Bone replacement grafts with guided tissue regeneration in treatment of grade II furcation defects: a systematic review and meta-analysis.

AIM: The present systematic review appended with meta-analysis aimed to evaluate the efficacy of bone replacement graft (BRG) with guided tissue regeneration (GTR) over BRG or open flap debridement (OFD) alone in the treatment of grade II furcation defects. MATERIALS AND METHODS: An electronic literature search of PubMed, Cochrane Library and Google Scholar databases accompanied with manual searching was done. Randomized controlled trials (RCTs) up to October 2019, comparing BRG+GTR with BRG or OFD in grade II furcation defects, were identified. Clinical attachment level (CAL) gain, changes in gingival marginal level (GML), vertical defect fill (VDF), horizontal defect fill (HDF) and reduction in defect volume were the outcome parameters. RESULTS: Of a total of 12, 9 studies compared BRG+GTR vs BRG while 3 compared BRG+GTR vs OFD. Meta-analysis was carried out for CAL gain, VDF, HDF and GML changes. In the BRG+GTR vs BRG comparison group, out of 9 studies, 6 RCTs showed standardized mean difference (SMD) of 0.513 for VDF, 9 RCTs showed SMD of 0.83 for HDF and 2 RCTs showed SMD of 0.651 for CAL gain, whereas only 2 studies in the same group reported reduction in defect volume. Three studies of the BRG+GTR vs OFD group exhibited significant VDF and CAL gain with SMD of 2.002 and 1.161 respectively. However, no significant change was recorded for GML in both groups. CONCLUSION: The present systematic review indicates supplemental benefits of combination therapy of BRG+GTR over monotherapy in resolving grade II furcation defects. CLINICAL RELEVANCE: In our quest to achieve maximum regeneration in grade II furcation defects, combination therapies such as BRG+GTR have been accepted as treatment choices over other modalities. Clinical situations warranting near-complete regeneration of the tissues in such defects are better suited for combination therapies.

Metals in coarse ambient aerosol as markers for source apportionment and their health risk assessment over an eastern coastal urban atmosphere in India.

Ambient PM10 (particulate matter with aerodynamic diameter ≤ 10 µm) samples were collected and characterized from July 2012 to August 2013 with the objective to evaluate the variation in elemental concentration and use the same as markers for source apportionment and health risk assessment for the first time over Bhubaneswar, India. The yearly average mass of PM10 was 82.28 µg/m3, which was ~ 37% higher than the national ambient air quality (NAAQ) standards. Maximum PM10 concentration was observed during winter season followed by post-monsoon, pre-monsoon, and monsoon months. Acid soluble components in the PM10 samples were analyzed using ICP-OES (inductive coupled plasma optical emission spectroscopy), and 19 different elements including heavy metals were determined. Enrichment factor analysis attributed the source to either crustal or non-crustal origin. Principal component analysis (PCA) revealed that crustal sources, industrial activities, and vehicular emissions were significant contributors to PM mass. The contribution of total average elemental concentration showed a seasonal variation with the lowest (11.96 µg/m3) and highest (17.77 µg/m3) during monsoon and winter, respectively, which is relatively less significant than the variation in total PM10 mass that ranged between 48.43 µg/m3 in monsoon and 138.24 µg/m3 during the winter season. This observation evidences the predominant contribution of local/regional emission sources to the metallic components in coarse PM10 mass, which is corroborated by the wind pattern studies carried out using polar plots and a Lagrangian Particle Dispersion Model (LPDM) FLEXPART. Further, carcinogenic and non-carcinogenic health risk assessments of the measured elements that find their way into the human body through different exposure pathways have been calculated using United State Environmental Protection Agency (USEPA) standards. The carcinogenic risk of most of the elements was insignificant. The potential risk assessment study revealed that regular exposure to heavy metals through the ingestion pathway caused detrimental health effects. These effects were observed to be more severe in children in comparison to adults.

Crystal Nucleation of Tolbutamide in Solution: Relationship to Solvent, Solute Conformation, and Solution Structure.

The influence of the solvent in nucleation of tolbutamide, a medium-sized, flexible and polymorphic organic molecule, has been explored by measuring nucleation induction times, estimating solvent-solute interaction enthalpies using molecular modelling and calorimetric data, probing interactions and clustering with spectroscopy, and modelling solvent-dependence of molecular conformation in solution. The nucleation driving force required to reach the same induction time is strongly solvent-dependent, increasing in the order: acetonitrile

First report of viral nervous necrosis-induced mass mortality in hatchery-reared larvae of clownfish, Amphiprion sebae Bleeker.

Frequent mortality was observed in the larval rearing facility of marine clownfish, Amphiprion sebae Bleeker. Mortality resulted in 80% loss of larval stock. Moribund larvae showed clinical signs typical of viral nervous necrosis, such as uncoordinated, corkscrew-like swimming behaviour, hypersensitivity to stimuli, darkening of body and assembly into large groups, similar to bunches of grapes. The aetiology of the disease was confirmed by gross observation of clinical signs, histopathology and molecular diagnosis. Histological studies revealed severe vacuolation in the brain and in the bipolar and ganglion layers of the eye. Molecular diagnosis by reverse transcription-polymerase chain reaction (RT-PCR) specific to piscine nodavirus yielded a positive result. The partial nucleotide sequences of the PCR-amplified fragment were 97-98% similar to other betanodavirus isolates reported globally and more closely aligned with red-spotted grouper nervous necrosis virus (RGNNV). This is the first report of susceptibility of clownfish, A. sebae, to betanodavirus and the presence of the RGNNV in India.

Clinico-radiographic comparative evaluation of 1% metformin gel plus platelet-rich fibrin over platelet-rich fibrin alone in the treatment of Grade II furcation defects: A randomized controlled double-blind clinical trial.

BACKGROUND: The present study was aimed to evaluate and compare the effects of 1% MF plus PRF over PRF alone in treatment of Grade II furcation defects, clinically and radiographically by using cone-beam computed tomography. METHODS: This split-mouth clinical trial randomly allotted 21 patients with 42 bilateral Grade II furcation defects into two groups. Group I was treated with PRF alone while Group II with 1% MF gel and PRF. The primary outcome parameters were clinical attachment level (CAL) and horizontal probing depth (HPD) while the secondary outcome parameters were probing depth (PD) and defect volume (DV). The clinical parameters were evaluated at 3, 6, and 12 months and the radiographic parameters at 12 months. RESULTS: Both the study groups yielded improvements in assessed parameters; however, significantly greater mean reduction of PD, HPD, and CAL gain was observed in Group II (3.90 ± 0.78 mm, 2.94 ± 0.80 mm, and 3.42 ± 0.93 mm) in comparison with Group I (3.23 ± 0.90 mm, 1.96 ± 0.80 mm, and 2.67 ± 0.88 mm) at 12 months, respectively. A significant reduction of DV was exhibited radiographically in Group II (12.61 ± 4.01 mm3 ) as compared with Group I (9.14 ± 4.31 mm3 ) at the end of 12 months. CONCLUSIONS: Better clinical and radiographic findings in terms of reduction in PD, HPD, CAL gain, and significant reduction in DV in Group II patients indicated that the combination therapy of 1% MF + PRF promotes regenerative ability within the periodontal tissues in Grade II furcation defects to a greater extent.

Surgeon education through a surgical cost feedback system reduces supply cost in endoscopic skull base surgery.

OBJECTIVE: A large proportion of healthcare expense is operating room (OR) costs. As a means of cost mitigation, several institutions have implemented surgeon education programs to bring awareness about supply costs. This study evaluates the impact of a surgical cost feedback system (surgical receipt) on the supply costs of endoscopic skull base surgery (ESBS) procedures. METHODS: The supply costs of each ESBS surgical case were prospectively collected and analyzed before and after the implementation of a nonincentivized, automated, and itemized weekly surgical receipt system between January 2017 and December 2019. Supply cost data collected 15 months prior to intervention were compared with cost data 21 months after implementation of the surgical receipt system. Demographics, surgical details, and OR time were collected retrospectively. RESULTS: Of 105 ESBS procedures analyzed, 36 preceded and 69 followed implementation of cost feedback. There were no significant differences in patient age (p = 0.064), sex (p = 0.489), surgical indication (p = 0.389), or OR anesthesia time (p = 0.51) for patients treated before and after implementation. The mean surgical supply cost decreased from $3824.41 to $3010.35 (p = 0.002) after implementation of receipt feedback. Usage of dural sealants (p = 0.043), microfibrillar collagen hemostat (p = 0.007), and oxidized regenerated cellulose hemostat (p < 0.0001) and reconstructive technique (p = 0.031) significantly affected cost. Mediation analysis confirmed that the overall cost reduction was predominantly driven by reduced use of dural sealant; this cost saving exceeded the incremental cost of greater use of packing materials such as microfibrillar collagen hemostat. CONCLUSIONS: Education of surgeons regarding surgical supply costs by a surgical receipt feedback system can reduce the supply cost per case of ESBS operations.

A structural element within the HUWE1 HECT domain modulates self-ubiquitination and substrate ubiquitination activities.

E3 ubiquitin ligases catalyze the final step of ubiquitin conjugation and regulate numerous cellular processes. The HECT class of E3 ubiquitin (Ub) ligases directly transfers Ub from bound E2 enzyme to a myriad of substrates. The catalytic domain of HECT Ub ligases has a bilobal architecture that separates the E2 binding region and catalytic site. An important question regarding HECT domain function is the control of ligase activity and specificity. Here we present a functional analysis of the HECT domain of the E3 ligase HUWE1 based on crystal structures and show that a single N-terminal helix significantly stabilizes the HECT domain. We observe that this element modulates HECT domain activity, as measured by self-ubiquitination induced in the absence of this helix, as distinct from its effects on Ub conjugation of substrate Mcl-1. Such subtle changes to the protein may be at the heart of the vast spectrum of substrate specificities displayed by HECT domain E3 ligases.

COVID-19 Pandemic-Frontline Experiences and Lessons Learned From a Tertiary Care Teaching Hospital at a Suburban Location of Southeastern India.

The key challenges to any health care setup during emergency situations, such as that of the COVID-19 pandemic would be to rapidly address hospital preparedness and response tailored to the local population, societal influences, political factors within the existing infrastructure, and workforce. Second, to adopt and moderate policies, standard operating procedures (SOPs) and guidelines issued by national and international agencies, such as WHO, CDC, and the Indian Council for Medical Research (ICMR) were tailor-made to the local conditions of the hospital and community. In this publication, we have discussed the challenges and experiences in preparation and responses to the ongoing COVID-19 pandemic at a tertiary teaching hospital situated at a suburban locale in a small union territory. Puducherry is located in the South Eastern Coromandel Coast of India. The core processes, such as hospital preparedness, adoption, and amendments to SOPs based on dynamic changes in guidelines released by the central and local government, training given to health care workers, setting up the in-house diagnostic facility, surge capacity, management of supplies during the lockdown, infection prevention, and control and patient care are discussed. We have also reinforced our experiences in translating COVID-related opportunities for research and innovation in the form of awards and research proposals for the faculty and students of our institute. The lessons learned in terms of strength and limitations on the ground level of public health during this process is worth sharing as it would provide guidance in preparing the health care setups for pre- and post-pandemic.

Melatonin-induced changes in ovarian function in the freshwater fish Channa punctatus (Bloch) held in long days and continuous light.

It is possible to manipulate fish gonadal function through exogenous melatonin. However gonadal responses to melatonin vary and depend on time, mode and duration of the administration of the hormone. The present study describes the effects of different photoperiods and melatonin treatments on the ovarian kinetics of the fish Channa punctatus. Fish held in long days (LD 14:10) were injected melatonin daily (10 microg im) either at 08.00 or 17.00 h, respectively or immersed in melatonin water (100 microg/l) for 24 or 15 h daily. In another experiment fish held in long days or continuous light (LL; LD 24.00) were immersed in melatonin water (100 microg/l) either for 24 or 15 h daily. Both experiments had appropriate controls. The GSI (Gonadosomatic index=gonadal wt./100g body weight) increased (P<0.01) in fish immersed in melatonin water daily for 24h when compared either with the GSI of control fish or with fish held in melatonin water daily for 15 h (17.00-08.00 h). The GSI decreased (P<0.01) in fish that received melatonin daily by injection mode. Data from follicular kinetics largely corroborate the GSI data. Fish exposed to melatonin water daily for 24h had more vitellogenic follicles (VF) and fewer atretic follicles (AF). There was a general decrease (P<0.01) in previtellogenic follicles (PVF) in all treated groups. Melatonin by injection mode did not affect the number of VF but it significantly increased (P<0.01) the AF. In the other experiment, the GSI increased (P<0.01) in fish held in long days and immersed in melatonin water 24h daily. However, the GSI decreased in fish held in long days and immersed in melatonin water for a restricted period (between 17.00 and 08.00 h). The GSI of fish held in LL and immersed in melatonin water daily for 24h increased (P<0.01), whereas it decreased (P<0.01) in fish that were immersed in melatonin water daily for 15 h. The data from follicular kinetics revealed a decrease in PVF of fish held in LL and in all the melatonin-exposed groups irrespective of the duration of exposure to melatonin. However the VF increased markedly in fish held in LL and immersed in melatonin water daily for 24h. VF of fish held in LL but immersed in melatonin water daily for restricted period decreased. In fish held in long days and immersed in melatonin water daily either for 24 or 15 h the VF number increased (P<0.01). Marked increase in AF was seen fish held in LL and exposed to melatonin-containing water daily for restricted period. The effect of melatonin on reproduction seems to depend on the photoperiod and duration of exposure to melatonin. In fish held either in long days or LL, daily restricted exposure to melatonin tends to inhibit gonads, whereas continuous exposure to melatonin either stimulate or has no effect. The results apparently support the view that duration of exposure to melatonin signals darkness.

Surgeon cost feedback through a surgical receipt program reduces cost in sinonasal surgery.

BACKGROUND: Operating room (OR) costs are a large portion of healthcare expenses. This study evaluates the impact of a surgeon-targeted surgical receipt cost feedback system on OR supply costs in sinonasal surgery and individual components contributing to procedural cost. METHODS: Itemized weekly surgical receipts detailing individual case supply costs were analyzed before and after the implementation of a non-incentivized surgeon cost feedback system between January 2017 and June 2019. Supply cost data collected 15 months prior to intervention was compared to cost data 15 months after implementation of the weekly automated receipt dissemination to surgeons. Chi square test was used for categorical data and the Wilcoxon test was used to compare change in cost. Univariate and mediation analyses were performed to assess variables impacting cost. RESULTS: Of 502 sinonasal procedures analyzed, 239 were before and 264 after cost feedback implementation. There were no significant differences in age/gender, or indication for surgery. The median OR supply cost decreased from $1229.64 to $1097.22 (p = 0.02) after receipt implementation. There were effects of procedure type (p = 0.02), circulating nurse specialization (p < 0.001), steroid eluting stent (p = 0.002), and sinus drill (p < 0.001) on cost. Mediation analysis confirmed full mediation by decreasing use of steroid-eluting stents. CONCLUSION: Surgeon cost feedback in the form of individualized OR surgical receipts is an effective model to reduce supply cost per case in sinonasal surgery.

Application of cardiovascular disease risk prediction models and the relevance of novel biomarkers to risk stratification in Asian Indians.

The increasing pressure on health resources has led to the emergence of risk assessment as an essential tool in the management of cardiovascular disease (CVD). Concern exists regarding the validity of their generalization to all populations. Existing risk scoring models do not incorporate emerging 'novel' risk factors. In this context, the aim of the study was to examine the relevance of British, European, and Framingham predictive CVD risk scores to the asymptomatic high risk Indian population. Blood samples drawn from the participants were analyzed for various 'traditional' and 'novel' biomarkers, and their CVD risk factor profiling was also done. The Framingham model defined only 5% of the study cohort to be at high risk, which appears to be an underestimation of CVD risk in this genetically predisposed population. These subjects at high risk had significantly elevated levels of lipid, pro-inflammatory, pro-thrombotic, and serological markers. It is more relevant to develop risk predictive scores for application to the Indian population. This study substantiates the argument that alternative approaches to risk stratification are required in order to make them more adaptable and applicable to different populations with varying risk factor and disease patterns.

Limitations of the endoscopic endonasal transcribriform approach.

The endoscopic endonasal transcribriform approach (EETA) has become a useful strategy in the treatment of various anterior skull base pathologies, including meningoencephaloceles, olfactory groove meningiomas, schwannomas, esthesioneuroblastomas, and other sinonasal malignancies. However, not all pathologies are optimally treated through this approach due to tumor size, extent of the lesion, vascular involvement, and the presence of intact olfaction. One must be prepared to use a transcranial approach if the EETA is not favorable. In some patients, a combined approach (transcranial-EETA) may be needed in appropriate cases. Therefore, patient selection is paramount for achieving a successful result with avoidance of complications. For certain tumors, the limitations of the EETA may result in lower rates of gross-total resection, higher rates of cerebrospinal fluid leakage, postoperative impairment of olfaction, and higher complication rates. In this paper, we discuss the limitations of the EETA when considering approach selection to treat anterior skull base lesions.

The Role of Fast Imaging Employing Steady-State Acquisition (FIESTA) Magnetic Resonance Imaging for Assessment of Delayed Enhancement of Fat Graft Packing on Postoperative Imaging After Vestibular Schwannoma Surgery.

OBJECTIVE: To investigate the role and efficacy of fast imaging employing steady-state acquisition (FIESTA) imaging in distinguishing fat graft enhancement from residual or recurrent tumor after vestibular schwannoma (VS) surgery. METHODS: A retrospective study of 33 patients who underwent VS resection via the retrosigmoid or translabyrinthine approach with fat graft reconstruction was performed. Magnetic resonance imaging (MRI) was collected at different time points: preoperative, immediate postoperative (24-48 hours), delayed postoperative (3-6 months after surgery), and yearly postoperative. The image sets contained T1, T2, fat-suppressed T1-weighted with gadolinium, and FIESTA. The radiographs were analyzed for tumor recurrence by the primary neurosurgeon and an independent blinded neuroradiologist. If fat-suppressed T1-weighted images demonstrated postoperative enhancement in the resection bed, a comparison was made with FIESTA imaging. RESULTS: At 3-6 months postoperatively and at 1 year and beyond, 28 (84.8%) and 33 (100%) of patients, respectively, displayed delayed enhancement of the fat graft on postgadolinium fat-suppressed T1-weighted MRI. The enhancement seen on postgadolinium, fat-suppressed, T1-weighted MRI consistently correlated with the characteristic fat graft signal on FIESTA imaging and not tumor recurrence. FIESTA imaging was able to distinguish residual tumor from enhancing fat graft compared with postgadolinium, fat-suppressed, T1-weighted MRI (P < 0.0001) due to distinctive signaling patterns. CONCLUSIONS: FIESTA is an effective tool in discerning fat graft enhancement from residual or recurrent tumor on delayed postoperative imaging after VS resection. Fat graft used in reconstruction consistently enhances on delayed postoperative postgadolinium, fat-suppressed, T1-weighted imaging, which correlates with the fat graft signal seen on FIESTA images.

The Impact of Duty-Hour Restrictions on Complication Rates Following Major Head and Neck Procedures.

OBJECTIVES/HYPOTHESIS: To assess the impact of resident duty-hour restrictions (DHR) in otolaryngology via comparison of postoperative outcomes between otolaryngology teaching hospitals (Oto-TH) and nonteaching hospitals (NTH) before and after complete implementation. STUDY DESIGN: Retrospective database review. METHODS: The Nationwide Inpatient Sample was queried for all major head and neck cases between 2000 and 2002 (n = 34,064) and 2008 and 2010 (n = 33,094). Cases were stratified into Oto-TH (n = 28,771) and NTH (n = 38,387) and assessed for procedure type, patient comorbidities, and complications. A subpopulation matched by procedure type was generated for direct comparison of complication rates using χ2 and binary logistic regression analyses. RESULTS: In the years following DHR, total case volume and average case complexity increased at Oto-TH only. Using a case-matched subpopulation, regression analysis found Oto-TH status to be protective for medical complications both before (odds ratio [OR]: 0.60, P < .001) and after (OR: 0.76, P = .001) DHR. In contrast, Oto-TH cases had lower risk for surgical complications in 2000 to 2002 (OR: 0.77, P < .001) but not 2008 to 2010 (OR: 1.07, P = .275). When comparing time periods, the years following DHR were associated with a significant decrease in medical complications and mortality across hospital cohorts. For surgical complications, rates significantly improved at NTH only (OR: 0.82, P = .002), with no difference at Oto-TH (OR: 0.95, P = .450). CONCLUSIONS: In the years following DHR, rates of medical complications, surgical complications, and mortality have significantly improved at NTH. At Oto-TH, there has been a lack of similar improvement in surgical complications, even after accounting for increasing case volume and complexity in more recent years. While the cause is likely multifactorial, DHR in otolaryngology residency may play a role. LEVEL OF EVIDENCE: 4 Laryngoscope, 128:2804-2810, 2018.

Characterization of neutrophil-to-lymphocyte ratio as a measure of inflammation in rheumatoid arthritis.

OBJECTIVES: The neutrophil to lymphocyte ratio (NLR) is one of the well-recognized sensitive measures of inflammation. This cross-sectional observational study was aimed at characterizing the relationship of NLR with the inflammatory markers erythrocyte sedimentation rate (ESR), C-reative protein (CRP), Disease Activity Score of 28 joints (DAS28)-CRP(3), joint counts and quality measures of rheumatoid arthritis (RA). MATERIALS AND METHODS: Patients with RA were recruited in two phases. The following were assessed for all patients: joint count, pain by visual analogue scale (VAS), complete blood count, ESR, CRP and quality index assessment using the Short Form health survey (SF-36) questionnaire. A subgroup analysis was also performed to evaluate the association between NLR and cytokines. RESULTS: Four hundred and eighty-nine subjects were recruited. Distribution of NLR values corresponded with DAS28-CRP(3) rather than CRP and ESR. A significant difference in VAS, swollen joint counts (SJC-28), inflammatory parameters and general health outcome measures was observed among the NLR groups. A weak correlation was observed between NLR and RA disease measures. It had least bias at lower ranges with DAS28-CRP(3) than CRP and ESR. The NLR cut-off value of 1.4 classified the patients in deep remission with 90% specificity, 24% sensitivity, likelihood ratio positive (LR+) 2.46 and likelihood ratio negative (LR-) 0.84. CRP was a significant baseline predictor of NLR. A significant influence of interleukin-6 on CRP was noted. CONCLUSION: In contrast to the traditional markers, NLR may serve as a less expensive and effective measure of inflammation in RA. Its efficacy is comparable to that of CRP and it is not impacted by the cytokines influencing CRP and ESR.

Gruber, Gradenigo, Dorello, and Vail: key personalities in the historical evolution and modern-day understanding of Dorello's canal.

A century ago an ambitious young anatomist in Rome, Primo Dorello, who sought to understand the cause of abducent nerve palsy that often occurred in patients with severe middle ear infections, conducted intricate studies on the intracranial course of the nerve. In his findings, he identified that the abducent nerve passes through a narrow sinus near the apex of the petrous bone, which formed an osteofibrous canal. Dorello suggested that in this enclosed region the abducent nerve may be particularly vulnerable to compression due to the vascular edema accompanying the infection. Although his work was widely appreciated, it was not well received by all. Interestingly, Giuseppe Gradenigo, one of the most prominent Italian otologists of the early 20th century, who was known for his work on a triad of symptoms (Gradenigo's syndrome) that accompanies petrous apicitis, a result of severe middle ear infections, was obstinate in his criticism of Dorello's findings. Thus a scientific duel began, with a series of correspondence between these two academics-one who was relatively new to the otological community (Dorello) and one who was well reputed in that community (Gradenigo). The disagreement ultimately ebbed in 1909, when Dorello published a report in response to Gradenigo's criticisms and convinced Gradenigo to change his views. Today Dorello's canal is widely recognized as a key landmark in skull base surgery of the petroclival region and holds clinical significance due to its relation to the abducent nerve and surrounding vascular structures. Yet, although academics such as Dorello and Gradenigo are recognized for their work on the canal, it is important not to forget the others throughout history who have contributed to the modern-day understanding of this anatomical structure. In fact, although the level of anatomical detail found in Dorello's work was previously unmatched, the first description of the canal was made by the experienced Austrian anatomist Wenzel Leopold Gruber in 1859, almost 50 years prior to Dorello's landmark publication. Another critical figure in building the understanding of Dorello's canal was Harris Holmes Vail, a young otolaryngologist from Harvard Medical School, who in 1922 became the first person to describe Dorello's canal in the English language. Vail conducted his own detailed anatomical studies on cadavers, and his publication not only reaffirmed Dorello's findings but also immortalized the eponym used today-"Dorello's canal." In this article the authors review the life and contributions of Gruber, Dorello, Gradenigo, and Vail, four men who played a critical role in the discovery of Dorello's canal and paved the way toward the current understanding of the canal as a key clinical and surgical entity.

Clinical outcomes in typhoid fever: adverse impact of infection with nalidixic acid-resistant Salmonella typhi.

BACKGROUND: Widespread use of fluoroquinolones has resulted in emergence of Salmonella typhi strains with decreased susceptibility to fluoroquinolones. These strains are identifiable by their nalidixic acid-resistance. We studied the impact of infection with nalidixic acid-resistant S. typhi (NARST) on clinical outcomes in patients with bacteriologically-confirmed typhoid fever. METHODS: Clinical and laboratory features, fever clearance time and complications were prospectively studied in patients with blood culture-proven typhoid fever, treated at a tertiary care hospital in north India, during the period from November 2001 to October 2003. Susceptibility to amoxycillin, co-trimoxazole, chloramphenicol, ciprofloxacin and ceftriaxone were tested by disc diffusion method. Minimum inhibitory concentrations (MIC) of ciprofloxacin and ceftriaxone were determined by E-test method. RESULTS: During a two-year period, 60 patients (age [mean +/- SD]: 15 +/- 9 years; males: 40 [67%]) were studied. All isolates were sensitive to ciprofloxacin and ceftriaxone by disc diffusion and MIC breakpoints. However, 11 patients had clinical failure of fluoroquinolone therapy. Infections with NARST isolates (47 [78%]) were significantly associated with longer duration of fever at presentation (median [IQR] 10 [7-15] vs. 4 [3-6] days; P = 0.000), higher frequency of hepatomegaly (57% vs. 15%; P = 0.021), higher levels of aspartate aminotransferase (121 [66-235] vs. 73 [44-119] IU/L; P = 0.033), and increased MIC of ciprofloxacin (0.37 +/- 0.21 vs. 0.17 +/- 0.14 microg/mL; P = 0.005), as compared to infections with nalidixic acid-susceptible isolates. All 11 patients with complications were infected with NARST isolates. Total duration of illness was significantly longer in patients who developed complications than in patients who did not (22 [14.8-32] vs. 12 [9.3-20.3] days; P = 0.011). Duration of prior antibiotic intake had a strong positive correlation with the duration of fever at presentation (r = 0.61; P = 0.000) as well as the total duration of illness (r = 0.53; P = 0.000). CONCLUSION: Typhoid fever caused by NARST infection is associated with poor clinical outcomes, probably due to delay in initiating appropriate antibiotic therapy. Fluoroquinolone breakpoints for S. typhi need to be redefined and fluoroquinolones should no longer be used as first-line therapy, if the prevalence of NARST is high.

Reduced susceptibility to ciprofloxacin and gyra gene mutation in North Indian strains of Salmonella enterica serotype Typhi and serotype Paratyphi A.

The emergence of reduced susceptibility to ciprofloxacin among Salmonella enterica serotype Typhi and serotype Paratyphi A leading to clinical failure of treatment poses a great therapeutic challenge. The mechanism of fluoroquinolone resistance in clinical isolates of S. Typhi and S. Paratyphi A is not very well documented. The present study was carried out with the objective of molecular characterization of reduced quinolone susceptibility amongst the strains of S. Typhi and S. Paratyphi A isolated from the patients with enteric fever during January, 2000, to April, 2003, in a North Indian hospital. A total of 422 culture-positive cases of enteric fever were reported to the hospital during the period of study, of which S. Typhi was isolated from 350 cases and S. Paratyphi A from 72 cases. The antimicrobial susceptibility of these strains was determined by disk diffusion and agar dilution method according to NCCLS guidelines, and E-test method. A total of 140 randomly selected strains, isolated during the years 1993-1999, that were available from the laboratory stocks were also studied to compare with the present strains. To study the quinolone susceptibility, the strains were divided into nalidixic acid sensitive (NAS), nalidixic acid intermediate resistant, (NAI) and nalidixic acid resistant (NAR) on the basis of susceptibility to nalidixic acid. Clinical history was available from 174 patients, of which 93 needed hospitalization due to severe disease. Of these, 82 patients were infected with NAR strains and 22 patients had a documented evidence of clinical failure to ciprofloxacin therapy. The patients infected with NAR strains were younger and had a significantly longer duration of fever (p value < 0.05) than those infected with NAS strains. It was observed that the proportion of NAR strains increased gradually over the years. These strains had a significantly higher range of MIC of ciprofloxacin (0.023-1.0 microg/ml) as compared to the NAS strains (0.002-0.125 microg/ml) (p value < 0.05). The sequencing of quinolone resistance determining region (QRDR) of the gyrA gene showed the presence of mutation at either Ser 83 or at Asp 87 in all the NAR and NAI strains. None of the NAS strains had a mutation, suggesting that the gyrA gene mutation is sufficient to confer resistance to nalidixic acid and reduced susceptibility to ciprofloxacin. This mutation, although phenotypically expressed as decreased susceptibility to ciprofloxacin, goes undetected by the disk diffusion method using the present NCCLS guidelines. Hence, it can increase morbidity and mortality due to delay in appropriate antibiotic treatment.