrum disorders (SSD). We sought to (Objective I) define the main functional phenotypes in SSD, then (Objective II) identify key biopsychosocial correlates, emphasizing interpretable data-driven methods. Objective I was tested on independent samples: Dataset I (N = 282) and Dataset II (N = 317), with SSD participants who underwent assessment of multiple functioning areas. Participants were clustered based on functioning. Objective II was evaluated in Dataset I by identifying key features for classifying functional phenotype clusters from among 65 sociodemographic, psychological, clinical, cognitive, and brain volume measures. Findings were replicated across latent discriminant analyses (LDA) and one-vs.-rest binomial regularized regressions to identify key predictors. We identified three clusters of participants in each dataset, demonstrating replicable functional phenotypes: Cluster 1-poor functioning across domains; Cluster 2-impaired Role Functioning, but partially preserved Independent and Social Functioning; Cluster 3-good functioning across domains. Key correlates were Avolition, anhedonia, left hippocampal volume, and measures of emotional intelligence and subjective social experience. Avolition appeared more closely tied to role functioning, and anhedonia to independent and social functioning. Thus, we found three replicable functional phenotypes with evidence that recovery may not be uniform across domains. Avolition and anhedonia were both critical but played different roles for different functional domains. It may be important to identify critical functional areas for individual patients and target interventions accordingly.

A Review of Pseudomyxoma Peritonei: Insights Into Diagnosis, Management, and Prognosis.

Pseudomyxoma peritonei (PMP) is a rare and complex clinical syndrome characterized by the accumulation of mucinous ascites within the peritoneal cavity, typically associated with mucinous tumours of appendiceal origin. Despite its rarity, PMP poses significant challenges in diagnosis and management due to its indolent yet locally aggressive nature. This comprehensive review provides insights into the diagnosis, management, and prognosis of PMP, synthesizing current evidence and emerging trends in the field. Challenges and opportunities in PMP management are discussed, along with recommendations for clinical practice emphasizing the importance of a multidisciplinary approach and specialized care. Despite ongoing challenges, advances in surgical techniques, perioperative chemotherapy, and emerging therapies offer hope for improved outcomes and quality of life for PMP patients.

ACR Appropriateness Criteria® Screening for Abdominal Aortic Aneurysm.

Abdominal aortic aneurysm (AAA) is a significant vascular disease found in 4% to 8% of the screening population. If ruptured, its mortality rate is between 75% and 90%, and it accounts for up to 5% of sudden deaths in the United States. Therefore, screening of AAA while asymptomatic has been a crucial portion of preventive health care worldwide. Ultrasound of the abdominal aorta is the primary imaging modality for screening of AAA recommended for asymptomatic adults regardless of their family history or smoking history. Alternatively, duplex ultrasound and CT abdomen and pelvis without contrast may be appropriate for screening. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

ACR Appropriateness Criteria® Pulmonary Arteriovenous Malformation (PAVM): 2023 Update.

Pulmonary arteriovenous malformations (PAVMs) occur in 30% to 50% of patients with hereditary hemorrhagic telangiectasia. Clinical presentations vary from asymptomatic disease to complications resulting from the right to left shunting of blood through the PAVM such as paradoxical stroke, brain abscesses, hypoxemia, and cardiac failure. Radiology plays an important role both in the diagnosis and treatment of PAVM. Based on different clinical scenarios, the appropriate imaging study has been reviewed and is presented in this document. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Enhancing P2/O3 Biphasic Cathode Performance for Sodium-Ion Batteries: A Metaheuristic Approach to Multi-Element Doping Design.

Sodium-ion batteries (SIBs) have emerged as a compelling alternative to lithium-ion batteries (LIBs), exhibiting comparable electrochemical performance while capitalizing on the abundant availability of sodium resources. In SIBs, P2/O3 biphasic cathodes, despite their high energy, require furthur improvements in stability to meet current energy demands. This study introduces a systematic methodology that leverages the meta-heuristically assisted NSGA-II algorithm to optimize multi-element doping in electrode materials, aiming to transcend conventional trial-and-error methods and enhance cathode capacity by the synergistic integration of P2 and O3 phases. A comprehensive phase analysis of the meta-heuristically designed cathode material Na0.76Ni0.20Mn0.42Fe0.30Mg0.04Ti0.015Zr0.025O2 (D-NFMO) is presented, showcasing its remarkable initial reversible capacity of 175.5 mAh g-1 and exceptional long-term cyclic stability in sodium cells. The investigation of structural composition and the stabilizing mechanisms is performed through the integration of multiple characterization techniques. Remarkably, the irreversible phase transition of P2→OP4 in D-NFMO is observed to be dramatically suppressed, leading to a substantial enhancement in cycling stability. The comparison with the pristine cathode (P-NFMO) offers profound insights into the long-term electrochemical stability of D-NFMO, highlighting its potential as a high-voltage cathode material utilizing abundant earth elements in SIBs. This study opens up new possibilities for future advancements in sodium-ion battery technology.

Loss of Epitranscriptomic Modification N6-Methyladenosine (m6A) Reader YTHDF1 Exacerbates Ischemic Brain Injury in a Sexually Dimorphic Manner.

N6-Methyladenosine (m6A) is a neuronal-enriched, reversible post-transcriptional modification that regulates RNA metabolism. The m6A-modified RNAs recruit various m6A-binding proteins that act as readers. Differential m6A methylation patterns are implicated in ischemic brain damage, yet the precise role of m6A readers in propagating post-stroke m6A signaling remains unclear. We presently evaluated the functional significance of the brain-enriched m6A reader YTHDF1, in post-stroke pathophysiology. Focal cerebral ischemia significantly increased YTHDF1 mRNA and protein expression in adult mice of both sexes. YTHDF1-/- male, but not female, mice subjected to transient middle cerebral artery occlusion (MCAO) showed worsened motor function recovery and increased infarction compared to sex-matched YTHDF1+/+ mice. YTHDF1-/- male, but not female, mice subjected to transient MCAO also showed significantly perturbed expression of genes related to inflammation, and increased infiltration of peripheral immune cells into the peri-infarct cortex, compared with sex-matched YTHDF1+/+ mice. Thus, this study demonstrates a sexual dimorphism of YTHDF1 in regulating post-ischemic inflammation and pathophysiology. Hence, post-stroke epitranscriptomic regulation might be sex-dependent.

Estimation of static and dynamic functional connectivity in resting-state fMRI using zero-frequency resonator.

Resting-state functional magnetic resonance imaging (rs-fMRI) is increasingly being used to infer the functional organization of the brain. Blood oxygen level-dependent (BOLD) features related to spontaneous neuronal activity, are yet to be clearly understood. Prior studies have hypothesized that rs-fMRI is spontaneous event-related and these events convey crucial information about the neuronal activity in estimating resting state functional connectivity (FC). Attempts have been made to extract these temporal events using a predetermined threshold. However, the thresholding methods in addition to being very sensitive to noise, may consider redundant events or exclude the low-valued inflection points. Here, we extract the event-related temporal onsets from the rs-fMRI time courses using a zero-frequency resonator (ZFR). The ZFR reflects the transient behavior of the BOLD events at its output. The conditional rate (CR) of the BOLD events occurring in a time course with respect to a seed time course is used to derive static FC. The temporal activity around the estimated events called high signal-to-noise ratio (SNR) segments are also obtained in the rs-fMRI time course and are then used to compute static and dynamic FCs during rest. Coactivation pattern (CAP) is the dynamic FC obtained using the high SNR segments driven by the ZFR. The static FC demonstrates that the ZFR-based CR distinguishes the coactivation and non-coactivation scores well in the distribution. CAP analysis demonstrated the stable and longer dwell time dominant resting state functional networks with high SNR segments driven by the ZFR. Static and dynamic FC analysis underpins that the ZFR-driven temporal onsets of BOLD events derive reliable and consistent FCs in the resting brain using a subset of the time points.

An unexpected role for the ketogenic diet in triggering tumor metastasis by modulating BACH1-mediated transcription.

We have found that the ketogenic (Keto) diet is able to, unexpectedly, promote the metastatic potential of cancer cells in complementary mouse models. Notably, the Keto diet-induced tumor metastasis is dependent on BTB domain and CNC homolog 1 (BACH1) and its up-regulation of pro-metastatic targets, including cell migration-inducing hyaluronidase 1, in response to the Keto diet. By contrast, upon genetic knockout or pharmacological inhibition of endogenous BACH1, the Keto diet-mediated activation of those targets is largely diminished, and the effects on tumor metastasis are completely abolished. Mechanistically, upon administration of the Keto diet, the levels of activating transcription factor 4 (ATF4) are markedly induced. Through direct interaction with BACH1, ATF4 is recruited to those pro-metastatic target promoters and enhances BACH1-mediated transcriptional activation. Together, these data implicate a distinct transcription regulatory program of BACH1 for tumor metastasis induced by the Keto diet. Our study also raises a potential health risk of the Keto diet in human patients with cancer.

Effectiveness of Mannheim's Peritonitis Index in Patients With Peritonitis Secondary to Hollow Viscus Perforation in a Tertiary Care Hospital in Jharkhand, India.

Introduction Peritonitis refers to the inflammation of the peritoneum and peritoneal cavity. Causes of peritonitis can be bacterial (gastrointestinal or non-gastrointestinal), chemical, traumatic, or ischemic. Peritonitis can be localized or diffuse, acute or chronic. Peritonitis can be primary, secondary, or tertiary, according to the pathogenesis. Peritonitis developed secondary to hollow viscus perforation is a life-threatening condition and a common cause of emergency surgery in India. The Mannheim peritonitis index (MPI) is a simple scoring system that can accurately predict the outcome of peritonitis. This study aimed to evaluate the effectiveness of MPI in predicting mortality risk or prognosis in patients with peritonitis due to hollow viscus perforation. Materials and methods This observational cross-sectional study at the Department of General Surgery, Rajendra Institute of Medical Sciences, Ranchi, involved 111 patients with peritonitis due to hollow viscus perforation from December 2021 to March 2022. Detailed history, clinical examination, relevant blood tests, and radiological investigations established a diagnosis of perforation peritonitis, followed by a score assessment. Data were analyzed using SPSS software (IBM Corp., Armonk, NY, USA). Results Patients >50 years had higher mortality (i.e., 18/43) than patients <50 years (i.e., 13/68). Overall mortality was 31, which included one in low risk, 12 in intermediate risk, and 18 in the high-risk group. Mortality was lowest in the low-risk group (i.e., 1/30), highest in the high-risk group (i.e., 18/40), and 12/41 in the intermediate-risk group; the p-value was <0.05, which was highly significant. Mortality was higher in patients presenting after 24 hours, having organ failure, and non-colonic sepsis. Conclusion The MPI scoring system is simple, easy to calculate, cost-effective, precise, and effective in assessing mortality and morbidity risk in patients with peritonitis due to hollow viscus perforation. It can also guide further management strategies.

Multi-location evaluation of field pea in Indian climates: eco-phenological dynamics, crop-environment relationships, and identification of mega-environments.

Characterization of crop-growing environments in relation to crop's genotypic performance is crucial to harness positive genotype-by-environment interactions (GEI) in systematic breeding programs. Given that, the study aimed to delineate the impact of diverse environments on crop phenology and yield traits of dwarf-statured field pea, pinpointing location(s) favoring higher yield and distinctiveness within breeding lines. We tested twelve field pea breeding lines across twenty locations in India, covering Central Zone (CZ), North Western Plain Zone (NWPZ), North Eastern Plain Zone (NEPZ), and Northern Hill Zone (NHZ). Across these locations, maximum and minimum temperatures during flowering (TMAXF, TMINF) and reproductive period (TMAXRP, TMINRP) ranged 18.9-28.3, 3.3-18.0, 15.0-30.8, and 7.9-22.1oC, respectively. Meanwhile, notable variations in phenological and agronomic traits (coefficient of variation) were observed: flowering (31%), days to maturity (21%), reproductive period (18%), grain yield (48%), and 100-seed weight (18%). Combined ANOVA demonstrated an oversized impact of environment (81%) on yield, while genotype and GEI effects were 2% and 14%, respectively. The variables TMINF, TMINRP, and cumulative growing degree-day showed positive correlations with yield, while extended vegetative and maturity durations negatively influenced yield (p < 0.05). Additionally, linear mixed-models and PCA results explained that instability in crop phenology had significant influence on field pea yield. Seed weight was markedly varied within the locations (9.9-20.8 g) and both higher and lower seed weights were associated with lower yields (Optimal = 17.1 g). HA-GGE biplot-based on environment focus-scaling demonstrated three mega-environments and specific locations viz. Kota (CZ), SK Nagar (CZ), Raipur (CZ), Sehore (CZ), and Pantnagar (NWPZ) as the ideal testing-environments with high efficiency in selecting new genotypes with wider adaptability. The study findings highlight distinct impact of environments on crop phenology and agronomic traits of field pea (dwarf-type), hold substantial value in designing efficient field pea (dwarf-type) breeding program at mega-environment scale.

Beyond the Norm: Navigating a Unique Papillary Carcinoma Journey in Breast Cancer.

The presence of papillary structures inside the tumor is a unique and uncommon characteristic of breast cancer, and it is known as papillary carcinoma. In contrast to other forms of breast cancer, this variant usually manifests as a well-defined mass in imaging investigations and is frequently linked to a good prognosis. We present a case of a 72-year-old female with papillary carcinoma of the breast identified after presenting with a palpable breast lump. Following a left simple mastectomy and adjuvant treatment, the presence of papillary structures inside the tumor was verified by a histopathological study. Understanding the clinical and pathological characteristics of breast papillary carcinoma is crucial for precise diagnosis and suitable therapy strategizing. More research is required to further understand the molecular traits and best practices for treating this uncommon subtype of breast cancer.

A blood-brain barrier-penetrant AAV gene therapy improves neurological function in symptomatic mucolipidosis IV mice.

Mucolipidosis IV (MLIV) is a rare, autosomal recessive, lysosomal disease characterized by intellectual disability, motor deficits, and progressive vision loss. Using adeno-associated vector 9 (AAV9) and AAV-PHP.B as delivery vectors, we previously demonstrated the feasibility of modifying disease course in a mouse model of MLIV by the human MCOLN1 gene transfer. Here, using a primate-enabling capsid AAV.CPP.16 (CPP16), we constructed a new, clinic-oriented MCOLN1 gene expression vector and demonstrated its efficacy in the preclinical model of MLIV. Systemic administration of CPP16-MCOLN1 in adult symptomatic Mcoln1 -/- mice at a dose of 1e12 vg per mouse resulted in MCOLN1 expression in the brain and peripheral tissues, alleviated brain pathology, rescued neuromotor function, and completely prevented paralysis. Notable expression of MCOLN1 transcripts was also detected in the retina of the mouse, which had exhibited significant degeneration at the time of the treatment. However, no increase in retinal thickness was observed after gene therapy treatment. Our results suggest a new AAV-based systemic gene replacement therapy for the treatment of MLIV that could be translated into clinical studies.

Primary Cytoreduction and Survival for Patients With Less-Common Epithelial Ovarian Cancer.

This cohort study examines the association between primary cytoreduction status and survival for patients with less-common, advanced-stage epithelial ovarian carcinoma.

A Case of Well-Differentiated Endometrial Adenocarcinoma in a Postmenopausal Woman.

Endometrial adenocarcinoma is a prevalent malignancy among postmenopausal women, often presenting with symptoms such as abnormal vaginal bleeding and pelvic pain. We present a case of a 60-year-old postmenopausal female who exhibited abnormal vaginal bleeding for three months, accompanied by pelvic pain and unintentional weight loss. Clinical evaluation, including physical examination, imaging studies, and histopathological examination, led to the diagnosis of well-differentiated endometrial adenocarcinoma. The patient underwent an abdominal hysterectomy with bilateral salpingo-oophorectomy, and histopathological analysis confirmed invasive tumor involvement in the lower uterine segment and cervix. The final pathological tumor, node, and metastasis (TNM) staging was reported as pT1b No Mx, FIGO (International Federation of Gynecology and Obstetrics) stage II. This case underscores the importance of considering endometrial adenocarcinoma in the differential diagnosis of postmenopausal bleeding and highlights the significance of timely diagnosis and multidisciplinary management for optimizing patient outcomes.

Circadian-Dependent Intermittent Fasting Influences Ischemic Tolerance and Dendritic Spine Remodeling.

BACKGROUND: Preconditioning by intermittent fasting is linked to improved cognition and motor function, and enhanced recovery after stroke. Although the duration of fasting was shown to elicit different levels of neuroprotection after ischemic stroke, the impact of time of fasting with respect to the circadian cycles remains unexplored. METHODS: Cohorts of mice were subjected to a daily 16-hour fast, either during the dark phase (active-phase intermittent fasting) or the light phase (inactive-phase intermittent fasting) or were fed ad libitum. Following a 6-week dietary regimen, mice were subjected to transient focal cerebral ischemia and underwent behavioral functional assessment. Brain samples were collected for RNA sequencing and histopathologic analyses. RESULTS: Active-phase intermittent fasting cohort exhibited better poststroke motor and cognitive recovery as well as reduced infarction, in contrast to inactive-phase intermittent fasting cohort, when compared with ad libitum cohort. In addition, protection of dendritic spine density/morphology and increased expression of postsynaptic density protein-95 were observed in the active-phase intermittent fasting. CONCLUSIONS: These findings indicate that the time of daily fasting is an important factor in inducing ischemic tolerance by intermittent fasting.

The risk and benefit profiles of US eligible lung cancer screening attendees vs. non-attendees.

BACKGROUND: The United States Preventive Services Task Force (USPSTF) recommend lung-cancer screening for individuals aged 50-80 with ≥20 pack-years and ≤15 quit-years, but uptake is low. The risk and benefit profiles of screening attendees are unknown; consequently, the impact and lost opportunity of ongoing lung-cancer screening in the US remains unclear. METHODS: We estimated lung-cancer death risk (using the Lung Cancer Death Risk Assessment Tool) and life gained from screening (using the LYFS-CT model) for individuals 50-79 who ever-smoked in the US-representative 2022 Behavioral Risk Factor Surveillance System. We compared lung-cancer death risk and life-gained among USPSTF-eligible individuals by screening status (self-reported screened vs not screened in past year), and estimated the number of lung-cancer deaths averted and life-years gained under current screening levels and if everyone eligible was screened. RESULTS: USPSTF-eligibility was 33.7% (95%CI:33.1-34.4%), of whom 17.9% (95%CI : 17.0-18.8%) self-reported screening. Screening uptake increased with increasing lung-cancer death risk quintile (Q1 = 5.2% (95%CI : 3.0%-8.8%); Q5 = 21.8% (95%CI : 20.3%-23.3%)) and life-gain from screening quintile (Q1 = 6.2% (95%CI : 3.8%-9.9%); Q5 = 20.8% (95%CI : 19.5%-22.2%)). Screened individuals had higher lung-cancer death risk (Risk Ratio [RR]=1.35, 95%CI : 1.26-1.46) and life-years gained (RR = 1.19, 95%CI : 1.12-1.25) than unscreened individuals. Currently screening averts 19,306 lung-cancer deaths and gains 237,564 life-years; screening everyone eligible would additionally avert 56,956 lung-cancer deaths and gain 751,850 life-years. Two-thirds of USPSTF-lung-eligible women were up-to-date with breast-cancer screening, but only 17.3% attended lung screening in the past year. CONCLUSIONS: Eligible screening attendees had higher lung-cancer death risk and benefit from screening. Higher rates of screening could substantially increase the number of lung-cancer deaths prevented.

Tumor niche network-defined subtypes predict immunotherapy response of esophageal squamous cell cancer.

Despite the promising outcomes of immune checkpoint inhibitors (ICIs), resistance to ICI presents a new challenge. Therefore, selecting patients for specific ICI applications is crucial for maximizing therapeutic efficacy. Herein, we curated 69 human esophageal squamous cell cancer (ESCC) patients' tumor microenvironment (TME) single-cell transcriptomic datasets to subtype ESCC. Integrative analyses of the cellular network and transcriptional signatures of T cells and myeloid cells define distinct ESCC subtypes characterized by T cell exhaustion, and interleukin (IL) and interferon (IFN) signaling. Furthermore, this approach classifies ESCC patients into ICI responders and non-responders, as validated by whole tumor transcriptomes and liquid biopsy-based single-cell transcriptomes of anti-PD-1 ICI responders and non-responders. Our study stratifies ESCC patients based on TME transcriptional network, providing novel insights into tumor niche remodeling and potentially predicting ICI responses in ESCC patients.

A ten-year experience of musculoskeletal tuberculosis at a tertiary care hospital in South India.

Background: The delayed identification and management of musculoskeletal tuberculosis (MSTB) poses substantial health challenges and leads to significant morbidity. This study aimed to collate ten years of hospital data and provide valuable insights into the clinical, diagnostics, and outcomes of the patients diagnosed with MSTB. Methods: A retrospective study was undertaken to review clinic records from 2013 to 2022 for all individuals diagnosed with MSTB in a tertiary care hospital in South India. Results: Over a decade, 400 cases of MSTB were diagnosed, revealing 57 % males and 43 % females with a mean age of 43.2 ± 18.9 years. Spinal TB constituted 72 % of cases, with the most common involvement of thoracic vertebrae (50.9 %). Extra-spinal MSTB accounted for 28 %, prevalent more in the pediatric age group (p < 0.05). Surgical intervention was required for 80 % of spinal TB cases and 58 % of extra-spinal MSTB cases. The average follow-up duration was two years, with 73 % completing treatment. Unfortunately, seven patients died, and three experienced relapse. Conclusion: Spinal TB is the most common type of MSTB and is predominant in young and middle-aged adults, while extra-spinal MSTB is more frequently observed in children. Where use of MRI facilitates early detection of spinal TB; histopathological and microbiological examination confirm the diagnosis. Combining anti-tubercular drugs with modern surgical approaches is essential for obtaining favorable outcomes and improving the quality of life of such patients. It is crucial to have advanced and affordable diagnostic facilities, along with increased public awareness, to reinforce tuberculosis control strategies.

Drug-Resistant Bone, Joint and Spine Tuberculosis: Evolution of Diagnosis and Treatment.

Background: Drug resistant (DR) osteoarticular TB (OATB) is a challenge in view of it being deep seated lesion and paucibacillary disease. Case definition, investigation protocol, treatment of proven DR and those cases where DR could not be demonstrated lacks clarity and evidence. Hence, a series of studies were conducted to develop an algorithm to investigate and treat therapeutically refractory disease (TRD) or presumptive drug resistance (PDR) cases of OATB. Patients and methods: 6 studies were conducted. Study one and two evaluated criteria to label TRD/PDR. Three subsequent studies were conducted where TDR/PDR or fresh cases of OATB cases were investigated by AFB smear, Bactec/liquid culture, histology and genotypic DST by CBNAAT & LPA. Sixth study was a retrospective evaluation of all DR cases treated for proven or clinical drug resistance (CDR). Results: Patient of bone/spine TB on ATT for 5 months or more show poor clinico-radiological treatment response as worsening of lesion, increased spinal deformity, persistent discharging sinus/ulcer, appearance of fresh lesion, recurrence of previous lesion, wound dehiscence of post-operative surgical scar cab labelled as PDR cases. These cases on histology ascertained TB and were proven DR on genotypic and phenotypic DST and are treated successfully. The patients of histologically ascertained TB and no/indeterminate phenotypic and genotypic DST were successfully treated as clinical drug resistance on MDR protocol. Conclusions: We described an algorithm. We must suspect PDR(TRD) based on criteria described. The tissue must be procured and submitted for AFB smear, histology and phenotypic and genotypic DST for diagnosis of TB. Genotypic and phenotypic DST will be useful to prove (90% instances) type of drug resistance. Remaining on strong clinical suspicion of DR and yet inconclusive on phenotypic/genotypic DST (<10%), may be treated as CDR as MDR. The adverse drug reactions and hepatic side-effects should be monitored diligently and these cases to be treated till healed status is demonstrated.