Vancomycin in adult prescribing: is it time to move on from trough-based dosing in the UK?

Vancomycin remains a useful agent in the infection doctor's toolkit, particularly for Staphylococcus aureus and MRSA infections. Therapeutic drug monitoring (TDM) is essential to maintain efficacy and avoid toxicity. Until recently, trough-based dosing has been the recommended method but in recent years the reliability of this has been questioned. The 2020 Infectious Diseases Society of America (IDSA) vancomycin guideline update has sent a clear message that trough-based dosing is not to be relied on, instead recommending dosing via 24 h AUC/MIC. The UK, however, has yet to follow suit in this, despite the wealth of evidence showing that trough-based dosing puts patients at higher risk of nephrotoxicity. Clearly, it is time to incorporate AUC/MIC-based dosing to utilize this effective antibiotic safely.

Particle composition and morphology over urban environment (New Delhi): Plausible effects on wheat leaves.

Particulate matter (PM) deposition on leaves adversely affects physical, chemical and biological nature of agricultural crops resulting in their loss of productivity and yield. Wheat being a staple food in major parts of Northern India and around the World, has been selected for research purpose by designing a study to explore the probable effects of PM deposition on wheat leaves and wheat crops to ensure the food security. PM5 (Particulate matter with aerodynamic diameter <5 µm) and Dry Deposited Particulate Matter (DDPM) on wheat leaves (Leaf_DDPM) were collected from the wheat crop field in Indian Agriculture Research Institute (IARI), New Delhi for growing and harvesting season of wheat crops (i.e. December 2014 to April 2015). The EDS (Energy Dispersive Spectroscopy) analysis was used for this study and the individual particle analysis revealed the presence of both acidic and alkaline components like C, Al, Si, Fe, Ca, K, S and Mg. The offline characterization tool i.e. SEM (Scanning Electron Microscope) was utilized for obtaining the micrographs which clearly showed the presence of some angular, sharp-edged and spherical particles consisting of both smooth and rough texture. Apart from that, prevalence of slightly non-spherical particles with aspect ratio of range (>1.20-1.40) and CIR (>0.70-0.80) for both PM5 and leaf_DDPM were observed. The size distribution of individual particles for both PM5(#194 particles) and Leaf_DDPM(#657 particles) revealed that Surface Equivalent Radius (SER) and Volume Equivalent Radius (VER) of particles observed to be 0.40-0.80 µm while surface area to be 0-1 µm2. These particles may easily block stomatal openings (with typical diameter range: 42-51 µm) of wheat leaves and damage internal leaf tissues while particle VER determines the interaction of incoming solar radiation with leaf surfaces. Average PM5 concentrations ± Standard deviations (µg/m3) were reported to be 231.05 ± 113.03. The XRF (X-Ray Fluorescence) spectrometer analysis of bulk PM5 revealed the concentrations of non-carbonaceous elements (µg/m3) as N (67.34 ± 16.09), Si (27.44 ± 11.01), Al (7.79 ± 3.37), S (3.88 ± 2.24), Na (2.29 ± 0.94), Mg (1.65 ± 0.62), K (0.51 ± 0.26), Ca (0.60 ± 0.26), Fe (0.54 ± 0.26), Cr (1.10 ± 0.70), Zn (0.05 ± 0.03), P (0.10 ± 0.03), Cu (0.07 ± 0.06). The dominant elemental oxides were calculated as SiO2, Al2O3, SO42-, Na2O, MgO, K2O, CaO, Fe2O3, Cr2O3, ZnO, P2O5, Cu2O with variable concentrations. In high humid conditions, with relative humidity (~85%) during the vegetative and flowering growth stages of wheat crops, presence of C and S rich acidic and hygroscopic particles may cause the corrosion of wheat leaves that ultimately affect the wheat crops.

Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model.

Fragile X syndrome (FXS) is an undertreated neurodevelopmental disorder characterized by low intelligence quotent and a wide range of other symptoms including disordered sleep and autism. Although FXS is the most prevalent inherited cause of intellectual disability, its mechanistic underpinnings are not well understood. Using Drosophila as a model of FXS, we showed that select expression of dfmr1 in the insulin-producing cells (IPCs) of the brain was sufficient to restore normal circadian behavior and to rescue the memory deficits in the fragile X mutant fly. Examination of the insulin signaling (IS) pathway revealed elevated levels of Drosophila insulin-like peptide 2 (Dilp2) in the IPCs and elevated IS in the dfmr1 mutant brain. Consistent with a causal role for elevated IS in dfmr1 mutant phenotypes, the expression of dfmr1 specifically in the IPCs reduced IS, and genetic reduction of the insulin pathway also led to amelioration of circadian and memory defects. Furthermore, we showed that treatment with the FDA-approved drug metformin also rescued memory. Finally, we showed that reduction of IS is required at different time points to rescue circadian behavior and memory. Our results indicate that insulin misregulation underlies the circadian and cognitive phenotypes displayed by the Drosophila fragile X model, and thus reveal a metabolic pathway that can be targeted by new and already approved drugs to treat fragile X patients.

A neuron-glia interaction involving GABA transaminase contributes to sleep loss in sleepless mutants.

Sleep is an essential process and yet mechanisms underlying it are not well understood. Loss of the Drosophila quiver/sleepless (qvr/sss) gene increases neuronal excitability and diminishes daily sleep, providing an excellent model for exploring the underpinnings of sleep regulation. Here, we used a proteomic approach to identify proteins altered in sss brains. We report that loss of sleepless post-transcriptionally elevates the CG7433 protein, a mitochondrial γ-aminobutyric acid transaminase (GABAT), and reduces GABA in fly brains. Loss of GABAT increases daily sleep and improves sleep consolidation, indicating that GABAT promotes wakefulness. Importantly, disruption of the GABAT gene completely suppresses the sleep phenotype of sss mutants, demonstrating that GABAT is required for loss of sleep in sss mutants. While SSS acts in distinct populations of neurons, GABAT acts in glia to reduce sleep in sss flies. Our results identify a novel mechanism of interaction between neurons and glia that is important for the regulation of sleep.

A COMPARATIVE ANALYSIS OF METHYLATION STATUS OF TUMOR SUPPRESSOR GENES IN PAIRED BIOPSY AND SERUM SAMPLES FROM CERVICAL CANCER PATIENTS AMONG NORTH INDIAN POPULATION.

Tumor-specific genetic or epigenetic alterations have been detected in serum DNA in case of various types of cancers. In breast cancer, the detection of tumor suppressor gene hypermethylation has been reported in several body fluids. Promoter hypermethylation of some genes like MYOD1, CALCA, hTERT etc. has also been detected in serum samples from cervical cancer. The present study is the first report on the comparison of promoter hypermethylation of tumor suppressor genes likep14, p15, p16, p21, p27, p57, p53, p73, RARß2, FHIT, DAPK, STAT1 and-RB1 genes in paired biopsy and serum samples from cervical cancer patients among north Indian population. This is also the first report on the hypermethylation of these genes in serum samples from cervical cancer patients among north Indian population. According to the results of the present study, promoter hypermethylation of these genes can also be detected in serum samples of cervical cancer patients. The sensitivity of detection of promoter hypermethylation in serum samples of cervical cancer patients as compared to paired biopsy samples was found to be around 83.3%. It was observed that promoter hypermethylation was mainly observed in the serum samples in the higher stages and very rarely in the lower stages. The present study clearly showed that serum of patients with cervical cancer can also be used to study methylated genes as biomarkers.

Correlation of the Geriatric Assessment with Overall Survival in Older Patients with Cancer.

AIMS: Global guidelines recommend that all older patients with cancer receiving chemotherapy should undergo a geriatric assessment. However, utilisation of the geriatric assessment is often constrained by its time-intensive nature, which limits its adoption in settings with limited resources and high demand. There is a lack of evidence correlating the results of the geriatric assessment with survival from the Indian subcontinent. Therefore, the aims of the present study were to assess the impact of the geriatric assessment on survival in older Indian patients with cancer and to identify the factors associated with survival in these older patients. MATERIALS AND METHODS: This was an observational study, conducted in the geriatric oncology clinic of the Tata Memorial Hospital (Mumbai, India). Patients aged 60 years and older with cancer who underwent a geriatric assessment were enrolled. We assessed the non-oncological geriatric domains of function and falls, nutrition, comorbidities, cognition, psychology, social support and medications. Patients exhibiting impairment in two or more domains were classified as frail. RESULTS: Between June 2018 and January 2022, we enrolled 897 patients. The median age was 69 (interquartile range 65-73) years. The common malignancies were lung (40.5%), oesophagus (31.9%) and genitourinary (12.1%); 54.6% had metastatic disease. Based on the results of the geriatric assessment, 767 (85.4%) patients were frail. The estimated median overall survival in fit patients was 24.3 (95% confidence interval 18.2-not reached) months, compared with 11.2 (10.1-12.8) months in frail patients (hazard ratio 0.54; 95% confidence interval 0.41-0.72, P < 0.001). This difference in overall survival remained significant after adjusting for age, sex, primary tumour and metastatic status (hazard ratio 0.56; 95% confidence interval 0.41-0.74, P < 0.001). In the patients with a performance status of 0 or 1 (n = 454), 365 (80.4%) were frail; the median overall survival in the performance status 0-1 group was 33.0 months (95% confidence interval 24.31-not reached) in the fit group versus 14.4 months (95% confidence interval 12.25-18.73) in the frail patients (hazard ratio 0.50; 95% confidence interval 0.34-0.74, P = 0.001). In the multivariate analysis, the geriatric assessment domains that were predictive of survival were function (hazard ratio 0.68; 95% confidence interval 0.52-0.88; P = 0.003), nutrition (hazard ratio 0.64; 95% confidence interval 0.48-0.85, P = 0.002) and cognition (hazard ratio 0.67; 95% confidence interval 0.49-0.91, P = 0.011). DISCUSSION: The geriatric assessment is a powerful prognostic tool for survival among older Indian patients with cancer. The geriatric assessment is prognostic even in the cohort of patients thought to be the fittest, i.e. performance status 0 and 1. Our study re-emphasises the critical importance of the geriatric assessment in all older patients planned for cancer-directed therapy.

The prognostic value of kidney transplant center report cards.

SRTR report cards provide the basis for quality measurement of US transplant centers. There is limited data evaluating the prognostic value of report cards, informing whether they are predictive of prospective patient outcomes. Using national SRTR data, we simulated report cards and calculated standardized mortality ratios (SMR) for kidney transplant centers over five distinct eras. We ranked centers based on SMR and evaluated outcomes for patients transplanted the year following reports. Recipients transplanted at the 50th, 100th and 200th ranked centers had 18% (AHR = 1.18, 1.13-1.22), 38% (AHR = 1.38, 1.28-1.49) and 91% (AHR = 1.91, 1.64-2.21) increased hazard for 1-year mortality relative to recipients at the top-ranked center. Risks were attenuated but remained significant for long-term outcomes. Patients transplanted at centers meeting low-performance criteria in the prior period had 40% (AHR = 1.40, 1.22-1.68) elevated hazard for 1-year mortality in the prospective period. Centers' SMR from the report card was highly predictive (c-statistics > 0.77) for prospective center SMRs and there was significant correlation between centers' SMR from the report card period and the year following (ρ = 0.57, p < 0.001). Although results do not mitigate potential biases of report cards for measuring quality, they do indicate strong prognostic value for future outcomes. Findings also highlight that outcomes are associated with center ranking across a continuum rather than solely at performance margins.

Prominent impact of community risk factors on kidney transplant candidate processes and outcomes.

Numerous factors impact patients' health beyond traditional clinical characteristics. We evaluated the association of risk factors in kidney transplant patients' communities with outcomes prior to transplantation. The primary exposure variable was a community risk score (range 0-40) derived from multiple databases and defined by factors including prevalence of comorbidities, access and quality of healthcare, self-reported physical and mental health and socioeconomic status for each U.S. county. We merged data with the Scientific Registry of Transplant Recipients (SRTR) and utilized risk-adjusted models to evaluate effects of community risk for adult candidates listed 2004-2010 (n = 209 198). Patients in highest risk communities were associated with increased mortality (adjusted hazard ratio [AHR] = 1.22, 1.16-1.28), decreased likelihood of living donor transplantation (adjusted odds ratio [AOR] = 0.90, 0.85-0.94), increased waitlist removal for health deterioration (AHR = 1.36, 1.22-1.51), decreased likelihood of preemptive listing (AOR = 0.85, 0.81-0.88), increased likelihood of inactive listing (AOR = 1.49, 1.43-1.55) and increased likelihood of listing for expanded criteria donor kidneys (AHR = 1.19, 1.15-1.24). Associations persisted with adjustment for rural-urban location; furthermore the independent effects of rural-urban location were largely eliminated with adjustment for community risk. Average community risk varied widely by region and transplant center (median = 21, range 5-37). Community risks are powerful factors associated with processes of care and outcomes for transplant candidates and may be important considerations for developing effective interventions and measuring quality of care of transplant centers.

Modulatory effects of curcumin in conjunction with piperine on benzo(a)pyrene-mediated DNA adducts and biotransformation enzymes.

The antigenotoxic effects of curcumin alone and with piperine on benzo(a)pyrene-diol (BaP) epoxide DNA adducts (BaPDE-DNA adducts), and carcinogen biotransformation enzymes was investigated in liver and lung of mice. Male Swiss albino mice received curcumin (100 mgkg(-1) body weight) and piperine (20 mgkg(-1) body weight) separately as well as in combination orally in corn oil for 7 days as pretreatments and thereafter 2 h, BaP (125 mgkg(-1) body weight) was administered orally in corn oil. A single dose of BaP to normal mice increased the activities of ethoxyresorufin o-deethylase (EROD), pentoxyresorufin o-depentylase (PROD) and levels of BaPDE-DNA adducts in both the tissues. Quinone reductase (QR) activity was also elevated in the BaP-treated group in both liver and lung when compared with normal control group. Pretreatment of curcumin and curcumin plus piperine before administration of BaP significantly decreased the activities of EROD, PROD, and the level of BaPDE-DNA adducts with consequent increase in QR activities. The study clearly indicates that curcumin, when given in combination with piperine, is more effective in modulating BaPDE-DNA adducts (liver and lung), and activity of EROD (liver).

VIA screening for cervical cancer in developing countries: potential role of the light source.

A total of 385 symptomatic patients presenting to the gynaecology and obstetrics outpatient department were screened by two sources of light: the yellow light of the tungsten bulb and the white light of the halogen bulb (100 Watt, 12 Volt), fitted with KODAK 80B filter and diffuser in an instrument called a 'Magnivisualizer' (developed by our Institute). Colposcopic examination was the gold standard for visualisation of the cervix. This study clearly brings out the significance of visual examination of the cervix using white light; as, in addition to having perfect correlation with colposcopy (0.86 for white vs 0.53 for yellow light), white light enables us to select the correct site of biopsy. Most of the rural clinics use torch or ordinary tungsten bulb, thus missing many significant lesions. In the light of our research findings, we strongly recommend the use of white light (complete spectrum of light) for screening purposes.

CT Perfusion Does Not Modify the Effect of Reperfusion in Patients with Acute Ischemic Stroke Undergoing Endovascular Treatment in the ESCAPE-NA1 Trial.

BACKGROUND AND PURPOSE: Although reperfusion is associated with improved outcomes in patients with acute ischemic stroke undergoing endovascular treatment, many patients still do poorly. We investigated whether CTP modifies the effect of near-complete reperfusion on clinical outcomes, ie, whether poor clinical outcomes despite near-complete reperfusion can be partly or fully explained by CTP findings. MATERIALS AND METHODS: Data are from the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) trial. Admission CTP was processed using RAPID software, generating relative CBF and CBV volume maps at standard thresholds. CTP lesion volumes were compared in patients with-versus-without near-complete reperfusion. Associations between each CTP metric and clinical outcome (90-day mRS) were tested using multivariable logistic regression, adjusted for baseline imaging and clinical variables. Treatment-effect modification was assessed by introducing CTP lesion volume × reperfusion interaction terms in the models. RESULTS: CTP lesion volumes and reperfusion status were available in 410/1105 patients. CTP lesion volumes were overall larger in patients without near-complete reperfusion, albeit not always statistically significant. Increased CBF <34%, CBV <34%, CBV <38%, and CBV <42% lesion volumes were associated with worse clinical outcome (ordinal mRS) at 90 days. CTP core lesion volumes did not modify the treatment effect of near-complete recanalization on clinical outcome. CONCLUSIONS: CTP did not modify the effect of near-complete reperfusion on clinical outcomes. Thus, CTP cannot explain why some patients with near-complete reperfusion have poor clinical outcomes.

Overweight, obesity and intentional weight loss in chronic kidney disease: NHANES 1999-2006.

OBJECTIVE: Obesity and chronic kidney disease (CKD) have emerged as major public health problems. We aimed to examine: (a) lifestyle and behavioral factors, (b) factors related to pursuing weight loss and (c) weight loss modalities pursued by CKD and non-CKD individuals who are overweight and obese. METHODS: Cross-sectional analysis of 10,971 overweight and obese adult participants in the National Health and Nutrition Examination Surveys conducted between 1999 and 2006. We examined the differences in lifestyle and behavioral factors between CKD and non-CKD participants and factors associated with pursuing weight loss using survey regression models. RESULTS: The total daily energy intake of the CKD population was lower than the non-CKD group (1987 kcal per day versus 2063 kcal per day, P=0.02) even after adjusting for relevant covariates. However, the percentage of energy derived from protein was similar between the groups. Sixty six percent of the CKD population did not meet the minimum recommended leisure time physical activity goals compared with 57% among non-CKD (P<0.001). Fifty percent of CKD participants pursued weight loss (vs fifty-five percent of non-CKD individuals, P=0.01), but the presence of CKD was not independently associated with the pursuit of weight loss in the multivariate model. Among participants pursuing weight loss, modalities including dietary interventions utilized by CKD and non-CKD participants were similar. Eight percent of CKD participants used medications to promote weight loss. CONCLUSIONS: Among the overweight and obese population, lifestyle and behavioral factors related to obesity and weight loss are similar between CKD and non-CKD participants. Insufficient data exist on the beneficial effects of intentional weight loss in CKD and these data show that a significant proportion of the CKD population use diets that may have high-protein content and medications to promote weight loss that may be harmful. Future clinical trials evaluating the efficacy and optimal modalities to treat obesity in the CKD population are warranted.

Diclofenac-tramadol vs. diclofenac-acetaminophen combinations for pain relief after caesarean section.

BACKGROUND: We compared the analgesic efficacy of diclofenac-acetaminophen combination with diclofenac-tramadol combination to optimize multimodal post-operative analgesia in women undergoing caesarean section. METHODS: In this randomized, double-blind, parallel-group controlled trial, 204 women undergoing caesarean section under spinal anaesthesia with bupivacaine received rectal suppository diclofenac 100 mg (8 hourly till 24 h) plus either intravenous acetaminophen (1 g 6 hourly) or tramadol (75 mg 6 hourly) post-operatively. The primary outcome measure was the summed pain intensities during the entire observation period, calculated as the sum of time-weighted pain intensity scores as an area under the curve (AUC). Secondary outcome was the use of rescue analgesic, administered if the patient's numeric rating scale (NRS) scores ≥ 4. RESULTS: The overall pain score for the entire observation period measured as AUC was significantly lower in the diclofenac-tramadol group. However, diclofenac-tramadol combination produced Bonferroni-corrected statistically significant lower NRS pain scores only on movement at 24 h. Rescue analgesic consumption was comparable between the groups (13% vs. 12%, P = 0.872). Overall, the pain scores were low in both of the groups across various time intervals (median NRS scores 0-2 for pain both at rest and on movement), indicating satisfactory pain control in both groups. Side effects were few and comparable, except nausea (significantly more in tramadol group than acetaminophen group, 15% vs. 2%, P = 0.001). CONCLUSION: Both diclofenac-tramadol and diclofenac-acetaminophen combinations can achieve satisfactory post-operative pain control in women undergoing caesarean section. The diclofenac-tramadol combination was overall more efficacious but associated with higher incidence of post-operative nausea.

Patient-Relevant Deficits Dictate Endovascular Thrombectomy Decision-Making in Patients with Low NIHSS Scores with Medium-Vessel Occlusion Stroke.

BACKGROUND AND PURPOSE: There is a paucity of evidence regarding the safety of endovascular treatment for patients with acute ischemic stroke due to primary medium-vessel occlusion. The aim of this study was to examine the willingness among stroke physicians to perform endovascular treatment in patients with mild-yet-disabling deficits due to medium-vessel occlusion. MATERIALS AND METHODS: In an international cross-sectional survey consisting of 7 primary medium-vessel occlusion case scenarios, participants were asked whether the presence of personally disabling deficits would influence their decision-making for endovascular treatment despite the patients having low NIHSS scores (<6). Decision rates were calculated on the basis of physician characteristics. Univariable logistic regression clustered by respondent and scenario identity was performed. RESULTS: Three hundred sixty-six participants from 44 countries provided 2562 answers to the 7 medium-vessel occlusion scenarios included in this study. In scenarios in which the deficit was relevant to the patient's profession, 56.9% of respondents opted to perform immediate endovascular treatment compared with 41.0% when no information regarding the patient's profession was provided (risk ratio = 1.39, P < .001). The largest effect sizes were seen for female participants (risk ratio = 1.68; 95% CI, 1.35-2.09), participants older than 60 years of age (risk ratio = 1.61; 95% CI, 1.23-2.10), those with more experience in neurointervention (risk ratio = 1.60; 95% CI, 1.24-2.06), and those who personally performed >100 endovascular treatments per year (risk ratio = 1.63; 95% CI, 1.22-2.17). CONCLUSIONS: The presence of a patient-relevant deficit in low-NIHSS acute ischemic stroke due to medium-vessel occlusion is an important factor for endovascular treatment decision-making. This may have relevance for the conduct and interpretation of low-NIHSS endovascular treatment in randomized trials.

Marked variation of the association of ESRD duration before and after wait listing on kidney transplant outcomes.

Numerous studies report a strong association between pretransplant end-stage renal disease (ESRD) duration and diminished transplant outcomes. However, cumulative waiting time may reflect distinct phases and processes related to patients' physiological condition as well as pre-existing morbidity and access to care. The relative impact of pre- and postlisting ESRD durations on transplant outcomes is unknown. We examined the impact of these intervals from a national cohort of kidney transplant recipients from 1999 to 2008 (n = 112,249). Primary factors explaining prelisting ESRD duration were insurance and race, while primary factors explaining postlisting ESRD duration were blood type, PRA% and variation between centers. Extended time from ESRD to waitlisting had significant dose-response association with overall graft loss (AHR = 1.26 for deceased donors [DD], AHR = 1.32 for living donors [LD], p values < 0.001). Contrarily, time from waitlisting (after ESRD) to transplantation had negligible effects (p = 0.10[DD], p = 0.57[LD]). There were significant associations between pre- and postlisting ESRD time with posttransplant patient survival, however prelisting time had over sixfold greater effect. Prelisting ESRD time predominately explains the association of waiting time with transplant outcomes suggesting that factors associated with this interval should be prioritized for interventions and allocation policy. The degree to which the effect of prelisting ESRD time is a proxy for comorbid conditions, socioeconomic status or access to care requires further study.

Trends in the epidemiology of larynx and lung cancer in south-east England, 1985-2004.

We analysed data on 8987 larynx and 174060 lung cancer patients diagnosed between 1985 and 2004, of which 17.3% of larynx and 35.5% of lung cancers were in females. The age-standardised rates for each cancer declined in both sexes, but since the 1990s, the rates in females over 70 years of age have been diverging.

A role for the proteasome in the light response of the timeless clock protein.

The cyclic expression of the period (PER) and timeless (TIM) proteins is critical for the molecular circadian feedback loop in Drosophila. The entrainment by light of the circadian clock is mediated by a reduction in TIM levels. To elucidate the mechanism of this process, the sensitivity of TIM regulation by light was tested in an in vitro assay with inhibitors of candidate proteolytic pathways. The data suggested that TIM is degraded through a ubiquitin-proteasome mechanism. In addition, in cultures from third-instar larvae, TIM degradation was blocked specifically by inhibitors of proteasome activity. Degradation appeared to be preceded by tyrosine phosphorylation. Finally, TIM was ubiquitinated in response to light in cultured cells.

Loss of circadian behavioral rhythms and per RNA oscillations in the Drosophila mutant timeless.

Eclosion, or emergence of adult flies from the pupa, and locomotor activity of adults occur rhythmically in Drosophila melanogaster, with a circadian period of about 24 hours. Here, a clock mutation, timeless (tim), is described that produces arrhythmia for both behaviors. The effects of tim on behavioral rhythms are likely to involve products of the X chromosome-linked clock gene period (per), because tim alters circadian oscillations of per RNA. Genetic mapping places tim on the left arm of the second chromosome between dumpy (dp) and decapentaplegic (dpp).