A retrospective review of the adverse effects of biological therapy and reasons for its discontinuation in a resource-limited setting.

BACKGROUND: Biological disease-modifying antirheumatic drug therapies have become the gold standard of treatment for refractory rheumatic conditions in well-resourced countries. There is a significant risk of infection and reactivation of latent infections, in particular tuberculosis, with the use of biological therapies. Their safety and reasons for discontinuation in a resource-limited environment are still unclear. OBJECTIVES: The primary objective was to describe the nature and frequency of adverse events as well as the main reason for discontinuation of biological treatment. METHODS: We conducted a retrospective, descriptive folder review of all patients started on biological therapy for rheumatic conditions from November 2011 to December 2016. RESULTS: A total of 31 patients were included. The rheumatic diseases included in the study were ankylosing spondylitis (AS) (35%), rheumatoid arthritis (RA) (19%), systemic lupus erythematosus (16%), juvenile idiopathic arthritis (13%), vasculitides (10%) and psoriatic arthritis (7%). Adverse events occurred in 26 patients (84%). Serious adverse events occurred in 14 patients (45%) with recurrent uveitis being the most common, occurring in 5 patients (16%). One patient developed pulmonary tuberculosis (PTB). Discontinuation or switching of biological therapy occurred in 13 patients (42%), with the main reasons being serious adverse events in 7 patients (23%) and treatment failure in 6 (19%). The median (interquartile range (IQR)) Bath Ankylosing Spondylitis Disease Activity Index score improved from 6.4 (5 - 7.4) to 2.8 (0.9 - 5.0), a statistically significant difference of -3.5 (p=0.001) (95% confidence interval (CI) -5.3 - -1.7) over a median (IQR) of 20 (9 - 30) months in the AS group. The median (IQR) Clinical Disease Activity Index score improved from 39 (34.5 - 43) to 21 (18.7 - 25.5), a statistically significant difference of -17.4 (p=0.044) (95% CI -34.1 - -0.7) over a median (IQR) of 39 (21 - 50) months in the RA group. CONCLUSIONS: Recurrent uveitis occurred in almost half of the patients with AS and was also the main reason for discontinuation of biological therapy. We did not document an increased risk of PTB. Disease activity scores showed significant improvement. The study is limited by the small number of patients on biological therapy, a reflection of the impact of severe resource constraints.

Bioanalysis of EGFRm inhibitor osimertinib, and its glutathione cycle- and desmethyl metabolites by liquid chromatography-tandem mass spectrometry.

Osimertinib is a "third-generation'' oral, irreversible, tyrosine kinase inhibitor. It is used in the treatment of non-small cellular lung carcinoma and spares wild-type EGFR. Due to its reactive nature, osimertinib is, in addition to oxidative routes, metabolized through GSH coupling and subsequent further metabolism of these conjugates. The extent of the non-oxidative metabolism of osimertinib is unknown, and methods to quantify this metabolic route have not been reported yet. To gain insight into this metabolic route, a sensitive bioanalytical assay was developed for osimertinib, the active desmethyl metabolite AZ5104, and the thio-metabolites osimertinibs glutathione, cysteinylglycine, and cysteine conjugates was developed. The ease of synthesis of these metabolites was a key-part in the development of this assay. This was done through simple one-step synthesis and subsequent LC-purification. The compounds were characterized by NMR and high-resolution mass spectrometry. Sample preparation was done by a simple protein crash with acetonitrile containing the stable isotopically labeled internal standards for osimertinib and the thio-metabolites, partial evaporation of solvents, and reconstitution in eluent, followed by UHPLC-MS/MS quantification. The assay was successfully validated in a 2-2000 nM calibration range for all compounds except the glutathione metabolite, where the LLOQ was set at 6 nM due to low accuracy at 2 nM. Limited stability was observed for osimertinib, AZ5104, and the glutathione metabolite. The clinical applicability of the assay was demonstrated in samples of patients treated with 80 mg osimertinib once daily, containing all investigated compounds at detectable and quantifiable levels.

Clostridial Genetics: Genetic Manipulation of the Pathogenic Clostridia.

The past 10 years have been revolutionary for clostridial genetics. The rise of next-generation sequencing led to the availability of annotated whole-genome sequences of the important pathogenic clostridia: Clostridium perfringens, Clostridioides (Clostridium) difficile, and Clostridium botulinum, but also Paeniclostridium (Clostridium) sordellii and Clostridium tetani. These sequences were a prerequisite for the development of functional, sophisticated genetic tools for the pathogenic clostridia. A breakthrough came in the early 2000s with the development of TargeTron-based technologies specific for the clostridia, such as ClosTron, an insertional gene inactivation tool. The following years saw a plethora of new technologies being developed, mostly for C. difficile, but also for other members of the genus, including C. perfringens. A range of tools is now available, allowing researchers to precisely delete genes, change single nucleotides in the genome, complement deletions, integrate novel DNA into genomes, or overexpress genes. There are tools for forward genetics, including an inducible transposon mutagenesis system for C. difficile. As the latest addition to the tool kit, clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 technologies have also been adopted for the construction of single and multiple gene deletions in C. difficile. This article summarizes the key genetic technologies available to manipulate, study, and understand the pathogenic clostridia.

Bioanalysis of ibrutinib, and its dihydrodiol- and glutathione cycle metabolites by liquid chromatography-tandem mass spectrometry.

Ibrutinib is a targeted covalent inhibitor frequently used for the treatment of various lymphomas. In addition to oxidative metabolism, it is metabolized through glutathione coupling. The quantitative insight into this kind of metabolism is scarce, and tools for quantitation are lacking. The non-oxidative metabolism could prove a more prominent role when oxidative metabolism is impaired. Also, in-vitro studies could over-estimate the effect of CYP450-inhibition. To gain quantitative insight into this relatively unknown biotransformation pathway of the drug we have developed a validated simple, fast and sensitive bio-analytical assay for ibrutinib, dihydrodiol-ibrutinib, and the glutathione, cysteinylglycine and cysteine conjugates of ibrutinib in human plasma. The method emphasizes on simplicity, the thiol-conjugates were synthesized by a simple one step synthesis, followed by LC-purification. Sample preparation was done by a simple protein crash with acetonitrile containing labeled internal standards, evaporation of solvents, and reconstitution in eluent. Finally, the compounds were quantified using UHPLC-MS/MS. The assay was successfully validated in a 0.5-500nM calibration range for all compounds, and also a lower range of 0.05-50 nM was demonstrated for ibrutinib to accommodate for even the lowest trough levels. This assay has a considerably higher sensitivity than previous published assays, with the previous lowest LLOQ being 1.14 nM. Both, ibrutinib, dihydrodiol-ibrutinib and the cysteine conjugate were deemed stable under refrigerated or frozen storage conditions. At room temperature, the glutathione conjugate showed rapid degradation into the cysteinylglycine conjugate in plasma. Finally, the applicability of the assay was demonstrated in patient samples.

Iron retention in iron-fortified rice and use of iron-fortified rice to treat women with iron deficiency: A pilot study.

OBJECTIVES: 1. Evaluate the effect of washing and cooking iron-fortified rice on iron retention and bioavailability. 2. Evaluate the effect of iron-fortified rice on women with iron deficiency anemia. METHODS: 1. Iron-fortified rice (18 mg/100 g as FeSO4) was cooked in Baton Rouge, Louisiana (C), rinsed and cooked (RC), fried and cooked (FC), cooked with extra water (CW), or soaked and cooked with extra water (SCW), and iron retention was determined. 2. Rice samples were cooked in Kampala, Uganda in a lab (C-Uganda) and households using traditional cooking method (TC-Uganda) and iron retention were determined. 3. Seventeen women with iron deficiency (low iron and/or low ferritin) anemia were randomized to 100 g/d of rice (two cooked 0.75 cup servings) for two weeks containing 18 mg/d iron (supplemented) or 0.5 mg/d iron (un-supplemented). Hemoglobin and hematocrit were evaluated at baseline and 2 weeks with other measures of iron metabolism. RESULTS: 1. Iron retention, from highest to lowest, was (C), (RC), (FC), (C-Uganda), (CW), (SCW) and (TC-Uganda). 2. Seventeen women were randomized and 15 completed the study (hemoglobin 10.6 ± 1.6 g, hematocrit 33.7 ± 4.1%), 9 in the iron-fortified rice group and 6 in the un-fortified rice group. The iron-fortified group had a greater increase in hemoglobin (0.82 g, p = 0.0035) and Hematocrit (1.83%, p = 0.0248) with directional differences in other measures of iron metabolism favoring the iron-fortified group. CONCLUSIONS: Iron-fortified rice increased hemoglobin and hematocrit in women with iron-deficient anemia. Iron deficiency and anemia are widespread in Southeast Asia and Africa and undermine development in these regions.

Shared decision-making and providing information among newly diagnosed patients with hematological malignancies and their informal caregivers: Not "one-size-fits-all".

OBJECTIVE: To optimize personalized medicine for patients with hematological malignancies (HM), we find that knowledge on patient preferences with regard to information provision and shared decision-making (SDM) is of the utmost importance. The aim of this study was to investigate the SDM preference and the satisfaction with and need for information among newly diagnosed HM patients and their informal caregivers, in relation to sociodemographic and clinical factors, cognitive coping style, and health related quality of life. METHODS: Newly diagnosed patients and their caregivers were asked to complete the Hematology Information Needs Questionnaire, the Information Satisfaction Questionnaire, and the Threatening Medical Situations Inventory. Medical records were consulted to retrieve sociodemographic and clinical factors and comorbidity by means of the ACE-27. RESULTS: Questionnaires were completed by 138 patients and 95 caregivers. Shared decision-making was preferred by the majority of patients (75%) and caregivers (88%), especially patients treated with curative intent (OR = 2.7, P = .041), and patients (OR = 1.2, P < .001) and caregivers (OR = 1.2, P = .001) with a higher monitoring cognitive coping style (MCCS). Among patients, total need for information was related to MCCS (P = .012), and need for specific information was related to MCCS and several clinical factors. Importantly, dissatisfaction with the information they received was reported by a third of the patients and caregivers, especially patients who wanted SDM (χ2  = 7.3, P = .007), and patients with a higher MCCS (OR = 0.94, P = .038). CONCLUSION: The majority of HM patients want to be involved in SDM, but the received information is not sufficient. Patient-tailored information is urgently needed, to improve SDM.

Markers of dietary protein intake are associated with successful weight loss in the POUNDS Lost trial.

To assess the association of markers for dietary protein intake, measures of dietary adherence and demographic variables with weight loss in the POUNDS Lost study over the first 6 months and again between 6 and 24 months using data from those who completed each period. This is a secondary analysis of pooled data on completers assigned to one of four diets: 65%C/15%P/20%F (AP/LF), 55%C/25%P/20%F (HP/LF), 45%C/15%P/40%F (AP/HF) or 35%C/25%P40%F (HP/HF) in the POUNDS Lost study. Urinary nitrogen excretion, dietary adherence measured by 24-h recall and attendance at sessions, age (above and below 50 years), gender, race/ethnicity and activity by pedometry were analysed. Increased spread between protein intake at baseline and protein at 6 or 24 months, assessed by urinary nitrogen excretion, was associated with greater weight loss from baseline to 2 years. At 6 and 24 months, older age, male gender, body mass index > 30 kg m-2 and adherence to the fat and protein diets were associated with more weight loss. None of these variables was associated with a regain from 6 to 24 months. Weight regain for women in the highest carbohydrate (65%) group was significantly greater (-4.4 kg [95% CI: -5.9, -3.0]) than for women in the lowest carbohydrate group (-1.8 kg [95% CI: -3.2, -0.4 kg]) (P for interaction = 0.012). An increased spread in the difference between baseline and follow-up protein intake was associated with greater weight loss, consistent with the 'protein spread theory'. Women eating the highest carbohydrate diet regained more weight from 6 to 24 months.

Thyroid hormones and changes in body weight and metabolic parameters in response to weight loss diets: the POUNDS LOST trial.

BACKGROUND: The role of thyroid hormones in diet-induced weight loss and subsequent weight regain is largely unknown. OBJECTIVES: To examine the associations between thyroid hormones and changes in body weight and resting metabolic rate (RMR) in a diet-induced weight loss setting. SUBJECTS/METHODS: Data analysis was conducted among 569 overweight and obese participants aged 30-70 years with normal thyroid function participating in the 2-year Prevention of Obesity Using Novel Dietary Strategies (POUNDS) LOST randomized clinical trial. Changes in body weight and RMR were assessed during the 2-year intervention. Thyroid hormones (free triiodothyronine (T3), free thyroxine (T4), total T3, total T4 and thyroid-stimulating hormone (TSH)), anthropometric measurements and biochemical parameters were assessed at baseline, 6 months and 24 months. RESULTS: Participants lost an average of 6.6 kg of body weight during the first 6 months and subsequently regained an average of 2.7 kg of body weight over the remaining period from 6 to 24 months. Baseline free T3 and total T3 were positively associated, whereas free T4 was inversely associated, with baseline body weight, body mass index and RMR. Total T4 and TSH were not associated with these parameters. Higher baseline free T3 and free T4 levels were significantly associated with a greater weight loss during the first 6 months (P<0.05) after multivariate adjustments including dietary intervention groups and baseline body weight. Comparing extreme tertiles, the multivariate-adjusted weight loss±s.e. was -3.87±0.9 vs -5.39±0.9 kg for free T3 (Ptrend=0.02) and -4.09±0.9 vs -5.88±0.9 kg for free T4 (Ptrend=0.004). The thyroid hormones did not predict weight regain in 6-24 months. A similar pattern of associations was also observed between baseline thyroid hormones and changes in RMR. In addition, changes in free T3 and total T3 levels were positively associated with changes in body weight, RMR, body fat mass, blood pressure, glucose, insulin, triglycerides and leptin at 6 months and 24 months (all P<0.05). CONCLUSIONS: In this diet-induced weight loss setting, higher baseline free T3 and free T4 predicted more weight loss, but not weight regain among overweight and obese adults with normal thyroid function. These findings reveal a novel role of thyroid hormones in body weight regulation and may help identify individuals more responsive to weight loss diets.

A case of renal cell carcinoma and angiomyolipoma in an adolescent girl.

We describe a case of renal cell carcinoma in the right kidney together with an angiomyolipoma in the left kidney, encountered in an adolescent girl at Potchefstroom Provincial Hospital, North West Province, South Africa.

Genetic variation of fasting glucose and changes in glycemia in response to 2-year weight-loss diet intervention: the POUNDS LOST trial.

OBJECTIVE: Weight-loss intervention through diet modification has been widely used to improve obesity-related hyperglycemia; however, little is known about whether genetic variation modifies the intervention effect. We examined the interaction between weight-loss diets and genetic variation of fasting glucose on changes in glycemic traits in a dietary intervention trial. RESEARCH DESIGN AND METHODS: The Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial is a randomized, controlled 2-year weight-loss trial. We assessed overall genetic variation of fasting glucose by calculating a genetic risk score (GRS) based on 14 fasting glucose-associated single nucleotide polymorphisms, and examined the progression in fasting glucose and insulin levels, and insulin resistance and insulin sensitivity in 733 adults from this trial. RESULTS: The GRS was associated with 6-month changes in fasting glucose (P<0.001), fasting insulin (P=0.042), homeostasis model assessment of insulin resistance (HOMA-IR, P=0.009) and insulin sensitivity (HOMA-S, P=0.043). We observed significant interaction between the GRS and dietary fat on 6-month changes in fasting glucose, HOMA-IR and HOMA-S after multivariable adjustment (P-interaction=0.007, 0.045 and 0.028, respectively). After further adjustment for weight loss, the interaction remained significant on change in fasting glucose (P=0.015). In the high-fat diet group, participants in the highest GRS tertile showed increased fasting glucose, whereas participants in the lowest tertile showed decreased fasting glucose (P-trend <0.001); in contrast, the genetic association was not significant in the low-fat diet group (P-trend=0.087). CONCLUSIONS: Our data suggest that participants with a higher genetic risk may benefit more by eating a low-fat diet to improve glucose metabolism.

Binding of Clostridium perfringens to collagen correlates with the ability to cause necrotic enteritis in chickens.

This study investigated the ability of Clostridium perfringens isolates derived from chickens to bind to collagen types I-V and gelatin. In total 21 strains from three distinct backgrounds were studied: (i) virulent strains isolated from birds suffering from necrotic enteritis, (ii) avirulent strains isolated from birds suffering from necrotic enteritis and (iii) strains isolated from healthy birds. All strains isolated from diseased birds had been assessed for virulence in a disease induction model. The virulent isolates all displayed collagen binding ability. However, most strains in the other two classes showed negligible binding to collagen. The prevalence of a previously described C. perfringens putative collagen adhesin-encoding gene was investigated by PCR screening. It was found that five of the strains carried the putative collagen adhesin-encoding gene and that all of these strains were virulent isolates. Based on these studies it is postulated that collagen adhesion may play a role in the pathogenesis of necrotic enteritis.

Physiochemical disparity of mismatched HLA class I alloantigens and risk of acute GVHD following HSCT.

We determined whether assessment of the immunogenicity of individual donor-recipient HLA mismatches based on differences in their amino-acid sequence and physiochemical properties predicts clinical outcome following haematopoietic SCT (HSCT). We examined patients transplanted with 9/10 single HLA class I-mismatched grafts (n=171) and 10/10 HLA-A-, -B-, -C-, -DRB1- and -DQB1-matched grafts (n=168). A computer algorithm was used to determine the physiochemical disparity (electrostatic mismatch score (EMS) and hydrophobic mismatch score (HMS)) of mismatched HLA class I specificities in the graft-versus-host direction. Patients transplanted with HLA-mismatched grafts with high EMS/HMS had increased incidence of ⩾grade II acute GVHD (aGVHD) compared with patients transplanted with low EMS/HMS grafts; patients transplanted with low and medium EMS/HMS grafts had similar incidence of aGVHD to patients transplanted with 10/10 HLA-matched grafts. Mortality was higher following single HLA-mismatched HSCT but was not correlated with HLA physiochemical disparity. Assessment of donor-recipient HLA incompatibility based on physiochemical HLA disparity may enable better selection of HLA-mismatched donors in HSCT.

Comparative neuropathology of ovine enterotoxemia produced by Clostridium perfringens type D wild-type strain CN1020 and its genetically modified derivatives.

Clostridium perfringens type D causes enterotoxemia in sheep and goats. The disease is mediated by epsilon toxin (ETX), which affects the cerebrovascular endothelium, increasing vascular permeability and leading to cerebral edema. In the present study, we compared the distribution and severity of the cerebrovascular changes induced in lambs by C. perfringens type D strain CN1020, its isogenic etx null mutant, and the ETX-producing complemented mutant. We also applied histochemical and immunohistochemical markers to further characterize the brain lesions induced by ETX. Both ETX-producing strains induced extensive cerebrovascular damage that did not differ significantly between each other in nature, neuroanatomic distribution, or severity. By contrast, lambs inoculated with the etx mutant or sterile, nontoxic culture medium did not develop detectable brain lesions, confirming that the neuropathologic effects observed in these infections are dependent on ETX production. Lambs treated with the wild-type and complemented strains showed perivascular and mural vascular edema, as well as serum albumin extravasation, particularly severe in the cerebral white matter, midbrain, medulla oblongata, and cerebellum. Brains of animals inoculated with the ETX-producing strains showed decreased expression of glial fibrillary acidic protein and increased expression of aquaporin-4 in the end-feet processes of the astrocytes around blood vessels. Early axonal injury was demonstrated with anti-amyloid precursor protein immunohistochemistry. Perivascular accumulation of macrophages/microglia with intracytoplasmic albumin globules was also observed in these animals. This study demonstrates that ETX is responsible for the major cerebrovascular changes in C. perfringens type D-induced disease.

Translating in vitro prediction of cytotoxic T cell alloreactivity to hematopoietic stem cell transplantation outcome.

INTRODUCTION: Previously we developed a weighted amino acid (AA) mismatch score predictive for cytotoxic T cell (CTL) alloreactivity (in vitro CTLp assay) based on the structure of the HLA class I molecule. The aim of this study is to confirm the clinical relevance of the CTLp assay and to validate the AA mismatch score as an alternative and easy to use tool to predict permissible mismatches in hematopoietic stem cell transplantation (HSCT). METHODS: We selected patients transplanted with a 9/10 single HLA class I mismatched graft (n=171) at three Dutch HSCT centers. A CTLp assay was performed in 73 donor-recipient pairs. As a control we selected 168 10/10 HLA matched pairs that were matched to the 9/10 single HLA class I mismatched pairs for HSCT year, donor type, patient age and diagnosis. RESULTS: We observed that pairs with negative a CTLp assay had statistically significant decreased incidence of mortality after HSCT comparable to that of 10/10 HLA matched pairs. However, the weighted AA mismatch score did not significantly predict any HSCT end point of interest. CONCLUSION: Further investigation is needed to unravel the mechanisms involved in causing the beneficial effect of a negative CTLp assay, before other alternative tools to predict HSCT outcome may be developed.

The application of clinical audit to improve pain control following third molar surgery.

UNLABELLED: A telephone survey was used to assess adequacy of pain control after third molar removal in a series of three audits. After each audit, factors contributing to failure to control pain adequately and poor patient compliance with our analgesic regimen were identified. Changes in practice were then introduced to remedy areas of weakness and improve outcome. Despite an apparently sound protocol for the prescription of analgesics for patients having third molar surgery, the first audit revealed that 53% of patients experienced moderate to severe pain. After the introduction of written patient instructions to clarify the use of post-operative analgesics, the second audit demonstrated that 86% had their pain managed successfully. After subsequently increasing the post-operative Ibuprofen doses from 400 mg to 600 mg, the third audit showed that 96% of patients had satisfactory pain control. The use of clinical audit with an evidence-based analgesic regimen and clear, written patient instruction has improved post-operative pain control. CLINICAL RELEVANCE: This paper demonstrates the usefulness of clinical audit for the monitoring and improvement of pain control and analgesic prescribing regimens following oral surgery, which in turn may improve patient experience and outcome.

Epsilon toxin is essential for the virulence of Clostridium perfringens type D infection in sheep, goats, and mice.

Clostridium perfringens type D causes disease in sheep, goats, and other ruminants. Type D isolates produce, at minimum, alpha and epsilon (ETX) toxins, but some express up to five different toxins, raising questions about which toxins are necessary for the virulence of these bacteria. We evaluated the contribution of ETX to C. perfringens type D pathogenicity in an intraduodenal challenge model in sheep, goats, and mice using a virulent C. perfringens type D wild-type strain (WT), an isogenic ETX null mutant (etx mutant), and a strain where the etx mutation has been reversed (etx complemented). All sheep and goats, and most mice, challenged with the WT isolate developed acute clinical disease followed by death in most cases. Sheep developed various gross and/or histological changes that included edema of brain, lungs, and heart as well as hydropericardium. Goats developed various effects, including necrotizing colitis, pulmonary edema, and hydropericardium. No significant gross or histological abnormalities were observed in any mice infected with the WT strain. All sheep, goats, and mice challenged with the isogenic etx mutant remained clinically healthy for ≥24 h, and no gross or histological abnormalities were observed in those animals. Complementation of etx knockout restored virulence; most goats, sheep, and mice receiving this complemented mutant developed clinical and pathological changes similar to those observed in WT-infected animals. These results indicate that ETX is necessary for type D isolates to induce disease, supporting a key role for this toxin in type D disease pathogenesis.

The impact of frequent HLA haplotypes in high linkage disequilibrium on donor search and clinical outcome after unrelated haematopoietic SCT.

The MHC region on chromosome 6 contains a large number of non-HLA genes next to the HLA genes. Matching for HLA in unrelated hematopoietic SCT (HSCT) does not necessarily mean that these non-HLA genes are also matched. We selected 348 Northwest European patients transplanted with an HLA-A-, -B-, -C-, -DRB1-, -DQB1-matched unrelated donor (MUD) between 1987 and 2008. Patients' haplotypes were identified via descend. We were unable to determine the haplotypes of the donor; therefore we used frequent haplotypes (FH) in high linkage disequilibrium (LD) as a proxy for haplotype matching. Presence of a FH in a patient positively affected the probability and speed of identifying a matched unrelated donor. Competing risk survival analysis showed that patients with one or two FH have a statistically significantly decreased probability of developing ≥ grade II acute GVDH (aGVHD) without increased risk of relapse compared to patients without FH (HR (95% CI): 0.53 (0.31-0.91)). This association was strongest for those FH with the highest LD between both HLA-A and -C or -B, and HLA-C or -B and -DRB1 (HR (95% CI): 0.49 (0.26-0.92)). These results extend evidence that non-HLA allele coding regions have a significant impact on development of ≥ grade II aGVHD. We conclude that there is more to successful HSCT than matching for HLA genes.

Elimination of permanent injuries to the inferior alveolar nerve following surgical intervention of the "high risk" third molar.

We aimed to find out whether improved preoperative assessment and surgical planning with cone beam computed tomography (CT) could reduce damage to the inferior alveolar nerve when high risk impacted mandibular third molars are extracted. We recorded the presence or absence of postoperative neuropathy after extraction of 200 lower third molars in 185 patients (where cone beam CT had shown contact between the nerve and root) after treatment in the oral surgery department of King's College Hospital. All patients had had cone beam CT of the teeth after panoramic radiography had indicated increased risk of injury to the nerve during extraction. Experienced oral surgeons did all the operations and postoperative reviews. Patients reported temporary alteration of sensation after operation in 12% of teeth but it resolved in all cases and no patient reported permanent loss of sensation. Permanent sensory disturbance in the distribution of the inferior alveolar nerve after third molars have been removed can be eliminated in high risk cases if operations are planned carefully (including cone beam CT), and the procedure is done by a skilled surgeon who has an appreciation of the anatomy of the nerve and roots, and an insight into the mechanical effect of their surgical manipulation. The incidence of permanent neurosensory dysfunction in this study was zero even though all teeth were intimately related to the inferior alveolar canal.